Journal of Clinical Outcomes Management

With coronavirus disease (COVID-19) reaching epidemic proportions, many US children are growing increasingly anxious about what this means for their own health and safety and that of their friends and family.

The constantly changing numbers of people affected by the virus and the evolving situation mean daily life for many children is affected in some way, with school trips, sports tournaments, and family vacations being postponed or canceled.

All children may have a heightened level of worry, and some who are normally anxious might be obsessing more about handwashing or getting sick.

Experts say there are ways to manage this fear to help children feel safe and appropriately informed.

Clinicians and other adults should provide children with honest and accurate information geared to their age and developmental level, said David Fassler, MD, clinical professor of psychiatry, University of Vermont Larner College of Medicine, Burlington, and member of the Consumer Issues Committee of the American Academy of Child and Adolescent Psychiatry.

That said, it’s also acceptable to let children know that some questions can’t be answered, said Fassler.
 

Be truthful, calm

“This is partly because the information keeps changing as we learn more about how the virus spreads, how to best protect communities, and how to treat people who get sick,” he added.

Clinicians and parents should remind children “that there are a lot of adults who are working very hard to keep them safe,” said Eli R. Lebowitz, PhD, associate professor in the Child Study Center, Yale School of Medicine, New Haven, Connecticut, who directs a program for anxiety.

It’s important for adults to pay attention not only to what they say to children but also how they say it, said Lebowitz. He highlighted the importance of talking about the virus “in a calm and matter-of-fact way” rather than in an anxious way.

“If you look scared or tense or your voice is conveying that you’re really scared, the child is going to absorb that and feel anxious as well,” he noted.

This advice also applies when adults are discussing the issue among themselves. They should be aware that “children are listening” and are picking up any anxiety or panic adults are expressing.

Children are soaking up information about this virus from the Internet, the media, friends, teachers, and elsewhere. Lebowitz suggests asking children what they have already heard, which provides an opportunity to correct rumors and inaccurate information.

“A child might have a very inflated sense of what the actual risk is. For example, they may think that anyone who gets the virus dies,” he said.
 

Myth busting

Adults should let children know that not everything they hear from friends or on the Internet “is necessarily correct,” he added.

Some children who have experienced serious illness or losses may be particularly vulnerable to experiencing intense reactions to graphic news reports or images of illness or death and may need extra support, said Fassler.

Adults could use the “framework of knowledge” that children already have, said Lebowitz. He noted that all children are aware of sickness.

“They know people get sick, and they themselves have probably been sick, so you can tell them that this is a sickness like a bad flu,” he said.

Children should be encouraged to approach adults they trust, such as their pediatrician, a parent, or a teacher, with their questions, said Lebowitz. “Those are the people who are able to give them the most accurate information.”

Fassler noted that accurate, up-to-date information is available via fact sheets developed by the Centers for Disease Control and Prevention and the World Health Organization.

Although it’s helpful and appropriate to be reassuring, Fassler advises not to make unrealistic promises.

“It’s fine to tell kids that you’ll deal with whatever happens, even if it means altering travel plans or work schedules, but you can’t promise that no one in your state or community will get sick,” he said.
 

Maintain healthy habits

Physicians and other adults can tell children “in an age-appropriate way” how the virus is transmitted and what the symptoms are, but it’s important to emphasize that most people who are sick don’t have COVID-19, said Lebowitz.

“I would emphasize that the people who are the sickest are the elderly who are already sick, rather than healthy younger people,” he said.

Lebowitz recommends continuing to follow guidelines on staying healthy, including coughing into a sleeve instead of your hand and regular handwashing.

It’s also important at this time for children to maintain healthy habits – getting enough physical activity and sleep, eating well, and being outside – because this regime will go a long way toward reducing anxiety, said Lebowitz. Deep breathing and muscle-relaxing exercises can also help, he said.

Lebowitz also suggests maintaining a supportive attitude and showing “some acceptance and validation of what children are feeling, as well as some confidence that they can cope and tolerate feeling uncomfortable sometimes, that they can handle some anxiety.”

While accepting that the child could be anxious, it’s important not to encourage excessive avoidance or unhealthy coping strategies. Fassler and Lebowitz agree that children who are overly anxious or preoccupied with concerns about the coronavirus should be evaluated by a trained, qualified mental health professional.

Signs that a child may need additional help include ongoing sleep difficulties, intrusive thoughts or worries, obsessive-compulsive behaviors, or reluctance or refusal to go to school, said Fassler.

The good news is that most children are resilient, said Fassler. “They’ll adjust, adapt, and go on with their lives.”

This article first appeared on Medscape.com.

With coronavirus disease (COVID-19) reaching epidemic proportions, many US children are growing increasingly anxious about what this means for their own health and safety and that of their friends and family.

The constantly changing numbers of people affected by the virus and the evolving situation mean daily life for many children is affected in some way, with school trips, sports tournaments, and family vacations being postponed or canceled.

All children may have a heightened level of worry, and some who are normally anxious might be obsessing more about handwashing or getting sick.

Experts say there are ways to manage this fear to help children feel safe and appropriately informed.

Clinicians and other adults should provide children with honest and accurate information geared to their age and developmental level, said David Fassler, MD, clinical professor of psychiatry, University of Vermont Larner College of Medicine, Burlington, and member of the Consumer Issues Committee of the American Academy of Child and Adolescent Psychiatry.

That said, it’s also acceptable to let children know that some questions can’t be answered, said Fassler.
 

Be truthful, calm

“This is partly because the information keeps changing as we learn more about how the virus spreads, how to best protect communities, and how to treat people who get sick,” he added.

Clinicians and parents should remind children “that there are a lot of adults who are working very hard to keep them safe,” said Eli R. Lebowitz, PhD, associate professor in the Child Study Center, Yale School of Medicine, New Haven, Connecticut, who directs a program for anxiety.

It’s important for adults to pay attention not only to what they say to children but also how they say it, said Lebowitz. He highlighted the importance of talking about the virus “in a calm and matter-of-fact way” rather than in an anxious way.

“If you look scared or tense or your voice is conveying that you’re really scared, the child is going to absorb that and feel anxious as well,” he noted.

This advice also applies when adults are discussing the issue among themselves. They should be aware that “children are listening” and are picking up any anxiety or panic adults are expressing.

Children are soaking up information about this virus from the Internet, the media, friends, teachers, and elsewhere. Lebowitz suggests asking children what they have already heard, which provides an opportunity to correct rumors and inaccurate information.

“A child might have a very inflated sense of what the actual risk is. For example, they may think that anyone who gets the virus dies,” he said.
 

Myth busting

Adults should let children know that not everything they hear from friends or on the Internet “is necessarily correct,” he added.

Some children who have experienced serious illness or losses may be particularly vulnerable to experiencing intense reactions to graphic news reports or images of illness or death and may need extra support, said Fassler.

Adults could use the “framework of knowledge” that children already have, said Lebowitz. He noted that all children are aware of sickness.

“They know people get sick, and they themselves have probably been sick, so you can tell them that this is a sickness like a bad flu,” he said.

Children should be encouraged to approach adults they trust, such as their pediatrician, a parent, or a teacher, with their questions, said Lebowitz. “Those are the people who are able to give them the most accurate information.”

Fassler noted that accurate, up-to-date information is available via fact sheets developed by the Centers for Disease Control and Prevention and the World Health Organization.

Although it’s helpful and appropriate to be reassuring, Fassler advises not to make unrealistic promises.

“It’s fine to tell kids that you’ll deal with whatever happens, even if it means altering travel plans or work schedules, but you can’t promise that no one in your state or community will get sick,” he said.
 

Maintain healthy habits

Physicians and other adults can tell children “in an age-appropriate way” how the virus is transmitted and what the symptoms are, but it’s important to emphasize that most people who are sick don’t have COVID-19, said Lebowitz.

“I would emphasize that the people who are the sickest are the elderly who are already sick, rather than healthy younger people,” he said.

Lebowitz recommends continuing to follow guidelines on staying healthy, including coughing into a sleeve instead of your hand and regular handwashing.

It’s also important at this time for children to maintain healthy habits – getting enough physical activity and sleep, eating well, and being outside – because this regime will go a long way toward reducing anxiety, said Lebowitz. Deep breathing and muscle-relaxing exercises can also help, he said.

Lebowitz also suggests maintaining a supportive attitude and showing “some acceptance and validation of what children are feeling, as well as some confidence that they can cope and tolerate feeling uncomfortable sometimes, that they can handle some anxiety.”

While accepting that the child could be anxious, it’s important not to encourage excessive avoidance or unhealthy coping strategies. Fassler and Lebowitz agree that children who are overly anxious or preoccupied with concerns about the coronavirus should be evaluated by a trained, qualified mental health professional.

Signs that a child may need additional help include ongoing sleep difficulties, intrusive thoughts or worries, obsessive-compulsive behaviors, or reluctance or refusal to go to school, said Fassler.

The good news is that most children are resilient, said Fassler. “They’ll adjust, adapt, and go on with their lives.”

This article first appeared on Medscape.com.

With coronavirus disease (COVID-19) reaching epidemic proportions, many US children are growing increasingly anxious about what this means for their own health and safety and that of their friends and family.

The constantly changing numbers of people affected by the virus and the evolving situation mean daily life for many children is affected in some way, with school trips, sports tournaments, and family vacations being postponed or canceled.

All children may have a heightened level of worry, and some who are normally anxious might be obsessing more about handwashing or getting sick.

Experts say there are ways to manage this fear to help children feel safe and appropriately informed.

Clinicians and other adults should provide children with honest and accurate information geared to their age and developmental level, said David Fassler, MD, clinical professor of psychiatry, University of Vermont Larner College of Medicine, Burlington, and member of the Consumer Issues Committee of the American Academy of Child and Adolescent Psychiatry.

That said, it’s also acceptable to let children know that some questions can’t be answered, said Fassler.
 

Be truthful, calm

“This is partly because the information keeps changing as we learn more about how the virus spreads, how to best protect communities, and how to treat people who get sick,” he added.

Clinicians and parents should remind children “that there are a lot of adults who are working very hard to keep them safe,” said Eli R. Lebowitz, PhD, associate professor in the Child Study Center, Yale School of Medicine, New Haven, Connecticut, who directs a program for anxiety.

It’s important for adults to pay attention not only to what they say to children but also how they say it, said Lebowitz. He highlighted the importance of talking about the virus “in a calm and matter-of-fact way” rather than in an anxious way.

“If you look scared or tense or your voice is conveying that you’re really scared, the child is going to absorb that and feel anxious as well,” he noted.

This advice also applies when adults are discussing the issue among themselves. They should be aware that “children are listening” and are picking up any anxiety or panic adults are expressing.

Children are soaking up information about this virus from the Internet, the media, friends, teachers, and elsewhere. Lebowitz suggests asking children what they have already heard, which provides an opportunity to correct rumors and inaccurate information.

“A child might have a very inflated sense of what the actual risk is. For example, they may think that anyone who gets the virus dies,” he said.
 

Myth busting

Adults should let children know that not everything they hear from friends or on the Internet “is necessarily correct,” he added.

Some children who have experienced serious illness or losses may be particularly vulnerable to experiencing intense reactions to graphic news reports or images of illness or death and may need extra support, said Fassler.

Adults could use the “framework of knowledge” that children already have, said Lebowitz. He noted that all children are aware of sickness.

“They know people get sick, and they themselves have probably been sick, so you can tell them that this is a sickness like a bad flu,” he said.

Children should be encouraged to approach adults they trust, such as their pediatrician, a parent, or a teacher, with their questions, said Lebowitz. “Those are the people who are able to give them the most accurate information.”

Fassler noted that accurate, up-to-date information is available via fact sheets developed by the Centers for Disease Control and Prevention and the World Health Organization.

Although it’s helpful and appropriate to be reassuring, Fassler advises not to make unrealistic promises.

“It’s fine to tell kids that you’ll deal with whatever happens, even if it means altering travel plans or work schedules, but you can’t promise that no one in your state or community will get sick,” he said.
 

Maintain healthy habits

Physicians and other adults can tell children “in an age-appropriate way” how the virus is transmitted and what the symptoms are, but it’s important to emphasize that most people who are sick don’t have COVID-19, said Lebowitz.

“I would emphasize that the people who are the sickest are the elderly who are already sick, rather than healthy younger people,” he said.

Lebowitz recommends continuing to follow guidelines on staying healthy, including coughing into a sleeve instead of your hand and regular handwashing.

It’s also important at this time for children to maintain healthy habits – getting enough physical activity and sleep, eating well, and being outside – because this regime will go a long way toward reducing anxiety, said Lebowitz. Deep breathing and muscle-relaxing exercises can also help, he said.

Lebowitz also suggests maintaining a supportive attitude and showing “some acceptance and validation of what children are feeling, as well as some confidence that they can cope and tolerate feeling uncomfortable sometimes, that they can handle some anxiety.”

While accepting that the child could be anxious, it’s important not to encourage excessive avoidance or unhealthy coping strategies. Fassler and Lebowitz agree that children who are overly anxious or preoccupied with concerns about the coronavirus should be evaluated by a trained, qualified mental health professional.

Signs that a child may need additional help include ongoing sleep difficulties, intrusive thoughts or worries, obsessive-compulsive behaviors, or reluctance or refusal to go to school, said Fassler.

The good news is that most children are resilient, said Fassler. “They’ll adjust, adapt, and go on with their lives.”

This article first appeared on Medscape.com.

The transmission rate of coronavirus disease 2019 (COVID-19) was 1%-5% among 38,000 Chinese people in close contact with infected patients, according to the chief epidemiologist of the Chinese Centers for Disease Control and Prevention, Beijing, Zunyou Wu, MD, PhD, who gave an update on the epidemic at the Conference on Retroviruses & Opportunistic Infections.

The rate of spread to family members – the driver of the infection in China – was 10% early in the outbreak, but fell to 3% with quicker recognition and isolation. The overall numbers are lower than might have been expected, and an important insight for clinicians trying to contain the outbreak in the United States.

Patients were most infectious at the onset of symptoms, when they spiked a fever and started coughing, but their ability to spread the infection dropped after that, Dr. Wu and others said at a special COVID-19 session at the meeting, which was scheduled to be in Boston, but was held online instead because of concerns about spreading the virus. The session has been posted.

Transmission from presymptomatic people is rare. Shedding persists to some degree for 7-12 days in mild/moderate cases, but 2 weeks or more in severe cases.

Dr. Wu said the numbers in China are moving in the right direction, which means that containment efforts there have worked.

The virus emerged in Wuhan, the capital of Hubei province in central China, in connection with a wildlife food market in December 2019. Bats are thought to be the reservoir, with perhaps an intermediate step between civet cats and raccoon dogs. Officials shut down the market.

