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A ‘setback’ for anti-inflammatory treatment in depression
In the MinoTRD trial, 6 weeks of minocycline 200 mg daily added to stable antidepressant therapy did not show a statistically significant advantage over placebo on the overall course of depressive symptoms.
“The failure of minocycline treatment to reduce depressive symptoms in a naturalistic sample of patients with TRD is a setback for anti-inflammatory treatment strategies in this clinical population,” Julian Hellmann-Regen, MD, department of psychiatry and neurosciences, Charité – Universitätsmedizin Berlin, and colleagues wrote.
The findings were published online in JAMA Network Open.
No additional benefit
The “inflammatory hypothesis” of depression maintains that depression arises from increased immune activation and neurotrophic mechanisms.
This view is supported by observations that depression is accompanied by increased levels of proinflammatory cytokines. In addition, low-grade inflammatory processes may interfere with response to typical antidepressant medications.
Minocycline has been put forth as a novel antidepressant, and a few small trials have hinted at a benefit.
In the MinoTRD trial, 168 patients (mean age, 46 years; 53% men) with TRD were randomly allocated minocycline 200 mg/day or matching placebo in addition to usual antidepressant treatment for 6 weeks.
Results showed minocycline was well tolerated but was not superior to placebo in reducing depressive symptoms, the researchers report.
Overall, the mean Montgomery-Åsberg Depression Rating Scale (MADRS) score at baseline was 26.5. There was no significant between-group difference in mean change in MADRS score from baseline to 6 weeks, the primary outcome.
After 6 weeks of treatment, the mean reduction in MADRS score was 8.46 points in the minocycline group versus 8.01 points in the placebo group, and the difference of 1.46 points was not significant (P = .25).
Six weeks of minocycline treatment did not alter the course of depression severity, compared with placebo, the investigators noted.
Minocycline treatment also showed no statistically significant effect on secondary outcomes of response, remission, and various other clinical rating scales.
Caveats and cautionary notes
The researchers noted that one explanation for the null result of the MinoTRD trial could be that the 6-week treatment duration was not long enough to reveal detectable differences. They point to a small study that showed a strong effect of minocycline, compared with placebo by and after 8 weeks of treatment.
However, a closer look at that study suggests the overall effect in the minocycline group was caused by an almost-complete lack of improvement in the placebo group, “which is very unusual,” the investigators wrote.
In the MinoTRD trial, the magnitude of improvement for placebo was as expected from similar trials in TRD, they pointed out.
They also noted that, unlike some other trials, the MinoTRD trial purposely recruited a naturalistic population of TRD, assuming (but not confirming) elevated baseline inflammation as a potential underlying cause in at least a subgroup of the patients.
Post hoc stratification by baseline CRP levels in MinoTRD participants did not yield any results supporting the hypothesis of minocycline treatment possibly being more effective in participants with higher-grade baseline inflammation, the researchers reported.
“Our results from this large randomized controlled trial of a pleiotropic anti-inflammatory drug in this difficult-to-treat patient population are of great clinical importance, robustly demonstrating that minocycline add-on treatment does not outperform placebo, not even in those participants with elevated levels of CRP prior to treatment initiation,” they wrote.
The trial was funded by a grant from the German Federal Ministry of Education and Research within the Consortium Optimizing Treatment of Depression, as part of the Research Network for Psychiatric Disorders. Dr. Hellmann-Regen reported no relevant financial relationship.
A version of this article first appeared on Medscape.com.
In the MinoTRD trial, 6 weeks of minocycline 200 mg daily added to stable antidepressant therapy did not show a statistically significant advantage over placebo on the overall course of depressive symptoms.
“The failure of minocycline treatment to reduce depressive symptoms in a naturalistic sample of patients with TRD is a setback for anti-inflammatory treatment strategies in this clinical population,” Julian Hellmann-Regen, MD, department of psychiatry and neurosciences, Charité – Universitätsmedizin Berlin, and colleagues wrote.
The findings were published online in JAMA Network Open.
No additional benefit
The “inflammatory hypothesis” of depression maintains that depression arises from increased immune activation and neurotrophic mechanisms.
This view is supported by observations that depression is accompanied by increased levels of proinflammatory cytokines. In addition, low-grade inflammatory processes may interfere with response to typical antidepressant medications.
Minocycline has been put forth as a novel antidepressant, and a few small trials have hinted at a benefit.
In the MinoTRD trial, 168 patients (mean age, 46 years; 53% men) with TRD were randomly allocated minocycline 200 mg/day or matching placebo in addition to usual antidepressant treatment for 6 weeks.
Results showed minocycline was well tolerated but was not superior to placebo in reducing depressive symptoms, the researchers report.
Overall, the mean Montgomery-Åsberg Depression Rating Scale (MADRS) score at baseline was 26.5. There was no significant between-group difference in mean change in MADRS score from baseline to 6 weeks, the primary outcome.
After 6 weeks of treatment, the mean reduction in MADRS score was 8.46 points in the minocycline group versus 8.01 points in the placebo group, and the difference of 1.46 points was not significant (P = .25).
Six weeks of minocycline treatment did not alter the course of depression severity, compared with placebo, the investigators noted.
Minocycline treatment also showed no statistically significant effect on secondary outcomes of response, remission, and various other clinical rating scales.
Caveats and cautionary notes
The researchers noted that one explanation for the null result of the MinoTRD trial could be that the 6-week treatment duration was not long enough to reveal detectable differences. They point to a small study that showed a strong effect of minocycline, compared with placebo by and after 8 weeks of treatment.
However, a closer look at that study suggests the overall effect in the minocycline group was caused by an almost-complete lack of improvement in the placebo group, “which is very unusual,” the investigators wrote.
In the MinoTRD trial, the magnitude of improvement for placebo was as expected from similar trials in TRD, they pointed out.
They also noted that, unlike some other trials, the MinoTRD trial purposely recruited a naturalistic population of TRD, assuming (but not confirming) elevated baseline inflammation as a potential underlying cause in at least a subgroup of the patients.
Post hoc stratification by baseline CRP levels in MinoTRD participants did not yield any results supporting the hypothesis of minocycline treatment possibly being more effective in participants with higher-grade baseline inflammation, the researchers reported.
“Our results from this large randomized controlled trial of a pleiotropic anti-inflammatory drug in this difficult-to-treat patient population are of great clinical importance, robustly demonstrating that minocycline add-on treatment does not outperform placebo, not even in those participants with elevated levels of CRP prior to treatment initiation,” they wrote.
The trial was funded by a grant from the German Federal Ministry of Education and Research within the Consortium Optimizing Treatment of Depression, as part of the Research Network for Psychiatric Disorders. Dr. Hellmann-Regen reported no relevant financial relationship.
A version of this article first appeared on Medscape.com.
In the MinoTRD trial, 6 weeks of minocycline 200 mg daily added to stable antidepressant therapy did not show a statistically significant advantage over placebo on the overall course of depressive symptoms.
“The failure of minocycline treatment to reduce depressive symptoms in a naturalistic sample of patients with TRD is a setback for anti-inflammatory treatment strategies in this clinical population,” Julian Hellmann-Regen, MD, department of psychiatry and neurosciences, Charité – Universitätsmedizin Berlin, and colleagues wrote.
The findings were published online in JAMA Network Open.
No additional benefit
The “inflammatory hypothesis” of depression maintains that depression arises from increased immune activation and neurotrophic mechanisms.
This view is supported by observations that depression is accompanied by increased levels of proinflammatory cytokines. In addition, low-grade inflammatory processes may interfere with response to typical antidepressant medications.
Minocycline has been put forth as a novel antidepressant, and a few small trials have hinted at a benefit.
In the MinoTRD trial, 168 patients (mean age, 46 years; 53% men) with TRD were randomly allocated minocycline 200 mg/day or matching placebo in addition to usual antidepressant treatment for 6 weeks.
Results showed minocycline was well tolerated but was not superior to placebo in reducing depressive symptoms, the researchers report.
Overall, the mean Montgomery-Åsberg Depression Rating Scale (MADRS) score at baseline was 26.5. There was no significant between-group difference in mean change in MADRS score from baseline to 6 weeks, the primary outcome.
After 6 weeks of treatment, the mean reduction in MADRS score was 8.46 points in the minocycline group versus 8.01 points in the placebo group, and the difference of 1.46 points was not significant (P = .25).
Six weeks of minocycline treatment did not alter the course of depression severity, compared with placebo, the investigators noted.
Minocycline treatment also showed no statistically significant effect on secondary outcomes of response, remission, and various other clinical rating scales.
Caveats and cautionary notes
The researchers noted that one explanation for the null result of the MinoTRD trial could be that the 6-week treatment duration was not long enough to reveal detectable differences. They point to a small study that showed a strong effect of minocycline, compared with placebo by and after 8 weeks of treatment.
However, a closer look at that study suggests the overall effect in the minocycline group was caused by an almost-complete lack of improvement in the placebo group, “which is very unusual,” the investigators wrote.
In the MinoTRD trial, the magnitude of improvement for placebo was as expected from similar trials in TRD, they pointed out.
They also noted that, unlike some other trials, the MinoTRD trial purposely recruited a naturalistic population of TRD, assuming (but not confirming) elevated baseline inflammation as a potential underlying cause in at least a subgroup of the patients.
Post hoc stratification by baseline CRP levels in MinoTRD participants did not yield any results supporting the hypothesis of minocycline treatment possibly being more effective in participants with higher-grade baseline inflammation, the researchers reported.
“Our results from this large randomized controlled trial of a pleiotropic anti-inflammatory drug in this difficult-to-treat patient population are of great clinical importance, robustly demonstrating that minocycline add-on treatment does not outperform placebo, not even in those participants with elevated levels of CRP prior to treatment initiation,” they wrote.
The trial was funded by a grant from the German Federal Ministry of Education and Research within the Consortium Optimizing Treatment of Depression, as part of the Research Network for Psychiatric Disorders. Dr. Hellmann-Regen reported no relevant financial relationship.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
When is an allergic reaction to raw plant food due to tree pollen?
A new guideline aims to help primary care doctors differentiate pollen food syndrome (PFS) – a cross-reactive allergic reaction to certain raw, but not cooked, plant foods – from other food allergies.
The guideline from the British Society of Allergy and Clinical Immunology (BSACI) focuses on birch tree pollen, the major sensitizing PFS allergen in Northern Europe. Providers may be able to diagnose PFS related to birch pollen from clinical history alone, including the foods involved and the rapidity of symptom onset, write lead author Isabel J. Skypala, PhD, RD, of Imperial College London, and her colleagues.
The new BSACI guideline for diagnosis and management of PFS was published in Clinical & Experimental Allergy.
PFS is common and increasingly prevalent
PFS – also called oral allergy syndrome and pollen food allergy syndrome – is common and increasingly prevalent. PFS can begin at any age but usually starts in pollen-sensitized school-age children and adults with seasonal allergic rhinitis.
Symptoms from similar proteins in food
Mild to moderate allergic symptoms develop quickly when people sensitized to birch pollen eat raw plant foods that contain proteins similar to those in the pollen, such as pathogenesis-related protein PR-10. The allergens are broken down by cooking or processing.
Symptoms usually occur immediately or within 15 minutes of eating. Patients may have tingling; itching or soreness in the mouth, throat, or ears; mild lip and oral mucosa angioedema; itchy hands, sneezing, or eye symptoms; tongue or pharynx angioedema; perioral rash; cough; abdominal pain; nausea; and/or worsening of eczema. In children, itch and rash may predominate.
Triggers depend on pollen type
PFS triggers vary depending on a person’s pollen sensitization, which is affected by their geographic area and local dietary habits. In the United Kingdom, almost 70% of birch-allergic adults and more than 40% of birch-allergic children have PFS, the authors write.
Typical triggers include eating apples, stone fruits, kiwis, carrots, celery, hazelnuts, almonds, walnuts, soymilk, and peanuts, as well as peeling potatoes or other root vegetables. Freshly prepared vegetable or fruit smoothies or juices, celery, soymilk, raw nuts, large quantities of roasted nuts, and concentrated nut products can cause more severe reactions.
Diagnostic clinical history
If a patient answers yes to these questions, they almost certainly have PFS, the authors write:
- Are symptoms caused by raw fruits, nuts, carrots, or celery?
- Are the same trigger foods tolerated when they’re cooked well or roasted?
- Do symptoms come immediately or within a few minutes of eating?
- Do symptoms occur in the oropharynx and include tingling, itching, or swelling?
- Does the patient have seasonal allergic rhinitis or sensitization to pollen?
Testing needed for some cases
Allergy tests may be needed for people who report atypical or severe reactions or who also react to cooked or processed plant foods, such as roasted nuts, nuts in foods, fruits or vegetables in juices and smoothies, and soy products other than milk. Tests may also be needed for people who react to foods that are not linked with PFS, such as cashews, pistachios, macadamias, sesame seeds, beans, lentils, and chickpeas.
Whether PFS reactions also occur to roasted hazelnuts, almonds, walnuts, Brazil nuts, or peanuts, either alone or in composite foods such as chocolates, spreads, desserts, and snacks, is unclear.
An oral food challenge to confirm PFS is needed only if the history and diagnostic tests are inconclusive or if the patient is avoiding multiple foods.
Dietary management
PFS is managed by excluding known trigger foods. This becomes challenging for patients with preexisting food allergies and for vegetarians and vegans.
Personalized dietary advice is needed to avoid nutritional imbalance, minimize anxiety and unnecessary food restrictions, and improve quality of life. Reactions after accidental exposure often resolve without medication, and if antihistamines are needed, they rarely require self-injectable devices.
Guideline helpful beyond the United Kingdom and birch pollen
Allyson S. Larkin, MD, associate professor of pediatrics at the University of Pittsburgh School of Medicine, told this news organization in an email that the guideline summarizes in great detail the pathophysiology behind PFS and highlights how component testing may help diagnose patients and manage the condition.
“Patients worry very much about the progression and severity of allergic reactions,” said Dr. Larkin, who was not involved in the guideline development.
“As the authors note, recognizing the nutritional consequences of dietary restrictions is important, and nutrition consults and suitable alternative suggestions are very helpful for these patients, especially for those with food allergy or who are vegetarian or vegan.”
Jill A. Poole, MD, professor of medicine and chief of the Division of Allergy and Immunology at the University of Nebraska College of Medicine, Omaha, noted that PFS, although common, is underrecognized by the public and by health care providers.
“People are not allergic to the specific food, but they are allergic to a seasonal allergen, such as birch tree, that cross-reacts with the food protein, which is typically changed with cooking,” she explained in an email.
“This differs from reactions by those who have moderate to severe allergic food-specific reactions that may include systemic reactions like anaphylaxis from eating certain foods,” she said.
“Importantly, the number of cross-reacting foods with seasonal pollens continues to grow, and the extent of testing has expanded in recent years,” advised Dr. Poole, who also was not involved in the guideline development.
The authors recommend further related research into food immunotherapy and other novel PFS treatments. They also want to raise awareness of factors affecting PFS prevalence, such as increased spread and allergenicity of pollen due to climate change, pollution, the global consumption of previously local traditional foods, and the increase in vegetarian and vegan diets.
The authors, Dr. Larkin, and Dr. Poole report no relevant financial relationships involving this guideline. The guideline was not funded.
A version of this article first appeared on Medscape.com.
A new guideline aims to help primary care doctors differentiate pollen food syndrome (PFS) – a cross-reactive allergic reaction to certain raw, but not cooked, plant foods – from other food allergies.
The guideline from the British Society of Allergy and Clinical Immunology (BSACI) focuses on birch tree pollen, the major sensitizing PFS allergen in Northern Europe. Providers may be able to diagnose PFS related to birch pollen from clinical history alone, including the foods involved and the rapidity of symptom onset, write lead author Isabel J. Skypala, PhD, RD, of Imperial College London, and her colleagues.
