MDedge Neurology

We live in historic times. A worldwide pandemic is surging in the United States, with millions infected and the world’s highest death rate. Many of our hospitals are overwhelmed. Schools have been closed for months. Businesses are struggling, and unemployment is at record levels. The murder of George Floyd unleashed an outpouring of grief and rage over police brutality and structural racism.

Thinkstock

The value of knowing about these risk factors would seem self-evident; it would inform a patient’s health care from screening for cancer or heart disease, referral for mild depressive symptoms, and counseling about alcohol consumption. But this research did not lead to the establishment of routine screening for childhood adversity in primary care practices. There are multiple reasons for this, including growing pressure on physician time and discomfort with starting conversations about potentially traumatic material. But perhaps the greatest obstacle has been uncertainty about what to offer patients who screened in. What is the treatment for a high ACE score?

Even without treatments, we have learned much about childhood adversity since Dr. Anda and Dr. Felitti published their landmark study. Other more chronic adverse childhood experiences also contribute to adult health risk, such as poverty, homelessness, discrimination, community violence, parental chronic illness, or disability or placement in foster care. Having a high ACE score does not only affect health in adulthood. Children with an ACE score of 4 are 2 times as likely to have asthma^2,3 and allergies³, 2 times as likely to be obese⁴, 3 times as likely to have headaches³ and dental problems^5,6, 4 times as likely to have depression^7,8, 5 times as likely to have ADHD^8,9, 7 times as likely to have high rates of school absenteeism³ and aggression¹⁰, and over 30 times as likely to have learning or behavioral problems at school⁴. There is a growing body of knowledge about how chronic, severe stress in childhood affects can lead to pathological alterations in neuroendocrine and immune function. But this has not led to any concrete treatments that may be preventive or reparative.

Movement toward expanding screening nonetheless has accelerated. In California, Nadine Burke-Harris, MD, a pediatrician who studied ACEs and children’s health was named the state’s first Surgeon General in 2019 and spearheaded an effort to make screening for ACEs easier. Starting in 2020, MediCal will pay for annual screenings, and the state is offering training and resources on how to screen and what to do with the information to help patients and families.

The coronavirus pandemic has only highlighted the risks of childhood adversity. The burden of infection and mortality has been borne disproportionately by people of color and those with multiple chronic medical conditions (obesity, cardiovascular disease, diabetes, etc.). While viruses do not discriminate, they are more likely to infect those with higher risk of exposure and to kill those who are physiologically vulnerable.

And the pandemic increases the risk for adversity for today’s children and families. When children cannot attend school, financially vulnerable parents may have to choose between supervising them or feeding them. Families who suddenly are all in a small apartment together without school or other outside supports may be at higher risk for domestic violence and child abuse. Unemployment and financial uncertainty will increase the rates of substance abuse and depression amongst parents. And the serious illness or death of a parent will be a more common event for children in the year ahead. One of these risk factors may increase the likelihood of others.

Beyond the obvious need for substantial policy changes focused on housing, education, and health care, there are immediate and concrete strategies that can build resilience in children and their families. And resilience can build on itself, as children face subsequent challenges with the support of caring connected adults.

The critical first step is asking. Then listen calmly and supportively, normalizing for parents and children how common these experiences are. Explain how they affect health and well-being. Explain that adversity and its consequences are not their fault. Then educate them about what is in their control: the skills they can practice to buffer against the consequences of adversity and build resilience. They sound simple, but still require effort and work. And the pandemic has created some difficulty (social distancing) and opportunity (more family time, fewer school demands).
 

Sleep

Help parents establish and protect consistent, restful sleep for their children. They can set a consistent bedtime and a calm routine, with screens all off at least 30 minutes before sleep and reading before sleep. Restful sleep is physiologically and psychologically protective to everyone in a family.

Movement

Beyond directly improving physical health, establishing habits of exercise – especially outside – every day can effectively manage ongoing stress, build skills of self-regulation, and help with sleep.

Find out what parents and their children like to do together (walking the dog, shooting hoops, even dancing) and help them devise ways to create family routines around exercise.
 

Nutrition

Food should be a source of pleasure, but stress can make food into a source of comfort or escape. Help parents to create realistic ways to consistently offer healthy family meals and discourage unhealthy habits.

Even small changes like water instead of soda can help, and there are nutritional and emotional benefits to eating a healthy breakfast or dinner together as a family.
 

Connections

Nourishing social connections are protective. Help parents think about protecting time to spend with their children for talking, playing games, or even singing.

They should support their children’s connections to other caring adults, through community organizations (church, community centers, or sports), and they should know who their children’s reliable friends are. Parents will benefit from these supports for themselves, which in turn will benefit the full family.
 

Self-awareness

Activities that cultivate mindfulness are protective. Parents can simply ask how their children are feeling, physically or emotionally, and be able to bear it when it is uncomfortable. Work towards nonjudgmental awareness of how they are feeling. Learning what is relaxing or recharging for them (exercise, music, a hot bath, a good book, time with a friend) will protect against defaulting into maladaptive coping such as escape, numbing, or avoidance.

Of course, if you learn about symptoms that suggest PTSD, depression, or addiction, you should help your patient connect with effective treatment. The difficulty of referring to a mental health provider does not mean you should not try and bring as many people onto the team and into the orbit of the child and family at risk. It may be easier to access some therapy given the new availability of telemedicine visits across many more systems of care. Although the heaviest burdens of adversity are not being borne equally, the fact that adversity is currently a shared experience makes this a moment of promise.

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Dr. Swick and Dr. Jellinek had no relevant financial disclosures. Email them at [email protected].

References
1. Am J Prev Med. 1998 May;14(4):245-58.
2. Ann Allergy Asthma Immunol. 2015;114: 379-84.
3. BMC Public Health. 2018. doi: 10.1186/s12889-018-5699-8.
4. Child Abuse Negl. 2011 Jun;35(6):408-13.
5. Community Dent Oral Epidemiol. 2015;43:193-9.
6. Community Dent Oral Epidemiol. 2018 Oct;46(5): 442-8.
7. Pediatrics 2016 Apr. doi: 10.1542/peds.2015-4016.
8. Matern Child Health J. 2016 Apr. doi: 10.1007/s10995-015-1915-7.
9. Acad Pediatr. 2017 May-Jun. doi: 10.1016/j.acap.2016.08.013.
10. Pediatrics. 2010 Apr. doi: 10.1542/peds.2009-0597.
 

This article was updated 7/27/2020.

We live in historic times. A worldwide pandemic is surging in the United States, with millions infected and the world’s highest death rate. Many of our hospitals are overwhelmed. Schools have been closed for months. Businesses are struggling, and unemployment is at record levels. The murder of George Floyd unleashed an outpouring of grief and rage over police brutality and structural racism.

Thinkstock

The value of knowing about these risk factors would seem self-evident; it would inform a patient’s health care from screening for cancer or heart disease, referral for mild depressive symptoms, and counseling about alcohol consumption. But this research did not lead to the establishment of routine screening for childhood adversity in primary care practices. There are multiple reasons for this, including growing pressure on physician time and discomfort with starting conversations about potentially traumatic material. But perhaps the greatest obstacle has been uncertainty about what to offer patients who screened in. What is the treatment for a high ACE score?

Even without treatments, we have learned much about childhood adversity since Dr. Anda and Dr. Felitti published their landmark study. Other more chronic adverse childhood experiences also contribute to adult health risk, such as poverty, homelessness, discrimination, community violence, parental chronic illness, or disability or placement in foster care. Having a high ACE score does not only affect health in adulthood. Children with an ACE score of 4 are 2 times as likely to have asthma^2,3 and allergies³, 2 times as likely to be obese⁴, 3 times as likely to have headaches³ and dental problems^5,6, 4 times as likely to have depression^7,8, 5 times as likely to have ADHD^8,9, 7 times as likely to have high rates of school absenteeism³ and aggression¹⁰, and over 30 times as likely to have learning or behavioral problems at school⁴. There is a growing body of knowledge about how chronic, severe stress in childhood affects can lead to pathological alterations in neuroendocrine and immune function. But this has not led to any concrete treatments that may be preventive or reparative.

Movement toward expanding screening nonetheless has accelerated. In California, Nadine Burke-Harris, MD, a pediatrician who studied ACEs and children’s health was named the state’s first Surgeon General in 2019 and spearheaded an effort to make screening for ACEs easier. Starting in 2020, MediCal will pay for annual screenings, and the state is offering training and resources on how to screen and what to do with the information to help patients and families.

The coronavirus pandemic has only highlighted the risks of childhood adversity. The burden of infection and mortality has been borne disproportionately by people of color and those with multiple chronic medical conditions (obesity, cardiovascular disease, diabetes, etc.). While viruses do not discriminate, they are more likely to infect those with higher risk of exposure and to kill those who are physiologically vulnerable.

And the pandemic increases the risk for adversity for today’s children and families. When children cannot attend school, financially vulnerable parents may have to choose between supervising them or feeding them. Families who suddenly are all in a small apartment together without school or other outside supports may be at higher risk for domestic violence and child abuse. Unemployment and financial uncertainty will increase the rates of substance abuse and depression amongst parents. And the serious illness or death of a parent will be a more common event for children in the year ahead. One of these risk factors may increase the likelihood of others.

Beyond the obvious need for substantial policy changes focused on housing, education, and health care, there are immediate and concrete strategies that can build resilience in children and their families. And resilience can build on itself, as children face subsequent challenges with the support of caring connected adults.

The critical first step is asking. Then listen calmly and supportively, normalizing for parents and children how common these experiences are. Explain how they affect health and well-being. Explain that adversity and its consequences are not their fault. Then educate them about what is in their control: the skills they can practice to buffer against the consequences of adversity and build resilience. They sound simple, but still require effort and work. And the pandemic has created some difficulty (social distancing) and opportunity (more family time, fewer school demands).
 

Sleep

Help parents establish and protect consistent, restful sleep for their children. They can set a consistent bedtime and a calm routine, with screens all off at least 30 minutes before sleep and reading before sleep. Restful sleep is physiologically and psychologically protective to everyone in a family.

Movement

Beyond directly improving physical health, establishing habits of exercise – especially outside – every day can effectively manage ongoing stress, build skills of self-regulation, and help with sleep.

Find out what parents and their children like to do together (walking the dog, shooting hoops, even dancing) and help them devise ways to create family routines around exercise.
 

Nutrition

Food should be a source of pleasure, but stress can make food into a source of comfort or escape. Help parents to create realistic ways to consistently offer healthy family meals and discourage unhealthy habits.

Even small changes like water instead of soda can help, and there are nutritional and emotional benefits to eating a healthy breakfast or dinner together as a family.
 

Connections

Nourishing social connections are protective. Help parents think about protecting time to spend with their children for talking, playing games, or even singing.

They should support their children’s connections to other caring adults, through community organizations (church, community centers, or sports), and they should know who their children’s reliable friends are. Parents will benefit from these supports for themselves, which in turn will benefit the full family.
 

Self-awareness

Activities that cultivate mindfulness are protective. Parents can simply ask how their children are feeling, physically or emotionally, and be able to bear it when it is uncomfortable. Work towards nonjudgmental awareness of how they are feeling. Learning what is relaxing or recharging for them (exercise, music, a hot bath, a good book, time with a friend) will protect against defaulting into maladaptive coping such as escape, numbing, or avoidance.

Of course, if you learn about symptoms that suggest PTSD, depression, or addiction, you should help your patient connect with effective treatment. The difficulty of referring to a mental health provider does not mean you should not try and bring as many people onto the team and into the orbit of the child and family at risk. It may be easier to access some therapy given the new availability of telemedicine visits across many more systems of care. Although the heaviest burdens of adversity are not being borne equally, the fact that adversity is currently a shared experience makes this a moment of promise.

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Dr. Swick and Dr. Jellinek had no relevant financial disclosures. Email them at [email protected].