Essentially, the entire population of China, more than a billion people, was told to stay home for 10 days to interrupt the transmission cycle after the virus spread throughout the country in a few weeks, and almost 60 million people in Hubei were put behind a cordon sanitaire, where they have been for 50 days and will remain “for a while,” Dr. Wu said.

It’s led to a steep drop in new cases and deaths in China since mid-February; both are now more common outside China than inside, and international numbers are lower than they were at the peak in China.

[email protected]

The transmission rate of coronavirus disease 2019 (COVID-19) was 1%-5% among 38,000 Chinese people in close contact with infected patients, according to the chief epidemiologist of the Chinese Centers for Disease Control and Prevention, Beijing, Zunyou Wu, MD, PhD, who gave an update on the epidemic at the Conference on Retroviruses & Opportunistic Infections.

The rate of spread to family members – the driver of the infection in China – was 10% early in the outbreak, but fell to 3% with quicker recognition and isolation. The overall numbers are lower than might have been expected, and an important insight for clinicians trying to contain the outbreak in the United States.

Patients were most infectious at the onset of symptoms, when they spiked a fever and started coughing, but their ability to spread the infection dropped after that, Dr. Wu and others said at a special COVID-19 session at the meeting, which was scheduled to be in Boston, but was held online instead because of concerns about spreading the virus. The session has been posted.

Transmission from presymptomatic people is rare. Shedding persists to some degree for 7-12 days in mild/moderate cases, but 2 weeks or more in severe cases.

Dr. Wu said the numbers in China are moving in the right direction, which means that containment efforts there have worked.

The virus emerged in Wuhan, the capital of Hubei province in central China, in connection with a wildlife food market in December 2019. Bats are thought to be the reservoir, with perhaps an intermediate step between civet cats and raccoon dogs. Officials shut down the market.

Essentially, the entire population of China, more than a billion people, was told to stay home for 10 days to interrupt the transmission cycle after the virus spread throughout the country in a few weeks, and almost 60 million people in Hubei were put behind a cordon sanitaire, where they have been for 50 days and will remain “for a while,” Dr. Wu said.

It’s led to a steep drop in new cases and deaths in China since mid-February; both are now more common outside China than inside, and international numbers are lower than they were at the peak in China.

[email protected]

The transmission rate of coronavirus disease 2019 (COVID-19) was 1%-5% among 38,000 Chinese people in close contact with infected patients, according to the chief epidemiologist of the Chinese Centers for Disease Control and Prevention, Beijing, Zunyou Wu, MD, PhD, who gave an update on the epidemic at the Conference on Retroviruses & Opportunistic Infections.

The rate of spread to family members – the driver of the infection in China – was 10% early in the outbreak, but fell to 3% with quicker recognition and isolation. The overall numbers are lower than might have been expected, and an important insight for clinicians trying to contain the outbreak in the United States.

Patients were most infectious at the onset of symptoms, when they spiked a fever and started coughing, but their ability to spread the infection dropped after that, Dr. Wu and others said at a special COVID-19 session at the meeting, which was scheduled to be in Boston, but was held online instead because of concerns about spreading the virus. The session has been posted.

Transmission from presymptomatic people is rare. Shedding persists to some degree for 7-12 days in mild/moderate cases, but 2 weeks or more in severe cases.

Dr. Wu said the numbers in China are moving in the right direction, which means that containment efforts there have worked.

The virus emerged in Wuhan, the capital of Hubei province in central China, in connection with a wildlife food market in December 2019. Bats are thought to be the reservoir, with perhaps an intermediate step between civet cats and raccoon dogs. Officials shut down the market.

Essentially, the entire population of China, more than a billion people, was told to stay home for 10 days to interrupt the transmission cycle after the virus spread throughout the country in a few weeks, and almost 60 million people in Hubei were put behind a cordon sanitaire, where they have been for 50 days and will remain “for a while,” Dr. Wu said.

It’s led to a steep drop in new cases and deaths in China since mid-February; both are now more common outside China than inside, and international numbers are lower than they were at the peak in China.

[email protected]

Patients with suspected migraine and a normal neurological examination without any atypical features or red flags do not need an MRI or CT, according to recent updated recommendations in a guideline released by the American Headache Society.

Migraine with atypical features may require neuroimaging, according to the guideline. These include an unusual aura; change in clinical features; a first or worst migraine; a migraine that presents with brainstem aura, confusion, or motor manifestation; migraine accompaniments in later life; headaches that are side-locked or posttraumatic; and aura that presents without headache.
 

Assessing the evidence

The recommendation to avoid MRI or CT in otherwise neurologically normal patients with migraine carried a grade A recommendation from the American Headache Society, while the specific considerations for neuroimaging was based on consensus and carried a grade C recommendation, according to lead author Randolph W. Evans, MD, of the department of neurology at Baylor College of Medicine in Houston, and colleagues.

The recommendations, published in the journal Headache (2020 Feb;60(2):318-36), came from a systematic review of 23 studies of adults at least 18 years old who underwent MRI or CT during outpatient treatment for migraine between 1973 and 2018. Ten studies looked at CT neuroimaging in patients with migraine, nine studies examined MRI neuroimaging alone in patients with migraine, and four studies contained adults with headache or migraine who underwent either MRI or CT. The majority of studies analyzed were retrospective or cross-sectional in nature, while four studies were prospective observational studies.

Dr. Evans and colleagues noted that neuroimaging for patients with suspected migraine is ordered for a variety of reasons, such as excluding conditions that aren’t migraine, diagnostic certainty, cognitive bias, practice workflow, medicolegal concerns, addressing patient and family anxiety, and addressing clinician anxiety. Neuroimaging also can be costly, they said, adding up to an estimated $1 billion annually according to one study, and can lead to additional testing from findings that may not be clinically significant.
 

Good advice, with caveats

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, said that while he generally does not like broad guideline recommendations, the recommendation made by the American Headache Society to avoid neuroimaging in patients with a normal neurological examination without any atypical features and red flags “takes most of the important factors into consideration and will work almost all the time.” The recommendation made by consensus for specific considerations of neuroimaging was issued by top headache specialists in the United States who reviewed the data, and it is unlikely a patient with a migraine as diagnosed by the International Classification of Headache Disorders with a normal neurological examination would have a significant abnormality that would appear with imaging, Dr. Rapoport said.

“If everyone caring for migraine patients knew these recommendations, and used them unless the patients fit the exclusions mentioned, we would have more efficient clinical practice and save lots of money on unnecessary scanning,” he said.

However, Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles, founder of the New England Center for Headache, and past president of The International Headache Society, said that not all clinicians will be convinced by the American Headache Society’s recommendations.

“Various third parties often jump on society recommendations or guidelines and prevent smart clinicians from doing what they need to do when they want to disregard the recommendation or guideline,” he explained. “More importantly, if a physician feels the need to think out of the box and image a patient without a clear reason, and the patient cannot pay for the scan when a medical insurance company refuses to authorize it, there can be a bad result if the patient does not get the study.”

Dr. Rapoport noted that the guideline does not address situations where neuroimaging may not pick up conditions that lead to migraine, such as a subarachnoid or subdural hemorrhage, reversible cerebral vasoconstriction syndrome, or early aspects of low cerebrospinal fluid pressure syndrome. Anxiety on the part of the patient or the clinician is another area that can be addressed by future research, he said.

“If the clinician does a good job of explaining the odds of anything significant being found with a typical migraine history and normal examination, and the patient says [they] need an MRI with contrast to be sure, it will be difficult to dissuade them,” said Dr. Rapoport. “If you don’t order one, they will find a way to get one. If it is abnormal, you could be in trouble. Also, if the clinician has no good reason to do a scan but has anxiety about what is being missed, it will probably get done.”

There was no funding source for the guidelines. The authors reported personal and institutional relationships in the form of advisory board memberships, investigator appointments, speakers bureau positions, research support, and consultancies for a variety of pharmaceutical companies, agencies, institutions, publishers, and other organizations.

Patients with suspected migraine and a normal neurological examination without any atypical features or red flags do not need an MRI or CT, according to recent updated recommendations in a guideline released by the American Headache Society.

Migraine with atypical features may require neuroimaging, according to the guideline. These include an unusual aura; change in clinical features; a first or worst migraine; a migraine that presents with brainstem aura, confusion, or motor manifestation; migraine accompaniments in later life; headaches that are side-locked or posttraumatic; and aura that presents without headache.
 

Assessing the evidence

The recommendation to avoid MRI or CT in otherwise neurologically normal patients with migraine carried a grade A recommendation from the American Headache Society, while the specific considerations for neuroimaging was based on consensus and carried a grade C recommendation, according to lead author Randolph W. Evans, MD, of the department of neurology at Baylor College of Medicine in Houston, and colleagues.

The recommendations, published in the journal Headache (2020 Feb;60(2):318-36), came from a systematic review of 23 studies of adults at least 18 years old who underwent MRI or CT during outpatient treatment for migraine between 1973 and 2018. Ten studies looked at CT neuroimaging in patients with migraine, nine studies examined MRI neuroimaging alone in patients with migraine, and four studies contained adults with headache or migraine who underwent either MRI or CT. The majority of studies analyzed were retrospective or cross-sectional in nature, while four studies were prospective observational studies.

Dr. Evans and colleagues noted that neuroimaging for patients with suspected migraine is ordered for a variety of reasons, such as excluding conditions that aren’t migraine, diagnostic certainty, cognitive bias, practice workflow, medicolegal concerns, addressing patient and family anxiety, and addressing clinician anxiety. Neuroimaging also can be costly, they said, adding up to an estimated $1 billion annually according to one study, and can lead to additional testing from findings that may not be clinically significant.
 

Good advice, with caveats

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, said that while he generally does not like broad guideline recommendations, the recommendation made by the American Headache Society to avoid neuroimaging in patients with a normal neurological examination without any atypical features and red flags “takes most of the important factors into consideration and will work almost all the time.” The recommendation made by consensus for specific considerations of neuroimaging was issued by top headache specialists in the United States who reviewed the data, and it is unlikely a patient with a migraine as diagnosed by the International Classification of Headache Disorders with a normal neurological examination would have a significant abnormality that would appear with imaging, Dr. Rapoport said.

“If everyone caring for migraine patients knew these recommendations, and used them unless the patients fit the exclusions mentioned, we would have more efficient clinical practice and save lots of money on unnecessary scanning,” he said.

However, Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles, founder of the New England Center for Headache, and past president of The International Headache Society, said that not all clinicians will be convinced by the American Headache Society’s recommendations.

“Various third parties often jump on society recommendations or guidelines and prevent smart clinicians from doing what they need to do when they want to disregard the recommendation or guideline,” he explained. “More importantly, if a physician feels the need to think out of the box and image a patient without a clear reason, and the patient cannot pay for the scan when a medical insurance company refuses to authorize it, there can be a bad result if the patient does not get the study.”

Dr. Rapoport noted that the guideline does not address situations where neuroimaging may not pick up conditions that lead to migraine, such as a subarachnoid or subdural hemorrhage, reversible cerebral vasoconstriction syndrome, or early aspects of low cerebrospinal fluid pressure syndrome. Anxiety on the part of the patient or the clinician is another area that can be addressed by future research, he said.

“If the clinician does a good job of explaining the odds of anything significant being found with a typical migraine history and normal examination, and the patient says [they] need an MRI with contrast to be sure, it will be difficult to dissuade them,” said Dr. Rapoport. “If you don’t order one, they will find a way to get one. If it is abnormal, you could be in trouble. Also, if the clinician has no good reason to do a scan but has anxiety about what is being missed, it will probably get done.”

There was no funding source for the guidelines. The authors reported personal and institutional relationships in the form of advisory board memberships, investigator appointments, speakers bureau positions, research support, and consultancies for a variety of pharmaceutical companies, agencies, institutions, publishers, and other organizations.

Patients with suspected migraine and a normal neurological examination without any atypical features or red flags do not need an MRI or CT, according to recent updated recommendations in a guideline released by the American Headache Society.

Migraine with atypical features may require neuroimaging, according to the guideline. These include an unusual aura; change in clinical features; a first or worst migraine; a migraine that presents with brainstem aura, confusion, or motor manifestation; migraine accompaniments in later life; headaches that are side-locked or posttraumatic; and aura that presents without headache.
 

Assessing the evidence

The recommendation to avoid MRI or CT in otherwise neurologically normal patients with migraine carried a grade A recommendation from the American Headache Society, while the specific considerations for neuroimaging was based on consensus and carried a grade C recommendation, according to lead author Randolph W. Evans, MD, of the department of neurology at Baylor College of Medicine in Houston, and colleagues.

The recommendations, published in the journal Headache (2020 Feb;60(2):318-36), came from a systematic review of 23 studies of adults at least 18 years old who underwent MRI or CT during outpatient treatment for migraine between 1973 and 2018. Ten studies looked at CT neuroimaging in patients with migraine, nine studies examined MRI neuroimaging alone in patients with migraine, and four studies contained adults with headache or migraine who underwent either MRI or CT. The majority of studies analyzed were retrospective or cross-sectional in nature, while four studies were prospective observational studies.

Dr. Evans and colleagues noted that neuroimaging for patients with suspected migraine is ordered for a variety of reasons, such as excluding conditions that aren’t migraine, diagnostic certainty, cognitive bias, practice workflow, medicolegal concerns, addressing patient and family anxiety, and addressing clinician anxiety. Neuroimaging also can be costly, they said, adding up to an estimated $1 billion annually according to one study, and can lead to additional testing from findings that may not be clinically significant.
 

Good advice, with caveats

In an interview, Alan M. Rapoport, MD, editor-in-chief of Neurology Reviews, said that while he generally does not like broad guideline recommendations, the recommendation made by the American Headache Society to avoid neuroimaging in patients with a normal neurological examination without any atypical features and red flags “takes most of the important factors into consideration and will work almost all the time.” The recommendation made by consensus for specific considerations of neuroimaging was issued by top headache specialists in the United States who reviewed the data, and it is unlikely a patient with a migraine as diagnosed by the International Classification of Headache Disorders with a normal neurological examination would have a significant abnormality that would appear with imaging, Dr. Rapoport said.

“If everyone caring for migraine patients knew these recommendations, and used them unless the patients fit the exclusions mentioned, we would have more efficient clinical practice and save lots of money on unnecessary scanning,” he said.

However, Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles, founder of the New England Center for Headache, and past president of The International Headache Society, said that not all clinicians will be convinced by the American Headache Society’s recommendations.

“Various third parties often jump on society recommendations or guidelines and prevent smart clinicians from doing what they need to do when they want to disregard the recommendation or guideline,” he explained. “More importantly, if a physician feels the need to think out of the box and image a patient without a clear reason, and the patient cannot pay for the scan when a medical insurance company refuses to authorize it, there can be a bad result if the patient does not get the study.”