The new BSACI guideline for diagnosis and management of PFS was published in Clinical & Experimental Allergy.
PFS is common and increasingly prevalent
PFS – also called oral allergy syndrome and pollen food allergy syndrome – is common and increasingly prevalent. PFS can begin at any age but usually starts in pollen-sensitized school-age children and adults with seasonal allergic rhinitis.
Symptoms from similar proteins in food
Mild to moderate allergic symptoms develop quickly when people sensitized to birch pollen eat raw plant foods that contain proteins similar to those in the pollen, such as pathogenesis-related protein PR-10. The allergens are broken down by cooking or processing.
Symptoms usually occur immediately or within 15 minutes of eating. Patients may have tingling; itching or soreness in the mouth, throat, or ears; mild lip and oral mucosa angioedema; itchy hands, sneezing, or eye symptoms; tongue or pharynx angioedema; perioral rash; cough; abdominal pain; nausea; and/or worsening of eczema. In children, itch and rash may predominate.
Triggers depend on pollen type
PFS triggers vary depending on a person’s pollen sensitization, which is affected by their geographic area and local dietary habits. In the United Kingdom, almost 70% of birch-allergic adults and more than 40% of birch-allergic children have PFS, the authors write.
Typical triggers include eating apples, stone fruits, kiwis, carrots, celery, hazelnuts, almonds, walnuts, soymilk, and peanuts, as well as peeling potatoes or other root vegetables. Freshly prepared vegetable or fruit smoothies or juices, celery, soymilk, raw nuts, large quantities of roasted nuts, and concentrated nut products can cause more severe reactions.
Diagnostic clinical history
If a patient answers yes to these questions, they almost certainly have PFS, the authors write:
- Are symptoms caused by raw fruits, nuts, carrots, or celery?
- Are the same trigger foods tolerated when they’re cooked well or roasted?
- Do symptoms come immediately or within a few minutes of eating?
- Do symptoms occur in the oropharynx and include tingling, itching, or swelling?
- Does the patient have seasonal allergic rhinitis or sensitization to pollen?
Testing needed for some cases
Allergy tests may be needed for people who report atypical or severe reactions or who also react to cooked or processed plant foods, such as roasted nuts, nuts in foods, fruits or vegetables in juices and smoothies, and soy products other than milk. Tests may also be needed for people who react to foods that are not linked with PFS, such as cashews, pistachios, macadamias, sesame seeds, beans, lentils, and chickpeas.
Whether PFS reactions also occur to roasted hazelnuts, almonds, walnuts, Brazil nuts, or peanuts, either alone or in composite foods such as chocolates, spreads, desserts, and snacks, is unclear.
An oral food challenge to confirm PFS is needed only if the history and diagnostic tests are inconclusive or if the patient is avoiding multiple foods.
Dietary management
PFS is managed by excluding known trigger foods. This becomes challenging for patients with preexisting food allergies and for vegetarians and vegans.
Personalized dietary advice is needed to avoid nutritional imbalance, minimize anxiety and unnecessary food restrictions, and improve quality of life. Reactions after accidental exposure often resolve without medication, and if antihistamines are needed, they rarely require self-injectable devices.
Guideline helpful beyond the United Kingdom and birch pollen
Allyson S. Larkin, MD, associate professor of pediatrics at the University of Pittsburgh School of Medicine, told this news organization in an email that the guideline summarizes in great detail the pathophysiology behind PFS and highlights how component testing may help diagnose patients and manage the condition.
“Patients worry very much about the progression and severity of allergic reactions,” said Dr. Larkin, who was not involved in the guideline development.
“As the authors note, recognizing the nutritional consequences of dietary restrictions is important, and nutrition consults and suitable alternative suggestions are very helpful for these patients, especially for those with food allergy or who are vegetarian or vegan.”
Jill A. Poole, MD, professor of medicine and chief of the Division of Allergy and Immunology at the University of Nebraska College of Medicine, Omaha, noted that PFS, although common, is underrecognized by the public and by health care providers.
“People are not allergic to the specific food, but they are allergic to a seasonal allergen, such as birch tree, that cross-reacts with the food protein, which is typically changed with cooking,” she explained in an email.
“This differs from reactions by those who have moderate to severe allergic food-specific reactions that may include systemic reactions like anaphylaxis from eating certain foods,” she said.
“Importantly, the number of cross-reacting foods with seasonal pollens continues to grow, and the extent of testing has expanded in recent years,” advised Dr. Poole, who also was not involved in the guideline development.
The authors recommend further related research into food immunotherapy and other novel PFS treatments. They also want to raise awareness of factors affecting PFS prevalence, such as increased spread and allergenicity of pollen due to climate change, pollution, the global consumption of previously local traditional foods, and the increase in vegetarian and vegan diets.
The authors, Dr. Larkin, and Dr. Poole report no relevant financial relationships involving this guideline. The guideline was not funded.
A version of this article first appeared on Medscape.com.
A new guideline aims to help primary care doctors differentiate pollen food syndrome (PFS) – a cross-reactive allergic reaction to certain raw, but not cooked, plant foods – from other food allergies.
The guideline from the British Society of Allergy and Clinical Immunology (BSACI) focuses on birch tree pollen, the major sensitizing PFS allergen in Northern Europe. Providers may be able to diagnose PFS related to birch pollen from clinical history alone, including the foods involved and the rapidity of symptom onset, write lead author Isabel J. Skypala, PhD, RD, of Imperial College London, and her colleagues.
The new BSACI guideline for diagnosis and management of PFS was published in Clinical & Experimental Allergy.
PFS is common and increasingly prevalent
PFS – also called oral allergy syndrome and pollen food allergy syndrome – is common and increasingly prevalent. PFS can begin at any age but usually starts in pollen-sensitized school-age children and adults with seasonal allergic rhinitis.
Symptoms from similar proteins in food
Mild to moderate allergic symptoms develop quickly when people sensitized to birch pollen eat raw plant foods that contain proteins similar to those in the pollen, such as pathogenesis-related protein PR-10. The allergens are broken down by cooking or processing.
Symptoms usually occur immediately or within 15 minutes of eating. Patients may have tingling; itching or soreness in the mouth, throat, or ears; mild lip and oral mucosa angioedema; itchy hands, sneezing, or eye symptoms; tongue or pharynx angioedema; perioral rash; cough; abdominal pain; nausea; and/or worsening of eczema. In children, itch and rash may predominate.
Triggers depend on pollen type
PFS triggers vary depending on a person’s pollen sensitization, which is affected by their geographic area and local dietary habits. In the United Kingdom, almost 70% of birch-allergic adults and more than 40% of birch-allergic children have PFS, the authors write.
Typical triggers include eating apples, stone fruits, kiwis, carrots, celery, hazelnuts, almonds, walnuts, soymilk, and peanuts, as well as peeling potatoes or other root vegetables. Freshly prepared vegetable or fruit smoothies or juices, celery, soymilk, raw nuts, large quantities of roasted nuts, and concentrated nut products can cause more severe reactions.
Diagnostic clinical history
If a patient answers yes to these questions, they almost certainly have PFS, the authors write:
- Are symptoms caused by raw fruits, nuts, carrots, or celery?
- Are the same trigger foods tolerated when they’re cooked well or roasted?
- Do symptoms come immediately or within a few minutes of eating?
- Do symptoms occur in the oropharynx and include tingling, itching, or swelling?
- Does the patient have seasonal allergic rhinitis or sensitization to pollen?
Testing needed for some cases
Allergy tests may be needed for people who report atypical or severe reactions or who also react to cooked or processed plant foods, such as roasted nuts, nuts in foods, fruits or vegetables in juices and smoothies, and soy products other than milk. Tests may also be needed for people who react to foods that are not linked with PFS, such as cashews, pistachios, macadamias, sesame seeds, beans, lentils, and chickpeas.
Whether PFS reactions also occur to roasted hazelnuts, almonds, walnuts, Brazil nuts, or peanuts, either alone or in composite foods such as chocolates, spreads, desserts, and snacks, is unclear.
An oral food challenge to confirm PFS is needed only if the history and diagnostic tests are inconclusive or if the patient is avoiding multiple foods.
Dietary management
PFS is managed by excluding known trigger foods. This becomes challenging for patients with preexisting food allergies and for vegetarians and vegans.
Personalized dietary advice is needed to avoid nutritional imbalance, minimize anxiety and unnecessary food restrictions, and improve quality of life. Reactions after accidental exposure often resolve without medication, and if antihistamines are needed, they rarely require self-injectable devices.
Guideline helpful beyond the United Kingdom and birch pollen
Allyson S. Larkin, MD, associate professor of pediatrics at the University of Pittsburgh School of Medicine, told this news organization in an email that the guideline summarizes in great detail the pathophysiology behind PFS and highlights how component testing may help diagnose patients and manage the condition.
“Patients worry very much about the progression and severity of allergic reactions,” said Dr. Larkin, who was not involved in the guideline development.
“As the authors note, recognizing the nutritional consequences of dietary restrictions is important, and nutrition consults and suitable alternative suggestions are very helpful for these patients, especially for those with food allergy or who are vegetarian or vegan.”
Jill A. Poole, MD, professor of medicine and chief of the Division of Allergy and Immunology at the University of Nebraska College of Medicine, Omaha, noted that PFS, although common, is underrecognized by the public and by health care providers.
“People are not allergic to the specific food, but they are allergic to a seasonal allergen, such as birch tree, that cross-reacts with the food protein, which is typically changed with cooking,” she explained in an email.
“This differs from reactions by those who have moderate to severe allergic food-specific reactions that may include systemic reactions like anaphylaxis from eating certain foods,” she said.
“Importantly, the number of cross-reacting foods with seasonal pollens continues to grow, and the extent of testing has expanded in recent years,” advised Dr. Poole, who also was not involved in the guideline development.
The authors recommend further related research into food immunotherapy and other novel PFS treatments. They also want to raise awareness of factors affecting PFS prevalence, such as increased spread and allergenicity of pollen due to climate change, pollution, the global consumption of previously local traditional foods, and the increase in vegetarian and vegan diets.
The authors, Dr. Larkin, and Dr. Poole report no relevant financial relationships involving this guideline. The guideline was not funded.
A version of this article first appeared on Medscape.com.
Shift in child hospice care is a lifeline for parents seeking a measure of comfort and hope
POMONA, CALIF. – When you first meet 17-month-old Aaron Martinez, it’s not obvious that something is catastrophically wrong.
What you see is a beautiful little boy with smooth, lustrous skin, an abundance of glossy brown hair, and a disarming smile. What you hear are coos and cries that don’t immediately signal anything is horribly awry.
But his parents, Adriana Pinedo and Hector Martinez, know the truth painfully well.
Although Ms. Pinedo’s doctors and midwife had described the pregnancy as “perfect” for all 9 months, Aaron was born with most of his brain cells dead, the result of two strokes and a massive bleed he sustained while in utero.
Doctors aren’t sure what caused the anomalies that left Aaron with virtually no cognitive function or physical mobility. His voluminous hair hides a head whose circumference is too small for his age. He has epilepsy that triggers multiple seizures each day, and his smile is not always what it seems. “It could be a smile; it could be a seizure,” Ms. Pinedo said.
Shortly after Aaron was born, doctors told Ms. Pinedo, 34, and Mr. Martinez, 35, there was no hope and they should “let nature take its course.” They would learn months later that the doctors had not expected the boy to live more than 5 days. It was on Day 5 that his parents put him in home hospice care, an arrangement that has continued into his second year of life.
The family gets weekly visits from hospice nurses, therapists, social workers, and a chaplain in the cramped one-bedroom apartment they rent from the people who live in the main house on the same lot on a quiet residential street in this Inland Empire city.
One of the main criteria for hospice care, established by Medicare largely for seniors but also applied to children, is a diagnosis of 6 months or less to live. Yet over the course of 17 months, Aaron’s medical team has repeatedly recertified his hospice eligibility.
Under a provision of the 2010 Affordable Care Act, children enrolled in Medicaid or the Children’s Health Insurance Program are allowed, unlike adults, to be in hospice while continuing to receive curative or life-extending care. Commercial insurers are not required to cover this “concurrent care,” but many now do.
More than a decade since its inception, concurrent care is widely credited with improving the quality of life for many terminally ill children, easing stress on the family and, in some cases, sustaining hope for a cure. But the arrangement can contribute to a painful dilemma for parents like Ms. Pinedo and Mr. Martinez, who are torn between their fierce commitment to their son and the futility of knowing that his condition leaves him with no future worth hoping for.
“We could lose a life, but if he continues to live this way, we’ll lose three,” said Ms. Pinedo. “There’s no quality of life for him or for us.”
Aaron’s doctors now say he could conceivably live for years. His body hasn’t stopped growing since he was born. He’s in the 96th percentile for height for his age, and his weight is about average.
His parents have talked about “graduating” him from hospice. But he is never stable for long, and they welcome the visits from their hospice team. The seizures, sometimes 30 a day, are a persistent assault on his brain and, as he grows, the medications intended to control them must be changed or the doses recalibrated. He is at continual risk of gastrointestinal problems and potentially deadly fluid buildup in his lungs.
Ms. Pinedo, who works from home for a nonprofit public health organization, spends much of her time with Aaron, while Mr. Martinez works as a landscaper. She has chosen to live in the moment, she said, because otherwise her mind wanders to a future in which either “he could die – or he won’t, and I’ll end up changing the diapers of a 40-year-old man.” Either of those “are going to suck.”
While cancer is one of the major illnesses afflicting children in hospice, many others, like Aaron, have rare congenital defects, severe neurological impairments, or uncommon metabolic deficiencies.
“We have diseases that families tell us are 1 of 10 cases in the world,” said Glen Komatsu, MD, medical director of Torrance, Calif.–based TrinityKids Care, which provides home hospice services to Aaron and more than 70 other kids in Los Angeles and Orange counties.
In the years leading up to the ACA’s implementation, pediatric health advocates lobbied hard for the concurrent care provision. Without the possibility of life-extending care or hope for a cure, many parents refused to put their terminally ill kids in hospice, thinking it was tantamount to giving up on them. That meant the whole family missed out on the support hospice can provide, not just pain relief and comfort for the dying child, but emotional and spiritual care for parents and siblings under extreme duress.
TrinityKids Care, run by the large national Catholic health system Providence, doesn’t just send nurses, social workers, and chaplains into homes. For patients able to participate, and their siblings, it also offers art and science projects, exercise classes, movies, and music. During the pandemic, these activities have been conducted via Zoom, and volunteers deliver needed supplies to the children’s homes.
The ability to get treatments that prolong their lives is a major reason children in concurrent care are more likely than adults to outlive the 6-months-to-live diagnosis required for hospice.
“Concurrent care, by its very intention, very clearly is going to extend their lives, and by extending their lives they’re no longer going to be hospice-eligible if you use the 6-month life expectancy criteria,” said David Steinhorn, MD, a pediatric intensive care physician in Virginia, who has helped develop numerous children’s hospice programs across the United States.
Another factor is that kids, even sick ones, are simply more robust than many older people.
“Sick kids are often otherwise healthy, except for one organ,” said Debra Lotstein, MD, chief of the division of comfort and palliative care at Children’s Hospital Los Angeles. “They may have cancer in their body, but their hearts are good and their lungs are good, compared to a 90-year-old who at baseline is just not as resilient.”
All of Aaron Martinez’s vital organs, except for his brain, seem to be working. “There have been times when we’ve brought him in, and the nurse looks at the chart and looks at him, and she can’t believe it’s that child,” said Mr. Martinez.
When kids live past the 6-month life expectancy, they must be recertified to stay in hospice. In many cases, Dr. Steinhorn said, he is willing to recertify his pediatric patients indefinitely.