References
1. Am J Prev Med. 1998 May;14(4):245-58.
2. Ann Allergy Asthma Immunol. 2015;114: 379-84.
3. BMC Public Health. 2018. doi: 10.1186/s12889-018-5699-8.
4. Child Abuse Negl. 2011 Jun;35(6):408-13.
5. Community Dent Oral Epidemiol. 2015;43:193-9.
6. Community Dent Oral Epidemiol. 2018 Oct;46(5): 442-8.
7. Pediatrics 2016 Apr. doi: 10.1542/peds.2015-4016.
8. Matern Child Health J. 2016 Apr. doi: 10.1007/s10995-015-1915-7.
9. Acad Pediatr. 2017 May-Jun. doi: 10.1016/j.acap.2016.08.013.
10. Pediatrics. 2010 Apr. doi: 10.1542/peds.2009-0597.
 

This article was updated 7/27/2020.

We live in historic times. A worldwide pandemic is surging in the United States, with millions infected and the world’s highest death rate. Many of our hospitals are overwhelmed. Schools have been closed for months. Businesses are struggling, and unemployment is at record levels. The murder of George Floyd unleashed an outpouring of grief and rage over police brutality and structural racism.

Thinkstock

The value of knowing about these risk factors would seem self-evident; it would inform a patient’s health care from screening for cancer or heart disease, referral for mild depressive symptoms, and counseling about alcohol consumption. But this research did not lead to the establishment of routine screening for childhood adversity in primary care practices. There are multiple reasons for this, including growing pressure on physician time and discomfort with starting conversations about potentially traumatic material. But perhaps the greatest obstacle has been uncertainty about what to offer patients who screened in. What is the treatment for a high ACE score?

Even without treatments, we have learned much about childhood adversity since Dr. Anda and Dr. Felitti published their landmark study. Other more chronic adverse childhood experiences also contribute to adult health risk, such as poverty, homelessness, discrimination, community violence, parental chronic illness, or disability or placement in foster care. Having a high ACE score does not only affect health in adulthood. Children with an ACE score of 4 are 2 times as likely to have asthma^2,3 and allergies³, 2 times as likely to be obese⁴, 3 times as likely to have headaches³ and dental problems^5,6, 4 times as likely to have depression^7,8, 5 times as likely to have ADHD^8,9, 7 times as likely to have high rates of school absenteeism³ and aggression¹⁰, and over 30 times as likely to have learning or behavioral problems at school⁴. There is a growing body of knowledge about how chronic, severe stress in childhood affects can lead to pathological alterations in neuroendocrine and immune function. But this has not led to any concrete treatments that may be preventive or reparative.

Movement toward expanding screening nonetheless has accelerated. In California, Nadine Burke-Harris, MD, a pediatrician who studied ACEs and children’s health was named the state’s first Surgeon General in 2019 and spearheaded an effort to make screening for ACEs easier. Starting in 2020, MediCal will pay for annual screenings, and the state is offering training and resources on how to screen and what to do with the information to help patients and families.

The coronavirus pandemic has only highlighted the risks of childhood adversity. The burden of infection and mortality has been borne disproportionately by people of color and those with multiple chronic medical conditions (obesity, cardiovascular disease, diabetes, etc.). While viruses do not discriminate, they are more likely to infect those with higher risk of exposure and to kill those who are physiologically vulnerable.

And the pandemic increases the risk for adversity for today’s children and families. When children cannot attend school, financially vulnerable parents may have to choose between supervising them or feeding them. Families who suddenly are all in a small apartment together without school or other outside supports may be at higher risk for domestic violence and child abuse. Unemployment and financial uncertainty will increase the rates of substance abuse and depression amongst parents. And the serious illness or death of a parent will be a more common event for children in the year ahead. One of these risk factors may increase the likelihood of others.

Beyond the obvious need for substantial policy changes focused on housing, education, and health care, there are immediate and concrete strategies that can build resilience in children and their families. And resilience can build on itself, as children face subsequent challenges with the support of caring connected adults.

The critical first step is asking. Then listen calmly and supportively, normalizing for parents and children how common these experiences are. Explain how they affect health and well-being. Explain that adversity and its consequences are not their fault. Then educate them about what is in their control: the skills they can practice to buffer against the consequences of adversity and build resilience. They sound simple, but still require effort and work. And the pandemic has created some difficulty (social distancing) and opportunity (more family time, fewer school demands).
 

Sleep

Help parents establish and protect consistent, restful sleep for their children. They can set a consistent bedtime and a calm routine, with screens all off at least 30 minutes before sleep and reading before sleep. Restful sleep is physiologically and psychologically protective to everyone in a family.

Movement

Beyond directly improving physical health, establishing habits of exercise – especially outside – every day can effectively manage ongoing stress, build skills of self-regulation, and help with sleep.

Find out what parents and their children like to do together (walking the dog, shooting hoops, even dancing) and help them devise ways to create family routines around exercise.
 

Nutrition

Food should be a source of pleasure, but stress can make food into a source of comfort or escape. Help parents to create realistic ways to consistently offer healthy family meals and discourage unhealthy habits.

Even small changes like water instead of soda can help, and there are nutritional and emotional benefits to eating a healthy breakfast or dinner together as a family.
 

Connections

Nourishing social connections are protective. Help parents think about protecting time to spend with their children for talking, playing games, or even singing.

They should support their children’s connections to other caring adults, through community organizations (church, community centers, or sports), and they should know who their children’s reliable friends are. Parents will benefit from these supports for themselves, which in turn will benefit the full family.
 

Self-awareness

Activities that cultivate mindfulness are protective. Parents can simply ask how their children are feeling, physically or emotionally, and be able to bear it when it is uncomfortable. Work towards nonjudgmental awareness of how they are feeling. Learning what is relaxing or recharging for them (exercise, music, a hot bath, a good book, time with a friend) will protect against defaulting into maladaptive coping such as escape, numbing, or avoidance.

Of course, if you learn about symptoms that suggest PTSD, depression, or addiction, you should help your patient connect with effective treatment. The difficulty of referring to a mental health provider does not mean you should not try and bring as many people onto the team and into the orbit of the child and family at risk. It may be easier to access some therapy given the new availability of telemedicine visits across many more systems of care. Although the heaviest burdens of adversity are not being borne equally, the fact that adversity is currently a shared experience makes this a moment of promise.

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Dr. Swick and Dr. Jellinek had no relevant financial disclosures. Email them at [email protected].

References
1. Am J Prev Med. 1998 May;14(4):245-58.
2. Ann Allergy Asthma Immunol. 2015;114: 379-84.
3. BMC Public Health. 2018. doi: 10.1186/s12889-018-5699-8.
4. Child Abuse Negl. 2011 Jun;35(6):408-13.
5. Community Dent Oral Epidemiol. 2015;43:193-9.
6. Community Dent Oral Epidemiol. 2018 Oct;46(5): 442-8.
7. Pediatrics 2016 Apr. doi: 10.1542/peds.2015-4016.
8. Matern Child Health J. 2016 Apr. doi: 10.1007/s10995-015-1915-7.
9. Acad Pediatr. 2017 May-Jun. doi: 10.1016/j.acap.2016.08.013.
10. Pediatrics. 2010 Apr. doi: 10.1542/peds.2009-0597.
 

This article was updated 7/27/2020.

Given an opportunity to see physicians’ notes about their visits, patients mostly understand and agree with them, a survey shows.

Overall, 93% of respondents said the notes accurately described the visit; only 6% reported that something important was missing, write Suzanne G. Leveille, RN, PhD, of the University of Massachusetts, Boston, and colleagues in the Journal of General Internal Medicine.

“I think it’s wonderful news,” commented Howard Levy, MD, PhD, who spearheaded the implementation of open notes at Johns Hopkins University, Baltimore. “I’m thrilled with this report.”

Currently, 50 million Americans have access to their notes, the researchers report. Starting Nov. 2, 2020, the 21st Century Cures Act will require all US physicians to provide this access.

The regulation follows a movement to involve patients more actively in their care. Previous research has shown that access to visit notes improves patients’ feelings of control, helps them adhere to their medication regimens, and enables them to better understand their care plans.

Although physicians often feel that giving patients access to notes will lead to unnecessary conversations that will waste their time, previous studies have not borne that out. “Most clinical providers don’t notice a thing,” Levy told Medscape Medical News. “There was no change in the volume of work.”

Leveille and colleagues wanted to know how patients viewed the clarity, accuracy, and completeness of the notes they were reading and whether they had suggestions for improvements.

They surveyed all 136,815 adult outpatients affiliated with Beth Israel Deaconess Medical Center in Boston, Massachusetts; the University of Washington Medicine, in Seattle; and the Geisinger Health System, based in Danville, Pennsylvania. These systems all offer patients access to physicians’ notes.

The researchers asked the patients to recall one note written by a doctor, nurse practitioner, physician assistant, or mental health professional.

They received responses from 21,664 patients who had read at least one note. Of these, two thirds were women, three quarters were aged 45 years or older, and 85% were White.

Seventy-two percent had completed college. Although 85% reported being in good or excellent health, more of the respondents than nonrespondents had chronic health problems.

Ninety-seven percent of those with college educations understood their notes, compared with 92% of those who had not completed college, a finding that conflicted with the researchers’ expectations. “Good gracious, that’s wonderful,” Levy said. “In medicine we almost never get a 92% success rate in anything we do.”

Of the patients in fair or poor health, 88.6% said the note was accurate, compared with 94.4% of those in better health. Those in worse health were also more likely to say something important was missing.

When patients didn’t understand something, 35% searched the Internet, 27% asked a clinician, 7% asked a friend or family member, and 27% didn’t get help. (The researchers did not account for the other 4%.)

Of those patients whose note was written by a physician, 95% reported that the note accurately described the visit, compared with 92% of those whose note was written by a nurse practitioner and 90% of those whose note was written by a physician assistant.

Of patients reporting on a primary care note, 97% understood the note, compared with 94% of those reporting on a note from a visit to a specialist.

Ninety-three percent of those who understood their note were likely to recommend their clinician, compared with 77% of those who didn’t completely understand their note.

Asked how the notes could be improved, 3,812 people responded with comments of at least five words. These responses were included in the analysis.

Most commonly, patients wanted new information to be prominently featured at the top of the note, with clear instructions about next steps, referrals, and explanations of test results.

Often, they complained of old information or templates that felt impersonal. They stumbled over medical jargon and suggested links to glossaries. They bristled at such terms as “obese” and “patient denies.” Some wanted a way to comment on the notes.

Regarding the portals in which the notes were found, some patients said the notes were sometimes hard to find. Some said the notes were not posted quickly enough after the visits.

Levy said physicians should learn to write notes more succinctly, and he expects new regulations from the Centers for Medicare & Medicaid Services to encourage that. Previous regulations may have given physicians the impression that longer notes would allow them to bill at higher rates, he said. “The change in billing requirements will make it easier for healthcare providers to feel comfortable that they don’t have to restate information that had already been stated,” he said.

On the other hand, physicians should continue to use medical terminology, he said. “At times we use jargon, because it conveys rich, dense information in a few words,” he said. “That’s something that we should not have to give up.” Patients can research terms they don’t understand, he said.

Family physician Doug Iliff, MD, thinks it’s about time that his colleagues share their notes. He’s been doing it since he opened his solo practice in Topeka, Kansas, in 1984.

He still does it the way he always did, with carbonless copy paper. After each visit, he simply tears off the copy and hands it to the patient.

“It makes them know we’re on the same page,” he told Medscape Medical News. “It gives them confidence that I’m telling them what I really think.”

He has one comment on the work of Leveille and her colleagues. “Why are they studying this? Isn’t it obvious that it’s a good thing?”

The study was funded by the Robert Wood Johnson Foundation, the Gordon and Betty Moore Foundation, the Peterson Center on Healthcare, and the Cambia Health Foundation. The study authors, Iliff, and Levy have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Given an opportunity to see physicians’ notes about their visits, patients mostly understand and agree with them, a survey shows.