Dr. Rapoport noted that the guideline does not address situations where neuroimaging may not pick up conditions that lead to migraine, such as a subarachnoid or subdural hemorrhage, reversible cerebral vasoconstriction syndrome, or early aspects of low cerebrospinal fluid pressure syndrome. Anxiety on the part of the patient or the clinician is another area that can be addressed by future research, he said.

“If the clinician does a good job of explaining the odds of anything significant being found with a typical migraine history and normal examination, and the patient says [they] need an MRI with contrast to be sure, it will be difficult to dissuade them,” said Dr. Rapoport. “If you don’t order one, they will find a way to get one. If it is abnormal, you could be in trouble. Also, if the clinician has no good reason to do a scan but has anxiety about what is being missed, it will probably get done.”

There was no funding source for the guidelines. The authors reported personal and institutional relationships in the form of advisory board memberships, investigator appointments, speakers bureau positions, research support, and consultancies for a variety of pharmaceutical companies, agencies, institutions, publishers, and other organizations.

A patient with HIV remission induced by stem cell transplantation continues to be disease free at the 30-month mark.

The individual, referred to as the London patient, received allogeneic hematopoietic stem cell transplantation (allo-HSCT) for stage IVB Hodgkin lymphoma. The transplant donor was homozygous for the CCR5 delta-32 mutation, which confers immunity to HIV because there’s no point of entry for the virus into immune cells.

After extensive sampling of various tissues, including gut, lymph node, blood, semen, and cerebrospinal fluid (CSF), Ravindra Kumar Gupta, MD, PhD, and colleagues found no detectable virus that was competent to replicate. However, they reported that the testing did detect some “fossilized” remnants of HIV DNA persisting in certain tissues.

The results were shared in a video presentation of the research during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.

The London patient’s HIV status had been reported the previous year at CROI 2019, but only blood samples were used in that analysis.

In a commentary accompanying the simultaneously published study in the Lancet, Jennifer Zerbato, PhD, and Sharon Lewin, FRACP, PHD, FAAHMS, asked: “A key question now for the area of HIV cure is how soon can one know if someone has been cured of HIV?

“We will need more than a handful of patients cured of HIV to really understand the duration of follow-up needed and the likelihood of an unexpected late rebound in virus replication,” continued Dr. Zerbato, of the University of Melbourne, and Dr. Lewin, of the Royal Melbourne Hospital and Monash University, also in Melbourne.

In their ongoing analysis of data from the London patient, Dr. Gupta, a virologist at the University of Cambridge (England), and associates constructed a mathematical model that maps the probability for lifetime remission or cure of HIV against several factors, including the degree of chimerism achieved with the stem cell transplant.

In this model, when chimerism reaches 80% in total HIV target cells, the probability of remission for life is 98%; when donor chimerism reaches 90%, the probability of lifetime remission is greater than 99%. Peripheral T-cell chimerism in the London patient has held steady at 99%.

Dr. Gupta and associates obtained some testing opportunistically: A PET-CT scan revealed an axillary lymph node that was biopsied after it was found to have avid radiotracer uptake. Similarly, the CSF sample was obtained in the course of a work-up for some neurologic symptoms that the London patient was having.

In contrast to the first patient who achieved ongoing HIV remission from a pair of stem cell transplants received over 13 years ago – the Berlin patient – the London patient did not receive whole-body radiation, but rather underwent a reduced-intensity conditioning regimen. The London patient experienced a bout of gut graft-versus-host disease (GVHD) about 2 months after his transplant, but has been free of GVHD in the interval. He hasn’t taken cytotoxic agents or any GVHD prophylaxis since 6 months post transplant.

Though there’s no sign of HIV that’s competent to replicate, “the London patient has shown somewhat slow CD4 reconstitution,” said Dr. Gupta and coauthors in discussing the results.

The patient had a reactivation of Epstein-Barr virus (EBV) about 21 months after analytic treatment interruption (ATI) of antiretroviral therapy that was managed without any specific treatment, but he hasn’t experienced any opportunistic infections. However, his CD4 count didn’t rebound to pretransplant levels until 28 months after ATI. At that point, his CD4 count was 430 cells per mcL, or 23.5% of total T cells. The CD4:CD8 ratio was 0.86; normal range is 1.5-2.5.

The researchers used quantitative real-time polymerase chain reaction (rt-PCR) to look for packaging site and envelope (env) DNA fragments, and droplet digital PCR to quantify HIV-1 DNA.

The patient’s HIV-1 plasma load measured at 30 months post ATI on an ultrasensitive assay was below the lower limit of detection (less than 1 copy per mL). Semen viremia measured at 21 months was also below the lower limit of detection, as was CSF measured at 25 months.

Samples were taken from the patient’s rectum, cecum, sigmoid colon, and terminal ileum during a colonoscopy conducted 22 months post ATI; all tested negative for HIV DNA via droplet digital PCR.

The lymph node had large numbers of EBV-positive cells and was positive for HIV-1 env and long-terminal repeat by double-drop PCR, but no integrase DNA was detected. Additionally, no intact proviral DNA was found on assay.

Dr. Gupta and associates speculated that “EBV reactivation could have triggered EBV-specific CD4 and CD8 T-cell responses and proliferation, potentially including CD4 T cells containing HIV-1 DNA.” Supporting this hypothesis, EBV-specific CD8 T-cell responses in peripheral blood were “robust,” and the researchers also saw some CD4 response.

“Similar to the Berlin patient, highly sensitive tests showed very low levels of so-called fossilized HIV-1 DNA in some tissue samples from the London patient. Residual HIV-1 DNA and axillary lymph node tissue could represent a defective clone that expanded during hyperplasia within the lymph note sampled,” noted Dr. Gupta and coauthors.

Responses of CD4 and CD8 T cells to HIV have also remained below the limit of detection, though cytomegalovirus-specific responses persist in the London patient.

As with the Berlin patient, standard enzyme-linked immunosorbent assay (ELISA) testing has remained positive in the London patient. “Standard ELISA testing, therefore, cannot be used as a marker for cure, although more work needs to be done to assess the role of detuned low-avidity antibody assays in defining cure,” noted Dr. Gupta and associates.

The ongoing follow-up plan for the London patient is to obtain viral load testing twice yearly up to 5 years post ATI, and then obtain yearly tests for a total of 10 years. Ongoing testing will confirm the investigators’ belief that “these findings probably represent the second recorded HIV-1 cure after CCR5 delta-32/delta-32 allo-HSCT, with evidence of residual low-level HIV-1 DNA.”

Dr. Zerbato and Dr. Lewin advised cautious optimism and ongoing surveillance: “In view of the many cells sampled in this case, and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow-up case report is certainly exciting and encouraging but, in the end, only time will tell.”

Dr. Gupta reported being a consultant for ViiV Healthcare and Gilead Sciences; several coauthors also reported financial relationships with pharmaceutical companies. The work was funded by amfAR, the American Foundation for AIDS Research, and the Wellcome Trust. Dr. Lewin reported grants from the National Health and Medical Research Council of Australia, the National Institutes of Health, the American Foundation for AIDS Research, Gilead Sciences, Merck, ViiV Healthcare, Leidos, the Wellcome Trust, the Australian Centre for HIV and Hepatitis Virology Research, and the Melbourne HIV Cure Consortium. Dr. Zerbato reported grants from the Melbourne HIV Cure Consortium,

[email protected]

SOURCE: Gupta R et al. Lancet. 2020 Mar 10. doi: 10.1016/ S2352-3018(20)30069-2.

A patient with HIV remission induced by stem cell transplantation continues to be disease free at the 30-month mark.

The individual, referred to as the London patient, received allogeneic hematopoietic stem cell transplantation (allo-HSCT) for stage IVB Hodgkin lymphoma. The transplant donor was homozygous for the CCR5 delta-32 mutation, which confers immunity to HIV because there’s no point of entry for the virus into immune cells.

After extensive sampling of various tissues, including gut, lymph node, blood, semen, and cerebrospinal fluid (CSF), Ravindra Kumar Gupta, MD, PhD, and colleagues found no detectable virus that was competent to replicate. However, they reported that the testing did detect some “fossilized” remnants of HIV DNA persisting in certain tissues.

The results were shared in a video presentation of the research during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.

The London patient’s HIV status had been reported the previous year at CROI 2019, but only blood samples were used in that analysis.

In a commentary accompanying the simultaneously published study in the Lancet, Jennifer Zerbato, PhD, and Sharon Lewin, FRACP, PHD, FAAHMS, asked: “A key question now for the area of HIV cure is how soon can one know if someone has been cured of HIV?

“We will need more than a handful of patients cured of HIV to really understand the duration of follow-up needed and the likelihood of an unexpected late rebound in virus replication,” continued Dr. Zerbato, of the University of Melbourne, and Dr. Lewin, of the Royal Melbourne Hospital and Monash University, also in Melbourne.

In their ongoing analysis of data from the London patient, Dr. Gupta, a virologist at the University of Cambridge (England), and associates constructed a mathematical model that maps the probability for lifetime remission or cure of HIV against several factors, including the degree of chimerism achieved with the stem cell transplant.

In this model, when chimerism reaches 80% in total HIV target cells, the probability of remission for life is 98%; when donor chimerism reaches 90%, the probability of lifetime remission is greater than 99%. Peripheral T-cell chimerism in the London patient has held steady at 99%.

Dr. Gupta and associates obtained some testing opportunistically: A PET-CT scan revealed an axillary lymph node that was biopsied after it was found to have avid radiotracer uptake. Similarly, the CSF sample was obtained in the course of a work-up for some neurologic symptoms that the London patient was having.

In contrast to the first patient who achieved ongoing HIV remission from a pair of stem cell transplants received over 13 years ago – the Berlin patient – the London patient did not receive whole-body radiation, but rather underwent a reduced-intensity conditioning regimen. The London patient experienced a bout of gut graft-versus-host disease (GVHD) about 2 months after his transplant, but has been free of GVHD in the interval. He hasn’t taken cytotoxic agents or any GVHD prophylaxis since 6 months post transplant.

Though there’s no sign of HIV that’s competent to replicate, “the London patient has shown somewhat slow CD4 reconstitution,” said Dr. Gupta and coauthors in discussing the results.

The patient had a reactivation of Epstein-Barr virus (EBV) about 21 months after analytic treatment interruption (ATI) of antiretroviral therapy that was managed without any specific treatment, but he hasn’t experienced any opportunistic infections. However, his CD4 count didn’t rebound to pretransplant levels until 28 months after ATI. At that point, his CD4 count was 430 cells per mcL, or 23.5% of total T cells. The CD4:CD8 ratio was 0.86; normal range is 1.5-2.5.

The researchers used quantitative real-time polymerase chain reaction (rt-PCR) to look for packaging site and envelope (env) DNA fragments, and droplet digital PCR to quantify HIV-1 DNA.

The patient’s HIV-1 plasma load measured at 30 months post ATI on an ultrasensitive assay was below the lower limit of detection (less than 1 copy per mL). Semen viremia measured at 21 months was also below the lower limit of detection, as was CSF measured at 25 months.

Samples were taken from the patient’s rectum, cecum, sigmoid colon, and terminal ileum during a colonoscopy conducted 22 months post ATI; all tested negative for HIV DNA via droplet digital PCR.

The lymph node had large numbers of EBV-positive cells and was positive for HIV-1 env and long-terminal repeat by double-drop PCR, but no integrase DNA was detected. Additionally, no intact proviral DNA was found on assay.

Dr. Gupta and associates speculated that “EBV reactivation could have triggered EBV-specific CD4 and CD8 T-cell responses and proliferation, potentially including CD4 T cells containing HIV-1 DNA.” Supporting this hypothesis, EBV-specific CD8 T-cell responses in peripheral blood were “robust,” and the researchers also saw some CD4 response.

“Similar to the Berlin patient, highly sensitive tests showed very low levels of so-called fossilized HIV-1 DNA in some tissue samples from the London patient. Residual HIV-1 DNA and axillary lymph node tissue could represent a defective clone that expanded during hyperplasia within the lymph note sampled,” noted Dr. Gupta and coauthors.

Responses of CD4 and CD8 T cells to HIV have also remained below the limit of detection, though cytomegalovirus-specific responses persist in the London patient.

As with the Berlin patient, standard enzyme-linked immunosorbent assay (ELISA) testing has remained positive in the London patient. “Standard ELISA testing, therefore, cannot be used as a marker for cure, although more work needs to be done to assess the role of detuned low-avidity antibody assays in defining cure,” noted Dr. Gupta and associates.

The ongoing follow-up plan for the London patient is to obtain viral load testing twice yearly up to 5 years post ATI, and then obtain yearly tests for a total of 10 years. Ongoing testing will confirm the investigators’ belief that “these findings probably represent the second recorded HIV-1 cure after CCR5 delta-32/delta-32 allo-HSCT, with evidence of residual low-level HIV-1 DNA.”

Dr. Zerbato and Dr. Lewin advised cautious optimism and ongoing surveillance: “In view of the many cells sampled in this case, and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow-up case report is certainly exciting and encouraging but, in the end, only time will tell.”

Dr. Gupta reported being a consultant for ViiV Healthcare and Gilead Sciences; several coauthors also reported financial relationships with pharmaceutical companies. The work was funded by amfAR, the American Foundation for AIDS Research, and the Wellcome Trust. Dr. Lewin reported grants from the National Health and Medical Research Council of Australia, the National Institutes of Health, the American Foundation for AIDS Research, Gilead Sciences, Merck, ViiV Healthcare, Leidos, the Wellcome Trust, the Australian Centre for HIV and Hepatitis Virology Research, and the Melbourne HIV Cure Consortium. Dr. Zerbato reported grants from the Melbourne HIV Cure Consortium,

[email protected]

SOURCE: Gupta R et al. Lancet. 2020 Mar 10. doi: 10.1016/ S2352-3018(20)30069-2.

A patient with HIV remission induced by stem cell transplantation continues to be disease free at the 30-month mark.

The individual, referred to as the London patient, received allogeneic hematopoietic stem cell transplantation (allo-HSCT) for stage IVB Hodgkin lymphoma. The transplant donor was homozygous for the CCR5 delta-32 mutation, which confers immunity to HIV because there’s no point of entry for the virus into immune cells.

After extensive sampling of various tissues, including gut, lymph node, blood, semen, and cerebrospinal fluid (CSF), Ravindra Kumar Gupta, MD, PhD, and colleagues found no detectable virus that was competent to replicate. However, they reported that the testing did detect some “fossilized” remnants of HIV DNA persisting in certain tissues.

The results were shared in a video presentation of the research during the Conference on Retroviruses & Opportunistic Infections, which was presented online this year. CROI organizers chose to hold a virtual meeting because of concerns about the spread of COVID-19.