Even with doctors advocating for them, it’s not always easy for children to get into hospice care. Most hospices care primarily for adults and are reluctant to take kids.
“The hospice will say: ‘We don’t have the capacity to treat children. Our nurses aren’t trained. It’s different. We just can’t do it,’ ” said Lori Butterworth, cofounder of the Children’s Hospice and Palliative Care Coalition of California in Watsonville. “The other reason is not wanting to, because it’s existentially devastating and sad and hard.”
Finances also play a role. Home hospice care is paid at a per diem rate set by Medicare – slightly over $200 a day for the first 2 months, about $161 a day after that – and it is typically the same for kids and adults. Children, particularly those with rare conditions, often require more intensive and innovative care, so the per diem doesn’t stretch as far.
The concurrent care provision has made taking pediatric patients more viable for hospice organizations, Dr. Steinhorn and others said. Under the ACA, many of the expenses for certain medications and medical services can be shifted to the patient’s primary insurance, leaving hospices responsible for pain relief and comfort care.
Even so, the relatively small number of kids who die each year from protracted ailments hardly makes pediatric hospice an appealing line of business in an industry craving growth, especially one in which private equity investors are active and seeking a big payday.
In California, only 21 of 1,336 hospices reported having a specialized pediatric hospice program, and 59 said they served at least one patient under age 21, according to an analysis of 2020 state data by Cordt Kassner, CEO of Hospice Analytics in Colorado Springs.
Hospice providers that do cater to children often face a more basic challenge: Even with the possibility of concurrent care, many parents still equate hospice with acceptance of death. That was the case initially for Matt and Reese Sonnen, Los Angeles residents whose daughter, Layla, was born with a seizure disorder that had no name: Her brain had simply failed to develop in the womb, and an MRI showed “fluid taking up space where the brain wasn’t,” her mother said.
When Layla’s team first mentioned hospice, “I was in the car on my phone, and I almost crashed the car,” Mrs. Sonnen recalled. “The first thought that came to mind was: ‘It is just the end,’ but we felt she was nowhere near it, because she was strong, she was mighty. She was my little girl. She was going to get through this.”
About 3 months later, as Layla’s nervous system deteriorated, causing her to writhe in pain, her parents agreed to enroll her in hospice with TrinityKids Care. She died weeks later, not long after her second birthday. She was in her mother’s arms, with Mr. Sonnen close by.
“All of a sudden, Layla breathed out a big rush of air. The nurse looked at me and said: ‘That was her last breath.’ I was literally breathing in her last breath,” Mrs. Sonnen recounted. “I never wanted to breathe again, because now I felt I had her in my lungs. Don’t make me laugh, don’t make me exhale.”
Layla’s parents have no regrets about their decision to put her in hospice. “It was the absolute right decision, and in hindsight we should have done it sooner,” Mr. Sonnen said. “She was suffering, and we had blinders on.”
Ms. Pinedo said she is “infinitely grateful” for hospice, despite the heartache of Aaron’s condition. Sometimes the social worker will stop by, she said, just to say hello and drop off a latte, a small gesture that can feel very uplifting. “They’ve been our lifeline,” she said.
Ms. Pinedo talks about a friend of hers with a healthy baby, also named Aaron, who is pregnant with her second child. “All the stuff that was on our list, they’re living. And I love them dearly. But it’s almost hard to look, because it’s like looking at the stuff that you didn’t get. It’s like Christmas Day, staring through the window at the neighbor’s house, and you’re sitting there in the cold.”
Yet she seems palpably torn between that bleak remorse and the unconditional love parents feel toward their children. At one point, Ms. Pinedo interrupted herself midsentence and turned to her son, who was in Mr. Martinez’s arms: “Yes, Papi, you are so stinking cute, and you are still my dream come true.”
This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
POMONA, CALIF. – When you first meet 17-month-old Aaron Martinez, it’s not obvious that something is catastrophically wrong.
What you see is a beautiful little boy with smooth, lustrous skin, an abundance of glossy brown hair, and a disarming smile. What you hear are coos and cries that don’t immediately signal anything is horribly awry.
But his parents, Adriana Pinedo and Hector Martinez, know the truth painfully well.
Although Ms. Pinedo’s doctors and midwife had described the pregnancy as “perfect” for all 9 months, Aaron was born with most of his brain cells dead, the result of two strokes and a massive bleed he sustained while in utero.
Doctors aren’t sure what caused the anomalies that left Aaron with virtually no cognitive function or physical mobility. His voluminous hair hides a head whose circumference is too small for his age. He has epilepsy that triggers multiple seizures each day, and his smile is not always what it seems. “It could be a smile; it could be a seizure,” Ms. Pinedo said.
Shortly after Aaron was born, doctors told Ms. Pinedo, 34, and Mr. Martinez, 35, there was no hope and they should “let nature take its course.” They would learn months later that the doctors had not expected the boy to live more than 5 days. It was on Day 5 that his parents put him in home hospice care, an arrangement that has continued into his second year of life.
The family gets weekly visits from hospice nurses, therapists, social workers, and a chaplain in the cramped one-bedroom apartment they rent from the people who live in the main house on the same lot on a quiet residential street in this Inland Empire city.
One of the main criteria for hospice care, established by Medicare largely for seniors but also applied to children, is a diagnosis of 6 months or less to live. Yet over the course of 17 months, Aaron’s medical team has repeatedly recertified his hospice eligibility.
Under a provision of the 2010 Affordable Care Act, children enrolled in Medicaid or the Children’s Health Insurance Program are allowed, unlike adults, to be in hospice while continuing to receive curative or life-extending care. Commercial insurers are not required to cover this “concurrent care,” but many now do.
More than a decade since its inception, concurrent care is widely credited with improving the quality of life for many terminally ill children, easing stress on the family and, in some cases, sustaining hope for a cure. But the arrangement can contribute to a painful dilemma for parents like Ms. Pinedo and Mr. Martinez, who are torn between their fierce commitment to their son and the futility of knowing that his condition leaves him with no future worth hoping for.
“We could lose a life, but if he continues to live this way, we’ll lose three,” said Ms. Pinedo. “There’s no quality of life for him or for us.”
Aaron’s doctors now say he could conceivably live for years. His body hasn’t stopped growing since he was born. He’s in the 96th percentile for height for his age, and his weight is about average.
His parents have talked about “graduating” him from hospice. But he is never stable for long, and they welcome the visits from their hospice team. The seizures, sometimes 30 a day, are a persistent assault on his brain and, as he grows, the medications intended to control them must be changed or the doses recalibrated. He is at continual risk of gastrointestinal problems and potentially deadly fluid buildup in his lungs.
Ms. Pinedo, who works from home for a nonprofit public health organization, spends much of her time with Aaron, while Mr. Martinez works as a landscaper. She has chosen to live in the moment, she said, because otherwise her mind wanders to a future in which either “he could die – or he won’t, and I’ll end up changing the diapers of a 40-year-old man.” Either of those “are going to suck.”
While cancer is one of the major illnesses afflicting children in hospice, many others, like Aaron, have rare congenital defects, severe neurological impairments, or uncommon metabolic deficiencies.
“We have diseases that families tell us are 1 of 10 cases in the world,” said Glen Komatsu, MD, medical director of Torrance, Calif.–based TrinityKids Care, which provides home hospice services to Aaron and more than 70 other kids in Los Angeles and Orange counties.
In the years leading up to the ACA’s implementation, pediatric health advocates lobbied hard for the concurrent care provision. Without the possibility of life-extending care or hope for a cure, many parents refused to put their terminally ill kids in hospice, thinking it was tantamount to giving up on them. That meant the whole family missed out on the support hospice can provide, not just pain relief and comfort for the dying child, but emotional and spiritual care for parents and siblings under extreme duress.
TrinityKids Care, run by the large national Catholic health system Providence, doesn’t just send nurses, social workers, and chaplains into homes. For patients able to participate, and their siblings, it also offers art and science projects, exercise classes, movies, and music. During the pandemic, these activities have been conducted via Zoom, and volunteers deliver needed supplies to the children’s homes.
The ability to get treatments that prolong their lives is a major reason children in concurrent care are more likely than adults to outlive the 6-months-to-live diagnosis required for hospice.
“Concurrent care, by its very intention, very clearly is going to extend their lives, and by extending their lives they’re no longer going to be hospice-eligible if you use the 6-month life expectancy criteria,” said David Steinhorn, MD, a pediatric intensive care physician in Virginia, who has helped develop numerous children’s hospice programs across the United States.
Another factor is that kids, even sick ones, are simply more robust than many older people.
“Sick kids are often otherwise healthy, except for one organ,” said Debra Lotstein, MD, chief of the division of comfort and palliative care at Children’s Hospital Los Angeles. “They may have cancer in their body, but their hearts are good and their lungs are good, compared to a 90-year-old who at baseline is just not as resilient.”
All of Aaron Martinez’s vital organs, except for his brain, seem to be working. “There have been times when we’ve brought him in, and the nurse looks at the chart and looks at him, and she can’t believe it’s that child,” said Mr. Martinez.
When kids live past the 6-month life expectancy, they must be recertified to stay in hospice. In many cases, Dr. Steinhorn said, he is willing to recertify his pediatric patients indefinitely.
Even with doctors advocating for them, it’s not always easy for children to get into hospice care. Most hospices care primarily for adults and are reluctant to take kids.
“The hospice will say: ‘We don’t have the capacity to treat children. Our nurses aren’t trained. It’s different. We just can’t do it,’ ” said Lori Butterworth, cofounder of the Children’s Hospice and Palliative Care Coalition of California in Watsonville. “The other reason is not wanting to, because it’s existentially devastating and sad and hard.”
Finances also play a role. Home hospice care is paid at a per diem rate set by Medicare – slightly over $200 a day for the first 2 months, about $161 a day after that – and it is typically the same for kids and adults. Children, particularly those with rare conditions, often require more intensive and innovative care, so the per diem doesn’t stretch as far.
The concurrent care provision has made taking pediatric patients more viable for hospice organizations, Dr. Steinhorn and others said. Under the ACA, many of the expenses for certain medications and medical services can be shifted to the patient’s primary insurance, leaving hospices responsible for pain relief and comfort care.
Even so, the relatively small number of kids who die each year from protracted ailments hardly makes pediatric hospice an appealing line of business in an industry craving growth, especially one in which private equity investors are active and seeking a big payday.
In California, only 21 of 1,336 hospices reported having a specialized pediatric hospice program, and 59 said they served at least one patient under age 21, according to an analysis of 2020 state data by Cordt Kassner, CEO of Hospice Analytics in Colorado Springs.
Hospice providers that do cater to children often face a more basic challenge: Even with the possibility of concurrent care, many parents still equate hospice with acceptance of death. That was the case initially for Matt and Reese Sonnen, Los Angeles residents whose daughter, Layla, was born with a seizure disorder that had no name: Her brain had simply failed to develop in the womb, and an MRI showed “fluid taking up space where the brain wasn’t,” her mother said.
When Layla’s team first mentioned hospice, “I was in the car on my phone, and I almost crashed the car,” Mrs. Sonnen recalled. “The first thought that came to mind was: ‘It is just the end,’ but we felt she was nowhere near it, because she was strong, she was mighty. She was my little girl. She was going to get through this.”
About 3 months later, as Layla’s nervous system deteriorated, causing her to writhe in pain, her parents agreed to enroll her in hospice with TrinityKids Care. She died weeks later, not long after her second birthday. She was in her mother’s arms, with Mr. Sonnen close by.
“All of a sudden, Layla breathed out a big rush of air. The nurse looked at me and said: ‘That was her last breath.’ I was literally breathing in her last breath,” Mrs. Sonnen recounted. “I never wanted to breathe again, because now I felt I had her in my lungs. Don’t make me laugh, don’t make me exhale.”
Layla’s parents have no regrets about their decision to put her in hospice. “It was the absolute right decision, and in hindsight we should have done it sooner,” Mr. Sonnen said. “She was suffering, and we had blinders on.”
Ms. Pinedo said she is “infinitely grateful” for hospice, despite the heartache of Aaron’s condition. Sometimes the social worker will stop by, she said, just to say hello and drop off a latte, a small gesture that can feel very uplifting. “They’ve been our lifeline,” she said.
Ms. Pinedo talks about a friend of hers with a healthy baby, also named Aaron, who is pregnant with her second child. “All the stuff that was on our list, they’re living. And I love them dearly. But it’s almost hard to look, because it’s like looking at the stuff that you didn’t get. It’s like Christmas Day, staring through the window at the neighbor’s house, and you’re sitting there in the cold.”
Yet she seems palpably torn between that bleak remorse and the unconditional love parents feel toward their children. At one point, Ms. Pinedo interrupted herself midsentence and turned to her son, who was in Mr. Martinez’s arms: “Yes, Papi, you are so stinking cute, and you are still my dream come true.”
This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
POMONA, CALIF. – When you first meet 17-month-old Aaron Martinez, it’s not obvious that something is catastrophically wrong.
What you see is a beautiful little boy with smooth, lustrous skin, an abundance of glossy brown hair, and a disarming smile. What you hear are coos and cries that don’t immediately signal anything is horribly awry.
But his parents, Adriana Pinedo and Hector Martinez, know the truth painfully well.
Although Ms. Pinedo’s doctors and midwife had described the pregnancy as “perfect” for all 9 months, Aaron was born with most of his brain cells dead, the result of two strokes and a massive bleed he sustained while in utero.
Doctors aren’t sure what caused the anomalies that left Aaron with virtually no cognitive function or physical mobility. His voluminous hair hides a head whose circumference is too small for his age. He has epilepsy that triggers multiple seizures each day, and his smile is not always what it seems. “It could be a smile; it could be a seizure,” Ms. Pinedo said.
Shortly after Aaron was born, doctors told Ms. Pinedo, 34, and Mr. Martinez, 35, there was no hope and they should “let nature take its course.” They would learn months later that the doctors had not expected the boy to live more than 5 days. It was on Day 5 that his parents put him in home hospice care, an arrangement that has continued into his second year of life.
The family gets weekly visits from hospice nurses, therapists, social workers, and a chaplain in the cramped one-bedroom apartment they rent from the people who live in the main house on the same lot on a quiet residential street in this Inland Empire city.
One of the main criteria for hospice care, established by Medicare largely for seniors but also applied to children, is a diagnosis of 6 months or less to live. Yet over the course of 17 months, Aaron’s medical team has repeatedly recertified his hospice eligibility.
Under a provision of the 2010 Affordable Care Act, children enrolled in Medicaid or the Children’s Health Insurance Program are allowed, unlike adults, to be in hospice while continuing to receive curative or life-extending care. Commercial insurers are not required to cover this “concurrent care,” but many now do.
More than a decade since its inception, concurrent care is widely credited with improving the quality of life for many terminally ill children, easing stress on the family and, in some cases, sustaining hope for a cure. But the arrangement can contribute to a painful dilemma for parents like Ms. Pinedo and Mr. Martinez, who are torn between their fierce commitment to their son and the futility of knowing that his condition leaves him with no future worth hoping for.
“We could lose a life, but if he continues to live this way, we’ll lose three,” said Ms. Pinedo. “There’s no quality of life for him or for us.”
Aaron’s doctors now say he could conceivably live for years. His body hasn’t stopped growing since he was born. He’s in the 96th percentile for height for his age, and his weight is about average.
His parents have talked about “graduating” him from hospice. But he is never stable for long, and they welcome the visits from their hospice team. The seizures, sometimes 30 a day, are a persistent assault on his brain and, as he grows, the medications intended to control them must be changed or the doses recalibrated. He is at continual risk of gastrointestinal problems and potentially deadly fluid buildup in his lungs.