Overall, 93% of respondents said the notes accurately described the visit; only 6% reported that something important was missing, write Suzanne G. Leveille, RN, PhD, of the University of Massachusetts, Boston, and colleagues in the Journal of General Internal Medicine.

“I think it’s wonderful news,” commented Howard Levy, MD, PhD, who spearheaded the implementation of open notes at Johns Hopkins University, Baltimore. “I’m thrilled with this report.”

Currently, 50 million Americans have access to their notes, the researchers report. Starting Nov. 2, 2020, the 21st Century Cures Act will require all US physicians to provide this access.

The regulation follows a movement to involve patients more actively in their care. Previous research has shown that access to visit notes improves patients’ feelings of control, helps them adhere to their medication regimens, and enables them to better understand their care plans.

Although physicians often feel that giving patients access to notes will lead to unnecessary conversations that will waste their time, previous studies have not borne that out. “Most clinical providers don’t notice a thing,” Levy told Medscape Medical News. “There was no change in the volume of work.”

Leveille and colleagues wanted to know how patients viewed the clarity, accuracy, and completeness of the notes they were reading and whether they had suggestions for improvements.

They surveyed all 136,815 adult outpatients affiliated with Beth Israel Deaconess Medical Center in Boston, Massachusetts; the University of Washington Medicine, in Seattle; and the Geisinger Health System, based in Danville, Pennsylvania. These systems all offer patients access to physicians’ notes.

The researchers asked the patients to recall one note written by a doctor, nurse practitioner, physician assistant, or mental health professional.

They received responses from 21,664 patients who had read at least one note. Of these, two thirds were women, three quarters were aged 45 years or older, and 85% were White.

Seventy-two percent had completed college. Although 85% reported being in good or excellent health, more of the respondents than nonrespondents had chronic health problems.

Ninety-seven percent of those with college educations understood their notes, compared with 92% of those who had not completed college, a finding that conflicted with the researchers’ expectations. “Good gracious, that’s wonderful,” Levy said. “In medicine we almost never get a 92% success rate in anything we do.”

Of the patients in fair or poor health, 88.6% said the note was accurate, compared with 94.4% of those in better health. Those in worse health were also more likely to say something important was missing.

When patients didn’t understand something, 35% searched the Internet, 27% asked a clinician, 7% asked a friend or family member, and 27% didn’t get help. (The researchers did not account for the other 4%.)

Of those patients whose note was written by a physician, 95% reported that the note accurately described the visit, compared with 92% of those whose note was written by a nurse practitioner and 90% of those whose note was written by a physician assistant.

Of patients reporting on a primary care note, 97% understood the note, compared with 94% of those reporting on a note from a visit to a specialist.

Ninety-three percent of those who understood their note were likely to recommend their clinician, compared with 77% of those who didn’t completely understand their note.

Asked how the notes could be improved, 3,812 people responded with comments of at least five words. These responses were included in the analysis.

Most commonly, patients wanted new information to be prominently featured at the top of the note, with clear instructions about next steps, referrals, and explanations of test results.

Often, they complained of old information or templates that felt impersonal. They stumbled over medical jargon and suggested links to glossaries. They bristled at such terms as “obese” and “patient denies.” Some wanted a way to comment on the notes.

Regarding the portals in which the notes were found, some patients said the notes were sometimes hard to find. Some said the notes were not posted quickly enough after the visits.

Levy said physicians should learn to write notes more succinctly, and he expects new regulations from the Centers for Medicare & Medicaid Services to encourage that. Previous regulations may have given physicians the impression that longer notes would allow them to bill at higher rates, he said. “The change in billing requirements will make it easier for healthcare providers to feel comfortable that they don’t have to restate information that had already been stated,” he said.

On the other hand, physicians should continue to use medical terminology, he said. “At times we use jargon, because it conveys rich, dense information in a few words,” he said. “That’s something that we should not have to give up.” Patients can research terms they don’t understand, he said.

Family physician Doug Iliff, MD, thinks it’s about time that his colleagues share their notes. He’s been doing it since he opened his solo practice in Topeka, Kansas, in 1984.

He still does it the way he always did, with carbonless copy paper. After each visit, he simply tears off the copy and hands it to the patient.

“It makes them know we’re on the same page,” he told Medscape Medical News. “It gives them confidence that I’m telling them what I really think.”

He has one comment on the work of Leveille and her colleagues. “Why are they studying this? Isn’t it obvious that it’s a good thing?”

The study was funded by the Robert Wood Johnson Foundation, the Gordon and Betty Moore Foundation, the Peterson Center on Healthcare, and the Cambia Health Foundation. The study authors, Iliff, and Levy have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Given an opportunity to see physicians’ notes about their visits, patients mostly understand and agree with them, a survey shows.

Overall, 93% of respondents said the notes accurately described the visit; only 6% reported that something important was missing, write Suzanne G. Leveille, RN, PhD, of the University of Massachusetts, Boston, and colleagues in the Journal of General Internal Medicine.

“I think it’s wonderful news,” commented Howard Levy, MD, PhD, who spearheaded the implementation of open notes at Johns Hopkins University, Baltimore. “I’m thrilled with this report.”

Currently, 50 million Americans have access to their notes, the researchers report. Starting Nov. 2, 2020, the 21st Century Cures Act will require all US physicians to provide this access.

The regulation follows a movement to involve patients more actively in their care. Previous research has shown that access to visit notes improves patients’ feelings of control, helps them adhere to their medication regimens, and enables them to better understand their care plans.

Although physicians often feel that giving patients access to notes will lead to unnecessary conversations that will waste their time, previous studies have not borne that out. “Most clinical providers don’t notice a thing,” Levy told Medscape Medical News. “There was no change in the volume of work.”

Leveille and colleagues wanted to know how patients viewed the clarity, accuracy, and completeness of the notes they were reading and whether they had suggestions for improvements.

They surveyed all 136,815 adult outpatients affiliated with Beth Israel Deaconess Medical Center in Boston, Massachusetts; the University of Washington Medicine, in Seattle; and the Geisinger Health System, based in Danville, Pennsylvania. These systems all offer patients access to physicians’ notes.

The researchers asked the patients to recall one note written by a doctor, nurse practitioner, physician assistant, or mental health professional.

They received responses from 21,664 patients who had read at least one note. Of these, two thirds were women, three quarters were aged 45 years or older, and 85% were White.

Seventy-two percent had completed college. Although 85% reported being in good or excellent health, more of the respondents than nonrespondents had chronic health problems.

Ninety-seven percent of those with college educations understood their notes, compared with 92% of those who had not completed college, a finding that conflicted with the researchers’ expectations. “Good gracious, that’s wonderful,” Levy said. “In medicine we almost never get a 92% success rate in anything we do.”

Of the patients in fair or poor health, 88.6% said the note was accurate, compared with 94.4% of those in better health. Those in worse health were also more likely to say something important was missing.

When patients didn’t understand something, 35% searched the Internet, 27% asked a clinician, 7% asked a friend or family member, and 27% didn’t get help. (The researchers did not account for the other 4%.)

Of those patients whose note was written by a physician, 95% reported that the note accurately described the visit, compared with 92% of those whose note was written by a nurse practitioner and 90% of those whose note was written by a physician assistant.

Of patients reporting on a primary care note, 97% understood the note, compared with 94% of those reporting on a note from a visit to a specialist.

Ninety-three percent of those who understood their note were likely to recommend their clinician, compared with 77% of those who didn’t completely understand their note.

Asked how the notes could be improved, 3,812 people responded with comments of at least five words. These responses were included in the analysis.

Most commonly, patients wanted new information to be prominently featured at the top of the note, with clear instructions about next steps, referrals, and explanations of test results.

Often, they complained of old information or templates that felt impersonal. They stumbled over medical jargon and suggested links to glossaries. They bristled at such terms as “obese” and “patient denies.” Some wanted a way to comment on the notes.

Regarding the portals in which the notes were found, some patients said the notes were sometimes hard to find. Some said the notes were not posted quickly enough after the visits.

Levy said physicians should learn to write notes more succinctly, and he expects new regulations from the Centers for Medicare & Medicaid Services to encourage that. Previous regulations may have given physicians the impression that longer notes would allow them to bill at higher rates, he said. “The change in billing requirements will make it easier for healthcare providers to feel comfortable that they don’t have to restate information that had already been stated,” he said.

On the other hand, physicians should continue to use medical terminology, he said. “At times we use jargon, because it conveys rich, dense information in a few words,” he said. “That’s something that we should not have to give up.” Patients can research terms they don’t understand, he said.

Family physician Doug Iliff, MD, thinks it’s about time that his colleagues share their notes. He’s been doing it since he opened his solo practice in Topeka, Kansas, in 1984.

He still does it the way he always did, with carbonless copy paper. After each visit, he simply tears off the copy and hands it to the patient.

“It makes them know we’re on the same page,” he told Medscape Medical News. “It gives them confidence that I’m telling them what I really think.”

He has one comment on the work of Leveille and her colleagues. “Why are they studying this? Isn’t it obvious that it’s a good thing?”

The study was funded by the Robert Wood Johnson Foundation, the Gordon and Betty Moore Foundation, the Peterson Center on Healthcare, and the Cambia Health Foundation. The study authors, Iliff, and Levy have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The absence of in-person school has harmed children in ways beyond loss of academic learning, according to Josh Sharfstein, MD, vice dean for public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health, Baltimore. In addition to learning, school is a place where many children receive breakfast and lunch every day, as well as support services and the benefits of being in a safe and secure environment, Dr. Sharfstein said in a press briefing sponsored by Johns Hopkins University.

However, although it is an important priority for children to return to school, “we are in the midst of a pandemic that poses real risk,” he said.

In the press briefing, several experts shared ideas and considerations for safely reopening K-12 schools in the fall of 2020.

Data from other countries where schools have reopened, notably Austria and Denmark, have been reassuring about the lack of transmission of SARS-CoV-2 among children in a school setting, said Jennifer Nuzzo, DrPH, an epidemiologist at the Johns Hopkins Center for Health Security. However, other countries where schools have reopened successfully have reported low levels of viral transmission locally, and a responsible strategy for school reopening in the United States should follow a similar plan, she said. In areas where transmission and infection rates are increasing “it may not be safe to reopen,” but in areas where rates are declining or stable, schools could potentially reopen if they follow safety measures.

Dr. Nuzzo suggested that schools should prioritize students who will benefit most from in-person learning, such as younger children and those with special needs. Considerations include protocols for handwashing and sanitation, and maintaining physical distance by creative use of outdoor classrooms (weather permitting) or other spaces within school buildings. Transportation to and from school also will be an issue to address, she noted.

None of the strategies being considered will completely eliminate risk of SARS-CoV-2 infection in school settings, so allowing parents and students to opt out and choose distance learning will be important as well, said Dr. Nuzzo. In addition, schools may need to consider alternative roles for teachers and staff who don’t feel comfortable being in contact with students and fellow staff members. “All of these things are going to be hard,” Dr. Nuzzo acknowledged. “Hard should not be a deterrent,” to reopening schools, but “we acknowledge the resources that schools will need in order to do this.”

At present, all 50 states and the District of Columbia have released some type of plan for reopening schools, said Megan Collins, MD, MPH, codirector the Johns Hopkins Consortium for School-Based Health Solutions.

Dr. Collins and colleagues have developed a school reopening tracker, which is “a national snapshot of current reopening plans that have been released,” she said. The tracker is being updated continuously as plans evolve. The eSchool+ K-12 School Reopening Tracker identifies 12 reopening categories that states could potentially address in the plans. These categories are divided into Operational and Ethics/Equity. The operational categories include:

• Core academics
• SARS-CoV-2 protection
• Before and after school programs
• School access and transportation
• Student health services
• Food and nutrition.

Ethics/equity categories include the following:

• Parent choice
• Teacher and staff choice
• Children of poverty and systemic disadvantage
• Children with special needs/English as second language/gifted and twice exceptional
• Privacy
• Engagement and transparency.