The London patient’s HIV status had been reported the previous year at CROI 2019, but only blood samples were used in that analysis.

In a commentary accompanying the simultaneously published study in the Lancet, Jennifer Zerbato, PhD, and Sharon Lewin, FRACP, PHD, FAAHMS, asked: “A key question now for the area of HIV cure is how soon can one know if someone has been cured of HIV?

“We will need more than a handful of patients cured of HIV to really understand the duration of follow-up needed and the likelihood of an unexpected late rebound in virus replication,” continued Dr. Zerbato, of the University of Melbourne, and Dr. Lewin, of the Royal Melbourne Hospital and Monash University, also in Melbourne.

In their ongoing analysis of data from the London patient, Dr. Gupta, a virologist at the University of Cambridge (England), and associates constructed a mathematical model that maps the probability for lifetime remission or cure of HIV against several factors, including the degree of chimerism achieved with the stem cell transplant.

In this model, when chimerism reaches 80% in total HIV target cells, the probability of remission for life is 98%; when donor chimerism reaches 90%, the probability of lifetime remission is greater than 99%. Peripheral T-cell chimerism in the London patient has held steady at 99%.

Dr. Gupta and associates obtained some testing opportunistically: A PET-CT scan revealed an axillary lymph node that was biopsied after it was found to have avid radiotracer uptake. Similarly, the CSF sample was obtained in the course of a work-up for some neurologic symptoms that the London patient was having.

In contrast to the first patient who achieved ongoing HIV remission from a pair of stem cell transplants received over 13 years ago – the Berlin patient – the London patient did not receive whole-body radiation, but rather underwent a reduced-intensity conditioning regimen. The London patient experienced a bout of gut graft-versus-host disease (GVHD) about 2 months after his transplant, but has been free of GVHD in the interval. He hasn’t taken cytotoxic agents or any GVHD prophylaxis since 6 months post transplant.

Though there’s no sign of HIV that’s competent to replicate, “the London patient has shown somewhat slow CD4 reconstitution,” said Dr. Gupta and coauthors in discussing the results.

The patient had a reactivation of Epstein-Barr virus (EBV) about 21 months after analytic treatment interruption (ATI) of antiretroviral therapy that was managed without any specific treatment, but he hasn’t experienced any opportunistic infections. However, his CD4 count didn’t rebound to pretransplant levels until 28 months after ATI. At that point, his CD4 count was 430 cells per mcL, or 23.5% of total T cells. The CD4:CD8 ratio was 0.86; normal range is 1.5-2.5.

The researchers used quantitative real-time polymerase chain reaction (rt-PCR) to look for packaging site and envelope (env) DNA fragments, and droplet digital PCR to quantify HIV-1 DNA.

The patient’s HIV-1 plasma load measured at 30 months post ATI on an ultrasensitive assay was below the lower limit of detection (less than 1 copy per mL). Semen viremia measured at 21 months was also below the lower limit of detection, as was CSF measured at 25 months.

Samples were taken from the patient’s rectum, cecum, sigmoid colon, and terminal ileum during a colonoscopy conducted 22 months post ATI; all tested negative for HIV DNA via droplet digital PCR.

The lymph node had large numbers of EBV-positive cells and was positive for HIV-1 env and long-terminal repeat by double-drop PCR, but no integrase DNA was detected. Additionally, no intact proviral DNA was found on assay.

Dr. Gupta and associates speculated that “EBV reactivation could have triggered EBV-specific CD4 and CD8 T-cell responses and proliferation, potentially including CD4 T cells containing HIV-1 DNA.” Supporting this hypothesis, EBV-specific CD8 T-cell responses in peripheral blood were “robust,” and the researchers also saw some CD4 response.

“Similar to the Berlin patient, highly sensitive tests showed very low levels of so-called fossilized HIV-1 DNA in some tissue samples from the London patient. Residual HIV-1 DNA and axillary lymph node tissue could represent a defective clone that expanded during hyperplasia within the lymph note sampled,” noted Dr. Gupta and coauthors.

Responses of CD4 and CD8 T cells to HIV have also remained below the limit of detection, though cytomegalovirus-specific responses persist in the London patient.

As with the Berlin patient, standard enzyme-linked immunosorbent assay (ELISA) testing has remained positive in the London patient. “Standard ELISA testing, therefore, cannot be used as a marker for cure, although more work needs to be done to assess the role of detuned low-avidity antibody assays in defining cure,” noted Dr. Gupta and associates.

The ongoing follow-up plan for the London patient is to obtain viral load testing twice yearly up to 5 years post ATI, and then obtain yearly tests for a total of 10 years. Ongoing testing will confirm the investigators’ belief that “these findings probably represent the second recorded HIV-1 cure after CCR5 delta-32/delta-32 allo-HSCT, with evidence of residual low-level HIV-1 DNA.”

Dr. Zerbato and Dr. Lewin advised cautious optimism and ongoing surveillance: “In view of the many cells sampled in this case, and the absence of any intact virus, is the London patient truly cured? The additional data provided in this follow-up case report is certainly exciting and encouraging but, in the end, only time will tell.”

Dr. Gupta reported being a consultant for ViiV Healthcare and Gilead Sciences; several coauthors also reported financial relationships with pharmaceutical companies. The work was funded by amfAR, the American Foundation for AIDS Research, and the Wellcome Trust. Dr. Lewin reported grants from the National Health and Medical Research Council of Australia, the National Institutes of Health, the American Foundation for AIDS Research, Gilead Sciences, Merck, ViiV Healthcare, Leidos, the Wellcome Trust, the Australian Centre for HIV and Hepatitis Virology Research, and the Melbourne HIV Cure Consortium. Dr. Zerbato reported grants from the Melbourne HIV Cure Consortium,

[email protected]

SOURCE: Gupta R et al. Lancet. 2020 Mar 10. doi: 10.1016/ S2352-3018(20)30069-2.

MAUI, HAWAII – Arguably the most important development in the field of rheumatology during the past year was the emergence of persuasive clinical trials data predictive of a bright future for the oral Janus kinase inhibitors as major new drugs for treating ankylosing spondylitis, two experts agreed at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

“These drugs are the first oral DMARDs [disease-modifying antirheumatic drugs], if you will, in AS [ankylosing spondylitis] ... I think obviously they are going to move forward to regulatory approval,” commented Arthur F. Kavanaugh, MD, professor of medicine at the University of California, San Diego, and the RWCS program director.

“I think they’re going to hit the ground running,” predicted Eric M. Ruderman, MD, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.

Upon approval, the Janus kinase (JAK) inhibitors will quickly change the treatment paradigm in AS, the rheumatologists forecast.

“I think this is a way forward to go with strictly oral therapy without necessarily going first with parenteral therapy in these patients. It gives you an alternative, and my guess is, by the time these drugs are approved in this space, there’ll be more and more of their preferential use over biologics in rheumatoid arthritis and potentially in psoriatic arthritis, so people will be more familiar with them. A lot of patients are much happier taking a pill once a day with none of the tolerability issues that we have with shots,” Dr. Ruderman said.

“And they act fast,” noted Dr. Kavanaugh. “You can make a case for trying a JAK inhibitor for a month or 2, and then if you’re not better, then we go to the other option.”

Dr. Ruderman cautioned that the increased need for laboratory monitoring with the oral JAK inhibitors as compared with the annual monitoring with tumor necrosis factor inhibitors could be an issue, especially since AS patients tend to be on the younger side and often dislike coming in regularly for office visits and laboratory tests.

“There may be more of a headache in having to tell patients, ‘You’re not getting your JAK inhibitor refilled until you get your labs done,’ ” he said.

In December 2019, rheumatologists received a holiday present in the form of publication of the results of SELECT-AXIS 1, a multicenter, double-blind, randomized, placebo-controlled phase 2/3 trial in which 187 patients with active AS were randomized to placebo or to the JAK inhibitor upadacitinib (Rinvoq) at the same 15-mg dose approved by the FDA earlier in the year for rheumatoid arthritis. In SELECT-AXIS 1, upadacitinib not only demonstrated clinical efficacy, with a week-14 Assessment of SpondyloArthritis International Society-40 (ASAS 40) response rate of 52% – twice that for placebo – but the active treatment arm also experienced significantly reduced inflammatory disease activity as measured by Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores of the spine and sacroiliac joint. In contrast, MRI scores remained unchanged from baseline in the placebo arm.

“This suggests a biologic effect, a hook beyond clinical disease. And the time of onset was pretty impressive, much like with our experience with JAK inhibitors in RA. Within 2 weeks, there was significant separation from placebo on the ASDAS [Ankylosing Spondylitis Disease Activity Score],” Dr. Ruderman noted.

Positive clinical trials in AS have also been reported for the oral JAK inhibitors filgotinib and tofacitinib (Xeljanz).

Dr. Ruderman and Dr. Kavanaugh also touched on other major developments in AS within the past year, including the landmark FDA approval of certolizumab pegol (Cimzia) as the first-ever drug for treatment of nonradiographic axial spondyloarthritis (nr-axSpA). Also, Dr. Kavanaugh and Dr. Ruderman gave two thumbs down to the 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

 

More biologics coming for nr-AxSpA

In order to gain an indication for treatment of nr-axSpA, the FDA requires completion of a 52-week, randomized, placebo-controlled clinical trial. That’s what UCB did with the company’s TNF inhibitor, certolizumab. Similarly, Eli Lilly sprang for the mandated 52-week trial in 303 nr-axSpA patients for its interleukin-17 inhibitor ixekizumab (Taltz), with positive findings (Lancet. 2020 Jan 4;395[10217]:53-64). And Novartis has done so with its IL-17 inhibitor secukinumab (Cosentyx) in the 555-patient PREVENT trial, again with positive outcomes. So the two IL-17 inhibitors, which are already approved for AS, are seemingly a lock for approval in nr-axSpA as well.

Will the makers of other TNF inhibitors already approved for AS fork over the considerable money entailed in a 52-week randomized trial, or will they ride on certolizumab’s coattails? Dr. Ruderman said he doesn’t know the answer, but it’s certain that, if they don’t complete the trial, they can’t market their biologic for nr-axSpA in the United States, even though there might well be a drug class effect at work.

 

ACR/SAA/SPARTAN guidelines critiqued

The two panelists had plenty to say about the 2019 update of the guidelines, none of it favorable. Among their criticisms: The guidelines are already out of date several months after their release, they are based heavily on opinion rather than on evidence, they appear to take medication cost into consideration when they’re not supposed to, they are complicated, and they are just not practical or useful.

“I don’t know when these guidelines would potentially be used,” Dr. Kavanaugh commented in response to an audience question.

Specifically, the guidelines strongly recommend a TNF inhibitor over the IL-17 inhibitors secukinumab or ixekizumab as the first-line biologic in AS patients with active disease while on NSAIDs, guidance that is already out of date.

“You’d almost think it would have been better just to wait a few months to see the published literature, which I think is going to have a tremendous impact on practice,” Dr. Kavanaugh said.

He also said he was troubled by the strong recommendation against switching to a TNF inhibitor–biosimilar after receiving treatment with an originator TNF inhibitor. That’s something rheumatologists all across Europe are routinely doing now for economic reasons without known harm, with the caveat that patients must be switched to a biosimilar of a different TNF inhibitor than the originator.

“There’s absolutely no data to support a recommendation against switching. I think they’re going out on a limb a little bit,” he added.

Dr. Ruderman said he struggles with the guideline development methodology, which involves posing a series of key questions at the outset, with a strict charge to provide answers.

“They always have to have an answer to the question. And in the event that there’s no data to support an answer, then it becomes a matter of the expert opinion of the people on the committee. I think many rheumatologists would say, ‘Why are they any more expert than a clinical rheumatologist who’s been seeing AS patients for 20 years?’ And the answer is they’re probably not. The fact that most of these are conditional recommendations, meaning they’re not supported by strong evidence, makes them less useful,” according to Dr. Ruderman.

Both he and Dr. Kavanaugh reported receiving research funding from and/or serving as a consultant to numerous pharmaceutical companies.

[email protected]

MAUI, HAWAII – Arguably the most important development in the field of rheumatology during the past year was the emergence of persuasive clinical trials data predictive of a bright future for the oral Janus kinase inhibitors as major new drugs for treating ankylosing spondylitis, two experts agreed at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

“These drugs are the first oral DMARDs [disease-modifying antirheumatic drugs], if you will, in AS [ankylosing spondylitis] ... I think obviously they are going to move forward to regulatory approval,” commented Arthur F. Kavanaugh, MD, professor of medicine at the University of California, San Diego, and the RWCS program director.

“I think they’re going to hit the ground running,” predicted Eric M. Ruderman, MD, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.

Upon approval, the Janus kinase (JAK) inhibitors will quickly change the treatment paradigm in AS, the rheumatologists forecast.

“I think this is a way forward to go with strictly oral therapy without necessarily going first with parenteral therapy in these patients. It gives you an alternative, and my guess is, by the time these drugs are approved in this space, there’ll be more and more of their preferential use over biologics in rheumatoid arthritis and potentially in psoriatic arthritis, so people will be more familiar with them. A lot of patients are much happier taking a pill once a day with none of the tolerability issues that we have with shots,” Dr. Ruderman said.

“And they act fast,” noted Dr. Kavanaugh. “You can make a case for trying a JAK inhibitor for a month or 2, and then if you’re not better, then we go to the other option.”

Dr. Ruderman cautioned that the increased need for laboratory monitoring with the oral JAK inhibitors as compared with the annual monitoring with tumor necrosis factor inhibitors could be an issue, especially since AS patients tend to be on the younger side and often dislike coming in regularly for office visits and laboratory tests.

“There may be more of a headache in having to tell patients, ‘You’re not getting your JAK inhibitor refilled until you get your labs done,’ ” he said.

In December 2019, rheumatologists received a holiday present in the form of publication of the results of SELECT-AXIS 1, a multicenter, double-blind, randomized, placebo-controlled phase 2/3 trial in which 187 patients with active AS were randomized to placebo or to the JAK inhibitor upadacitinib (Rinvoq) at the same 15-mg dose approved by the FDA earlier in the year for rheumatoid arthritis. In SELECT-AXIS 1, upadacitinib not only demonstrated clinical efficacy, with a week-14 Assessment of SpondyloArthritis International Society-40 (ASAS 40) response rate of 52% – twice that for placebo – but the active treatment arm also experienced significantly reduced inflammatory disease activity as measured by Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores of the spine and sacroiliac joint. In contrast, MRI scores remained unchanged from baseline in the placebo arm.