Ms. Pinedo, who works from home for a nonprofit public health organization, spends much of her time with Aaron, while Mr. Martinez works as a landscaper. She has chosen to live in the moment, she said, because otherwise her mind wanders to a future in which either “he could die – or he won’t, and I’ll end up changing the diapers of a 40-year-old man.” Either of those “are going to suck.”
While cancer is one of the major illnesses afflicting children in hospice, many others, like Aaron, have rare congenital defects, severe neurological impairments, or uncommon metabolic deficiencies.
“We have diseases that families tell us are 1 of 10 cases in the world,” said Glen Komatsu, MD, medical director of Torrance, Calif.–based TrinityKids Care, which provides home hospice services to Aaron and more than 70 other kids in Los Angeles and Orange counties.
In the years leading up to the ACA’s implementation, pediatric health advocates lobbied hard for the concurrent care provision. Without the possibility of life-extending care or hope for a cure, many parents refused to put their terminally ill kids in hospice, thinking it was tantamount to giving up on them. That meant the whole family missed out on the support hospice can provide, not just pain relief and comfort for the dying child, but emotional and spiritual care for parents and siblings under extreme duress.
TrinityKids Care, run by the large national Catholic health system Providence, doesn’t just send nurses, social workers, and chaplains into homes. For patients able to participate, and their siblings, it also offers art and science projects, exercise classes, movies, and music. During the pandemic, these activities have been conducted via Zoom, and volunteers deliver needed supplies to the children’s homes.
The ability to get treatments that prolong their lives is a major reason children in concurrent care are more likely than adults to outlive the 6-months-to-live diagnosis required for hospice.
“Concurrent care, by its very intention, very clearly is going to extend their lives, and by extending their lives they’re no longer going to be hospice-eligible if you use the 6-month life expectancy criteria,” said David Steinhorn, MD, a pediatric intensive care physician in Virginia, who has helped develop numerous children’s hospice programs across the United States.
Another factor is that kids, even sick ones, are simply more robust than many older people.
“Sick kids are often otherwise healthy, except for one organ,” said Debra Lotstein, MD, chief of the division of comfort and palliative care at Children’s Hospital Los Angeles. “They may have cancer in their body, but their hearts are good and their lungs are good, compared to a 90-year-old who at baseline is just not as resilient.”
All of Aaron Martinez’s vital organs, except for his brain, seem to be working. “There have been times when we’ve brought him in, and the nurse looks at the chart and looks at him, and she can’t believe it’s that child,” said Mr. Martinez.
When kids live past the 6-month life expectancy, they must be recertified to stay in hospice. In many cases, Dr. Steinhorn said, he is willing to recertify his pediatric patients indefinitely.
Even with doctors advocating for them, it’s not always easy for children to get into hospice care. Most hospices care primarily for adults and are reluctant to take kids.
“The hospice will say: ‘We don’t have the capacity to treat children. Our nurses aren’t trained. It’s different. We just can’t do it,’ ” said Lori Butterworth, cofounder of the Children’s Hospice and Palliative Care Coalition of California in Watsonville. “The other reason is not wanting to, because it’s existentially devastating and sad and hard.”
Finances also play a role. Home hospice care is paid at a per diem rate set by Medicare – slightly over $200 a day for the first 2 months, about $161 a day after that – and it is typically the same for kids and adults. Children, particularly those with rare conditions, often require more intensive and innovative care, so the per diem doesn’t stretch as far.
The concurrent care provision has made taking pediatric patients more viable for hospice organizations, Dr. Steinhorn and others said. Under the ACA, many of the expenses for certain medications and medical services can be shifted to the patient’s primary insurance, leaving hospices responsible for pain relief and comfort care.
Even so, the relatively small number of kids who die each year from protracted ailments hardly makes pediatric hospice an appealing line of business in an industry craving growth, especially one in which private equity investors are active and seeking a big payday.
In California, only 21 of 1,336 hospices reported having a specialized pediatric hospice program, and 59 said they served at least one patient under age 21, according to an analysis of 2020 state data by Cordt Kassner, CEO of Hospice Analytics in Colorado Springs.
Hospice providers that do cater to children often face a more basic challenge: Even with the possibility of concurrent care, many parents still equate hospice with acceptance of death. That was the case initially for Matt and Reese Sonnen, Los Angeles residents whose daughter, Layla, was born with a seizure disorder that had no name: Her brain had simply failed to develop in the womb, and an MRI showed “fluid taking up space where the brain wasn’t,” her mother said.
When Layla’s team first mentioned hospice, “I was in the car on my phone, and I almost crashed the car,” Mrs. Sonnen recalled. “The first thought that came to mind was: ‘It is just the end,’ but we felt she was nowhere near it, because she was strong, she was mighty. She was my little girl. She was going to get through this.”
About 3 months later, as Layla’s nervous system deteriorated, causing her to writhe in pain, her parents agreed to enroll her in hospice with TrinityKids Care. She died weeks later, not long after her second birthday. She was in her mother’s arms, with Mr. Sonnen close by.
“All of a sudden, Layla breathed out a big rush of air. The nurse looked at me and said: ‘That was her last breath.’ I was literally breathing in her last breath,” Mrs. Sonnen recounted. “I never wanted to breathe again, because now I felt I had her in my lungs. Don’t make me laugh, don’t make me exhale.”
Layla’s parents have no regrets about their decision to put her in hospice. “It was the absolute right decision, and in hindsight we should have done it sooner,” Mr. Sonnen said. “She was suffering, and we had blinders on.”
Ms. Pinedo said she is “infinitely grateful” for hospice, despite the heartache of Aaron’s condition. Sometimes the social worker will stop by, she said, just to say hello and drop off a latte, a small gesture that can feel very uplifting. “They’ve been our lifeline,” she said.
Ms. Pinedo talks about a friend of hers with a healthy baby, also named Aaron, who is pregnant with her second child. “All the stuff that was on our list, they’re living. And I love them dearly. But it’s almost hard to look, because it’s like looking at the stuff that you didn’t get. It’s like Christmas Day, staring through the window at the neighbor’s house, and you’re sitting there in the cold.”
Yet she seems palpably torn between that bleak remorse and the unconditional love parents feel toward their children. At one point, Ms. Pinedo interrupted herself midsentence and turned to her son, who was in Mr. Martinez’s arms: “Yes, Papi, you are so stinking cute, and you are still my dream come true.”
This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
COVID vaccination does not appear to worsen symptoms of Parkinson’s disease
Nonmotor symptoms seemed to improve after SARS-CoV-2 vaccination, although the investigators could not verify a causal relationship.
Vaccination programs should continue for patients with Parkinson’s disease, they said, reporting their clinical results at the International Congress of Parkinson’s Disease and Movement Disorders.
The International Parkinson and Movement Disorder Society has recommended vaccining patients with Parkinson’s disease. “All approved mRNA-based and viral vector vaccines are not expected to interact with Parkinson’s disease, but patients [still] report concern with regard to the benefits, risks, and safeness in Parkinson’s disease,” Mayela Rodríguez-Violante, MD, MSc, and colleagues wrote in an abstract of their findings.
Social isolation may be contributing to these beliefs and concerns, though this is inconclusive.
Investigators from Mexico City conducted a retrospective study of patients with Parkinson’s disease to see how COVID-19 vaccination affected motor and nonmotor symptoms. They enlisted 60 patients (66.7% were male; aged 65.7 ± 11.35 years) who received either a vector-viral vaccine (Vaxzevria Coronavirus) or an mRNA vaccine (BNT162b2).
A Wilcoxon signed-rank test assessed scale differences before and after vaccination, measuring motor involvement (Unified Parkinson’s Disease Rating Scale), nonmotor involvement (Non-Motor Rating Scale [NMSS]), cognitive impairment (Montreal Cognitive Assessment), and quality of life (8-item Parkinson’s Disease Questionnaire index).
Investigators found no significant difference between scales, although they did notice a marked improvement in non-motor symptoms.
“The main takeaway is that vaccination against COVID-19 does not appear to worsen motor or nonmotor symptoms in persons with Parkinson’s disease. The benefits outweigh the risks,” said Dr. Rodríguez-Violante, the study’s lead author and a movement disorder specialist at the National Institute of Neurology and Neurosurgery, Mexico City.
Next steps are to increase the sample size to see if it’s possible to have a similar number in terms of type of vaccine, said Dr. Rodríguez-Violante. “Also, the data presented refers to primary series doses so booster effects will also be studied.”
Few studies have looked at vaccines and their possible effects on this patient population. However, a 2021 study of 181 patients with Parkinson’s disease reported that 2 (1.1%) had adverse effects after receiving the BNT162b2 mRNA vaccine. One of the patients, a 61-year-old woman with a decade-long history of Parkinson’s disease, developed severe, continuous, generalized dyskinesia 6 hours after a first dose of vaccine. The second patient was 79 years old and had Parkinson’s disease for 5 years. She developed fever, confusion, delusions, and continuous severe dyskinesia for 3 days following her vaccination.
“This highlights that there is a variability in the response triggered by the vaccine that might likely depend on individual immunological profiles … clinicians should be aware of this possibility and monitor their patients after they receive their vaccination,” Roberto Erro, MD, PhD and colleagues wrote in the Movement Disorders journal.
Nonmotor symptoms seemed to improve after SARS-CoV-2 vaccination, although the investigators could not verify a causal relationship.
Vaccination programs should continue for patients with Parkinson’s disease, they said, reporting their clinical results at the International Congress of Parkinson’s Disease and Movement Disorders.
The International Parkinson and Movement Disorder Society has recommended vaccining patients with Parkinson’s disease. “All approved mRNA-based and viral vector vaccines are not expected to interact with Parkinson’s disease, but patients [still] report concern with regard to the benefits, risks, and safeness in Parkinson’s disease,” Mayela Rodríguez-Violante, MD, MSc, and colleagues wrote in an abstract of their findings.
Social isolation may be contributing to these beliefs and concerns, though this is inconclusive.
Investigators from Mexico City conducted a retrospective study of patients with Parkinson’s disease to see how COVID-19 vaccination affected motor and nonmotor symptoms. They enlisted 60 patients (66.7% were male; aged 65.7 ± 11.35 years) who received either a vector-viral vaccine (Vaxzevria Coronavirus) or an mRNA vaccine (BNT162b2).
A Wilcoxon signed-rank test assessed scale differences before and after vaccination, measuring motor involvement (Unified Parkinson’s Disease Rating Scale), nonmotor involvement (Non-Motor Rating Scale [NMSS]), cognitive impairment (Montreal Cognitive Assessment), and quality of life (8-item Parkinson’s Disease Questionnaire index).
Investigators found no significant difference between scales, although they did notice a marked improvement in non-motor symptoms.
“The main takeaway is that vaccination against COVID-19 does not appear to worsen motor or nonmotor symptoms in persons with Parkinson’s disease. The benefits outweigh the risks,” said Dr. Rodríguez-Violante, the study’s lead author and a movement disorder specialist at the National Institute of Neurology and Neurosurgery, Mexico City.
Next steps are to increase the sample size to see if it’s possible to have a similar number in terms of type of vaccine, said Dr. Rodríguez-Violante. “Also, the data presented refers to primary series doses so booster effects will also be studied.”
Few studies have looked at vaccines and their possible effects on this patient population. However, a 2021 study of 181 patients with Parkinson’s disease reported that 2 (1.1%) had adverse effects after receiving the BNT162b2 mRNA vaccine. One of the patients, a 61-year-old woman with a decade-long history of Parkinson’s disease, developed severe, continuous, generalized dyskinesia 6 hours after a first dose of vaccine. The second patient was 79 years old and had Parkinson’s disease for 5 years. She developed fever, confusion, delusions, and continuous severe dyskinesia for 3 days following her vaccination.
“This highlights that there is a variability in the response triggered by the vaccine that might likely depend on individual immunological profiles … clinicians should be aware of this possibility and monitor their patients after they receive their vaccination,” Roberto Erro, MD, PhD and colleagues wrote in the Movement Disorders journal.
Nonmotor symptoms seemed to improve after SARS-CoV-2 vaccination, although the investigators could not verify a causal relationship.
Vaccination programs should continue for patients with Parkinson’s disease, they said, reporting their clinical results at the International Congress of Parkinson’s Disease and Movement Disorders.
The International Parkinson and Movement Disorder Society has recommended vaccining patients with Parkinson’s disease. “All approved mRNA-based and viral vector vaccines are not expected to interact with Parkinson’s disease, but patients [still] report concern with regard to the benefits, risks, and safeness in Parkinson’s disease,” Mayela Rodríguez-Violante, MD, MSc, and colleagues wrote in an abstract of their findings.
Social isolation may be contributing to these beliefs and concerns, though this is inconclusive.
Investigators from Mexico City conducted a retrospective study of patients with Parkinson’s disease to see how COVID-19 vaccination affected motor and nonmotor symptoms. They enlisted 60 patients (66.7% were male; aged 65.7 ± 11.35 years) who received either a vector-viral vaccine (Vaxzevria Coronavirus) or an mRNA vaccine (BNT162b2).
A Wilcoxon signed-rank test assessed scale differences before and after vaccination, measuring motor involvement (Unified Parkinson’s Disease Rating Scale), nonmotor involvement (Non-Motor Rating Scale [NMSS]), cognitive impairment (Montreal Cognitive Assessment), and quality of life (8-item Parkinson’s Disease Questionnaire index).
Investigators found no significant difference between scales, although they did notice a marked improvement in non-motor symptoms.
“The main takeaway is that vaccination against COVID-19 does not appear to worsen motor or nonmotor symptoms in persons with Parkinson’s disease. The benefits outweigh the risks,” said Dr. Rodríguez-Violante, the study’s lead author and a movement disorder specialist at the National Institute of Neurology and Neurosurgery, Mexico City.
Next steps are to increase the sample size to see if it’s possible to have a similar number in terms of type of vaccine, said Dr. Rodríguez-Violante. “Also, the data presented refers to primary series doses so booster effects will also be studied.”
Few studies have looked at vaccines and their possible effects on this patient population. However, a 2021 study of 181 patients with Parkinson’s disease reported that 2 (1.1%) had adverse effects after receiving the BNT162b2 mRNA vaccine. One of the patients, a 61-year-old woman with a decade-long history of Parkinson’s disease, developed severe, continuous, generalized dyskinesia 6 hours after a first dose of vaccine. The second patient was 79 years old and had Parkinson’s disease for 5 years. She developed fever, confusion, delusions, and continuous severe dyskinesia for 3 days following her vaccination.
“This highlights that there is a variability in the response triggered by the vaccine that might likely depend on individual immunological profiles … clinicians should be aware of this possibility and monitor their patients after they receive their vaccination,” Roberto Erro, MD, PhD and colleagues wrote in the Movement Disorders journal.
FROM MDS 2022
FDA okays terlipressin (Terlivaz) injection for hepatorenal syndrome
The Food and Drug Administration has approved terlipressin (Terlivaz), the first and only drug approved for patients with hepatorenal syndrome (HRS).
HRS is characterized by progressive deterioration in kidney function in people with advanced liver disease.
Terlipressin is an injectable synthetic vasopressin analogue indicated for patients with HRS who are experiencing rapid deterioration of kidney function (type 1 HRS). The condition affects an estimated 35,000 Americans annually.
The safety and efficacy of terlipressin for type 1 HRS was assessed in the phase 3 CONFIRM trial, which involved 300 patients in the United States and Canada.
Patients received an injection of terlipressin (0.85 mg) or placebo every 6 hours for a maximum of 14 days. The dose was adjusted on the basis of changes in kidney function.
Twenty-nine percent of patients in the terlipressin group experienced improvement in kidney function, vs. 16% in the placebo group.
The CONFIRM trial met its primary endpoint of verified HRS reversal, defined as renal function improvement, avoidance of dialysis, and short-term survival (P = .012).
To achieve this endpoint, patients had to have two consecutive serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 2 hours apart by day 14 or be discharged from the hospital.