As of July 15, 2020, 16 states (Arizona, Colorado, Connecticut, Georgia, Maryland, Minnesota, New Mexico, North Carolina, North Dakota, Ohio, Rhode Island, Tennessee, Texas, Virginia, Washington, and Wisconsin) had addressed all 12 categories in their reopening plans, Dr. Collins said.

School reopening plans must take equity issues into account, said Annette Anderson, PhD, of the Johns Hopkins University School of Education.

Specifically, developing learning plans for special education students and others at the most risk for learning loss will be essential. “The digital divide has become a digital canyon” in some areas, Dr. Anderson noted, and schools need to rethink eligibility and work to provide access to devices for online learning for all students.

In addition, schools need to convince parents that schools are safe. She recommended that schools consider inviting parents and families to visit buildings in advance of reopening so they can see the safety measures, such as space between desks, cleaning stations, and other protective strategies.

The message to pediatricians and health care professionals when counseling families about returning individual children to school is to consider the risk to the child and the family directly in the context of the local plans, Dr. Sharfstein said during a question and answer session. “One school system’s plan is one school system’s plan,” he said, and added that families who are concerned about the risk should have an online option. However, “if you see a thoughtful approach” to reopening, with safety steps taken and parents informed, with protocols such as keeping small groups of children together to reduce transmission, “it is a pretty good trade-off,” and that is why the American Academy of Pediatrics currently favors children returning to school, he said.

The briefing participants had no relevant financial conflicts to disclose.

The absence of in-person school has harmed children in ways beyond loss of academic learning, according to Josh Sharfstein, MD, vice dean for public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health, Baltimore. In addition to learning, school is a place where many children receive breakfast and lunch every day, as well as support services and the benefits of being in a safe and secure environment, Dr. Sharfstein said in a press briefing sponsored by Johns Hopkins University.

However, although it is an important priority for children to return to school, “we are in the midst of a pandemic that poses real risk,” he said.

In the press briefing, several experts shared ideas and considerations for safely reopening K-12 schools in the fall of 2020.

Data from other countries where schools have reopened, notably Austria and Denmark, have been reassuring about the lack of transmission of SARS-CoV-2 among children in a school setting, said Jennifer Nuzzo, DrPH, an epidemiologist at the Johns Hopkins Center for Health Security. However, other countries where schools have reopened successfully have reported low levels of viral transmission locally, and a responsible strategy for school reopening in the United States should follow a similar plan, she said. In areas where transmission and infection rates are increasing “it may not be safe to reopen,” but in areas where rates are declining or stable, schools could potentially reopen if they follow safety measures.

Dr. Nuzzo suggested that schools should prioritize students who will benefit most from in-person learning, such as younger children and those with special needs. Considerations include protocols for handwashing and sanitation, and maintaining physical distance by creative use of outdoor classrooms (weather permitting) or other spaces within school buildings. Transportation to and from school also will be an issue to address, she noted.

None of the strategies being considered will completely eliminate risk of SARS-CoV-2 infection in school settings, so allowing parents and students to opt out and choose distance learning will be important as well, said Dr. Nuzzo. In addition, schools may need to consider alternative roles for teachers and staff who don’t feel comfortable being in contact with students and fellow staff members. “All of these things are going to be hard,” Dr. Nuzzo acknowledged. “Hard should not be a deterrent,” to reopening schools, but “we acknowledge the resources that schools will need in order to do this.”

At present, all 50 states and the District of Columbia have released some type of plan for reopening schools, said Megan Collins, MD, MPH, codirector the Johns Hopkins Consortium for School-Based Health Solutions.

Dr. Collins and colleagues have developed a school reopening tracker, which is “a national snapshot of current reopening plans that have been released,” she said. The tracker is being updated continuously as plans evolve. The eSchool+ K-12 School Reopening Tracker identifies 12 reopening categories that states could potentially address in the plans. These categories are divided into Operational and Ethics/Equity. The operational categories include:

• Core academics
• SARS-CoV-2 protection
• Before and after school programs
• School access and transportation
• Student health services
• Food and nutrition.

Ethics/equity categories include the following:

• Parent choice
• Teacher and staff choice
• Children of poverty and systemic disadvantage
• Children with special needs/English as second language/gifted and twice exceptional
• Privacy
• Engagement and transparency.

As of July 15, 2020, 16 states (Arizona, Colorado, Connecticut, Georgia, Maryland, Minnesota, New Mexico, North Carolina, North Dakota, Ohio, Rhode Island, Tennessee, Texas, Virginia, Washington, and Wisconsin) had addressed all 12 categories in their reopening plans, Dr. Collins said.

School reopening plans must take equity issues into account, said Annette Anderson, PhD, of the Johns Hopkins University School of Education.

Specifically, developing learning plans for special education students and others at the most risk for learning loss will be essential. “The digital divide has become a digital canyon” in some areas, Dr. Anderson noted, and schools need to rethink eligibility and work to provide access to devices for online learning for all students.

In addition, schools need to convince parents that schools are safe. She recommended that schools consider inviting parents and families to visit buildings in advance of reopening so they can see the safety measures, such as space between desks, cleaning stations, and other protective strategies.

The message to pediatricians and health care professionals when counseling families about returning individual children to school is to consider the risk to the child and the family directly in the context of the local plans, Dr. Sharfstein said during a question and answer session. “One school system’s plan is one school system’s plan,” he said, and added that families who are concerned about the risk should have an online option. However, “if you see a thoughtful approach” to reopening, with safety steps taken and parents informed, with protocols such as keeping small groups of children together to reduce transmission, “it is a pretty good trade-off,” and that is why the American Academy of Pediatrics currently favors children returning to school, he said.

The briefing participants had no relevant financial conflicts to disclose.

The absence of in-person school has harmed children in ways beyond loss of academic learning, according to Josh Sharfstein, MD, vice dean for public health practice and community engagement at the Johns Hopkins Bloomberg School of Public Health, Baltimore. In addition to learning, school is a place where many children receive breakfast and lunch every day, as well as support services and the benefits of being in a safe and secure environment, Dr. Sharfstein said in a press briefing sponsored by Johns Hopkins University.

However, although it is an important priority for children to return to school, “we are in the midst of a pandemic that poses real risk,” he said.

In the press briefing, several experts shared ideas and considerations for safely reopening K-12 schools in the fall of 2020.

Data from other countries where schools have reopened, notably Austria and Denmark, have been reassuring about the lack of transmission of SARS-CoV-2 among children in a school setting, said Jennifer Nuzzo, DrPH, an epidemiologist at the Johns Hopkins Center for Health Security. However, other countries where schools have reopened successfully have reported low levels of viral transmission locally, and a responsible strategy for school reopening in the United States should follow a similar plan, she said. In areas where transmission and infection rates are increasing “it may not be safe to reopen,” but in areas where rates are declining or stable, schools could potentially reopen if they follow safety measures.

Dr. Nuzzo suggested that schools should prioritize students who will benefit most from in-person learning, such as younger children and those with special needs. Considerations include protocols for handwashing and sanitation, and maintaining physical distance by creative use of outdoor classrooms (weather permitting) or other spaces within school buildings. Transportation to and from school also will be an issue to address, she noted.

None of the strategies being considered will completely eliminate risk of SARS-CoV-2 infection in school settings, so allowing parents and students to opt out and choose distance learning will be important as well, said Dr. Nuzzo. In addition, schools may need to consider alternative roles for teachers and staff who don’t feel comfortable being in contact with students and fellow staff members. “All of these things are going to be hard,” Dr. Nuzzo acknowledged. “Hard should not be a deterrent,” to reopening schools, but “we acknowledge the resources that schools will need in order to do this.”

At present, all 50 states and the District of Columbia have released some type of plan for reopening schools, said Megan Collins, MD, MPH, codirector the Johns Hopkins Consortium for School-Based Health Solutions.

Dr. Collins and colleagues have developed a school reopening tracker, which is “a national snapshot of current reopening plans that have been released,” she said. The tracker is being updated continuously as plans evolve. The eSchool+ K-12 School Reopening Tracker identifies 12 reopening categories that states could potentially address in the plans. These categories are divided into Operational and Ethics/Equity. The operational categories include:

• Core academics
• SARS-CoV-2 protection
• Before and after school programs
• School access and transportation
• Student health services
• Food and nutrition.

Ethics/equity categories include the following:

• Parent choice
• Teacher and staff choice
• Children of poverty and systemic disadvantage
• Children with special needs/English as second language/gifted and twice exceptional
• Privacy
• Engagement and transparency.

As of July 15, 2020, 16 states (Arizona, Colorado, Connecticut, Georgia, Maryland, Minnesota, New Mexico, North Carolina, North Dakota, Ohio, Rhode Island, Tennessee, Texas, Virginia, Washington, and Wisconsin) had addressed all 12 categories in their reopening plans, Dr. Collins said.

School reopening plans must take equity issues into account, said Annette Anderson, PhD, of the Johns Hopkins University School of Education.

Specifically, developing learning plans for special education students and others at the most risk for learning loss will be essential. “The digital divide has become a digital canyon” in some areas, Dr. Anderson noted, and schools need to rethink eligibility and work to provide access to devices for online learning for all students.

In addition, schools need to convince parents that schools are safe. She recommended that schools consider inviting parents and families to visit buildings in advance of reopening so they can see the safety measures, such as space between desks, cleaning stations, and other protective strategies.

The message to pediatricians and health care professionals when counseling families about returning individual children to school is to consider the risk to the child and the family directly in the context of the local plans, Dr. Sharfstein said during a question and answer session. “One school system’s plan is one school system’s plan,” he said, and added that families who are concerned about the risk should have an online option. However, “if you see a thoughtful approach” to reopening, with safety steps taken and parents informed, with protocols such as keeping small groups of children together to reduce transmission, “it is a pretty good trade-off,” and that is why the American Academy of Pediatrics currently favors children returning to school, he said.

The briefing participants had no relevant financial conflicts to disclose.

Cardiovascular risk factors (CVRFs), including hypertension, diabetes, and smoking, are linked to a significantly increased risk for cognitive decline in midlife in a dose-dependent manner, new research shows. The findings suggest that the relationship between CVRFs and cognition becomes evident much earlier than previously realized. Investigators found that individuals who smoked were 65% more likely to have accelerated cognitive decline, those with hypertension were 87% more likely, and individuals with diabetes had nearly a 200% increased risk.

“What is new here is that almost no one has looked at cardiovascular risk factors in such a young age [mean, 50 years] and cognitive change in middle age from 50 to 55 or so. Almost all other studies have looked at mid- or late-life cardiovascular risk factors and late-life cognition or dementia,” said study investigator Kristine Yaffe, MD.

The research was published online July 15 in Neurology.
 

New insight

Previous research has shown a strong association between CVRFs and a greater risk for cognitive decline and dementia in late life, but the investigators note that data about the influence of CVRFs on cognition in midlife are “sparse.” Longitudinal studies have also shown that several cognitive domains – particularly processing speed and executive function – may start to decline in midlife, but whether CVRFs, many of which also emerge in midlife, contribute to these changes is unclear.

To assess the effect of CVRFs on cognitive changes in midlife, the investigators analyzed data from the ongoing Coronary Artery Risk Development in Young Adults (CARDIA) study. CARDIA is a multicenter longitudinal study designed to measure risk factors for coronary artery disease in a large cohort of Black and White men and women.

The analysis was based on data from 2,675 participants who underwent CVRF assessment and cognitive testing at baseline and 5 years later. At baseline, participants’ mean age was 50.2 years. Approximately 57% of participants were women, 55% were White, and the mean number of years of education was 15. At study outset, 43% (n = 1,133) of participants were considered obese, 31% (n = 826) had hypertension, 15% (n = 701) were current smokers, 11% (n = 290) had diabetes, and 9% (n = 248) had high cholesterol.

Cognition was assessed using the Digit Symbol Substitution Test, which measures processing speed and executive function; the Stroop Test, which measures executive function; and the Rey Auditory Verbal Learning Test, which measures verbal memory.
 