“This suggests a biologic effect, a hook beyond clinical disease. And the time of onset was pretty impressive, much like with our experience with JAK inhibitors in RA. Within 2 weeks, there was significant separation from placebo on the ASDAS [Ankylosing Spondylitis Disease Activity Score],” Dr. Ruderman noted.

Positive clinical trials in AS have also been reported for the oral JAK inhibitors filgotinib and tofacitinib (Xeljanz).

Dr. Ruderman and Dr. Kavanaugh also touched on other major developments in AS within the past year, including the landmark FDA approval of certolizumab pegol (Cimzia) as the first-ever drug for treatment of nonradiographic axial spondyloarthritis (nr-axSpA). Also, Dr. Kavanaugh and Dr. Ruderman gave two thumbs down to the 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

 

More biologics coming for nr-AxSpA

In order to gain an indication for treatment of nr-axSpA, the FDA requires completion of a 52-week, randomized, placebo-controlled clinical trial. That’s what UCB did with the company’s TNF inhibitor, certolizumab. Similarly, Eli Lilly sprang for the mandated 52-week trial in 303 nr-axSpA patients for its interleukin-17 inhibitor ixekizumab (Taltz), with positive findings (Lancet. 2020 Jan 4;395[10217]:53-64). And Novartis has done so with its IL-17 inhibitor secukinumab (Cosentyx) in the 555-patient PREVENT trial, again with positive outcomes. So the two IL-17 inhibitors, which are already approved for AS, are seemingly a lock for approval in nr-axSpA as well.

Will the makers of other TNF inhibitors already approved for AS fork over the considerable money entailed in a 52-week randomized trial, or will they ride on certolizumab’s coattails? Dr. Ruderman said he doesn’t know the answer, but it’s certain that, if they don’t complete the trial, they can’t market their biologic for nr-axSpA in the United States, even though there might well be a drug class effect at work.

 

ACR/SAA/SPARTAN guidelines critiqued

The two panelists had plenty to say about the 2019 update of the guidelines, none of it favorable. Among their criticisms: The guidelines are already out of date several months after their release, they are based heavily on opinion rather than on evidence, they appear to take medication cost into consideration when they’re not supposed to, they are complicated, and they are just not practical or useful.

“I don’t know when these guidelines would potentially be used,” Dr. Kavanaugh commented in response to an audience question.

Specifically, the guidelines strongly recommend a TNF inhibitor over the IL-17 inhibitors secukinumab or ixekizumab as the first-line biologic in AS patients with active disease while on NSAIDs, guidance that is already out of date.

“You’d almost think it would have been better just to wait a few months to see the published literature, which I think is going to have a tremendous impact on practice,” Dr. Kavanaugh said.

He also said he was troubled by the strong recommendation against switching to a TNF inhibitor–biosimilar after receiving treatment with an originator TNF inhibitor. That’s something rheumatologists all across Europe are routinely doing now for economic reasons without known harm, with the caveat that patients must be switched to a biosimilar of a different TNF inhibitor than the originator.

“There’s absolutely no data to support a recommendation against switching. I think they’re going out on a limb a little bit,” he added.

Dr. Ruderman said he struggles with the guideline development methodology, which involves posing a series of key questions at the outset, with a strict charge to provide answers.

“They always have to have an answer to the question. And in the event that there’s no data to support an answer, then it becomes a matter of the expert opinion of the people on the committee. I think many rheumatologists would say, ‘Why are they any more expert than a clinical rheumatologist who’s been seeing AS patients for 20 years?’ And the answer is they’re probably not. The fact that most of these are conditional recommendations, meaning they’re not supported by strong evidence, makes them less useful,” according to Dr. Ruderman.

Both he and Dr. Kavanaugh reported receiving research funding from and/or serving as a consultant to numerous pharmaceutical companies.

[email protected]

MAUI, HAWAII – Arguably the most important development in the field of rheumatology during the past year was the emergence of persuasive clinical trials data predictive of a bright future for the oral Janus kinase inhibitors as major new drugs for treating ankylosing spondylitis, two experts agreed at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

“These drugs are the first oral DMARDs [disease-modifying antirheumatic drugs], if you will, in AS [ankylosing spondylitis] ... I think obviously they are going to move forward to regulatory approval,” commented Arthur F. Kavanaugh, MD, professor of medicine at the University of California, San Diego, and the RWCS program director.

“I think they’re going to hit the ground running,” predicted Eric M. Ruderman, MD, professor of medicine and associate chief for clinical affairs in the division of rheumatology at Northwestern University, Chicago.

Upon approval, the Janus kinase (JAK) inhibitors will quickly change the treatment paradigm in AS, the rheumatologists forecast.

“I think this is a way forward to go with strictly oral therapy without necessarily going first with parenteral therapy in these patients. It gives you an alternative, and my guess is, by the time these drugs are approved in this space, there’ll be more and more of their preferential use over biologics in rheumatoid arthritis and potentially in psoriatic arthritis, so people will be more familiar with them. A lot of patients are much happier taking a pill once a day with none of the tolerability issues that we have with shots,” Dr. Ruderman said.

“And they act fast,” noted Dr. Kavanaugh. “You can make a case for trying a JAK inhibitor for a month or 2, and then if you’re not better, then we go to the other option.”

Dr. Ruderman cautioned that the increased need for laboratory monitoring with the oral JAK inhibitors as compared with the annual monitoring with tumor necrosis factor inhibitors could be an issue, especially since AS patients tend to be on the younger side and often dislike coming in regularly for office visits and laboratory tests.

“There may be more of a headache in having to tell patients, ‘You’re not getting your JAK inhibitor refilled until you get your labs done,’ ” he said.

In December 2019, rheumatologists received a holiday present in the form of publication of the results of SELECT-AXIS 1, a multicenter, double-blind, randomized, placebo-controlled phase 2/3 trial in which 187 patients with active AS were randomized to placebo or to the JAK inhibitor upadacitinib (Rinvoq) at the same 15-mg dose approved by the FDA earlier in the year for rheumatoid arthritis. In SELECT-AXIS 1, upadacitinib not only demonstrated clinical efficacy, with a week-14 Assessment of SpondyloArthritis International Society-40 (ASAS 40) response rate of 52% – twice that for placebo – but the active treatment arm also experienced significantly reduced inflammatory disease activity as measured by Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores of the spine and sacroiliac joint. In contrast, MRI scores remained unchanged from baseline in the placebo arm.

“This suggests a biologic effect, a hook beyond clinical disease. And the time of onset was pretty impressive, much like with our experience with JAK inhibitors in RA. Within 2 weeks, there was significant separation from placebo on the ASDAS [Ankylosing Spondylitis Disease Activity Score],” Dr. Ruderman noted.

Positive clinical trials in AS have also been reported for the oral JAK inhibitors filgotinib and tofacitinib (Xeljanz).

Dr. Ruderman and Dr. Kavanaugh also touched on other major developments in AS within the past year, including the landmark FDA approval of certolizumab pegol (Cimzia) as the first-ever drug for treatment of nonradiographic axial spondyloarthritis (nr-axSpA). Also, Dr. Kavanaugh and Dr. Ruderman gave two thumbs down to the 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

 

More biologics coming for nr-AxSpA

In order to gain an indication for treatment of nr-axSpA, the FDA requires completion of a 52-week, randomized, placebo-controlled clinical trial. That’s what UCB did with the company’s TNF inhibitor, certolizumab. Similarly, Eli Lilly sprang for the mandated 52-week trial in 303 nr-axSpA patients for its interleukin-17 inhibitor ixekizumab (Taltz), with positive findings (Lancet. 2020 Jan 4;395[10217]:53-64). And Novartis has done so with its IL-17 inhibitor secukinumab (Cosentyx) in the 555-patient PREVENT trial, again with positive outcomes. So the two IL-17 inhibitors, which are already approved for AS, are seemingly a lock for approval in nr-axSpA as well.

Will the makers of other TNF inhibitors already approved for AS fork over the considerable money entailed in a 52-week randomized trial, or will they ride on certolizumab’s coattails? Dr. Ruderman said he doesn’t know the answer, but it’s certain that, if they don’t complete the trial, they can’t market their biologic for nr-axSpA in the United States, even though there might well be a drug class effect at work.

 

ACR/SAA/SPARTAN guidelines critiqued

The two panelists had plenty to say about the 2019 update of the guidelines, none of it favorable. Among their criticisms: The guidelines are already out of date several months after their release, they are based heavily on opinion rather than on evidence, they appear to take medication cost into consideration when they’re not supposed to, they are complicated, and they are just not practical or useful.

“I don’t know when these guidelines would potentially be used,” Dr. Kavanaugh commented in response to an audience question.

Specifically, the guidelines strongly recommend a TNF inhibitor over the IL-17 inhibitors secukinumab or ixekizumab as the first-line biologic in AS patients with active disease while on NSAIDs, guidance that is already out of date.

“You’d almost think it would have been better just to wait a few months to see the published literature, which I think is going to have a tremendous impact on practice,” Dr. Kavanaugh said.

He also said he was troubled by the strong recommendation against switching to a TNF inhibitor–biosimilar after receiving treatment with an originator TNF inhibitor. That’s something rheumatologists all across Europe are routinely doing now for economic reasons without known harm, with the caveat that patients must be switched to a biosimilar of a different TNF inhibitor than the originator.

“There’s absolutely no data to support a recommendation against switching. I think they’re going out on a limb a little bit,” he added.

Dr. Ruderman said he struggles with the guideline development methodology, which involves posing a series of key questions at the outset, with a strict charge to provide answers.

“They always have to have an answer to the question. And in the event that there’s no data to support an answer, then it becomes a matter of the expert opinion of the people on the committee. I think many rheumatologists would say, ‘Why are they any more expert than a clinical rheumatologist who’s been seeing AS patients for 20 years?’ And the answer is they’re probably not. The fact that most of these are conditional recommendations, meaning they’re not supported by strong evidence, makes them less useful,” according to Dr. Ruderman.

Both he and Dr. Kavanaugh reported receiving research funding from and/or serving as a consultant to numerous pharmaceutical companies.

[email protected]

Although a 14-day quarantine after exposure to novel coronavirus is “well supported” by evidence, some infected individuals will not become symptomatic until after that period, according to authors of a recent analysis published in Annals of Internal Medicine.

Most individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will develop symptoms by day 12 of the infection, which is within the 14-day period of active monitoring currently recommended by the Centers for Disease Control and Prevention, the authors wrote.

However, an estimated 101 out of 10,000 cases could become symptomatic after the end of that 14-day monitoring period, they cautioned.

“Our analyses do not preclude that estimate from being higher,” said the investigators, led by Stephen A. Lauer, PhD, MD, of Johns Hopkins Bloomberg School of Public Health, Baltimore.

The analysis, based on 181 confirmed cases of coronavirus disease 2019 (COVID-19) that were documented outside of the outbreak epicenter, Wuhan, China, makes “more conservative assumptions” about the window of symptom onset and potential for continued exposure, compared with analyses in previous studies, the researchers wrote.

The estimated incubation period for SARS-CoV-2 in the 181-patient study was a median of 5.1 days, which is comparable with previous estimates based on COVID-19 cases outside of Wuhan and consistent with other known human coronavirus diseases, such as SARS, which had a reported mean incubation period of 5 days, Dr. Lauer and colleagues noted.

Symptoms developed within 11.5 days for 97.5% of patients in the study.

Whether it’s acceptable to have 101 out of 10,000 cases becoming symptomatic beyond the recommended quarantine window depends on two factors, according to the authors. The first is the expected infection risk in the population that is being monitored, and the second is “judgment about the cost of missing cases,” wrote the authors.

In an interview, Aaron Eli Glatt, MD, chair of medicine at Mount Sinai South Nassau, Oceanside, N.Y., said that in practical terms, the results suggest that the majority of patients with COVID-19 will be identified within 14 days, with an “outside chance” of an infected individual leaving quarantine and transmitting virus for a short period of time before becoming symptomatic.

“I think the proper message to give those patients [who are asymptomatic upon leaving quarantine] is, ‘after 14 days, we’re pretty sure you’re out of the woods, but should you get any symptoms, immediately requarantine yourself and seek medical care,” he said.

Study coauthor Kyra H. Grantz, a doctoral graduate student at the Johns Hopkins Bloomberg School of Public Health, said that extending a quarantine beyond 14 days might be considered in the highest-risk scenarios, though the benefits of doing so would have to be weighed against the costs to public health and to the individuals under quarantine.

“Our estimate of the incubation period definitely supports the 14-day recommendation that the CDC has been using,” she said in an interview.

Dr. Grantz emphasized that the estimate of 101 out of 10,000 cases developing symptoms after day 14 of active monitoring – representing the 99th percentile of cases – assumes the “most conservative, worst-case scenario” in a population that is fully infected.

“If you’re looking at a following a cohort of 1,000 people whom you think may have been exposed, only a certain percentage will be infected, and only a certain percentage of those will even develop symptoms – before we get to this idea of how many people would we miss,” she said.

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Allergy and Infectious Diseases, the National Institute of General Medical Sciences, and the Alexander von Humboldt Foundation. Four authors reported disclosures related to those entities, and the remaining five reported no conflicts of interest.
 

SOURCE: Lauer SA et al. Ann Intern Med. 2020 Mar 9. doi:10.1101/2020.02.02.20020016.

Although a 14-day quarantine after exposure to novel coronavirus is “well supported” by evidence, some infected individuals will not become symptomatic until after that period, according to authors of a recent analysis published in Annals of Internal Medicine.

Most individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will develop symptoms by day 12 of the infection, which is within the 14-day period of active monitoring currently recommended by the Centers for Disease Control and Prevention, the authors wrote.

However, an estimated 101 out of 10,000 cases could become symptomatic after the end of that 14-day monitoring period, they cautioned.

“Our analyses do not preclude that estimate from being higher,” said the investigators, led by Stephen A. Lauer, PhD, MD, of Johns Hopkins Bloomberg School of Public Health, Baltimore.

The analysis, based on 181 confirmed cases of coronavirus disease 2019 (COVID-19) that were documented outside of the outbreak epicenter, Wuhan, China, makes “more conservative assumptions” about the window of symptom onset and potential for continued exposure, compared with analyses in previous studies, the researchers wrote.

The estimated incubation period for SARS-CoV-2 in the 181-patient study was a median of 5.1 days, which is comparable with previous estimates based on COVID-19 cases outside of Wuhan and consistent with other known human coronavirus diseases, such as SARS, which had a reported mean incubation period of 5 days, Dr. Lauer and colleagues noted.

Symptoms developed within 11.5 days for 97.5% of patients in the study.

Whether it’s acceptable to have 101 out of 10,000 cases becoming symptomatic beyond the recommended quarantine window depends on two factors, according to the authors. The first is the expected infection risk in the population that is being monitored, and the second is “judgment about the cost of missing cases,” wrote the authors.