The most commonly observed adverse reactions that occurred in at least 4% of patients treated with terlipressin were abdominal pain (19.5%), nausea (16%), respiratory failure (15.5%), diarrhea (13%), and dyspnea (12.5%).
Results of the CONFIRM trial were published in The New England Journal of Medicine.
“Diagnosing and treating HRS can be challenging, and every minute counts when managing patients who have it,” said Steven Romano, MD, executive vice president and chief scientific officer at Mallinckrodt, which makes the drug.
“Terlivaz gives physicians the first FDA-approved option for treating HRS patients with rapid reduction in kidney function that may help them improve kidney function and lessen the associated need for renal replacement therapy, such as dialysis,” Dr. Romano said.
The company plans to launch the product in the coming weeks.
The application for terlipressin for HRS was granted priority review and fast-track status, as well as orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved terlipressin (Terlivaz), the first and only drug approved for patients with hepatorenal syndrome (HRS).
HRS is characterized by progressive deterioration in kidney function in people with advanced liver disease.
Terlipressin is an injectable synthetic vasopressin analogue indicated for patients with HRS who are experiencing rapid deterioration of kidney function (type 1 HRS). The condition affects an estimated 35,000 Americans annually.
The safety and efficacy of terlipressin for type 1 HRS was assessed in the phase 3 CONFIRM trial, which involved 300 patients in the United States and Canada.
Patients received an injection of terlipressin (0.85 mg) or placebo every 6 hours for a maximum of 14 days. The dose was adjusted on the basis of changes in kidney function.
Twenty-nine percent of patients in the terlipressin group experienced improvement in kidney function, vs. 16% in the placebo group.
The CONFIRM trial met its primary endpoint of verified HRS reversal, defined as renal function improvement, avoidance of dialysis, and short-term survival (P = .012).
To achieve this endpoint, patients had to have two consecutive serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 2 hours apart by day 14 or be discharged from the hospital.
The most commonly observed adverse reactions that occurred in at least 4% of patients treated with terlipressin were abdominal pain (19.5%), nausea (16%), respiratory failure (15.5%), diarrhea (13%), and dyspnea (12.5%).
Results of the CONFIRM trial were published in The New England Journal of Medicine.
“Diagnosing and treating HRS can be challenging, and every minute counts when managing patients who have it,” said Steven Romano, MD, executive vice president and chief scientific officer at Mallinckrodt, which makes the drug.
“Terlivaz gives physicians the first FDA-approved option for treating HRS patients with rapid reduction in kidney function that may help them improve kidney function and lessen the associated need for renal replacement therapy, such as dialysis,” Dr. Romano said.
The company plans to launch the product in the coming weeks.
The application for terlipressin for HRS was granted priority review and fast-track status, as well as orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration has approved terlipressin (Terlivaz), the first and only drug approved for patients with hepatorenal syndrome (HRS).
HRS is characterized by progressive deterioration in kidney function in people with advanced liver disease.
Terlipressin is an injectable synthetic vasopressin analogue indicated for patients with HRS who are experiencing rapid deterioration of kidney function (type 1 HRS). The condition affects an estimated 35,000 Americans annually.
The safety and efficacy of terlipressin for type 1 HRS was assessed in the phase 3 CONFIRM trial, which involved 300 patients in the United States and Canada.
Patients received an injection of terlipressin (0.85 mg) or placebo every 6 hours for a maximum of 14 days. The dose was adjusted on the basis of changes in kidney function.
Twenty-nine percent of patients in the terlipressin group experienced improvement in kidney function, vs. 16% in the placebo group.
The CONFIRM trial met its primary endpoint of verified HRS reversal, defined as renal function improvement, avoidance of dialysis, and short-term survival (P = .012).
To achieve this endpoint, patients had to have two consecutive serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 2 hours apart by day 14 or be discharged from the hospital.
The most commonly observed adverse reactions that occurred in at least 4% of patients treated with terlipressin were abdominal pain (19.5%), nausea (16%), respiratory failure (15.5%), diarrhea (13%), and dyspnea (12.5%).
Results of the CONFIRM trial were published in The New England Journal of Medicine.
“Diagnosing and treating HRS can be challenging, and every minute counts when managing patients who have it,” said Steven Romano, MD, executive vice president and chief scientific officer at Mallinckrodt, which makes the drug.
“Terlivaz gives physicians the first FDA-approved option for treating HRS patients with rapid reduction in kidney function that may help them improve kidney function and lessen the associated need for renal replacement therapy, such as dialysis,” Dr. Romano said.
The company plans to launch the product in the coming weeks.
The application for terlipressin for HRS was granted priority review and fast-track status, as well as orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
A version of this article first appeared on Medscape.com.
Cell-killing cancer therapy treats lupus successfully
In a first-of-its-kind clinical trial, researchers in Germany used a cancer-killing cell therapy to successfully treat lupus in a small number of patients.
Their study, published online in Nature Medicine, included five patients with systemic lupus erythematosus (SLE). All of the patients were treated with chimeric antigen receptor (CAR) T-cell therapy, a treatment regularly used to kill cancer cells. Researchers harvested the patients’ immune cells and engineered them to destroy dysfunctional cells when infused back into the body.
The five patients – all of whom had an aggressive form of the autoimmune disease – underwent a single infusion of the experimental treatment. All five patients were able to stop their standard treatments for as long as 17 months following the therapy, the study found. The patients also stopped experiencing severe symptoms such as lung inflammation, fibrosis of the heart valves, arthritis, and fatigue. The patients have not relapsed.
“Our data reveal unexpected insights for a role of CAR T cells in nonmalignant diseases that could provide new opportunities for the treatment of autoimmune disease,” the study authors wrote.
Lupus is a chronic inflammatory disease in which the immune system attacks the body’s own cells. Both antibody-producing B and T cells in individuals with lupus become overactive, which can lead to a flare of symptoms that range from mild pain and fatigue to life-threatening inflammation and tissue damage. They are often treated with medications that deplete their B cells or change the way they function to help wipe out infected cells.
The approach used by the study researchers is similar to monoclonal antibody therapies that destroy dysfunctional B cells, such as rituximab (Rituxan and biosimilars) and obinutuzumab (Gazyva), according to Michael Belmont, MD, codirector of New York University’s Lupus Center and medical director of Bellevue Hospital Lupus Clinic, also in New York.
“Previously, this has been accomplished with monoclonal antibodies that target surface markers on B cells and results in their removal,” said Dr. Belmont, who was not connected to the study. “The report describes a novel approach that harnesses a patient’s own T cells, another type of white blood cell, to eliminate that patient’s own B cells.”
Preclinical studies involving mice previously showed that CAR T-cell therapy could help to reset the immune system. However, this latest study also found that patients did not need to continue any of their previous therapies, even after they regained their B cells about 4 months after the therapy.
“A deep depletion of CD19+ B cells and plasmablasts in the tissues could trigger an immune reset in SLE that could allow the cessation of immunosuppressive treatment,” said Mehrnaz Hojjati, MD, a rheumatologist and director of rheumatology operations at Loma Linda (Calif.) University Health. Dr. Hojjati was not affiliated with the study.
While the single-treatment therapy is promising, transfused T cells do carry risks. Some of the patients in the study experienced fever and muscle pain following the procedure, the authors noted. Dr. Belmont said more serious risks for this kind of therapy may include organ injury.
“This treatment can [also] increase incidence, for example, of pneumonia or shingles,” he said.
The study authors initially documented their work in a correspondence published in August 2021 in the New England Journal of Medicine. At that time, they reported that a 20-year-old woman with a severe refractory SLE went into remission following the treatment.
The five patients in the current study – four women and one man – were aged 18-24 years. All of the patients had previously been treated with several immunosuppressive medications, the study authors noted.
“This is an exciting approach, but many more patients need to be treated to really understand the efficacy and safety,” Dr. Belmont said.
Experts, including Dr. Belmont, also said the procedure is also costly and requires access to labs that can engineer a patient’s own T cells after they’ve been donated.
“The entire process must maintain sterility to avoid contamination, which would be harmful when reinfused into the patient,” he said.
According to Arthur Kavanaugh, MD, professor of medicine at UC San Diego Health, this form of therapy may be an option for severe refractory patients who have not responded well to other more established therapies.
“[It’s] exciting data, but very intense and so not likely to be something for an average patient in the near future,” said Dr. Kavanaugh, who was not affiliated with the study.
The study authors say they intend to create a larger trial to further explore which type of patient may benefit the most from this treatment, and for how long.
The study was supported by the German Research Foundation, the German Federal Ministry of Education and Research, the European Union, and the Innovative Medicines Initiative–funded project, Rheuma Tolerance for Cure. The study received no commercial funding, and the authors said they had no competing interests related to the study. None of the experts interviewed reported relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a first-of-its-kind clinical trial, researchers in Germany used a cancer-killing cell therapy to successfully treat lupus in a small number of patients.
Their study, published online in Nature Medicine, included five patients with systemic lupus erythematosus (SLE). All of the patients were treated with chimeric antigen receptor (CAR) T-cell therapy, a treatment regularly used to kill cancer cells. Researchers harvested the patients’ immune cells and engineered them to destroy dysfunctional cells when infused back into the body.
The five patients – all of whom had an aggressive form of the autoimmune disease – underwent a single infusion of the experimental treatment. All five patients were able to stop their standard treatments for as long as 17 months following the therapy, the study found. The patients also stopped experiencing severe symptoms such as lung inflammation, fibrosis of the heart valves, arthritis, and fatigue. The patients have not relapsed.
“Our data reveal unexpected insights for a role of CAR T cells in nonmalignant diseases that could provide new opportunities for the treatment of autoimmune disease,” the study authors wrote.
Lupus is a chronic inflammatory disease in which the immune system attacks the body’s own cells. Both antibody-producing B and T cells in individuals with lupus become overactive, which can lead to a flare of symptoms that range from mild pain and fatigue to life-threatening inflammation and tissue damage. They are often treated with medications that deplete their B cells or change the way they function to help wipe out infected cells.
The approach used by the study researchers is similar to monoclonal antibody therapies that destroy dysfunctional B cells, such as rituximab (Rituxan and biosimilars) and obinutuzumab (Gazyva), according to Michael Belmont, MD, codirector of New York University’s Lupus Center and medical director of Bellevue Hospital Lupus Clinic, also in New York.
“Previously, this has been accomplished with monoclonal antibodies that target surface markers on B cells and results in their removal,” said Dr. Belmont, who was not connected to the study. “The report describes a novel approach that harnesses a patient’s own T cells, another type of white blood cell, to eliminate that patient’s own B cells.”
Preclinical studies involving mice previously showed that CAR T-cell therapy could help to reset the immune system. However, this latest study also found that patients did not need to continue any of their previous therapies, even after they regained their B cells about 4 months after the therapy.
“A deep depletion of CD19+ B cells and plasmablasts in the tissues could trigger an immune reset in SLE that could allow the cessation of immunosuppressive treatment,” said Mehrnaz Hojjati, MD, a rheumatologist and director of rheumatology operations at Loma Linda (Calif.) University Health. Dr. Hojjati was not affiliated with the study.
While the single-treatment therapy is promising, transfused T cells do carry risks. Some of the patients in the study experienced fever and muscle pain following the procedure, the authors noted. Dr. Belmont said more serious risks for this kind of therapy may include organ injury.
“This treatment can [also] increase incidence, for example, of pneumonia or shingles,” he said.
The study authors initially documented their work in a correspondence published in August 2021 in the New England Journal of Medicine. At that time, they reported that a 20-year-old woman with a severe refractory SLE went into remission following the treatment.
The five patients in the current study – four women and one man – were aged 18-24 years. All of the patients had previously been treated with several immunosuppressive medications, the study authors noted.
“This is an exciting approach, but many more patients need to be treated to really understand the efficacy and safety,” Dr. Belmont said.
Experts, including Dr. Belmont, also said the procedure is also costly and requires access to labs that can engineer a patient’s own T cells after they’ve been donated.
“The entire process must maintain sterility to avoid contamination, which would be harmful when reinfused into the patient,” he said.
According to Arthur Kavanaugh, MD, professor of medicine at UC San Diego Health, this form of therapy may be an option for severe refractory patients who have not responded well to other more established therapies.
“[It’s] exciting data, but very intense and so not likely to be something for an average patient in the near future,” said Dr. Kavanaugh, who was not affiliated with the study.
The study authors say they intend to create a larger trial to further explore which type of patient may benefit the most from this treatment, and for how long.
The study was supported by the German Research Foundation, the German Federal Ministry of Education and Research, the European Union, and the Innovative Medicines Initiative–funded project, Rheuma Tolerance for Cure. The study received no commercial funding, and the authors said they had no competing interests related to the study. None of the experts interviewed reported relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a first-of-its-kind clinical trial, researchers in Germany used a cancer-killing cell therapy to successfully treat lupus in a small number of patients.
Their study, published online in Nature Medicine, included five patients with systemic lupus erythematosus (SLE). All of the patients were treated with chimeric antigen receptor (CAR) T-cell therapy, a treatment regularly used to kill cancer cells. Researchers harvested the patients’ immune cells and engineered them to destroy dysfunctional cells when infused back into the body.
The five patients – all of whom had an aggressive form of the autoimmune disease – underwent a single infusion of the experimental treatment. All five patients were able to stop their standard treatments for as long as 17 months following the therapy, the study found. The patients also stopped experiencing severe symptoms such as lung inflammation, fibrosis of the heart valves, arthritis, and fatigue. The patients have not relapsed.
“Our data reveal unexpected insights for a role of CAR T cells in nonmalignant diseases that could provide new opportunities for the treatment of autoimmune disease,” the study authors wrote.
Lupus is a chronic inflammatory disease in which the immune system attacks the body’s own cells. Both antibody-producing B and T cells in individuals with lupus become overactive, which can lead to a flare of symptoms that range from mild pain and fatigue to life-threatening inflammation and tissue damage. They are often treated with medications that deplete their B cells or change the way they function to help wipe out infected cells.
The approach used by the study researchers is similar to monoclonal antibody therapies that destroy dysfunctional B cells, such as rituximab (Rituxan and biosimilars) and obinutuzumab (Gazyva), according to Michael Belmont, MD, codirector of New York University’s Lupus Center and medical director of Bellevue Hospital Lupus Clinic, also in New York.
“Previously, this has been accomplished with monoclonal antibodies that target surface markers on B cells and results in their removal,” said Dr. Belmont, who was not connected to the study. “The report describes a novel approach that harnesses a patient’s own T cells, another type of white blood cell, to eliminate that patient’s own B cells.”
Preclinical studies involving mice previously showed that CAR T-cell therapy could help to reset the immune system. However, this latest study also found that patients did not need to continue any of their previous therapies, even after they regained their B cells about 4 months after the therapy.
“A deep depletion of CD19+ B cells and plasmablasts in the tissues could trigger an immune reset in SLE that could allow the cessation of immunosuppressive treatment,” said Mehrnaz Hojjati, MD, a rheumatologist and director of rheumatology operations at Loma Linda (Calif.) University Health. Dr. Hojjati was not affiliated with the study.
While the single-treatment therapy is promising, transfused T cells do carry risks. Some of the patients in the study experienced fever and muscle pain following the procedure, the authors noted. Dr. Belmont said more serious risks for this kind of therapy may include organ injury.
“This treatment can [also] increase incidence, for example, of pneumonia or shingles,” he said.
The study authors initially documented their work in a correspondence published in August 2021 in the New England Journal of Medicine. At that time, they reported that a 20-year-old woman with a severe refractory SLE went into remission following the treatment.
The five patients in the current study – four women and one man – were aged 18-24 years. All of the patients had previously been treated with several immunosuppressive medications, the study authors noted.