Dose-dependent effect

Overall results showed that, for 5% of participants, cognitive decline was accelerated at 5 years. In unadjusted models, the odds of developing accelerated cognitive decline over 5 years was associated with hypertension (7.5% vs. 4.3%; odds ratio, 1.79, 95% confidence interval, 1.27-2.52), diabetes (10.3% vs. 4.7%; OR, 2.33; 95% CI, 1.53-3.56), and smoking (7.7% current smokers vs. 4.3% never smokers; OR, 1.87; 95% CI, 1.21-2.90). After adjusting for age, sex, and race, the associations remained significant.

The researchers found no significant effect of high cholesterol (6.9% vs. 5.2%; OR, 1.35; 95% CI, 0.80-2.28) or obesity (6.1% vs. 4.8%; OR, 1.29; 95% CI, 0.92-1.82) on accelerated cognitive decline.

Compared with participants with no CVRFs, the likelihood of accelerated cognitive decline was higher for individuals with one or two risk factors (OR, 1.94; 95% CI, 1.16-3.25) and was higher still for those with three or more risk factors (OR, 3.51; 95% CI, 2.05-6.00).

The fact that there was no association between midlife cognitive decline and obesity or high cholesterol did not come as a surprise, said Dr. Yaffe. “Most studies have not shown a consistent finding with high cholesterol and later-life cognition, so it is not surprising we did not see one in midlife, when there is not as much cognitive change.”

The study’s results, said Dr. Yaffe, provide physicians with another good reason to help patients address CVRFs and to work with them to lower blood pressure, stop smoking, reduce diabetes incidence, or control diabetes.

Dr. Yaffe said she and her colleagues plan further research into CVRFs and accelerated cognitive decline. “We want to know if this earlier cognitive decline [in midlife] is connected to greater decline later in life. We also want to know if improving these risk factors in midlife might prevent or slow dementia later.”
 

More to explore

Commenting on the findings, Michelle M. Mielke, PhD, professor of epidemiology and neurology at Mayo Clinic, Rochester, Minn., said one of the study’s main implications “is that the prevention and treatment of midlife hypertension and diabetes and smoking cessation directly impacts shorter-term changes in cognition.”

She added that the study also provides a foundation for answering further questions about the effects of CVRFs on cognition in midlife. For example, questions about sex differences remain unanswered. Men develop CVRFs earlier than women, but the investigators did not provide the prevalence of cardiovascular risk factors by sex.

“It was also not reported whether a specific midlife cardiovascular risk factor was more strongly associated with accelerated cognitive decline for women or for men,” she said. In addition, the mean age of the population at baseline is the approximate age of the onset of menopause, after which cardiovascular risk factors increase among women.

“Additional research is needed to understand the emergence of cardiovascular risk factors pre- versus post menopause on subsequent cognition and also consider the use of menopausal hormone therapy,” said Dr. Mielke.

“Another future research avenue is to further understand the impact of antihypertensive and diabetes medications,” she continued. “For example, in the current study, it was not clear how many [participants] with hypertension were treated versus untreated and whether this impacted subsequent cognition. Similarly, it is not known whether specific antihypertensives are more beneficial for cognition in midlife.”

CARDIA is supported by the National Heart, Lung, and Blood Institute; the University of Alabama at Birmingham; Northwestern University, Chicago; the University of Minnesota; and the Kaiser Foundation Research Institute. Dr. Yaffe serves on data safety monitoring boards for Eli Lilly and studies sponsored by the National Institute on Aging. She is a board member of Alector and is a member of the Beeson Scientific Advisory Board and the Global Council on Brain Health. Dr. Mielke has disclosed no relevant financial relationships.

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

Cardiovascular risk factors (CVRFs), including hypertension, diabetes, and smoking, are linked to a significantly increased risk for cognitive decline in midlife in a dose-dependent manner, new research shows. The findings suggest that the relationship between CVRFs and cognition becomes evident much earlier than previously realized. Investigators found that individuals who smoked were 65% more likely to have accelerated cognitive decline, those with hypertension were 87% more likely, and individuals with diabetes had nearly a 200% increased risk.

“What is new here is that almost no one has looked at cardiovascular risk factors in such a young age [mean, 50 years] and cognitive change in middle age from 50 to 55 or so. Almost all other studies have looked at mid- or late-life cardiovascular risk factors and late-life cognition or dementia,” said study investigator Kristine Yaffe, MD.

The research was published online July 15 in Neurology.
 

New insight

Previous research has shown a strong association between CVRFs and a greater risk for cognitive decline and dementia in late life, but the investigators note that data about the influence of CVRFs on cognition in midlife are “sparse.” Longitudinal studies have also shown that several cognitive domains – particularly processing speed and executive function – may start to decline in midlife, but whether CVRFs, many of which also emerge in midlife, contribute to these changes is unclear.

To assess the effect of CVRFs on cognitive changes in midlife, the investigators analyzed data from the ongoing Coronary Artery Risk Development in Young Adults (CARDIA) study. CARDIA is a multicenter longitudinal study designed to measure risk factors for coronary artery disease in a large cohort of Black and White men and women.

The analysis was based on data from 2,675 participants who underwent CVRF assessment and cognitive testing at baseline and 5 years later. At baseline, participants’ mean age was 50.2 years. Approximately 57% of participants were women, 55% were White, and the mean number of years of education was 15. At study outset, 43% (n = 1,133) of participants were considered obese, 31% (n = 826) had hypertension, 15% (n = 701) were current smokers, 11% (n = 290) had diabetes, and 9% (n = 248) had high cholesterol.

Cognition was assessed using the Digit Symbol Substitution Test, which measures processing speed and executive function; the Stroop Test, which measures executive function; and the Rey Auditory Verbal Learning Test, which measures verbal memory.
 

Dose-dependent effect

Overall results showed that, for 5% of participants, cognitive decline was accelerated at 5 years. In unadjusted models, the odds of developing accelerated cognitive decline over 5 years was associated with hypertension (7.5% vs. 4.3%; odds ratio, 1.79, 95% confidence interval, 1.27-2.52), diabetes (10.3% vs. 4.7%; OR, 2.33; 95% CI, 1.53-3.56), and smoking (7.7% current smokers vs. 4.3% never smokers; OR, 1.87; 95% CI, 1.21-2.90). After adjusting for age, sex, and race, the associations remained significant.

The researchers found no significant effect of high cholesterol (6.9% vs. 5.2%; OR, 1.35; 95% CI, 0.80-2.28) or obesity (6.1% vs. 4.8%; OR, 1.29; 95% CI, 0.92-1.82) on accelerated cognitive decline.

Compared with participants with no CVRFs, the likelihood of accelerated cognitive decline was higher for individuals with one or two risk factors (OR, 1.94; 95% CI, 1.16-3.25) and was higher still for those with three or more risk factors (OR, 3.51; 95% CI, 2.05-6.00).

The fact that there was no association between midlife cognitive decline and obesity or high cholesterol did not come as a surprise, said Dr. Yaffe. “Most studies have not shown a consistent finding with high cholesterol and later-life cognition, so it is not surprising we did not see one in midlife, when there is not as much cognitive change.”

The study’s results, said Dr. Yaffe, provide physicians with another good reason to help patients address CVRFs and to work with them to lower blood pressure, stop smoking, reduce diabetes incidence, or control diabetes.

Dr. Yaffe said she and her colleagues plan further research into CVRFs and accelerated cognitive decline. “We want to know if this earlier cognitive decline [in midlife] is connected to greater decline later in life. We also want to know if improving these risk factors in midlife might prevent or slow dementia later.”
 

More to explore

Commenting on the findings, Michelle M. Mielke, PhD, professor of epidemiology and neurology at Mayo Clinic, Rochester, Minn., said one of the study’s main implications “is that the prevention and treatment of midlife hypertension and diabetes and smoking cessation directly impacts shorter-term changes in cognition.”

She added that the study also provides a foundation for answering further questions about the effects of CVRFs on cognition in midlife. For example, questions about sex differences remain unanswered. Men develop CVRFs earlier than women, but the investigators did not provide the prevalence of cardiovascular risk factors by sex.

“It was also not reported whether a specific midlife cardiovascular risk factor was more strongly associated with accelerated cognitive decline for women or for men,” she said. In addition, the mean age of the population at baseline is the approximate age of the onset of menopause, after which cardiovascular risk factors increase among women.

“Additional research is needed to understand the emergence of cardiovascular risk factors pre- versus post menopause on subsequent cognition and also consider the use of menopausal hormone therapy,” said Dr. Mielke.

“Another future research avenue is to further understand the impact of antihypertensive and diabetes medications,” she continued. “For example, in the current study, it was not clear how many [participants] with hypertension were treated versus untreated and whether this impacted subsequent cognition. Similarly, it is not known whether specific antihypertensives are more beneficial for cognition in midlife.”

CARDIA is supported by the National Heart, Lung, and Blood Institute; the University of Alabama at Birmingham; Northwestern University, Chicago; the University of Minnesota; and the Kaiser Foundation Research Institute. Dr. Yaffe serves on data safety monitoring boards for Eli Lilly and studies sponsored by the National Institute on Aging. She is a board member of Alector and is a member of the Beeson Scientific Advisory Board and the Global Council on Brain Health. Dr. Mielke has disclosed no relevant financial relationships.

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

Cardiovascular risk factors (CVRFs), including hypertension, diabetes, and smoking, are linked to a significantly increased risk for cognitive decline in midlife in a dose-dependent manner, new research shows. The findings suggest that the relationship between CVRFs and cognition becomes evident much earlier than previously realized. Investigators found that individuals who smoked were 65% more likely to have accelerated cognitive decline, those with hypertension were 87% more likely, and individuals with diabetes had nearly a 200% increased risk.

“What is new here is that almost no one has looked at cardiovascular risk factors in such a young age [mean, 50 years] and cognitive change in middle age from 50 to 55 or so. Almost all other studies have looked at mid- or late-life cardiovascular risk factors and late-life cognition or dementia,” said study investigator Kristine Yaffe, MD.

The research was published online July 15 in Neurology.
 

New insight

Previous research has shown a strong association between CVRFs and a greater risk for cognitive decline and dementia in late life, but the investigators note that data about the influence of CVRFs on cognition in midlife are “sparse.” Longitudinal studies have also shown that several cognitive domains – particularly processing speed and executive function – may start to decline in midlife, but whether CVRFs, many of which also emerge in midlife, contribute to these changes is unclear.

To assess the effect of CVRFs on cognitive changes in midlife, the investigators analyzed data from the ongoing Coronary Artery Risk Development in Young Adults (CARDIA) study. CARDIA is a multicenter longitudinal study designed to measure risk factors for coronary artery disease in a large cohort of Black and White men and women.

The analysis was based on data from 2,675 participants who underwent CVRF assessment and cognitive testing at baseline and 5 years later. At baseline, participants’ mean age was 50.2 years. Approximately 57% of participants were women, 55% were White, and the mean number of years of education was 15. At study outset, 43% (n = 1,133) of participants were considered obese, 31% (n = 826) had hypertension, 15% (n = 701) were current smokers, 11% (n = 290) had diabetes, and 9% (n = 248) had high cholesterol.

Cognition was assessed using the Digit Symbol Substitution Test, which measures processing speed and executive function; the Stroop Test, which measures executive function; and the Rey Auditory Verbal Learning Test, which measures verbal memory.
 

Dose-dependent effect

Overall results showed that, for 5% of participants, cognitive decline was accelerated at 5 years. In unadjusted models, the odds of developing accelerated cognitive decline over 5 years was associated with hypertension (7.5% vs. 4.3%; odds ratio, 1.79, 95% confidence interval, 1.27-2.52), diabetes (10.3% vs. 4.7%; OR, 2.33; 95% CI, 1.53-3.56), and smoking (7.7% current smokers vs. 4.3% never smokers; OR, 1.87; 95% CI, 1.21-2.90). After adjusting for age, sex, and race, the associations remained significant.