In an interview, Aaron Eli Glatt, MD, chair of medicine at Mount Sinai South Nassau, Oceanside, N.Y., said that in practical terms, the results suggest that the majority of patients with COVID-19 will be identified within 14 days, with an “outside chance” of an infected individual leaving quarantine and transmitting virus for a short period of time before becoming symptomatic.

“I think the proper message to give those patients [who are asymptomatic upon leaving quarantine] is, ‘after 14 days, we’re pretty sure you’re out of the woods, but should you get any symptoms, immediately requarantine yourself and seek medical care,” he said.

Study coauthor Kyra H. Grantz, a doctoral graduate student at the Johns Hopkins Bloomberg School of Public Health, said that extending a quarantine beyond 14 days might be considered in the highest-risk scenarios, though the benefits of doing so would have to be weighed against the costs to public health and to the individuals under quarantine.

“Our estimate of the incubation period definitely supports the 14-day recommendation that the CDC has been using,” she said in an interview.

Dr. Grantz emphasized that the estimate of 101 out of 10,000 cases developing symptoms after day 14 of active monitoring – representing the 99th percentile of cases – assumes the “most conservative, worst-case scenario” in a population that is fully infected.

“If you’re looking at a following a cohort of 1,000 people whom you think may have been exposed, only a certain percentage will be infected, and only a certain percentage of those will even develop symptoms – before we get to this idea of how many people would we miss,” she said.

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Allergy and Infectious Diseases, the National Institute of General Medical Sciences, and the Alexander von Humboldt Foundation. Four authors reported disclosures related to those entities, and the remaining five reported no conflicts of interest.
 

SOURCE: Lauer SA et al. Ann Intern Med. 2020 Mar 9. doi:10.1101/2020.02.02.20020016.

Although a 14-day quarantine after exposure to novel coronavirus is “well supported” by evidence, some infected individuals will not become symptomatic until after that period, according to authors of a recent analysis published in Annals of Internal Medicine.

Most individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will develop symptoms by day 12 of the infection, which is within the 14-day period of active monitoring currently recommended by the Centers for Disease Control and Prevention, the authors wrote.

However, an estimated 101 out of 10,000 cases could become symptomatic after the end of that 14-day monitoring period, they cautioned.

“Our analyses do not preclude that estimate from being higher,” said the investigators, led by Stephen A. Lauer, PhD, MD, of Johns Hopkins Bloomberg School of Public Health, Baltimore.

The analysis, based on 181 confirmed cases of coronavirus disease 2019 (COVID-19) that were documented outside of the outbreak epicenter, Wuhan, China, makes “more conservative assumptions” about the window of symptom onset and potential for continued exposure, compared with analyses in previous studies, the researchers wrote.

The estimated incubation period for SARS-CoV-2 in the 181-patient study was a median of 5.1 days, which is comparable with previous estimates based on COVID-19 cases outside of Wuhan and consistent with other known human coronavirus diseases, such as SARS, which had a reported mean incubation period of 5 days, Dr. Lauer and colleagues noted.

Symptoms developed within 11.5 days for 97.5% of patients in the study.

Whether it’s acceptable to have 101 out of 10,000 cases becoming symptomatic beyond the recommended quarantine window depends on two factors, according to the authors. The first is the expected infection risk in the population that is being monitored, and the second is “judgment about the cost of missing cases,” wrote the authors.

In an interview, Aaron Eli Glatt, MD, chair of medicine at Mount Sinai South Nassau, Oceanside, N.Y., said that in practical terms, the results suggest that the majority of patients with COVID-19 will be identified within 14 days, with an “outside chance” of an infected individual leaving quarantine and transmitting virus for a short period of time before becoming symptomatic.

“I think the proper message to give those patients [who are asymptomatic upon leaving quarantine] is, ‘after 14 days, we’re pretty sure you’re out of the woods, but should you get any symptoms, immediately requarantine yourself and seek medical care,” he said.

Study coauthor Kyra H. Grantz, a doctoral graduate student at the Johns Hopkins Bloomberg School of Public Health, said that extending a quarantine beyond 14 days might be considered in the highest-risk scenarios, though the benefits of doing so would have to be weighed against the costs to public health and to the individuals under quarantine.

“Our estimate of the incubation period definitely supports the 14-day recommendation that the CDC has been using,” she said in an interview.

Dr. Grantz emphasized that the estimate of 101 out of 10,000 cases developing symptoms after day 14 of active monitoring – representing the 99th percentile of cases – assumes the “most conservative, worst-case scenario” in a population that is fully infected.

“If you’re looking at a following a cohort of 1,000 people whom you think may have been exposed, only a certain percentage will be infected, and only a certain percentage of those will even develop symptoms – before we get to this idea of how many people would we miss,” she said.

The study was supported by the Centers for Disease Control and Prevention, the National Institute of Allergy and Infectious Diseases, the National Institute of General Medical Sciences, and the Alexander von Humboldt Foundation. Four authors reported disclosures related to those entities, and the remaining five reported no conflicts of interest.
 

SOURCE: Lauer SA et al. Ann Intern Med. 2020 Mar 9. doi:10.1101/2020.02.02.20020016.

Current trends in the incidence and mortality of colorectal cancer (CRC) in the United States suggest CRC will become a disease that largely affects young and middle-aged adults, according to a report published in CA: A Cancer Journal for Clinicians.

As the second leading cause of cancer-related death in the United States, and with modifiable risk factors accounting for over 50% of cases and deaths, CRC is largely a preventable disease, explained study author Rebecca L. Siegel, of the American Cancer Society, and colleagues.

According to the investigators, CRC incidence dropped by 3.3% per year from 2011 through 2016 among individuals aged 65 years or older, but the opposite was observed for those aged 50-64 years, with rates increasing by 1% per year. The increase was even greater for those younger than 50 years, with an increase of 2.2% per year.

The CRC incidence from 2012 through 2016 was highest among Alaska Natives (89 cases per 100,000 persons) and lowest among Asian/Pacific Islanders (30 cases per 100,000 persons).

“CRC has been the most commonly diagnosed cancer in Alaska Natives since the early 1970s for reasons that are unknown but may include a higher prevalence of risk factors,” the investigators wrote.

The risk of developing CRC is related to several factors, including obesity, vitamin D deficiency, diabetes, smoking, and other dietary factors, the team further explained.

Among those aged 65 years or older, CRC death rates decreased by 3% per year from 2008 through 2017. For those aged 50-64 years, death rates dropped by 0.6% per year. In contrast, death rates rose by 1.3% per year for those younger than 50 years.

“The uptick in young adults, which is most rapid among non-Hispanic whites (2% per year), began around 2004 and was preceded by declines of 1% to 2% per year since at least 1975,” the investigators wrote.

The reduction in incidence and mortality among older adults is partially attributable to higher uptake of CRC screening. According to recent data, CRC screening rates were lower for those aged 50-64 years compared with individuals aged 65 years and older.

Based on current recommendations from the American Cancer Society, CRC screening should begin at age 45, with some higher-risk patients starting at age 40.

“Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults,” the investigators concluded.

The authors disclosed financial affiliations with the American Cancer Society, which funded the study, as well as Array Biopharma, Bayer, RGenix, Tesaro, and Seattle Genetics.

SOURCE: Siegel RL et al. CA Cancer J Clin. 2020 Mar 5. doi: 10.3322/caac.21601.

Current trends in the incidence and mortality of colorectal cancer (CRC) in the United States suggest CRC will become a disease that largely affects young and middle-aged adults, according to a report published in CA: A Cancer Journal for Clinicians.

As the second leading cause of cancer-related death in the United States, and with modifiable risk factors accounting for over 50% of cases and deaths, CRC is largely a preventable disease, explained study author Rebecca L. Siegel, of the American Cancer Society, and colleagues.

According to the investigators, CRC incidence dropped by 3.3% per year from 2011 through 2016 among individuals aged 65 years or older, but the opposite was observed for those aged 50-64 years, with rates increasing by 1% per year. The increase was even greater for those younger than 50 years, with an increase of 2.2% per year.

The CRC incidence from 2012 through 2016 was highest among Alaska Natives (89 cases per 100,000 persons) and lowest among Asian/Pacific Islanders (30 cases per 100,000 persons).

“CRC has been the most commonly diagnosed cancer in Alaska Natives since the early 1970s for reasons that are unknown but may include a higher prevalence of risk factors,” the investigators wrote.

The risk of developing CRC is related to several factors, including obesity, vitamin D deficiency, diabetes, smoking, and other dietary factors, the team further explained.

Among those aged 65 years or older, CRC death rates decreased by 3% per year from 2008 through 2017. For those aged 50-64 years, death rates dropped by 0.6% per year. In contrast, death rates rose by 1.3% per year for those younger than 50 years.

“The uptick in young adults, which is most rapid among non-Hispanic whites (2% per year), began around 2004 and was preceded by declines of 1% to 2% per year since at least 1975,” the investigators wrote.

The reduction in incidence and mortality among older adults is partially attributable to higher uptake of CRC screening. According to recent data, CRC screening rates were lower for those aged 50-64 years compared with individuals aged 65 years and older.

Based on current recommendations from the American Cancer Society, CRC screening should begin at age 45, with some higher-risk patients starting at age 40.

“Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults,” the investigators concluded.

The authors disclosed financial affiliations with the American Cancer Society, which funded the study, as well as Array Biopharma, Bayer, RGenix, Tesaro, and Seattle Genetics.

SOURCE: Siegel RL et al. CA Cancer J Clin. 2020 Mar 5. doi: 10.3322/caac.21601.

Current trends in the incidence and mortality of colorectal cancer (CRC) in the United States suggest CRC will become a disease that largely affects young and middle-aged adults, according to a report published in CA: A Cancer Journal for Clinicians.

As the second leading cause of cancer-related death in the United States, and with modifiable risk factors accounting for over 50% of cases and deaths, CRC is largely a preventable disease, explained study author Rebecca L. Siegel, of the American Cancer Society, and colleagues.

According to the investigators, CRC incidence dropped by 3.3% per year from 2011 through 2016 among individuals aged 65 years or older, but the opposite was observed for those aged 50-64 years, with rates increasing by 1% per year. The increase was even greater for those younger than 50 years, with an increase of 2.2% per year.

The CRC incidence from 2012 through 2016 was highest among Alaska Natives (89 cases per 100,000 persons) and lowest among Asian/Pacific Islanders (30 cases per 100,000 persons).

“CRC has been the most commonly diagnosed cancer in Alaska Natives since the early 1970s for reasons that are unknown but may include a higher prevalence of risk factors,” the investigators wrote.

The risk of developing CRC is related to several factors, including obesity, vitamin D deficiency, diabetes, smoking, and other dietary factors, the team further explained.

Among those aged 65 years or older, CRC death rates decreased by 3% per year from 2008 through 2017. For those aged 50-64 years, death rates dropped by 0.6% per year. In contrast, death rates rose by 1.3% per year for those younger than 50 years.

“The uptick in young adults, which is most rapid among non-Hispanic whites (2% per year), began around 2004 and was preceded by declines of 1% to 2% per year since at least 1975,” the investigators wrote.

The reduction in incidence and mortality among older adults is partially attributable to higher uptake of CRC screening. According to recent data, CRC screening rates were lower for those aged 50-64 years compared with individuals aged 65 years and older.

Based on current recommendations from the American Cancer Society, CRC screening should begin at age 45, with some higher-risk patients starting at age 40.

“Progress against CRC can be accelerated by increasing access to guideline-recommended screening and high quality treatment, particularly among Alaska Natives, and elucidating causes for rising incidence in young and middle-aged adults,” the investigators concluded.

The authors disclosed financial affiliations with the American Cancer Society, which funded the study, as well as Array Biopharma, Bayer, RGenix, Tesaro, and Seattle Genetics.

SOURCE: Siegel RL et al. CA Cancer J Clin. 2020 Mar 5. doi: 10.3322/caac.21601.

Stress-related disorders may put individuals at increased risk of neurodegenerative conditions such as Alzheimer’s disease later in life, conceivably through a cerebrovascular pathway, according to authors of a large population- and sibling-matched cohort study. Individuals with posttraumatic stress disorder (PTSD), acute stress reaction, adjustment disorder, or other stress reactions had an 80% increased risk of vascular neurodegenerative diseases, according to results of the study, which was based on Swedish population registry data.

Risk of primary neurodegenerative diseases was increased as well in people with those conditions, but only by 31%, according to lead author Huan Song, MD, PhD, of Sichuan University in Chengdu, China.

“The stronger association observed for neurodegenerative diseases with a vascular component, compared with primary neurodegenerative diseases, suggested a considerable role of a possible cerebrovascular pathway,” Dr. Song and coauthors said in a report on the study appearing in JAMA Neurology.

While some previous studies have linked stress-related disorders to neurodegenerative diseases – particularly PTSD and dementia – this is believed to be the first, according to the investigators, to comprehensively evaluate all stress-related disorders in relation to the most common neurodegenerative conditions.

When considering neurodegenerative conditions separately, they found a statistically significant association between stress-related disorders and Alzheimer’s disease, while linkages with Parkinson’s disease and amyotrophic lateral sclerosis (ALS) were “comparable” but associations did not reach statistical significance, according to investigators.

Based on these findings, stress reduction should be recommended in addition to daily physical activity, mental activity, and a heart-healthy diet to potentially reduce risk of onset or worsening of cognitive decline, according to Chun Lim, MD, PhD, medical director of the cognitive neurology unit at Beth Israel Deaconess Medical Center in Boston.

“We don’t really have great evidence that anything slows down the progression of Alzheimer’s disease, but there are some suggestions that for people who lead heart-healthy lifestyles or adhere to a Mediterranean diet, fewer develop cognitive issues over 5-10 years,” Dr. Lim said in an interview. “Because of this paper, stress reduction may be one additional way to hopefully help these patients these patients that have or are concerned about cognitive issues.”

The population-matched cohort of the study included 61,748 individuals with stress-related disorders and 595,335 matched individuals without those disorders, while the sibling-matched cohort included 44,839 individuals with those disorders and 78,482 without. The median age at the start of follow-up was 47 years and 39.4% of those with stress-related disorders were male.

During follow-up, the incidence of neurodegenerative diseases per 1,000 person-years was 1.50 for individuals with stress-related disorders, versus 0.82 for those without stress-related disorders, according to the report. Risk of primary neurodegenerative diseases was increased among those with stress-related disorders, compared with those without, with a hazard ratio of 1.31 (95% confidence interval, 1.15-1.48). However, the risk of vascular neurodegenerative diseases was significantly higher, with an HR of 1.80 (95% CI, 1.40-2.31; P = .03 for the difference between hazard ratios).