“This is an exciting approach, but many more patients need to be treated to really understand the efficacy and safety,” Dr. Belmont said.
Experts, including Dr. Belmont, also said the procedure is also costly and requires access to labs that can engineer a patient’s own T cells after they’ve been donated.
“The entire process must maintain sterility to avoid contamination, which would be harmful when reinfused into the patient,” he said.
According to Arthur Kavanaugh, MD, professor of medicine at UC San Diego Health, this form of therapy may be an option for severe refractory patients who have not responded well to other more established therapies.
“[It’s] exciting data, but very intense and so not likely to be something for an average patient in the near future,” said Dr. Kavanaugh, who was not affiliated with the study.
The study authors say they intend to create a larger trial to further explore which type of patient may benefit the most from this treatment, and for how long.
The study was supported by the German Research Foundation, the German Federal Ministry of Education and Research, the European Union, and the Innovative Medicines Initiative–funded project, Rheuma Tolerance for Cure. The study received no commercial funding, and the authors said they had no competing interests related to the study. None of the experts interviewed reported relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM NATURE MEDICINE
FDA OKs sodium thiosulfate injection to reduce ototoxicity risk in children with cancer
This approval makes sodium thiosulfate the first and only treatment FDA-approved in this area.
“Historically, there have been no approved treatments for preventing cisplatin-induced hearing loss,” said David R. Freyer, DO, of Children’s Hospital Los Angeles and primary investigator of one of the two trials, COG ACCL0431. The FDA’s approval “addresses an enormous unmet need for many children and young adults.”
The approval was based on safety and efficacy data from two multicenter open-label, randomized controlled phase 3 trials – SIOPEL 6 and COG ACCL0431 – comparing sodium thiosulfate plus a cisplatin-based regimen to a cisplatin-based regimen alone in pediatric patients. SIOPEL 6 included patients with standard risk hepatoblastoma, and COG ACCL0431 included pediatric patients with solid tumors.
In both studies, the incidence of hearing loss was significantly lower in the sodium thiosulfate group, compared with the cisplatin-only group. In SIOPEL 6, hearing loss of grade 1 or higher occurred in 33% of children (18 of 55) in the cisplatin–sodium thiosulfate group and 63% (29 of 46) in the cisplatin-only group, indicating a 48% lower incidence of hearing loss for those receiving sodium thiosulfate. In COG ACCL0431, hearing loss was identified in 28.6% of patients (14 of 49) receiving sodium thiosulfate, compared with 56.4% (31 of 55) in the control group, indicating a 69% lower risk for hearing loss in the sodium thiosulfate group.
The FDA reported the same overall trend but highlighted slightly different figures. In SIOPEL 6, hearing loss incidence occurred in 39% of patients (24 of 61) in the sodium thiosulfate arm versus 68% (36 of 53) in the control group; in COG ACCL0431, hearing loss incidence occurred among 44% of patients (17 of 39) in the sodium thiosulfate group versus 58% (22 of 38) in the control group.
The recommended dose is based on surface area according to body weight. Sodium thiosulfate is administered as an intravenous infusion over 15 minutes following cisplatin infusions that are 1 to 6 hours in duration.
Serious adverse reactions occurred in 40% of patients who received cisplatin–sodium thiosulfate in SIOPEL 6 and 36% of these patients in COG ACCL0431. The most common adverse reactions in the trials included vomiting, infection, nausea, decreased hemoglobin, hypernatremia, and hypokalemia.
A version of this article first appeared on Medscape.com.
This approval makes sodium thiosulfate the first and only treatment FDA-approved in this area.
“Historically, there have been no approved treatments for preventing cisplatin-induced hearing loss,” said David R. Freyer, DO, of Children’s Hospital Los Angeles and primary investigator of one of the two trials, COG ACCL0431. The FDA’s approval “addresses an enormous unmet need for many children and young adults.”
The approval was based on safety and efficacy data from two multicenter open-label, randomized controlled phase 3 trials – SIOPEL 6 and COG ACCL0431 – comparing sodium thiosulfate plus a cisplatin-based regimen to a cisplatin-based regimen alone in pediatric patients. SIOPEL 6 included patients with standard risk hepatoblastoma, and COG ACCL0431 included pediatric patients with solid tumors.
In both studies, the incidence of hearing loss was significantly lower in the sodium thiosulfate group, compared with the cisplatin-only group. In SIOPEL 6, hearing loss of grade 1 or higher occurred in 33% of children (18 of 55) in the cisplatin–sodium thiosulfate group and 63% (29 of 46) in the cisplatin-only group, indicating a 48% lower incidence of hearing loss for those receiving sodium thiosulfate. In COG ACCL0431, hearing loss was identified in 28.6% of patients (14 of 49) receiving sodium thiosulfate, compared with 56.4% (31 of 55) in the control group, indicating a 69% lower risk for hearing loss in the sodium thiosulfate group.
The FDA reported the same overall trend but highlighted slightly different figures. In SIOPEL 6, hearing loss incidence occurred in 39% of patients (24 of 61) in the sodium thiosulfate arm versus 68% (36 of 53) in the control group; in COG ACCL0431, hearing loss incidence occurred among 44% of patients (17 of 39) in the sodium thiosulfate group versus 58% (22 of 38) in the control group.
The recommended dose is based on surface area according to body weight. Sodium thiosulfate is administered as an intravenous infusion over 15 minutes following cisplatin infusions that are 1 to 6 hours in duration.
Serious adverse reactions occurred in 40% of patients who received cisplatin–sodium thiosulfate in SIOPEL 6 and 36% of these patients in COG ACCL0431. The most common adverse reactions in the trials included vomiting, infection, nausea, decreased hemoglobin, hypernatremia, and hypokalemia.
A version of this article first appeared on Medscape.com.
This approval makes sodium thiosulfate the first and only treatment FDA-approved in this area.
“Historically, there have been no approved treatments for preventing cisplatin-induced hearing loss,” said David R. Freyer, DO, of Children’s Hospital Los Angeles and primary investigator of one of the two trials, COG ACCL0431. The FDA’s approval “addresses an enormous unmet need for many children and young adults.”
The approval was based on safety and efficacy data from two multicenter open-label, randomized controlled phase 3 trials – SIOPEL 6 and COG ACCL0431 – comparing sodium thiosulfate plus a cisplatin-based regimen to a cisplatin-based regimen alone in pediatric patients. SIOPEL 6 included patients with standard risk hepatoblastoma, and COG ACCL0431 included pediatric patients with solid tumors.
In both studies, the incidence of hearing loss was significantly lower in the sodium thiosulfate group, compared with the cisplatin-only group. In SIOPEL 6, hearing loss of grade 1 or higher occurred in 33% of children (18 of 55) in the cisplatin–sodium thiosulfate group and 63% (29 of 46) in the cisplatin-only group, indicating a 48% lower incidence of hearing loss for those receiving sodium thiosulfate. In COG ACCL0431, hearing loss was identified in 28.6% of patients (14 of 49) receiving sodium thiosulfate, compared with 56.4% (31 of 55) in the control group, indicating a 69% lower risk for hearing loss in the sodium thiosulfate group.
The FDA reported the same overall trend but highlighted slightly different figures. In SIOPEL 6, hearing loss incidence occurred in 39% of patients (24 of 61) in the sodium thiosulfate arm versus 68% (36 of 53) in the control group; in COG ACCL0431, hearing loss incidence occurred among 44% of patients (17 of 39) in the sodium thiosulfate group versus 58% (22 of 38) in the control group.
The recommended dose is based on surface area according to body weight. Sodium thiosulfate is administered as an intravenous infusion over 15 minutes following cisplatin infusions that are 1 to 6 hours in duration.
Serious adverse reactions occurred in 40% of patients who received cisplatin–sodium thiosulfate in SIOPEL 6 and 36% of these patients in COG ACCL0431. The most common adverse reactions in the trials included vomiting, infection, nausea, decreased hemoglobin, hypernatremia, and hypokalemia.
A version of this article first appeared on Medscape.com.
Genetic tests create treatment opportunities and confusion for breast cancer patients
The past decade has witnessed a rapid expansion of genetic tests, including new instruments to inform patients who have been diagnosed with breast cancer about the risk of recurrence and to guide their treatment.
Patients are sometimes left paying out-of-pocket for exams that are not yet the standard of care, and even the most up-to-date oncologists may be uncertain how to incorporate the flood of new information into what used to be standard treatment protocols.
A quarter-century ago, Myriad Genetics introduced the first breast cancer genetic test for BRCA mutations, two genes associated with a substantially elevated risk of getting breast cancer, opening the door to a new era in genetic testing. BRCA1 and BRCA2 mutations account for as many as half of all hereditary breast cancers, and people with a problematic mutation on one of those genes have a 45%-72% chance of developing breast cancer during their lifetimes. They may also be at higher risk for ovarian and other cancers than people without harmful BRCA mutations.
But the clinical significance is murkier for many other genetic tests.
Testing for BRCA1 and BRCA2 genes used to cost thousands of dollars. Now, for a fraction of that, doctors can order multigene test panels from commercial labs that look for mutations in dozens of genes. Some direct-to-consumer companies offer screening panels for a few hundred dollars, though their reliability varies.
When Jen Carbary was diagnosed with breast cancer in 2017 at age 44, genetic testing identified a mutation in a gene called PALB2 that significantly increases the risk of developing breast cancer. Guidelines suggest that breast cancer patients with a PALB2 mutation, much like those with BRCA1 and BRCA2 mutations, consider having a mastectomy to reduce the chance of a breast cancer recurrence.
“I wish genetic testing was the standard of care,” said Ms. Carbary, who owed nothing for the test because her insurer covered the cost.
Ms. Carbary, who lives in Sterling Heights, Mich., said the test results affirmed the decision she had already made to have a double mastectomy and provided important information for family members, including her 21-year-old daughter and 18-year-old son, who will likely be tested in their mid-20s or early 30s.
But some breast cancer experts are concerned that widespread testing may also identify genetic mutations whose impact is unclear, creating anxiety and leading to further testing and to treatment of questionable value that could raise costs for the health care system.
It can also confuse patients.
“It happens a lot, that patients find their way to us after getting confusing results elsewhere,” said Mark Robson, MD, chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York. Robson said the cancer center has a clinical genetics service, staffed by doctors and genetic counselors, that helps people make decisions about how to manage genetic testing results.
For people diagnosed with breast cancer, many professional groups, including the influential National Comprehensive Cancer Network, recommend limiting testing to certain people, including those with high-risk factors, such as a family history of breast cancer; those who are 45 or younger when they’re diagnosed; and those with Ashkenazi Jewish ancestry.
But in 2019, the American Society of Breast Surgeons recommended a different approach: Offer genetic testing to all patients who are diagnosed with or have a personal history of breast cancer. The recommendation was controversial.
“The NCCN guidelines [cover] most of the women who needed testing, but we wanted to get them all,” said Eric Manahan, MD, a general surgeon in Dalton, Georgia, and a member of the surgeons group’s board of directors.
Mutations on other genes that are associated with breast cancer are much less common than BRCA1 and BRCA2 mutations and generally don’t increase the risk of developing breast cancer as much. The cancer-causing impact of these genes may be less clear than that of the BRCA genes, which have been tested for since the mid-1990s.
And the appropriate response to the less common mutations – whether to consider a risk-reducing mastectomy or stepped-up screening – is often unclear.
“Things get sloppier and sloppier when you look at other genes,” said Steven Katz, MD, MPH, a professor of medicine and health management and policy at the University of Michigan. “The risks tend to be lower for different cancers, and less certain and more variable. You might walk away wondering: ‘Why’d I have to know that?’ ”
After people are diagnosed with breast cancer, genetic testing can help inform their decisions about the types of surgery to pursue – for example, a high risk of recurrence or a new breast cancer might persuade some to opt for more extensive surgery, such as a double mastectomy. Testing can also provide important information to family members about their potential cancer risk.
(This type of “germline” genetic testing, as it’s called, looks at mutations in the genes that people inherit from their parents. It is different from genomic tumor tests that look at specific genes or proteins in the cancer cells and can help doctors understand the rate at which the cancer cells are dividing, for example, and the likelihood of a cancer recurrence.)
Increasingly, germline genetic testing can also help guide other treatment decisions. Some patients with metastatic breast cancer who have BRCA1 or BRCA2 mutations may be good candidates for poly (ADP-ribose) polymerase inhibitors, cancer drugs that target tumors with mutations in those genes.
But genetic testing that uncovers inherited mutations in many other genes yields less clearly actionable information, even though positive results may alarm people.
At Memorial Sloan Kettering, cancer specialists focus on “therapeutic actionability,” said Dr. Robson. Will testing help someone decide whether she should get a double mastectomy or provide other important guidance? “A policy of testing everyone will identify very few additional BRCA breast mutations but will cost a lot.”
As a result, doctors are debating how best to deploy and incorporate new genetic knowledge. Insurers are trying to figure out which to pay for.
There is both underuse of tests that science says are relevant and overuse of tests that experts say provide information that can’t be interpreted with any scientific certainty.
The result may be confusion for patients newly diagnosed with breast cancer as they confront the expense of genetic tests and sometimes little guidance on the proper treatment.
Some doctors say the first step is to make sure that the small group of people who would clearly benefit are getting the genetic tests whose meaning is clearly understood. Only 15% of breast cancer patients who met select NCCN testing guidelines for inherited cancer received genetic testing, according to a 2017 study that examined data from a national household health survey between 2005 and 2015.
“I would argue that our focus needs to be on the people who are at high risk for breast cancer that aren’t even identified yet,” said Tuya Pal, MD, associate director for cancer health disparities at Vanderbilt-Ingram Cancer Center and vice chair of the NCCN guidelines panel for genetic/familial high-risk assessment of breast, ovarian, and pancreatic cancers.
Patients may fall through the cracks because no one tells them they should be tested. In one analysis, 56% of high-risk breast cancer patients who didn’t get genetic testing said their doctors didn’t recommend it.
Even if doctors recommend genetic testing, they may lack the expertise to determine which tests people need and how to interpret the results. That’s the role of genetic counselors, but their ranks are stretched thin.
The consequences can be serious. In a study of 666 breast cancer patients who received genetic testing, half of those at average risk for inherited cancer got double mastectomies based on test results that found “variants of uncertain significance,” which aren’t clinically actionable. As many as half of surgeons reported managing such patients the same way as those with cancer-causing mutations.
“The bulk of our research would say that there is still room for improvement in terms of clinicians getting the understanding they need,” said Allison Kurian, MD, director of the women’s clinical cancer genetics program at Stanford (Calif.) University and a coauthor of the study.
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
The past decade has witnessed a rapid expansion of genetic tests, including new instruments to inform patients who have been diagnosed with breast cancer about the risk of recurrence and to guide their treatment.
Patients are sometimes left paying out-of-pocket for exams that are not yet the standard of care, and even the most up-to-date oncologists may be uncertain how to incorporate the flood of new information into what used to be standard treatment protocols.
A quarter-century ago, Myriad Genetics introduced the first breast cancer genetic test for BRCA mutations, two genes associated with a substantially elevated risk of getting breast cancer, opening the door to a new era in genetic testing. BRCA1 and BRCA2 mutations account for as many as half of all hereditary breast cancers, and people with a problematic mutation on one of those genes have a 45%-72% chance of developing breast cancer during their lifetimes. They may also be at higher risk for ovarian and other cancers than people without harmful BRCA mutations.
But the clinical significance is murkier for many other genetic tests.
Testing for BRCA1 and BRCA2 genes used to cost thousands of dollars. Now, for a fraction of that, doctors can order multigene test panels from commercial labs that look for mutations in dozens of genes. Some direct-to-consumer companies offer screening panels for a few hundred dollars, though their reliability varies.