The researchers found no significant effect of high cholesterol (6.9% vs. 5.2%; OR, 1.35; 95% CI, 0.80-2.28) or obesity (6.1% vs. 4.8%; OR, 1.29; 95% CI, 0.92-1.82) on accelerated cognitive decline.

Compared with participants with no CVRFs, the likelihood of accelerated cognitive decline was higher for individuals with one or two risk factors (OR, 1.94; 95% CI, 1.16-3.25) and was higher still for those with three or more risk factors (OR, 3.51; 95% CI, 2.05-6.00).

The fact that there was no association between midlife cognitive decline and obesity or high cholesterol did not come as a surprise, said Dr. Yaffe. “Most studies have not shown a consistent finding with high cholesterol and later-life cognition, so it is not surprising we did not see one in midlife, when there is not as much cognitive change.”

The study’s results, said Dr. Yaffe, provide physicians with another good reason to help patients address CVRFs and to work with them to lower blood pressure, stop smoking, reduce diabetes incidence, or control diabetes.

Dr. Yaffe said she and her colleagues plan further research into CVRFs and accelerated cognitive decline. “We want to know if this earlier cognitive decline [in midlife] is connected to greater decline later in life. We also want to know if improving these risk factors in midlife might prevent or slow dementia later.”
 

More to explore

Commenting on the findings, Michelle M. Mielke, PhD, professor of epidemiology and neurology at Mayo Clinic, Rochester, Minn., said one of the study’s main implications “is that the prevention and treatment of midlife hypertension and diabetes and smoking cessation directly impacts shorter-term changes in cognition.”

She added that the study also provides a foundation for answering further questions about the effects of CVRFs on cognition in midlife. For example, questions about sex differences remain unanswered. Men develop CVRFs earlier than women, but the investigators did not provide the prevalence of cardiovascular risk factors by sex.

“It was also not reported whether a specific midlife cardiovascular risk factor was more strongly associated with accelerated cognitive decline for women or for men,” she said. In addition, the mean age of the population at baseline is the approximate age of the onset of menopause, after which cardiovascular risk factors increase among women.

“Additional research is needed to understand the emergence of cardiovascular risk factors pre- versus post menopause on subsequent cognition and also consider the use of menopausal hormone therapy,” said Dr. Mielke.

“Another future research avenue is to further understand the impact of antihypertensive and diabetes medications,” she continued. “For example, in the current study, it was not clear how many [participants] with hypertension were treated versus untreated and whether this impacted subsequent cognition. Similarly, it is not known whether specific antihypertensives are more beneficial for cognition in midlife.”

CARDIA is supported by the National Heart, Lung, and Blood Institute; the University of Alabama at Birmingham; Northwestern University, Chicago; the University of Minnesota; and the Kaiser Foundation Research Institute. Dr. Yaffe serves on data safety monitoring boards for Eli Lilly and studies sponsored by the National Institute on Aging. She is a board member of Alector and is a member of the Beeson Scientific Advisory Board and the Global Council on Brain Health. Dr. Mielke has disclosed no relevant financial relationships.

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

Israel Shippy doesn’t remember much about having COVID-19 – or the unusual autoimmune disease it triggered – other than being groggy and uncomfortable for a bunch of days. He’s a 5-year-old boy and would much rather talk about cartoons or the ideas for inventions that constantly pop into his head.

“Hold your horses, I think I know what I’m gonna make,” he said, holding up a finger in the middle of a conversation. “I’m gonna make something that lights up and attaches to things with glue, so if you don’t have a flashlight, you can just use it!”

In New York, at least 237 kids, including Israel, appear to have Multisystem Inflammatory Syndrome in Children (MIS-C). And state officials continue to track the syndrome, but the Centers for Disease Control and Prevention did not respond to repeated requests for information on how many children nationwide have been diagnosed so far with MIS-C.

A study published June 29 in the New England Journal of Medicine reported on 186 patients in 26 states who had been diagnosed with MIS-C. A researcher writing in the same issue added reports from other countries, finding that about 1,000 children worldwide have been diagnosed with MIS-C.
 

Tracking the long-term health effects of MIS-C

Israel is friendly and energetic, but he’s also really good at sitting still. During a recent checkup at the Children’s Hospital at Montefiore, New York, he had no complaints about all the stickers and wires a health aide attached to him for an EKG. And when Marc Foca, MD, an infectious disease specialist, came by to listen to his heart and lungs, and prod his abdomen, Israel barely seemed to notice.

There were still some tests pending, but overall, Dr. Foca said, “Israel looks like a totally healthy 5-year-old.”

“Stay safe!” Israel called out, as Dr. Foca left. It’s his new sign-off, instead of goodbye. His mother, Janelle Moholland, explained Israel came up with it himself. And she’s also hoping that, after a harrowing couple of weeks in early May, Israel himself will “stay safe.”

That’s why they’ve been returning to Montefiore for the periodic checkups, even though Israel seems to have recovered fully from both COVID-19 and MIS-C.

MIS-C is relatively rare, and it apparently responds well to treatment, but it is new enough – and mysterious enough – that doctors here want to make sure the children who recover don’t experience any related health complications in the future.

“We’ve seen these kids get really sick, and get better and recover and go home, yet we don’t know what the long-term outcomes are,” said Nadine Choueiter, MD, a pediatric cardiologist at Montefiore. “So that’s why we will be seeing them.”

When Israel first got sick at the end of April, his illness didn’t exactly look like COVID-19. He had persistent high fevers, with his temperature reaching 104° F – but no problems breathing. He wasn’t eating. He was barely drinking. He wasn’t using the bathroom. He had abdominal pains. His eyes were red.

They went to the ED a couple of times and visited an urgent care center, but the doctors sent them home without testing him for the coronavirus. Ms. Moholland, 29, said she felt powerless.

“There was nothing I could do but make him comfortable,” she said. “I literally had to just trust in a higher power and just hope that He would come through for us. It taught me a lot about patience and faith.”

As Israel grew sicker, and they still had no answers, Ms. Moholland grew frustrated. “I wish his pediatrician and [the ED and urgent care staff] had done what they were supposed to do and given him a test” when Israel first got sick, Ms. Moholland said. “What harm would it have done? He suffered for about 10 or 11 days that could have been avoided.”

In a later interview, she talked with NPR about how COVID-19 has disproportionately affected the African American community because of a combination of underlying health conditions and lack of access to good health care. She said she felt she, too, had fallen victim to those disparities.

“It affects me, personally, because I am African American, but you just never know,” she said. “It’s hard. We’re living in uncertain times – very uncertain times.”

Finally, the Children’s Hospital at Montefiore admitted Israel – and the test she’d been trying to get for days confirmed he had the virus.

“I was literally in tears, like begging them not to discharge me because I knew he was not fine,” she recalled.

Israel was in shock, and by the time he got to the hospital, doctors were on the lookout for MIS-C, so they recognized his symptoms – which were distinct from most people with COVID-19.

Doctors gave Israel fluids and intravenous immunoglobulin, a substance obtained from donated human plasma, which is used to treat deficiencies in the immune system.

Immunoglobulin has been effective in children like Israel because MIS-C appears to be caused by an immune overreaction to the initial coronavirus infection, according to Dr. Choueiter.

“The immune system starts attacking the body itself, including the arteries of the heart,” she said.

In some MIS-C cases – though not Israel’s – the attack occurs in the coronary arteries, inflaming and dilating them. That also happens in a different syndrome affecting children, Kawasaki disease. About 5% of Kawasaki patients experience aneurysms – which can fatally rupture blood vessels – after the initial condition subsides.

Dr. Choueiter and colleagues want to make sure MIS-C patients don’t face similar risks. So far, they’re cautiously optimistic.

“We have not seen any new decrease in heart function or any new coronary artery dilations,” she said. “When we check their blood, their inflammatory markers are back to normal. For the parents, the child is back to baseline, and it’s as if this illness is a nightmare that’s long gone.”
 

For a Pennsylvania teen, the MIS-C diagnosis came much later

Not every child who develops MIS-C tests positive for the coronavirus, though many will test positive for antibodies to the coronavirus, indicating they had been infected previously. That was the case with Andrew Lis, a boy from Pennsylvania who was the first MIS-C patient seen at the Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del.

Andrew had been a healthy 14-year-old boy before he got sick. He and his twin brother love sports and video games. He said the first symptom was a bad headache. He developed a fever the next day, then constipation and intense stomach pain.

“It was terrible,” Andrew said. “It was unbearable. I couldn’t really move a lot.”

His mother, Ingrid Lis, said they were thinking appendicitis, not coronavirus, at first. In fact, she hesitated to take Andrew to the hospital, for fear of exposing him to the virus. But after Andrew stopped eating because of his headache and stomach discomfort, “I knew I couldn’t keep him home anymore,” Mrs. Lis said.

Andrew was admitted to the hospital April 12, but that was before reports of the mysterious syndrome had started trickling out of Europe.

Over about 5 days in the pediatric ICU, Andrew’s condition deteriorated rapidly, as doctors struggled to figure out what was wrong. Puzzled, they tried treatments for scarlet fever, strep throat, and toxic shock syndrome. Andrew’s body broke out in rashes, then his heart began failing and he was put on a ventilator. Andrew’s father, Ed Lis, said doctors told the family to brace for the worst: “We’ve got a healthy kid who a few days ago was just having these sort of strange symptoms. And now they’re telling us that we could lose him.”

Though Andrew’s symptoms were atypical for Kawasaki disease, doctors decided to give him the standard treatment for that condition – administering intravenous immunoglobulin, the same treatment Israel Shippy received.

“Within the 24 hours of the infusion, he was a different person,” Mrs. Lis said. Andrew was removed from the ventilator, and his appetite eventually returned. “That’s when we knew that we had turned that corner.”

It wasn’t until after Andrew’s discharge that his doctors learned about MIS-C from colleagues in Europe. They recommended the whole family be tested for antibodies to the coronavirus. Although Andrew tested positive, the rest of the family – both parents, Andrew’s twin brother and two older siblings – all tested negative. Andrew’s mother is still not sure how he was exposed since the family had been observing a strict lockdown since mid-March. Both she and her husband were working remotely from home, and she says they all wore masks and were conscientious about hand-washing when they ventured out for groceries. She thinks Andrew must have been exposed at least a month before his illness began.

And she’s puzzled why the rest of her close-knit family wasn’t infected as well. “We are a Latino family,” Mrs. Lis said. “We are very used to being together, clustering in the same room.” Even when Andrew was sick, she says, all six of them huddled in his bedroom to comfort him.

Meanwhile, Andrew has made a quick recovery. Not long after his discharge in April, he turned 15 and resumed an exercise routine involving running, push-ups, and sit-ups. A few weeks later, an ECG showed Andrew’s heart was “perfect,” Mr. Lis said. Still, doctors have asked Andrew to follow up with a cardiologist every 3 months.
 

An eye on the long-term effects

The medical team at Montefiore is tracking the 40 children they have already treated and discharged. With kids showing few symptoms in the immediate aftermath, Dr. Choueiter hopes the long-term trajectory after MIS-C will be similar to what happens after Kawasaki disease.

“Usually children who have had coronary artery dilations [from Kawasaki disease] that have resolved within the first 6 weeks of the illness do well long-term,” said Dr. Choueiter, who runs the Kawasaki disease program at Montefiore.

The Montefiore team is asking patients affected by MIS-C to return for a checkup 1 week after discharge, then after 1 month, 3 months, 6 months, and a year. They will be evaluated by pediatric cardiologists, hematologists, rheumatologists and infectious disease specialists.

Montefiore and other children’s hospitals around the country are sharing information. Dr. Choueiter wants to establish an even longer-term monitoring program for MIS-C, comparable with registries that exist for other diseases.

Ms. Moholland is glad the hospital is being vigilant.

“The uncertainty of not knowing whether it could come back in his future is a little unsettling,” she said. “But I am hopeful.”

This story is part of a partnership that includes WNYC, NPR, and Kaiser Health News. A version of this article originally appeared on Kaiser Health News.