Results of the matched sibling cohort supported results of the population-matched cohort, though the elevated risk of vascular neurodegenerative diseases among those with stress-related disorders was “slightly lower” than in the population-based cohort, Dr. Song and coauthors wrote in their report.

Beyond causing a host of hormonal and medical issues, stress can lead to sleep issues that may have long-term consequences, Dr. Lim noted in the interview.

“There’s some thought that quality sleep is important for memory formation, and if people are under a fair amount of stress and they have really poor sleep, that can also lead to cognitive issues including memory impairment,” he said.

“There are these multiple avenues that may be contributing to the accelerated development of these kinds of issues,” he added, “so I think this paper suggests more ways to counsel the patients about using lifestyle modifications to slow down the development of these cognitive impairments.”

Funding for the study came from the Swedish Research Council, Icelandic Research Fund; ,European Research Council the Karolinska Institutet, Swedish Research Council, and West China Hospital. Authors of the study provided disclosures related to those organizations as well as Shire/Takeda and Evolan.

SOURCE: Song H et al. JAMA Neurol. 2020 Mar 9. doi: 10.1001/jamaneurol.2020.0117.

Stress-related disorders may put individuals at increased risk of neurodegenerative conditions such as Alzheimer’s disease later in life, conceivably through a cerebrovascular pathway, according to authors of a large population- and sibling-matched cohort study. Individuals with posttraumatic stress disorder (PTSD), acute stress reaction, adjustment disorder, or other stress reactions had an 80% increased risk of vascular neurodegenerative diseases, according to results of the study, which was based on Swedish population registry data.

Risk of primary neurodegenerative diseases was increased as well in people with those conditions, but only by 31%, according to lead author Huan Song, MD, PhD, of Sichuan University in Chengdu, China.

“The stronger association observed for neurodegenerative diseases with a vascular component, compared with primary neurodegenerative diseases, suggested a considerable role of a possible cerebrovascular pathway,” Dr. Song and coauthors said in a report on the study appearing in JAMA Neurology.

While some previous studies have linked stress-related disorders to neurodegenerative diseases – particularly PTSD and dementia – this is believed to be the first, according to the investigators, to comprehensively evaluate all stress-related disorders in relation to the most common neurodegenerative conditions.

When considering neurodegenerative conditions separately, they found a statistically significant association between stress-related disorders and Alzheimer’s disease, while linkages with Parkinson’s disease and amyotrophic lateral sclerosis (ALS) were “comparable” but associations did not reach statistical significance, according to investigators.

Based on these findings, stress reduction should be recommended in addition to daily physical activity, mental activity, and a heart-healthy diet to potentially reduce risk of onset or worsening of cognitive decline, according to Chun Lim, MD, PhD, medical director of the cognitive neurology unit at Beth Israel Deaconess Medical Center in Boston.

“We don’t really have great evidence that anything slows down the progression of Alzheimer’s disease, but there are some suggestions that for people who lead heart-healthy lifestyles or adhere to a Mediterranean diet, fewer develop cognitive issues over 5-10 years,” Dr. Lim said in an interview. “Because of this paper, stress reduction may be one additional way to hopefully help these patients these patients that have or are concerned about cognitive issues.”

The population-matched cohort of the study included 61,748 individuals with stress-related disorders and 595,335 matched individuals without those disorders, while the sibling-matched cohort included 44,839 individuals with those disorders and 78,482 without. The median age at the start of follow-up was 47 years and 39.4% of those with stress-related disorders were male.

During follow-up, the incidence of neurodegenerative diseases per 1,000 person-years was 1.50 for individuals with stress-related disorders, versus 0.82 for those without stress-related disorders, according to the report. Risk of primary neurodegenerative diseases was increased among those with stress-related disorders, compared with those without, with a hazard ratio of 1.31 (95% confidence interval, 1.15-1.48). However, the risk of vascular neurodegenerative diseases was significantly higher, with an HR of 1.80 (95% CI, 1.40-2.31; P = .03 for the difference between hazard ratios).

Results of the matched sibling cohort supported results of the population-matched cohort, though the elevated risk of vascular neurodegenerative diseases among those with stress-related disorders was “slightly lower” than in the population-based cohort, Dr. Song and coauthors wrote in their report.

Beyond causing a host of hormonal and medical issues, stress can lead to sleep issues that may have long-term consequences, Dr. Lim noted in the interview.

“There’s some thought that quality sleep is important for memory formation, and if people are under a fair amount of stress and they have really poor sleep, that can also lead to cognitive issues including memory impairment,” he said.

“There are these multiple avenues that may be contributing to the accelerated development of these kinds of issues,” he added, “so I think this paper suggests more ways to counsel the patients about using lifestyle modifications to slow down the development of these cognitive impairments.”

Funding for the study came from the Swedish Research Council, Icelandic Research Fund; ,European Research Council the Karolinska Institutet, Swedish Research Council, and West China Hospital. Authors of the study provided disclosures related to those organizations as well as Shire/Takeda and Evolan.

SOURCE: Song H et al. JAMA Neurol. 2020 Mar 9. doi: 10.1001/jamaneurol.2020.0117.

Stress-related disorders may put individuals at increased risk of neurodegenerative conditions such as Alzheimer’s disease later in life, conceivably through a cerebrovascular pathway, according to authors of a large population- and sibling-matched cohort study. Individuals with posttraumatic stress disorder (PTSD), acute stress reaction, adjustment disorder, or other stress reactions had an 80% increased risk of vascular neurodegenerative diseases, according to results of the study, which was based on Swedish population registry data.

Risk of primary neurodegenerative diseases was increased as well in people with those conditions, but only by 31%, according to lead author Huan Song, MD, PhD, of Sichuan University in Chengdu, China.

“The stronger association observed for neurodegenerative diseases with a vascular component, compared with primary neurodegenerative diseases, suggested a considerable role of a possible cerebrovascular pathway,” Dr. Song and coauthors said in a report on the study appearing in JAMA Neurology.

While some previous studies have linked stress-related disorders to neurodegenerative diseases – particularly PTSD and dementia – this is believed to be the first, according to the investigators, to comprehensively evaluate all stress-related disorders in relation to the most common neurodegenerative conditions.

When considering neurodegenerative conditions separately, they found a statistically significant association between stress-related disorders and Alzheimer’s disease, while linkages with Parkinson’s disease and amyotrophic lateral sclerosis (ALS) were “comparable” but associations did not reach statistical significance, according to investigators.

Based on these findings, stress reduction should be recommended in addition to daily physical activity, mental activity, and a heart-healthy diet to potentially reduce risk of onset or worsening of cognitive decline, according to Chun Lim, MD, PhD, medical director of the cognitive neurology unit at Beth Israel Deaconess Medical Center in Boston.

“We don’t really have great evidence that anything slows down the progression of Alzheimer’s disease, but there are some suggestions that for people who lead heart-healthy lifestyles or adhere to a Mediterranean diet, fewer develop cognitive issues over 5-10 years,” Dr. Lim said in an interview. “Because of this paper, stress reduction may be one additional way to hopefully help these patients these patients that have or are concerned about cognitive issues.”

The population-matched cohort of the study included 61,748 individuals with stress-related disorders and 595,335 matched individuals without those disorders, while the sibling-matched cohort included 44,839 individuals with those disorders and 78,482 without. The median age at the start of follow-up was 47 years and 39.4% of those with stress-related disorders were male.

During follow-up, the incidence of neurodegenerative diseases per 1,000 person-years was 1.50 for individuals with stress-related disorders, versus 0.82 for those without stress-related disorders, according to the report. Risk of primary neurodegenerative diseases was increased among those with stress-related disorders, compared with those without, with a hazard ratio of 1.31 (95% confidence interval, 1.15-1.48). However, the risk of vascular neurodegenerative diseases was significantly higher, with an HR of 1.80 (95% CI, 1.40-2.31; P = .03 for the difference between hazard ratios).

Results of the matched sibling cohort supported results of the population-matched cohort, though the elevated risk of vascular neurodegenerative diseases among those with stress-related disorders was “slightly lower” than in the population-based cohort, Dr. Song and coauthors wrote in their report.

Beyond causing a host of hormonal and medical issues, stress can lead to sleep issues that may have long-term consequences, Dr. Lim noted in the interview.

“There’s some thought that quality sleep is important for memory formation, and if people are under a fair amount of stress and they have really poor sleep, that can also lead to cognitive issues including memory impairment,” he said.

“There are these multiple avenues that may be contributing to the accelerated development of these kinds of issues,” he added, “so I think this paper suggests more ways to counsel the patients about using lifestyle modifications to slow down the development of these cognitive impairments.”

Funding for the study came from the Swedish Research Council, Icelandic Research Fund; ,European Research Council the Karolinska Institutet, Swedish Research Council, and West China Hospital. Authors of the study provided disclosures related to those organizations as well as Shire/Takeda and Evolan.

SOURCE: Song H et al. JAMA Neurol. 2020 Mar 9. doi: 10.1001/jamaneurol.2020.0117.

Rotavirus vaccination was not associated with the incidence of type 1 diabetes in a study of more than 385,000 children published in JAMA Pediatrics.

Previous findings from a number of studies have indicated a possible association between rotavirus and type 1 diabetes, according to Jason M. Glanz, PhD, and colleagues. “Epidemiologic data suggest an association between gastrointestinal infection and incidence of type 1 diabetes in children followed from birth to age 10 years. Given these findings, it is biologically plausible that live, attenuated rotavirus vaccine could either increase or decrease the risk for type 1 diabetes in early childhood,” they wrote.

To examine the association between rotavirus vaccination and the incidence of type 1 diabetes in a cohort of U.S. children, Dr. Glanz, a senior investigator at the Kaiser Permanente Colorado Institute for Health Research in Aurora, and colleagues retrospectively analyzed data from seven health care organizations that participate in the Vaccine Safety Datalink.

The researchers identified children born between 2006 and 2014 who had continuous enrollment from age 6 weeks to 2 years. They excluded children with a medical contraindication to vaccination or fewer than two well-child visits by age 12 months. They followed children until a type 1 diabetes diagnosis, disenrollment, or Dec. 31, 2017. The researchers adjusted for sex, birth year, mother’s age, birth weight, gestational age, and race or ethnicity.

The cohort included 386,937 children who were followed up a median of 5.4 years for a total person-time follow-up of 2,253,879 years. In all, 386,937 children (93.1%) were fully exposed to rotavirus vaccination; 15,765 (4.1%) were partially exposed to rotavirus vaccination, meaning that they received some, but not all, vaccine doses; and 11,003 (2.8%) were unexposed to rotavirus vaccination but had received all other recommended vaccines.

There were 464 cases of type 1 diabetes in the cohort, with an incidence rate of 20 cases per 100,000 person-years in the fully exposed group, 31.2 cases per 100,000 person-years in the partially exposed group, and 22.4 cases per 100,000 person-years in the unexposed group.

The incidence of type 1 diabetes was not significantly different across the rotavirus vaccine–exposure groups. The researchers reported that, compared with children unexposed to rotavirus vaccination, the adjusted hazard ratio for children fully exposed to rotavirus vaccination was 1.03 (95% confidence interval, 0.62-1.72), and for those partially exposed to the vaccination, it was 1.50 (95% CI, 0.81-2.77).

“Since licensure, rotavirus vaccination has been associated with a reduction in morbidity and mortality due to rotavirus infection in the United States and worldwide. ... Although rotavirus vaccination may not prevent type 1 diabetes, these results should provide additional reassurance to the public that rotavirus vaccination can be safely administered to infants,” they wrote.

The limited follow-up duration and relatively small proportion of patients unexposed to rotavirus vaccination are limitations of the study, the authors noted.

The Centers for Disease Control and Prevention funded the study. Several authors reported having received grants from the CDC. One author received grants from the National Institute of Diabetes and Digestive and Kidney Diseases, and another from pharmaceutical companies not involved in the study.

SOURCE: Glanz JM et al. JAMA Pediatr. 2020 Mar 9. doi: 10.1001/jamapediatrics.2019.6324.

Rotavirus vaccination was not associated with the incidence of type 1 diabetes in a study of more than 385,000 children published in JAMA Pediatrics.

Previous findings from a number of studies have indicated a possible association between rotavirus and type 1 diabetes, according to Jason M. Glanz, PhD, and colleagues. “Epidemiologic data suggest an association between gastrointestinal infection and incidence of type 1 diabetes in children followed from birth to age 10 years. Given these findings, it is biologically plausible that live, attenuated rotavirus vaccine could either increase or decrease the risk for type 1 diabetes in early childhood,” they wrote.

To examine the association between rotavirus vaccination and the incidence of type 1 diabetes in a cohort of U.S. children, Dr. Glanz, a senior investigator at the Kaiser Permanente Colorado Institute for Health Research in Aurora, and colleagues retrospectively analyzed data from seven health care organizations that participate in the Vaccine Safety Datalink.

The researchers identified children born between 2006 and 2014 who had continuous enrollment from age 6 weeks to 2 years. They excluded children with a medical contraindication to vaccination or fewer than two well-child visits by age 12 months. They followed children until a type 1 diabetes diagnosis, disenrollment, or Dec. 31, 2017. The researchers adjusted for sex, birth year, mother’s age, birth weight, gestational age, and race or ethnicity.

The cohort included 386,937 children who were followed up a median of 5.4 years for a total person-time follow-up of 2,253,879 years. In all, 386,937 children (93.1%) were fully exposed to rotavirus vaccination; 15,765 (4.1%) were partially exposed to rotavirus vaccination, meaning that they received some, but not all, vaccine doses; and 11,003 (2.8%) were unexposed to rotavirus vaccination but had received all other recommended vaccines.

There were 464 cases of type 1 diabetes in the cohort, with an incidence rate of 20 cases per 100,000 person-years in the fully exposed group, 31.2 cases per 100,000 person-years in the partially exposed group, and 22.4 cases per 100,000 person-years in the unexposed group.

The incidence of type 1 diabetes was not significantly different across the rotavirus vaccine–exposure groups. The researchers reported that, compared with children unexposed to rotavirus vaccination, the adjusted hazard ratio for children fully exposed to rotavirus vaccination was 1.03 (95% confidence interval, 0.62-1.72), and for those partially exposed to the vaccination, it was 1.50 (95% CI, 0.81-2.77).

“Since licensure, rotavirus vaccination has been associated with a reduction in morbidity and mortality due to rotavirus infection in the United States and worldwide. ... Although rotavirus vaccination may not prevent type 1 diabetes, these results should provide additional reassurance to the public that rotavirus vaccination can be safely administered to infants,” they wrote.

The limited follow-up duration and relatively small proportion of patients unexposed to rotavirus vaccination are limitations of the study, the authors noted.