When Jen Carbary was diagnosed with breast cancer in 2017 at age 44, genetic testing identified a mutation in a gene called PALB2 that significantly increases the risk of developing breast cancer. Guidelines suggest that breast cancer patients with a PALB2 mutation, much like those with BRCA1 and BRCA2 mutations, consider having a mastectomy to reduce the chance of a breast cancer recurrence.
“I wish genetic testing was the standard of care,” said Ms. Carbary, who owed nothing for the test because her insurer covered the cost.
Ms. Carbary, who lives in Sterling Heights, Mich., said the test results affirmed the decision she had already made to have a double mastectomy and provided important information for family members, including her 21-year-old daughter and 18-year-old son, who will likely be tested in their mid-20s or early 30s.
But some breast cancer experts are concerned that widespread testing may also identify genetic mutations whose impact is unclear, creating anxiety and leading to further testing and to treatment of questionable value that could raise costs for the health care system.
It can also confuse patients.
“It happens a lot, that patients find their way to us after getting confusing results elsewhere,” said Mark Robson, MD, chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York. Robson said the cancer center has a clinical genetics service, staffed by doctors and genetic counselors, that helps people make decisions about how to manage genetic testing results.
For people diagnosed with breast cancer, many professional groups, including the influential National Comprehensive Cancer Network, recommend limiting testing to certain people, including those with high-risk factors, such as a family history of breast cancer; those who are 45 or younger when they’re diagnosed; and those with Ashkenazi Jewish ancestry.
But in 2019, the American Society of Breast Surgeons recommended a different approach: Offer genetic testing to all patients who are diagnosed with or have a personal history of breast cancer. The recommendation was controversial.
“The NCCN guidelines [cover] most of the women who needed testing, but we wanted to get them all,” said Eric Manahan, MD, a general surgeon in Dalton, Georgia, and a member of the surgeons group’s board of directors.
Mutations on other genes that are associated with breast cancer are much less common than BRCA1 and BRCA2 mutations and generally don’t increase the risk of developing breast cancer as much. The cancer-causing impact of these genes may be less clear than that of the BRCA genes, which have been tested for since the mid-1990s.
And the appropriate response to the less common mutations – whether to consider a risk-reducing mastectomy or stepped-up screening – is often unclear.
“Things get sloppier and sloppier when you look at other genes,” said Steven Katz, MD, MPH, a professor of medicine and health management and policy at the University of Michigan. “The risks tend to be lower for different cancers, and less certain and more variable. You might walk away wondering: ‘Why’d I have to know that?’ ”
After people are diagnosed with breast cancer, genetic testing can help inform their decisions about the types of surgery to pursue – for example, a high risk of recurrence or a new breast cancer might persuade some to opt for more extensive surgery, such as a double mastectomy. Testing can also provide important information to family members about their potential cancer risk.
(This type of “germline” genetic testing, as it’s called, looks at mutations in the genes that people inherit from their parents. It is different from genomic tumor tests that look at specific genes or proteins in the cancer cells and can help doctors understand the rate at which the cancer cells are dividing, for example, and the likelihood of a cancer recurrence.)
Increasingly, germline genetic testing can also help guide other treatment decisions. Some patients with metastatic breast cancer who have BRCA1 or BRCA2 mutations may be good candidates for poly (ADP-ribose) polymerase inhibitors, cancer drugs that target tumors with mutations in those genes.
But genetic testing that uncovers inherited mutations in many other genes yields less clearly actionable information, even though positive results may alarm people.
At Memorial Sloan Kettering, cancer specialists focus on “therapeutic actionability,” said Dr. Robson. Will testing help someone decide whether she should get a double mastectomy or provide other important guidance? “A policy of testing everyone will identify very few additional BRCA breast mutations but will cost a lot.”
As a result, doctors are debating how best to deploy and incorporate new genetic knowledge. Insurers are trying to figure out which to pay for.
There is both underuse of tests that science says are relevant and overuse of tests that experts say provide information that can’t be interpreted with any scientific certainty.
The result may be confusion for patients newly diagnosed with breast cancer as they confront the expense of genetic tests and sometimes little guidance on the proper treatment.
Some doctors say the first step is to make sure that the small group of people who would clearly benefit are getting the genetic tests whose meaning is clearly understood. Only 15% of breast cancer patients who met select NCCN testing guidelines for inherited cancer received genetic testing, according to a 2017 study that examined data from a national household health survey between 2005 and 2015.
“I would argue that our focus needs to be on the people who are at high risk for breast cancer that aren’t even identified yet,” said Tuya Pal, MD, associate director for cancer health disparities at Vanderbilt-Ingram Cancer Center and vice chair of the NCCN guidelines panel for genetic/familial high-risk assessment of breast, ovarian, and pancreatic cancers.
Patients may fall through the cracks because no one tells them they should be tested. In one analysis, 56% of high-risk breast cancer patients who didn’t get genetic testing said their doctors didn’t recommend it.
Even if doctors recommend genetic testing, they may lack the expertise to determine which tests people need and how to interpret the results. That’s the role of genetic counselors, but their ranks are stretched thin.
The consequences can be serious. In a study of 666 breast cancer patients who received genetic testing, half of those at average risk for inherited cancer got double mastectomies based on test results that found “variants of uncertain significance,” which aren’t clinically actionable. As many as half of surgeons reported managing such patients the same way as those with cancer-causing mutations.
“The bulk of our research would say that there is still room for improvement in terms of clinicians getting the understanding they need,” said Allison Kurian, MD, director of the women’s clinical cancer genetics program at Stanford (Calif.) University and a coauthor of the study.
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
The past decade has witnessed a rapid expansion of genetic tests, including new instruments to inform patients who have been diagnosed with breast cancer about the risk of recurrence and to guide their treatment.
Patients are sometimes left paying out-of-pocket for exams that are not yet the standard of care, and even the most up-to-date oncologists may be uncertain how to incorporate the flood of new information into what used to be standard treatment protocols.
A quarter-century ago, Myriad Genetics introduced the first breast cancer genetic test for BRCA mutations, two genes associated with a substantially elevated risk of getting breast cancer, opening the door to a new era in genetic testing. BRCA1 and BRCA2 mutations account for as many as half of all hereditary breast cancers, and people with a problematic mutation on one of those genes have a 45%-72% chance of developing breast cancer during their lifetimes. They may also be at higher risk for ovarian and other cancers than people without harmful BRCA mutations.
But the clinical significance is murkier for many other genetic tests.
Testing for BRCA1 and BRCA2 genes used to cost thousands of dollars. Now, for a fraction of that, doctors can order multigene test panels from commercial labs that look for mutations in dozens of genes. Some direct-to-consumer companies offer screening panels for a few hundred dollars, though their reliability varies.
When Jen Carbary was diagnosed with breast cancer in 2017 at age 44, genetic testing identified a mutation in a gene called PALB2 that significantly increases the risk of developing breast cancer. Guidelines suggest that breast cancer patients with a PALB2 mutation, much like those with BRCA1 and BRCA2 mutations, consider having a mastectomy to reduce the chance of a breast cancer recurrence.
“I wish genetic testing was the standard of care,” said Ms. Carbary, who owed nothing for the test because her insurer covered the cost.
Ms. Carbary, who lives in Sterling Heights, Mich., said the test results affirmed the decision she had already made to have a double mastectomy and provided important information for family members, including her 21-year-old daughter and 18-year-old son, who will likely be tested in their mid-20s or early 30s.
But some breast cancer experts are concerned that widespread testing may also identify genetic mutations whose impact is unclear, creating anxiety and leading to further testing and to treatment of questionable value that could raise costs for the health care system.
It can also confuse patients.
“It happens a lot, that patients find their way to us after getting confusing results elsewhere,” said Mark Robson, MD, chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York. Robson said the cancer center has a clinical genetics service, staffed by doctors and genetic counselors, that helps people make decisions about how to manage genetic testing results.
For people diagnosed with breast cancer, many professional groups, including the influential National Comprehensive Cancer Network, recommend limiting testing to certain people, including those with high-risk factors, such as a family history of breast cancer; those who are 45 or younger when they’re diagnosed; and those with Ashkenazi Jewish ancestry.
But in 2019, the American Society of Breast Surgeons recommended a different approach: Offer genetic testing to all patients who are diagnosed with or have a personal history of breast cancer. The recommendation was controversial.
“The NCCN guidelines [cover] most of the women who needed testing, but we wanted to get them all,” said Eric Manahan, MD, a general surgeon in Dalton, Georgia, and a member of the surgeons group’s board of directors.
Mutations on other genes that are associated with breast cancer are much less common than BRCA1 and BRCA2 mutations and generally don’t increase the risk of developing breast cancer as much. The cancer-causing impact of these genes may be less clear than that of the BRCA genes, which have been tested for since the mid-1990s.
And the appropriate response to the less common mutations – whether to consider a risk-reducing mastectomy or stepped-up screening – is often unclear.
“Things get sloppier and sloppier when you look at other genes,” said Steven Katz, MD, MPH, a professor of medicine and health management and policy at the University of Michigan. “The risks tend to be lower for different cancers, and less certain and more variable. You might walk away wondering: ‘Why’d I have to know that?’ ”
After people are diagnosed with breast cancer, genetic testing can help inform their decisions about the types of surgery to pursue – for example, a high risk of recurrence or a new breast cancer might persuade some to opt for more extensive surgery, such as a double mastectomy. Testing can also provide important information to family members about their potential cancer risk.
(This type of “germline” genetic testing, as it’s called, looks at mutations in the genes that people inherit from their parents. It is different from genomic tumor tests that look at specific genes or proteins in the cancer cells and can help doctors understand the rate at which the cancer cells are dividing, for example, and the likelihood of a cancer recurrence.)
Increasingly, germline genetic testing can also help guide other treatment decisions. Some patients with metastatic breast cancer who have BRCA1 or BRCA2 mutations may be good candidates for poly (ADP-ribose) polymerase inhibitors, cancer drugs that target tumors with mutations in those genes.
But genetic testing that uncovers inherited mutations in many other genes yields less clearly actionable information, even though positive results may alarm people.
At Memorial Sloan Kettering, cancer specialists focus on “therapeutic actionability,” said Dr. Robson. Will testing help someone decide whether she should get a double mastectomy or provide other important guidance? “A policy of testing everyone will identify very few additional BRCA breast mutations but will cost a lot.”
As a result, doctors are debating how best to deploy and incorporate new genetic knowledge. Insurers are trying to figure out which to pay for.
There is both underuse of tests that science says are relevant and overuse of tests that experts say provide information that can’t be interpreted with any scientific certainty.
The result may be confusion for patients newly diagnosed with breast cancer as they confront the expense of genetic tests and sometimes little guidance on the proper treatment.
Some doctors say the first step is to make sure that the small group of people who would clearly benefit are getting the genetic tests whose meaning is clearly understood. Only 15% of breast cancer patients who met select NCCN testing guidelines for inherited cancer received genetic testing, according to a 2017 study that examined data from a national household health survey between 2005 and 2015.
“I would argue that our focus needs to be on the people who are at high risk for breast cancer that aren’t even identified yet,” said Tuya Pal, MD, associate director for cancer health disparities at Vanderbilt-Ingram Cancer Center and vice chair of the NCCN guidelines panel for genetic/familial high-risk assessment of breast, ovarian, and pancreatic cancers.
Patients may fall through the cracks because no one tells them they should be tested. In one analysis, 56% of high-risk breast cancer patients who didn’t get genetic testing said their doctors didn’t recommend it.
Even if doctors recommend genetic testing, they may lack the expertise to determine which tests people need and how to interpret the results. That’s the role of genetic counselors, but their ranks are stretched thin.
The consequences can be serious. In a study of 666 breast cancer patients who received genetic testing, half of those at average risk for inherited cancer got double mastectomies based on test results that found “variants of uncertain significance,” which aren’t clinically actionable. As many as half of surgeons reported managing such patients the same way as those with cancer-causing mutations.
“The bulk of our research would say that there is still room for improvement in terms of clinicians getting the understanding they need,” said Allison Kurian, MD, director of the women’s clinical cancer genetics program at Stanford (Calif.) University and a coauthor of the study.
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
Could cold exposure, especially shivering, combat type 2 diabetes?
STOCKHOLM – Shivering upon repeated short exposures to cold improves glucose tolerance, decreases fasting blood glucose and lipid levels, and markedly reduces blood pressure, show new study results in adults with obesity and overweight.
Presenting the preliminary findings at the annual meeting of the European Association for the Study of Diabetes, Adam Sellers, a PhD student from Maastricht (the Netherlands) University, said: “The results are highly promising and may eventually suggest an alternative treatment or preventative measure for type 2 diabetes.”
Dr. Sellers found that 10 daily 1-hour sessions of shivering at 10° C led to 85% of participants showing a drop in fasting glucose, and a 32% drop in lipid levels, as well as a blood pressure drop of around 8% overall.
Although cold exposure is known to increase brown fat, Dr. Sellers doesn’t believe this explains his findings. “This research, in addition to two other prior studies, suggest that shivering and skeletal muscle may play a more important role than brown fat,” he said.
“Muscle can contract mechanically – [the concept of the] shivers – thereby generating heat, and there is considerably more muscle than brown fat in a human, so shivering can burn more calories and produce more heat,” he explained.
He added that, in the future, “in a similar way to saunas and steam rooms, there might be cold rooms where people go and sit in the cold room and shiver, or possibly patients attend hospital and shivering is induced.”
Audience member Anna Krook, PhD, professor of integrative physiology at the Karolinska Institute, Stockholm, commented on the work, saying the results are “potent” and demonstrate the metabolic effect of shivering. “One thing that struck me was, given the time the subject had to spend – 1 hour shivering over 10 days, I wonder if 1 hour of exercise would show similarly potent effects, and perhaps for those people who cannot perform exercise for whatever reason this might be a good alternative.”
She pointed out that, in terms of translation into practice, it “really depends on how tolerable this is. It also shows how important our muscle is in regulating metabolism. The study showed that you had to be shivering, and it wasn’t just enough to be cold, which has implications for the role of brown fat, especially when we consider the small amount of brown fat we have compared to muscle, which can be half of body weight.”
And Denis P. Blondin, PhD, said: “The reality is that we know it can be difficult and even painful for individuals with obesity to perform exercise, and therefore, cold exposure offers a passive way of improving our metabolic profile and cardiovascular health.”
“Some will argue that it is unrealistic to propose cold exposure as a therapy, but people overlook the fact that cold exposure [mostly through cold-water immersion] has increased in popularity over the past 5 years and has also been a cultural staple for many Nordic countries, albeit often performed with heat exposure as well [see the use of saunas and cold-water swimming in Finland and other Nordic countries],” added Dr. Blondin, of the faculty of medicine and health sciences, University of Sherbrooke (Que.)
“While it can certainly be uncomfortable at first (like starting an exercise program), we adapt very quickly,” he added.
1 hour in a cold-water suit to induce shivering
In the current study, Dr. Sellers exposed adults (aged 40-75 years; 11 men and 4 postmenopausal women) with overweight/obesity (body mass index, 27-35 kg/m2) to 10 consecutive cold exposures of at least 1 hour of shivering per cold exposure.
“The shivering in this new research was more intense [than in prior studies] and was induced with a different cold exposure method – a 10° C water-perfused suit [compared with a prior study of 14-15° C, 6 hours/day]. This facilitated a shorter cold exposure duration, deemed feasible for the participants,” explained Dr. Sellers.
“At baseline, participants had glucose and A1c levels at the upper end of the normal criteria [5.5 mmol/l and 5.4%, respectively],” he said, referring to measurements that were suggestive of possible progression to type 2 diabetes.
He explained how the cold exposure was applied. “We induced the cold with a water-perfused suit worn by the participant, through which water flows at 10° C, and this cools the participant. Eventually, the participant starts to shiver, and does so for at least 1 hour every morning for 10 days.”