Israel Shippy doesn’t remember much about having COVID-19 – or the unusual autoimmune disease it triggered – other than being groggy and uncomfortable for a bunch of days. He’s a 5-year-old boy and would much rather talk about cartoons or the ideas for inventions that constantly pop into his head.

“Hold your horses, I think I know what I’m gonna make,” he said, holding up a finger in the middle of a conversation. “I’m gonna make something that lights up and attaches to things with glue, so if you don’t have a flashlight, you can just use it!”

In New York, at least 237 kids, including Israel, appear to have Multisystem Inflammatory Syndrome in Children (MIS-C). And state officials continue to track the syndrome, but the Centers for Disease Control and Prevention did not respond to repeated requests for information on how many children nationwide have been diagnosed so far with MIS-C.

A study published June 29 in the New England Journal of Medicine reported on 186 patients in 26 states who had been diagnosed with MIS-C. A researcher writing in the same issue added reports from other countries, finding that about 1,000 children worldwide have been diagnosed with MIS-C.
 

Tracking the long-term health effects of MIS-C

Israel is friendly and energetic, but he’s also really good at sitting still. During a recent checkup at the Children’s Hospital at Montefiore, New York, he had no complaints about all the stickers and wires a health aide attached to him for an EKG. And when Marc Foca, MD, an infectious disease specialist, came by to listen to his heart and lungs, and prod his abdomen, Israel barely seemed to notice.

There were still some tests pending, but overall, Dr. Foca said, “Israel looks like a totally healthy 5-year-old.”

“Stay safe!” Israel called out, as Dr. Foca left. It’s his new sign-off, instead of goodbye. His mother, Janelle Moholland, explained Israel came up with it himself. And she’s also hoping that, after a harrowing couple of weeks in early May, Israel himself will “stay safe.”

That’s why they’ve been returning to Montefiore for the periodic checkups, even though Israel seems to have recovered fully from both COVID-19 and MIS-C.

MIS-C is relatively rare, and it apparently responds well to treatment, but it is new enough – and mysterious enough – that doctors here want to make sure the children who recover don’t experience any related health complications in the future.

“We’ve seen these kids get really sick, and get better and recover and go home, yet we don’t know what the long-term outcomes are,” said Nadine Choueiter, MD, a pediatric cardiologist at Montefiore. “So that’s why we will be seeing them.”

When Israel first got sick at the end of April, his illness didn’t exactly look like COVID-19. He had persistent high fevers, with his temperature reaching 104° F – but no problems breathing. He wasn’t eating. He was barely drinking. He wasn’t using the bathroom. He had abdominal pains. His eyes were red.

They went to the ED a couple of times and visited an urgent care center, but the doctors sent them home without testing him for the coronavirus. Ms. Moholland, 29, said she felt powerless.

“There was nothing I could do but make him comfortable,” she said. “I literally had to just trust in a higher power and just hope that He would come through for us. It taught me a lot about patience and faith.”

As Israel grew sicker, and they still had no answers, Ms. Moholland grew frustrated. “I wish his pediatrician and [the ED and urgent care staff] had done what they were supposed to do and given him a test” when Israel first got sick, Ms. Moholland said. “What harm would it have done? He suffered for about 10 or 11 days that could have been avoided.”

In a later interview, she talked with NPR about how COVID-19 has disproportionately affected the African American community because of a combination of underlying health conditions and lack of access to good health care. She said she felt she, too, had fallen victim to those disparities.

“It affects me, personally, because I am African American, but you just never know,” she said. “It’s hard. We’re living in uncertain times – very uncertain times.”

Finally, the Children’s Hospital at Montefiore admitted Israel – and the test she’d been trying to get for days confirmed he had the virus.

“I was literally in tears, like begging them not to discharge me because I knew he was not fine,” she recalled.

Israel was in shock, and by the time he got to the hospital, doctors were on the lookout for MIS-C, so they recognized his symptoms – which were distinct from most people with COVID-19.

Doctors gave Israel fluids and intravenous immunoglobulin, a substance obtained from donated human plasma, which is used to treat deficiencies in the immune system.

Immunoglobulin has been effective in children like Israel because MIS-C appears to be caused by an immune overreaction to the initial coronavirus infection, according to Dr. Choueiter.

“The immune system starts attacking the body itself, including the arteries of the heart,” she said.

In some MIS-C cases – though not Israel’s – the attack occurs in the coronary arteries, inflaming and dilating them. That also happens in a different syndrome affecting children, Kawasaki disease. About 5% of Kawasaki patients experience aneurysms – which can fatally rupture blood vessels – after the initial condition subsides.

Dr. Choueiter and colleagues want to make sure MIS-C patients don’t face similar risks. So far, they’re cautiously optimistic.

“We have not seen any new decrease in heart function or any new coronary artery dilations,” she said. “When we check their blood, their inflammatory markers are back to normal. For the parents, the child is back to baseline, and it’s as if this illness is a nightmare that’s long gone.”
 

For a Pennsylvania teen, the MIS-C diagnosis came much later

Not every child who develops MIS-C tests positive for the coronavirus, though many will test positive for antibodies to the coronavirus, indicating they had been infected previously. That was the case with Andrew Lis, a boy from Pennsylvania who was the first MIS-C patient seen at the Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del.

Andrew had been a healthy 14-year-old boy before he got sick. He and his twin brother love sports and video games. He said the first symptom was a bad headache. He developed a fever the next day, then constipation and intense stomach pain.

“It was terrible,” Andrew said. “It was unbearable. I couldn’t really move a lot.”

His mother, Ingrid Lis, said they were thinking appendicitis, not coronavirus, at first. In fact, she hesitated to take Andrew to the hospital, for fear of exposing him to the virus. But after Andrew stopped eating because of his headache and stomach discomfort, “I knew I couldn’t keep him home anymore,” Mrs. Lis said.

Andrew was admitted to the hospital April 12, but that was before reports of the mysterious syndrome had started trickling out of Europe.

Over about 5 days in the pediatric ICU, Andrew’s condition deteriorated rapidly, as doctors struggled to figure out what was wrong. Puzzled, they tried treatments for scarlet fever, strep throat, and toxic shock syndrome. Andrew’s body broke out in rashes, then his heart began failing and he was put on a ventilator. Andrew’s father, Ed Lis, said doctors told the family to brace for the worst: “We’ve got a healthy kid who a few days ago was just having these sort of strange symptoms. And now they’re telling us that we could lose him.”

Though Andrew’s symptoms were atypical for Kawasaki disease, doctors decided to give him the standard treatment for that condition – administering intravenous immunoglobulin, the same treatment Israel Shippy received.

“Within the 24 hours of the infusion, he was a different person,” Mrs. Lis said. Andrew was removed from the ventilator, and his appetite eventually returned. “That’s when we knew that we had turned that corner.”

It wasn’t until after Andrew’s discharge that his doctors learned about MIS-C from colleagues in Europe. They recommended the whole family be tested for antibodies to the coronavirus. Although Andrew tested positive, the rest of the family – both parents, Andrew’s twin brother and two older siblings – all tested negative. Andrew’s mother is still not sure how he was exposed since the family had been observing a strict lockdown since mid-March. Both she and her husband were working remotely from home, and she says they all wore masks and were conscientious about hand-washing when they ventured out for groceries. She thinks Andrew must have been exposed at least a month before his illness began.

And she’s puzzled why the rest of her close-knit family wasn’t infected as well. “We are a Latino family,” Mrs. Lis said. “We are very used to being together, clustering in the same room.” Even when Andrew was sick, she says, all six of them huddled in his bedroom to comfort him.

Meanwhile, Andrew has made a quick recovery. Not long after his discharge in April, he turned 15 and resumed an exercise routine involving running, push-ups, and sit-ups. A few weeks later, an ECG showed Andrew’s heart was “perfect,” Mr. Lis said. Still, doctors have asked Andrew to follow up with a cardiologist every 3 months.
 

An eye on the long-term effects

The medical team at Montefiore is tracking the 40 children they have already treated and discharged. With kids showing few symptoms in the immediate aftermath, Dr. Choueiter hopes the long-term trajectory after MIS-C will be similar to what happens after Kawasaki disease.

“Usually children who have had coronary artery dilations [from Kawasaki disease] that have resolved within the first 6 weeks of the illness do well long-term,” said Dr. Choueiter, who runs the Kawasaki disease program at Montefiore.

The Montefiore team is asking patients affected by MIS-C to return for a checkup 1 week after discharge, then after 1 month, 3 months, 6 months, and a year. They will be evaluated by pediatric cardiologists, hematologists, rheumatologists and infectious disease specialists.

Montefiore and other children’s hospitals around the country are sharing information. Dr. Choueiter wants to establish an even longer-term monitoring program for MIS-C, comparable with registries that exist for other diseases.

Ms. Moholland is glad the hospital is being vigilant.

“The uncertainty of not knowing whether it could come back in his future is a little unsettling,” she said. “But I am hopeful.”

This story is part of a partnership that includes WNYC, NPR, and Kaiser Health News. A version of this article originally appeared on Kaiser Health News.

Israel Shippy doesn’t remember much about having COVID-19 – or the unusual autoimmune disease it triggered – other than being groggy and uncomfortable for a bunch of days. He’s a 5-year-old boy and would much rather talk about cartoons or the ideas for inventions that constantly pop into his head.

“Hold your horses, I think I know what I’m gonna make,” he said, holding up a finger in the middle of a conversation. “I’m gonna make something that lights up and attaches to things with glue, so if you don’t have a flashlight, you can just use it!”

In New York, at least 237 kids, including Israel, appear to have Multisystem Inflammatory Syndrome in Children (MIS-C). And state officials continue to track the syndrome, but the Centers for Disease Control and Prevention did not respond to repeated requests for information on how many children nationwide have been diagnosed so far with MIS-C.

A study published June 29 in the New England Journal of Medicine reported on 186 patients in 26 states who had been diagnosed with MIS-C. A researcher writing in the same issue added reports from other countries, finding that about 1,000 children worldwide have been diagnosed with MIS-C.
 

Tracking the long-term health effects of MIS-C

Israel is friendly and energetic, but he’s also really good at sitting still. During a recent checkup at the Children’s Hospital at Montefiore, New York, he had no complaints about all the stickers and wires a health aide attached to him for an EKG. And when Marc Foca, MD, an infectious disease specialist, came by to listen to his heart and lungs, and prod his abdomen, Israel barely seemed to notice.

There were still some tests pending, but overall, Dr. Foca said, “Israel looks like a totally healthy 5-year-old.”

“Stay safe!” Israel called out, as Dr. Foca left. It’s his new sign-off, instead of goodbye. His mother, Janelle Moholland, explained Israel came up with it himself. And she’s also hoping that, after a harrowing couple of weeks in early May, Israel himself will “stay safe.”

That’s why they’ve been returning to Montefiore for the periodic checkups, even though Israel seems to have recovered fully from both COVID-19 and MIS-C.

MIS-C is relatively rare, and it apparently responds well to treatment, but it is new enough – and mysterious enough – that doctors here want to make sure the children who recover don’t experience any related health complications in the future.

“We’ve seen these kids get really sick, and get better and recover and go home, yet we don’t know what the long-term outcomes are,” said Nadine Choueiter, MD, a pediatric cardiologist at Montefiore. “So that’s why we will be seeing them.”

When Israel first got sick at the end of April, his illness didn’t exactly look like COVID-19. He had persistent high fevers, with his temperature reaching 104° F – but no problems breathing. He wasn’t eating. He was barely drinking. He wasn’t using the bathroom. He had abdominal pains. His eyes were red.

They went to the ED a couple of times and visited an urgent care center, but the doctors sent them home without testing him for the coronavirus. Ms. Moholland, 29, said she felt powerless.

“There was nothing I could do but make him comfortable,” she said. “I literally had to just trust in a higher power and just hope that He would come through for us. It taught me a lot about patience and faith.”

As Israel grew sicker, and they still had no answers, Ms. Moholland grew frustrated. “I wish his pediatrician and [the ED and urgent care staff] had done what they were supposed to do and given him a test” when Israel first got sick, Ms. Moholland said. “What harm would it have done? He suffered for about 10 or 11 days that could have been avoided.”