The Centers for Disease Control and Prevention funded the study. Several authors reported having received grants from the CDC. One author received grants from the National Institute of Diabetes and Digestive and Kidney Diseases, and another from pharmaceutical companies not involved in the study.

SOURCE: Glanz JM et al. JAMA Pediatr. 2020 Mar 9. doi: 10.1001/jamapediatrics.2019.6324.

Rotavirus vaccination was not associated with the incidence of type 1 diabetes in a study of more than 385,000 children published in JAMA Pediatrics.

Previous findings from a number of studies have indicated a possible association between rotavirus and type 1 diabetes, according to Jason M. Glanz, PhD, and colleagues. “Epidemiologic data suggest an association between gastrointestinal infection and incidence of type 1 diabetes in children followed from birth to age 10 years. Given these findings, it is biologically plausible that live, attenuated rotavirus vaccine could either increase or decrease the risk for type 1 diabetes in early childhood,” they wrote.

To examine the association between rotavirus vaccination and the incidence of type 1 diabetes in a cohort of U.S. children, Dr. Glanz, a senior investigator at the Kaiser Permanente Colorado Institute for Health Research in Aurora, and colleagues retrospectively analyzed data from seven health care organizations that participate in the Vaccine Safety Datalink.

The researchers identified children born between 2006 and 2014 who had continuous enrollment from age 6 weeks to 2 years. They excluded children with a medical contraindication to vaccination or fewer than two well-child visits by age 12 months. They followed children until a type 1 diabetes diagnosis, disenrollment, or Dec. 31, 2017. The researchers adjusted for sex, birth year, mother’s age, birth weight, gestational age, and race or ethnicity.

The cohort included 386,937 children who were followed up a median of 5.4 years for a total person-time follow-up of 2,253,879 years. In all, 386,937 children (93.1%) were fully exposed to rotavirus vaccination; 15,765 (4.1%) were partially exposed to rotavirus vaccination, meaning that they received some, but not all, vaccine doses; and 11,003 (2.8%) were unexposed to rotavirus vaccination but had received all other recommended vaccines.

There were 464 cases of type 1 diabetes in the cohort, with an incidence rate of 20 cases per 100,000 person-years in the fully exposed group, 31.2 cases per 100,000 person-years in the partially exposed group, and 22.4 cases per 100,000 person-years in the unexposed group.

The incidence of type 1 diabetes was not significantly different across the rotavirus vaccine–exposure groups. The researchers reported that, compared with children unexposed to rotavirus vaccination, the adjusted hazard ratio for children fully exposed to rotavirus vaccination was 1.03 (95% confidence interval, 0.62-1.72), and for those partially exposed to the vaccination, it was 1.50 (95% CI, 0.81-2.77).

“Since licensure, rotavirus vaccination has been associated with a reduction in morbidity and mortality due to rotavirus infection in the United States and worldwide. ... Although rotavirus vaccination may not prevent type 1 diabetes, these results should provide additional reassurance to the public that rotavirus vaccination can be safely administered to infants,” they wrote.

The limited follow-up duration and relatively small proportion of patients unexposed to rotavirus vaccination are limitations of the study, the authors noted.

The Centers for Disease Control and Prevention funded the study. Several authors reported having received grants from the CDC. One author received grants from the National Institute of Diabetes and Digestive and Kidney Diseases, and another from pharmaceutical companies not involved in the study.

SOURCE: Glanz JM et al. JAMA Pediatr. 2020 Mar 9. doi: 10.1001/jamapediatrics.2019.6324.

A high-risk profile from the urinary biomarker CKD273 was significantly associated with an increased risk of microalbuminuria in patients with diabetes, according to findings from a multicenter European trial.

“Although microalbuminuria is the earliest clinical index of renal damage, histological changes might already be advanced by the time it is detectable. Thus, earlier identification of at-risk individuals is essential to guide targeted preventive therapy,” wrote Nete Tofte, MD, of the Steno Diabetes Center in Copenhagen, and colleagues.

“Increases in urinary albumin to microalbuminuria levels, or higher, are not only strongly associated with progression to more serious clinical endpoints, such as clinically significant loss of renal function and eventually, end-stage kidney disease, but also with an increased risk of cardiovascular complications,” the researchers noted in the Lancet Diabetes & Endocrinology.

They identified 1,775 adults with type 2 diabetes who had normal albumin levels and preserved renal function at baseline. The average age of the patients was 62 years, and 62% were men. The participants underwent urine proteomics testing via capillary electrophoresis–mass spectrometry analysis to generate a renal risk profile based on 273 peptides (CKD273). On the basis of their CKD273 scores, 216 patients (12%) were designated to the high-risk group, and 1,556 (88%) to the low-risk group.

Over a median follow-up of 2.5 years, 61 patients (28%) in the high-risk group progressed to microalbuminuria (the primary endpoint), compared with 139 patients (9%) in the low-risk group.

Of the original 216 high-risk patients, 209 were randomized to treatment with 25 mg of the mineralocorticoid receptor antagonist spironolactone (102 patients) or placebo (107) to examine whether spironolactone would stall progression to microalbuminuria.

The researchers found, however, that spironolactone did not prevent progression to microalbuminuria. In all, 26 of the 102 patients (25%) patients in the spironolactone group developed microalbuminuria, and 35 of the 107 patients (33%) in the placebo group developed it (hazard ratio, 0.81; 95% confidence interval, 0.49-1.34; P = .41).

The total number of adverse events was not significantly different between the spironolactone and placebo groups (312 vs. 321, respectively), although more patients in the spironolactone group experienced adverse events that led to drug discontinuation (25 vs. 9, respectively).

The study findings were limited by several factors, including the use of a single urine sample for risk stratification; the lower-than-expected number of high-risk patients; not testing spironolactone in the low-risk group; and the fact that microalbuminuria, although an accepted surrogate for diabetic kidney disease, is not approved as such by regulatory agencies, the researchers noted. However, the results were strengthened by the large study population and prospective design, as well as the additional register-based follow-up that is planned when possible.

In an accompanying editorial, Susanne B. Nicholas, MD, of the University of California, Los Angeles, reiterated that microalbuminuria cannot be used to track responses to therapy even if it is an acceptable indicator of potential renal damage.

“In fact, regression from microalbuminuria to normoalbuminuria is more likely than progression toward overt proteinuria, [which exposes] a need for a more dependable biomarker for diabetic kidney disease,” she wrote.

However, Dr. Nicholas supported the potential of proteomics as a tool “that could bridge the gap between discovery of diabetic kidney disease – possibly providing a panel, rather than a single or few urinary indicators of structural changes that predate microalbuminuria – and response to therapy, given the promise of targeted therapies for this complex disease.” Additional research into patient selection, comparators to verify findings, and cost containment is needed before proteomics can become part of routine care, she added.

The study was supported by the European Union Seventh Framework Programme. Dr. Tofte had no financial conflicts to disclose. Several other authors disclosed relationships with multiple companies, including Amgen, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Sanofi. Dr. Nicholas had no financial conflicts to disclose.

SOURCES: Tofte N et al. Lancet Diabetes Endocrinol. 2020 Mar 2. doi: 10.1016/S2213-8587(20)30026-7; Nicholas SB. Lancet Diabetes Endocrinol. 2020 Mar 2. doi: 10.1016/S2213-8587(20)30067-X.

A high-risk profile from the urinary biomarker CKD273 was significantly associated with an increased risk of microalbuminuria in patients with diabetes, according to findings from a multicenter European trial.

“Although microalbuminuria is the earliest clinical index of renal damage, histological changes might already be advanced by the time it is detectable. Thus, earlier identification of at-risk individuals is essential to guide targeted preventive therapy,” wrote Nete Tofte, MD, of the Steno Diabetes Center in Copenhagen, and colleagues.

“Increases in urinary albumin to microalbuminuria levels, or higher, are not only strongly associated with progression to more serious clinical endpoints, such as clinically significant loss of renal function and eventually, end-stage kidney disease, but also with an increased risk of cardiovascular complications,” the researchers noted in the Lancet Diabetes & Endocrinology.

They identified 1,775 adults with type 2 diabetes who had normal albumin levels and preserved renal function at baseline. The average age of the patients was 62 years, and 62% were men. The participants underwent urine proteomics testing via capillary electrophoresis–mass spectrometry analysis to generate a renal risk profile based on 273 peptides (CKD273). On the basis of their CKD273 scores, 216 patients (12%) were designated to the high-risk group, and 1,556 (88%) to the low-risk group.

Over a median follow-up of 2.5 years, 61 patients (28%) in the high-risk group progressed to microalbuminuria (the primary endpoint), compared with 139 patients (9%) in the low-risk group.

Of the original 216 high-risk patients, 209 were randomized to treatment with 25 mg of the mineralocorticoid receptor antagonist spironolactone (102 patients) or placebo (107) to examine whether spironolactone would stall progression to microalbuminuria.

The researchers found, however, that spironolactone did not prevent progression to microalbuminuria. In all, 26 of the 102 patients (25%) patients in the spironolactone group developed microalbuminuria, and 35 of the 107 patients (33%) in the placebo group developed it (hazard ratio, 0.81; 95% confidence interval, 0.49-1.34; P = .41).

The total number of adverse events was not significantly different between the spironolactone and placebo groups (312 vs. 321, respectively), although more patients in the spironolactone group experienced adverse events that led to drug discontinuation (25 vs. 9, respectively).

The study findings were limited by several factors, including the use of a single urine sample for risk stratification; the lower-than-expected number of high-risk patients; not testing spironolactone in the low-risk group; and the fact that microalbuminuria, although an accepted surrogate for diabetic kidney disease, is not approved as such by regulatory agencies, the researchers noted. However, the results were strengthened by the large study population and prospective design, as well as the additional register-based follow-up that is planned when possible.

In an accompanying editorial, Susanne B. Nicholas, MD, of the University of California, Los Angeles, reiterated that microalbuminuria cannot be used to track responses to therapy even if it is an acceptable indicator of potential renal damage.

“In fact, regression from microalbuminuria to normoalbuminuria is more likely than progression toward overt proteinuria, [which exposes] a need for a more dependable biomarker for diabetic kidney disease,” she wrote.

However, Dr. Nicholas supported the potential of proteomics as a tool “that could bridge the gap between discovery of diabetic kidney disease – possibly providing a panel, rather than a single or few urinary indicators of structural changes that predate microalbuminuria – and response to therapy, given the promise of targeted therapies for this complex disease.” Additional research into patient selection, comparators to verify findings, and cost containment is needed before proteomics can become part of routine care, she added.

The study was supported by the European Union Seventh Framework Programme. Dr. Tofte had no financial conflicts to disclose. Several other authors disclosed relationships with multiple companies, including Amgen, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Sanofi. Dr. Nicholas had no financial conflicts to disclose.

SOURCES: Tofte N et al. Lancet Diabetes Endocrinol. 2020 Mar 2. doi: 10.1016/S2213-8587(20)30026-7; Nicholas SB. Lancet Diabetes Endocrinol. 2020 Mar 2. doi: 10.1016/S2213-8587(20)30067-X.

A high-risk profile from the urinary biomarker CKD273 was significantly associated with an increased risk of microalbuminuria in patients with diabetes, according to findings from a multicenter European trial.

“Although microalbuminuria is the earliest clinical index of renal damage, histological changes might already be advanced by the time it is detectable. Thus, earlier identification of at-risk individuals is essential to guide targeted preventive therapy,” wrote Nete Tofte, MD, of the Steno Diabetes Center in Copenhagen, and colleagues.

“Increases in urinary albumin to microalbuminuria levels, or higher, are not only strongly associated with progression to more serious clinical endpoints, such as clinically significant loss of renal function and eventually, end-stage kidney disease, but also with an increased risk of cardiovascular complications,” the researchers noted in the Lancet Diabetes & Endocrinology.

They identified 1,775 adults with type 2 diabetes who had normal albumin levels and preserved renal function at baseline. The average age of the patients was 62 years, and 62% were men. The participants underwent urine proteomics testing via capillary electrophoresis–mass spectrometry analysis to generate a renal risk profile based on 273 peptides (CKD273). On the basis of their CKD273 scores, 216 patients (12%) were designated to the high-risk group, and 1,556 (88%) to the low-risk group.

Over a median follow-up of 2.5 years, 61 patients (28%) in the high-risk group progressed to microalbuminuria (the primary endpoint), compared with 139 patients (9%) in the low-risk group.

Of the original 216 high-risk patients, 209 were randomized to treatment with 25 mg of the mineralocorticoid receptor antagonist spironolactone (102 patients) or placebo (107) to examine whether spironolactone would stall progression to microalbuminuria.

The researchers found, however, that spironolactone did not prevent progression to microalbuminuria. In all, 26 of the 102 patients (25%) patients in the spironolactone group developed microalbuminuria, and 35 of the 107 patients (33%) in the placebo group developed it (hazard ratio, 0.81; 95% confidence interval, 0.49-1.34; P = .41).

The total number of adverse events was not significantly different between the spironolactone and placebo groups (312 vs. 321, respectively), although more patients in the spironolactone group experienced adverse events that led to drug discontinuation (25 vs. 9, respectively).

The study findings were limited by several factors, including the use of a single urine sample for risk stratification; the lower-than-expected number of high-risk patients; not testing spironolactone in the low-risk group; and the fact that microalbuminuria, although an accepted surrogate for diabetic kidney disease, is not approved as such by regulatory agencies, the researchers noted. However, the results were strengthened by the large study population and prospective design, as well as the additional register-based follow-up that is planned when possible.

In an accompanying editorial, Susanne B. Nicholas, MD, of the University of California, Los Angeles, reiterated that microalbuminuria cannot be used to track responses to therapy even if it is an acceptable indicator of potential renal damage.

“In fact, regression from microalbuminuria to normoalbuminuria is more likely than progression toward overt proteinuria, [which exposes] a need for a more dependable biomarker for diabetic kidney disease,” she wrote.

However, Dr. Nicholas supported the potential of proteomics as a tool “that could bridge the gap between discovery of diabetic kidney disease – possibly providing a panel, rather than a single or few urinary indicators of structural changes that predate microalbuminuria – and response to therapy, given the promise of targeted therapies for this complex disease.” Additional research into patient selection, comparators to verify findings, and cost containment is needed before proteomics can become part of routine care, she added.

The study was supported by the European Union Seventh Framework Programme. Dr. Tofte had no financial conflicts to disclose. Several other authors disclosed relationships with multiple companies, including Amgen, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, and Sanofi. Dr. Nicholas had no financial conflicts to disclose.

SOURCES: Tofte N et al. Lancet Diabetes Endocrinol. 2020 Mar 2. doi: 10.1016/S2213-8587(20)30026-7; Nicholas SB. Lancet Diabetes Endocrinol. 2020 Mar 2. doi: 10.1016/S2213-8587(20)30067-X.