Participants’ shivering-induced heat production was measured via surface electromyography and visual observation to confirm the presence of shivering. Both before and after the 10-day course of shivering, physiological measurements were taken in the morning while participants were at rest in an overnight fasted state, and under thermoneutral conditions. Blood pressure and fasting blood glucose were measured.
A 2-hour oral glucose tolerance test (OGTT) was conducted twice for each participant: on the morning before the 10-day course of shivering and again on the morning after the final 10th day of shivering.
The primary endpoint was change from before to after the 10-day shivering intervention, as represented by the total area under the curve of glucose levels over time during the OGTT.
“This provides a measure of the glucose concentrations in the blood before and after the 10 shivering sessions over the 10 days.”
Fasting glucose and blood lipids fall, glucose tolerance improves
After 10 shivering sessions, mean fasting plasma glucose decreased significantly in 13 out of the 15 participants, compared with before the first session (from 5.84 mmol/L to 5.67 mmol/L; P = .013).
Glucose tolerance during the OGTT improved by 6% (P = .041). “We can see that this was not due to a change in their insulin concentrations in the blood,” remarked Dr. Sellers, referring to the finding that plasma insulin concentrations at baseline and during the OGTT did not change.
Fasting plasma triglyceride and free-fatty acid concentrations also decreased significantly by 32% (P = .001) and 11% (P = .036), respectively.
“This is important because free-fatty acids are involved in the role of insulin resistance,” said Dr. Sellers. “In addition, the large reduction in serum triglycerides could have implications for atherosclerosis, which may also be beneficial.”
Dr. Sellers also found that systolic blood pressure decreased by 10 mm Hg or 7.4% (P < .001), while diastolic blood pressure decreased by 7 mm Hg or 8.1% (P < .001) on average. This lowering was seen in all participants.
“Again, quite strikingly, all participants showed” a reduction in blood pressure, said Dr. Sellers, which he noted relates to a decrease in resting heart rate (P = .062).
Brown fat or skeletal muscle contraction?
Dr. Sellers pointed out that, despite nonshivering thermogenesis being involved in mild cold acclimation, the data so far suggest that some level of mild muscle activity or shivering appears crucial in provoking the beneficial metabolic effects of cold acclimation.
“Brown fat is a metabolic heating system inside our bodies, burning calories”, explained Dr. Sellers. “This generates heat and prevents calories from being deposited as normal white fat. Brown fat is activated during cold and when we eat, but its activity is less in older adults and in individuals with obesity and diabetes.”
“Going forward, we might investigate the effects of shorter duration – so more intense shivering – to try and elucidate more precisely the optimum duration and intensity of shivering needed,” said Dr. Sellers.
“Our findings are promising and may have important health implications. In future studies, we plan to assess the effect of shivering in adults with type 2 diabetes,” he concluded.
Dr. Seller and Dr. Krook have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
STOCKHOLM – Shivering upon repeated short exposures to cold improves glucose tolerance, decreases fasting blood glucose and lipid levels, and markedly reduces blood pressure, show new study results in adults with obesity and overweight.
Presenting the preliminary findings at the annual meeting of the European Association for the Study of Diabetes, Adam Sellers, a PhD student from Maastricht (the Netherlands) University, said: “The results are highly promising and may eventually suggest an alternative treatment or preventative measure for type 2 diabetes.”
Dr. Sellers found that 10 daily 1-hour sessions of shivering at 10° C led to 85% of participants showing a drop in fasting glucose, and a 32% drop in lipid levels, as well as a blood pressure drop of around 8% overall.
Although cold exposure is known to increase brown fat, Dr. Sellers doesn’t believe this explains his findings. “This research, in addition to two other prior studies, suggest that shivering and skeletal muscle may play a more important role than brown fat,” he said.
“Muscle can contract mechanically – [the concept of the] shivers – thereby generating heat, and there is considerably more muscle than brown fat in a human, so shivering can burn more calories and produce more heat,” he explained.
He added that, in the future, “in a similar way to saunas and steam rooms, there might be cold rooms where people go and sit in the cold room and shiver, or possibly patients attend hospital and shivering is induced.”
Audience member Anna Krook, PhD, professor of integrative physiology at the Karolinska Institute, Stockholm, commented on the work, saying the results are “potent” and demonstrate the metabolic effect of shivering. “One thing that struck me was, given the time the subject had to spend – 1 hour shivering over 10 days, I wonder if 1 hour of exercise would show similarly potent effects, and perhaps for those people who cannot perform exercise for whatever reason this might be a good alternative.”
She pointed out that, in terms of translation into practice, it “really depends on how tolerable this is. It also shows how important our muscle is in regulating metabolism. The study showed that you had to be shivering, and it wasn’t just enough to be cold, which has implications for the role of brown fat, especially when we consider the small amount of brown fat we have compared to muscle, which can be half of body weight.”
And Denis P. Blondin, PhD, said: “The reality is that we know it can be difficult and even painful for individuals with obesity to perform exercise, and therefore, cold exposure offers a passive way of improving our metabolic profile and cardiovascular health.”
“Some will argue that it is unrealistic to propose cold exposure as a therapy, but people overlook the fact that cold exposure [mostly through cold-water immersion] has increased in popularity over the past 5 years and has also been a cultural staple for many Nordic countries, albeit often performed with heat exposure as well [see the use of saunas and cold-water swimming in Finland and other Nordic countries],” added Dr. Blondin, of the faculty of medicine and health sciences, University of Sherbrooke (Que.)
“While it can certainly be uncomfortable at first (like starting an exercise program), we adapt very quickly,” he added.
1 hour in a cold-water suit to induce shivering
In the current study, Dr. Sellers exposed adults (aged 40-75 years; 11 men and 4 postmenopausal women) with overweight/obesity (body mass index, 27-35 kg/m2) to 10 consecutive cold exposures of at least 1 hour of shivering per cold exposure.
“The shivering in this new research was more intense [than in prior studies] and was induced with a different cold exposure method – a 10° C water-perfused suit [compared with a prior study of 14-15° C, 6 hours/day]. This facilitated a shorter cold exposure duration, deemed feasible for the participants,” explained Dr. Sellers.
“At baseline, participants had glucose and A1c levels at the upper end of the normal criteria [5.5 mmol/l and 5.4%, respectively],” he said, referring to measurements that were suggestive of possible progression to type 2 diabetes.
He explained how the cold exposure was applied. “We induced the cold with a water-perfused suit worn by the participant, through which water flows at 10° C, and this cools the participant. Eventually, the participant starts to shiver, and does so for at least 1 hour every morning for 10 days.”
Participants’ shivering-induced heat production was measured via surface electromyography and visual observation to confirm the presence of shivering. Both before and after the 10-day course of shivering, physiological measurements were taken in the morning while participants were at rest in an overnight fasted state, and under thermoneutral conditions. Blood pressure and fasting blood glucose were measured.
A 2-hour oral glucose tolerance test (OGTT) was conducted twice for each participant: on the morning before the 10-day course of shivering and again on the morning after the final 10th day of shivering.
The primary endpoint was change from before to after the 10-day shivering intervention, as represented by the total area under the curve of glucose levels over time during the OGTT.
“This provides a measure of the glucose concentrations in the blood before and after the 10 shivering sessions over the 10 days.”
Fasting glucose and blood lipids fall, glucose tolerance improves
After 10 shivering sessions, mean fasting plasma glucose decreased significantly in 13 out of the 15 participants, compared with before the first session (from 5.84 mmol/L to 5.67 mmol/L; P = .013).
Glucose tolerance during the OGTT improved by 6% (P = .041). “We can see that this was not due to a change in their insulin concentrations in the blood,” remarked Dr. Sellers, referring to the finding that plasma insulin concentrations at baseline and during the OGTT did not change.
Fasting plasma triglyceride and free-fatty acid concentrations also decreased significantly by 32% (P = .001) and 11% (P = .036), respectively.
“This is important because free-fatty acids are involved in the role of insulin resistance,” said Dr. Sellers. “In addition, the large reduction in serum triglycerides could have implications for atherosclerosis, which may also be beneficial.”
Dr. Sellers also found that systolic blood pressure decreased by 10 mm Hg or 7.4% (P < .001), while diastolic blood pressure decreased by 7 mm Hg or 8.1% (P < .001) on average. This lowering was seen in all participants.
“Again, quite strikingly, all participants showed” a reduction in blood pressure, said Dr. Sellers, which he noted relates to a decrease in resting heart rate (P = .062).
Brown fat or skeletal muscle contraction?
Dr. Sellers pointed out that, despite nonshivering thermogenesis being involved in mild cold acclimation, the data so far suggest that some level of mild muscle activity or shivering appears crucial in provoking the beneficial metabolic effects of cold acclimation.
“Brown fat is a metabolic heating system inside our bodies, burning calories”, explained Dr. Sellers. “This generates heat and prevents calories from being deposited as normal white fat. Brown fat is activated during cold and when we eat, but its activity is less in older adults and in individuals with obesity and diabetes.”
“Going forward, we might investigate the effects of shorter duration – so more intense shivering – to try and elucidate more precisely the optimum duration and intensity of shivering needed,” said Dr. Sellers.
“Our findings are promising and may have important health implications. In future studies, we plan to assess the effect of shivering in adults with type 2 diabetes,” he concluded.
Dr. Seller and Dr. Krook have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
STOCKHOLM – Shivering upon repeated short exposures to cold improves glucose tolerance, decreases fasting blood glucose and lipid levels, and markedly reduces blood pressure, show new study results in adults with obesity and overweight.
Presenting the preliminary findings at the annual meeting of the European Association for the Study of Diabetes, Adam Sellers, a PhD student from Maastricht (the Netherlands) University, said: “The results are highly promising and may eventually suggest an alternative treatment or preventative measure for type 2 diabetes.”
Dr. Sellers found that 10 daily 1-hour sessions of shivering at 10° C led to 85% of participants showing a drop in fasting glucose, and a 32% drop in lipid levels, as well as a blood pressure drop of around 8% overall.
Although cold exposure is known to increase brown fat, Dr. Sellers doesn’t believe this explains his findings. “This research, in addition to two other prior studies, suggest that shivering and skeletal muscle may play a more important role than brown fat,” he said.
“Muscle can contract mechanically – [the concept of the] shivers – thereby generating heat, and there is considerably more muscle than brown fat in a human, so shivering can burn more calories and produce more heat,” he explained.
He added that, in the future, “in a similar way to saunas and steam rooms, there might be cold rooms where people go and sit in the cold room and shiver, or possibly patients attend hospital and shivering is induced.”
Audience member Anna Krook, PhD, professor of integrative physiology at the Karolinska Institute, Stockholm, commented on the work, saying the results are “potent” and demonstrate the metabolic effect of shivering. “One thing that struck me was, given the time the subject had to spend – 1 hour shivering over 10 days, I wonder if 1 hour of exercise would show similarly potent effects, and perhaps for those people who cannot perform exercise for whatever reason this might be a good alternative.”
She pointed out that, in terms of translation into practice, it “really depends on how tolerable this is. It also shows how important our muscle is in regulating metabolism. The study showed that you had to be shivering, and it wasn’t just enough to be cold, which has implications for the role of brown fat, especially when we consider the small amount of brown fat we have compared to muscle, which can be half of body weight.”
And Denis P. Blondin, PhD, said: “The reality is that we know it can be difficult and even painful for individuals with obesity to perform exercise, and therefore, cold exposure offers a passive way of improving our metabolic profile and cardiovascular health.”
“Some will argue that it is unrealistic to propose cold exposure as a therapy, but people overlook the fact that cold exposure [mostly through cold-water immersion] has increased in popularity over the past 5 years and has also been a cultural staple for many Nordic countries, albeit often performed with heat exposure as well [see the use of saunas and cold-water swimming in Finland and other Nordic countries],” added Dr. Blondin, of the faculty of medicine and health sciences, University of Sherbrooke (Que.)
“While it can certainly be uncomfortable at first (like starting an exercise program), we adapt very quickly,” he added.
1 hour in a cold-water suit to induce shivering
In the current study, Dr. Sellers exposed adults (aged 40-75 years; 11 men and 4 postmenopausal women) with overweight/obesity (body mass index, 27-35 kg/m2) to 10 consecutive cold exposures of at least 1 hour of shivering per cold exposure.
“The shivering in this new research was more intense [than in prior studies] and was induced with a different cold exposure method – a 10° C water-perfused suit [compared with a prior study of 14-15° C, 6 hours/day]. This facilitated a shorter cold exposure duration, deemed feasible for the participants,” explained Dr. Sellers.
“At baseline, participants had glucose and A1c levels at the upper end of the normal criteria [5.5 mmol/l and 5.4%, respectively],” he said, referring to measurements that were suggestive of possible progression to type 2 diabetes.
He explained how the cold exposure was applied. “We induced the cold with a water-perfused suit worn by the participant, through which water flows at 10° C, and this cools the participant. Eventually, the participant starts to shiver, and does so for at least 1 hour every morning for 10 days.”
Participants’ shivering-induced heat production was measured via surface electromyography and visual observation to confirm the presence of shivering. Both before and after the 10-day course of shivering, physiological measurements were taken in the morning while participants were at rest in an overnight fasted state, and under thermoneutral conditions. Blood pressure and fasting blood glucose were measured.
A 2-hour oral glucose tolerance test (OGTT) was conducted twice for each participant: on the morning before the 10-day course of shivering and again on the morning after the final 10th day of shivering.
The primary endpoint was change from before to after the 10-day shivering intervention, as represented by the total area under the curve of glucose levels over time during the OGTT.
“This provides a measure of the glucose concentrations in the blood before and after the 10 shivering sessions over the 10 days.”
Fasting glucose and blood lipids fall, glucose tolerance improves
After 10 shivering sessions, mean fasting plasma glucose decreased significantly in 13 out of the 15 participants, compared with before the first session (from 5.84 mmol/L to 5.67 mmol/L; P = .013).
Glucose tolerance during the OGTT improved by 6% (P = .041). “We can see that this was not due to a change in their insulin concentrations in the blood,” remarked Dr. Sellers, referring to the finding that plasma insulin concentrations at baseline and during the OGTT did not change.
Fasting plasma triglyceride and free-fatty acid concentrations also decreased significantly by 32% (P = .001) and 11% (P = .036), respectively.
“This is important because free-fatty acids are involved in the role of insulin resistance,” said Dr. Sellers. “In addition, the large reduction in serum triglycerides could have implications for atherosclerosis, which may also be beneficial.”
Dr. Sellers also found that systolic blood pressure decreased by 10 mm Hg or 7.4% (P < .001), while diastolic blood pressure decreased by 7 mm Hg or 8.1% (P < .001) on average. This lowering was seen in all participants.
“Again, quite strikingly, all participants showed” a reduction in blood pressure, said Dr. Sellers, which he noted relates to a decrease in resting heart rate (P = .062).
Brown fat or skeletal muscle contraction?
Dr. Sellers pointed out that, despite nonshivering thermogenesis being involved in mild cold acclimation, the data so far suggest that some level of mild muscle activity or shivering appears crucial in provoking the beneficial metabolic effects of cold acclimation.
“Brown fat is a metabolic heating system inside our bodies, burning calories”, explained Dr. Sellers. “This generates heat and prevents calories from being deposited as normal white fat. Brown fat is activated during cold and when we eat, but its activity is less in older adults and in individuals with obesity and diabetes.”
“Going forward, we might investigate the effects of shorter duration – so more intense shivering – to try and elucidate more precisely the optimum duration and intensity of shivering needed,” said Dr. Sellers.
“Our findings are promising and may have important health implications. In future studies, we plan to assess the effect of shivering in adults with type 2 diabetes,” he concluded.
Dr. Seller and Dr. Krook have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
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