In a later interview, she talked with NPR about how COVID-19 has disproportionately affected the African American community because of a combination of underlying health conditions and lack of access to good health care. She said she felt she, too, had fallen victim to those disparities.

“It affects me, personally, because I am African American, but you just never know,” she said. “It’s hard. We’re living in uncertain times – very uncertain times.”

Finally, the Children’s Hospital at Montefiore admitted Israel – and the test she’d been trying to get for days confirmed he had the virus.

“I was literally in tears, like begging them not to discharge me because I knew he was not fine,” she recalled.

Israel was in shock, and by the time he got to the hospital, doctors were on the lookout for MIS-C, so they recognized his symptoms – which were distinct from most people with COVID-19.

Doctors gave Israel fluids and intravenous immunoglobulin, a substance obtained from donated human plasma, which is used to treat deficiencies in the immune system.

Immunoglobulin has been effective in children like Israel because MIS-C appears to be caused by an immune overreaction to the initial coronavirus infection, according to Dr. Choueiter.

“The immune system starts attacking the body itself, including the arteries of the heart,” she said.

In some MIS-C cases – though not Israel’s – the attack occurs in the coronary arteries, inflaming and dilating them. That also happens in a different syndrome affecting children, Kawasaki disease. About 5% of Kawasaki patients experience aneurysms – which can fatally rupture blood vessels – after the initial condition subsides.

Dr. Choueiter and colleagues want to make sure MIS-C patients don’t face similar risks. So far, they’re cautiously optimistic.

“We have not seen any new decrease in heart function or any new coronary artery dilations,” she said. “When we check their blood, their inflammatory markers are back to normal. For the parents, the child is back to baseline, and it’s as if this illness is a nightmare that’s long gone.”
 

For a Pennsylvania teen, the MIS-C diagnosis came much later

Not every child who develops MIS-C tests positive for the coronavirus, though many will test positive for antibodies to the coronavirus, indicating they had been infected previously. That was the case with Andrew Lis, a boy from Pennsylvania who was the first MIS-C patient seen at the Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del.

Andrew had been a healthy 14-year-old boy before he got sick. He and his twin brother love sports and video games. He said the first symptom was a bad headache. He developed a fever the next day, then constipation and intense stomach pain.

“It was terrible,” Andrew said. “It was unbearable. I couldn’t really move a lot.”

His mother, Ingrid Lis, said they were thinking appendicitis, not coronavirus, at first. In fact, she hesitated to take Andrew to the hospital, for fear of exposing him to the virus. But after Andrew stopped eating because of his headache and stomach discomfort, “I knew I couldn’t keep him home anymore,” Mrs. Lis said.

Andrew was admitted to the hospital April 12, but that was before reports of the mysterious syndrome had started trickling out of Europe.

Over about 5 days in the pediatric ICU, Andrew’s condition deteriorated rapidly, as doctors struggled to figure out what was wrong. Puzzled, they tried treatments for scarlet fever, strep throat, and toxic shock syndrome. Andrew’s body broke out in rashes, then his heart began failing and he was put on a ventilator. Andrew’s father, Ed Lis, said doctors told the family to brace for the worst: “We’ve got a healthy kid who a few days ago was just having these sort of strange symptoms. And now they’re telling us that we could lose him.”

Though Andrew’s symptoms were atypical for Kawasaki disease, doctors decided to give him the standard treatment for that condition – administering intravenous immunoglobulin, the same treatment Israel Shippy received.

“Within the 24 hours of the infusion, he was a different person,” Mrs. Lis said. Andrew was removed from the ventilator, and his appetite eventually returned. “That’s when we knew that we had turned that corner.”

It wasn’t until after Andrew’s discharge that his doctors learned about MIS-C from colleagues in Europe. They recommended the whole family be tested for antibodies to the coronavirus. Although Andrew tested positive, the rest of the family – both parents, Andrew’s twin brother and two older siblings – all tested negative. Andrew’s mother is still not sure how he was exposed since the family had been observing a strict lockdown since mid-March. Both she and her husband were working remotely from home, and she says they all wore masks and were conscientious about hand-washing when they ventured out for groceries. She thinks Andrew must have been exposed at least a month before his illness began.

And she’s puzzled why the rest of her close-knit family wasn’t infected as well. “We are a Latino family,” Mrs. Lis said. “We are very used to being together, clustering in the same room.” Even when Andrew was sick, she says, all six of them huddled in his bedroom to comfort him.

Meanwhile, Andrew has made a quick recovery. Not long after his discharge in April, he turned 15 and resumed an exercise routine involving running, push-ups, and sit-ups. A few weeks later, an ECG showed Andrew’s heart was “perfect,” Mr. Lis said. Still, doctors have asked Andrew to follow up with a cardiologist every 3 months.
 

An eye on the long-term effects

The medical team at Montefiore is tracking the 40 children they have already treated and discharged. With kids showing few symptoms in the immediate aftermath, Dr. Choueiter hopes the long-term trajectory after MIS-C will be similar to what happens after Kawasaki disease.

“Usually children who have had coronary artery dilations [from Kawasaki disease] that have resolved within the first 6 weeks of the illness do well long-term,” said Dr. Choueiter, who runs the Kawasaki disease program at Montefiore.

The Montefiore team is asking patients affected by MIS-C to return for a checkup 1 week after discharge, then after 1 month, 3 months, 6 months, and a year. They will be evaluated by pediatric cardiologists, hematologists, rheumatologists and infectious disease specialists.

Montefiore and other children’s hospitals around the country are sharing information. Dr. Choueiter wants to establish an even longer-term monitoring program for MIS-C, comparable with registries that exist for other diseases.

Ms. Moholland is glad the hospital is being vigilant.

“The uncertainty of not knowing whether it could come back in his future is a little unsettling,” she said. “But I am hopeful.”

This story is part of a partnership that includes WNYC, NPR, and Kaiser Health News. A version of this article originally appeared on Kaiser Health News.

As COVID-19 cases mounted in Texas in late June, a local Houston news station shadowed Joseph Varon, MD, making rounds in the intensive care unit at United Memorial Medical Center in Houston. An unseen newscaster tells viewers that Varon credits his success against COVID-19 so far to an experimental and “controversial” drug protocol consisting of vitamins, steroids, and blood thinners.

“This is war. There’s no time to double-blind anything,” Varon tells the camera. “This is working. And if it’s working, I’m going to keep on doing it.”

Varon is one of 10 physicians behind the protocol known as MATH+, which in media interviews and congressional testimony they say has worked to treat COVID-19 patients and save lives in their intensive care units across the country. But response to the protocol among other critical care physicians is mixed, with several physicians, in interviews with Medscape Medical News, urging caution because the benefits and relative risks of the combined medications have not been tested in randomized control trials.

From the earliest days of the pandemic, there’s been tension between the need for rigorous scientific study to understand a novel disease, which takes time, and the need to treat seriously ill patients immediately. Some treatments, like hydroxychloroquine, were promoted without randomized clinical trial data and then later were shown to be ineffective or even potentially harmful when tested.

“This pandemic has shown us there’s lots of ideas out there and they need to be tested and a theoretical basis is insufficient,” says Daniel Kaul, MD, a professor of infectious disease at the University of Michigan in Ann Arbor. The ups and downs with hydroxychloroquine offer a sobering example, he says. “I would argue we have an ethical obligation to do randomized controlled trials to see if our treatments work.”
 

Creating MATH+

MATH+ stands for methylprednisolone, ascorbic acid, thiamine, and heparin. The “+” holds a place for additional therapies like vitamin D, zinc, and melatonin. The protocol originated as a variation of the “HAT therapy,” a combination of hydrocortisone, ascorbic acid, and thiamine, which critical care specialist Paul Marik, MD, created for treating critically ill patients with sepsis.

Over a few weeks, the protocol evolved as Marik, chief of the division of pulmonary and critical care medicine at Eastern Virginia Medical School in Norfolk, emailed with a small group of colleagues about treatments and their observations of SARS-CoV-2 in action, swapping in methylprednisolone and adding the anticoagulant heparin.

When Marik and colleagues created the protocol in early March, many healthcare organizations like the World Health Organization (WHO) were advising against steroids for COVID-19 patients. The MATH+ physicians decided they needed to spread a different message, and began publicizing the protocol with a website and a small communications team.

Marik says they tried to get their protocol in front of healthcare organizations – including the WHO, the Centers for Disease Control and Prevention, and the National Institutes of Health – but received no response. Marik went on Newt Gingrich’s podcast to discuss the protocol in the hopes it would make its way to the White House.

Senator Ron Johnson of Wisconsin saw the protocol and invited Pierre Kory, MD, MPA, who practices in Johnson’s home state, to testify remotely in front of the Senate Homeland Security Committee. Kory is a pulmonary critical care specialist about to start a new job at Aurora St. Luke’s Medical Center in Milwaukee.

In his testimony, Kory shared his positive experience using the protocol to treat patients and expressed his dismay that national healthcare organizations came out against the use of corticosteroids for COVID-19 from the early days of the pandemic based on what he called a “tragic error in analysis of medical data.” Although an analysis by national organizations suggested corticosteroids might be dangerous in COVID-19 patients, one of his colleagues came to the opposite conclusion, he said. But these organizations advised supportive care only, and against steroids. “We think that is a fatal and tragic flaw,” Kory said.

“The problem with the protocol early on was that it was heresy,” says Kory, referring to the protocol’s inclusion of corticosteroids before official treatment guidelines. During the height of the pandemic in New York this spring, Kory spent 5 weeks working in the ICU at Mount Sinai Beth Israel in Manhattan. Seeing patients flounder on supportive care, Kory says he used MATH+ successfully during his time in New York, using escalating and pulse doses of corticosteroids to stabilize rapidly deteriorating patients.

The website’s home page initially included an invitation for visitors to donate money to support “getting word of this effective treatment protocol out to physicians and hospitals around the world.” After Medscape Medical News brought up the donation prompt in questions, the physicians decided to remove all calls for donations from the website and social media, communications representative Betsy Ashton said. “Critics are misinterpreting this as some kind of fund-raising operation, when that could hardly be the case,” Ashton said in an email. “They are horrified that anyone would impugn their motives.”

Donations paid for the website designer, webmaster, and her work, Ashton said, and the physicians now have donors who will support publicizing the protocol without online calls for donations. “We have no commercial or vested interest,” Marik said. “I’m not going to make a single cent out of this and it’s obviously very time-consuming.”
 

The basis for the protocol

The protocol is based on common sense, an understanding of scientific literature, and an understanding of COVID-19, Marik says. The website includes links to past research trials and observational studies examining ascorbic acid and thiamine in critically ill patients and early looks at anticoagulants in COVID-19 patients.

They chose methylprednisolone as their corticosteroid based on the expertise of group member G. Umberto Meduri, MD, professor of medicine at the University of Tennessee Health Science Center in Memphis, Tennessee, who had found the steroid effective in treating acute respiratory distress syndrome. On the MATH+ website, the physicians link to multiple observational studies posted on preprint servers in April and May that suggest methylprednisolone helped COVID-19 patients.

“What’s happened with time is all the elements have been validated by scientific studies, which makes this so cool,” says Marik. The RECOVERY Trial results in particular validated the push to use corticosteroids in COVID-19 patients, he says. But that study used a different steroid, dexamethasone, in much smaller doses than what MATH+ recommends. Revised guidance from the Infectious Diseases Society of America recommends dexamethasone for severely ill patients, but says methylprednisolone and prednisone can be used as substitutes at equivalent doses.

Marik and Kory say that mortality rates for COVID-19 patients at their respective hospitals decreased after they began using the protocol. The physicians have been collecting observational data on their patients, but have not yet published any, and do not plan to conduct a randomized trial.

Several physicians who were not involved in the creation of the protocol say the evidence the physicians cite is not robust enough to warrant the promotion of MATH+ and call for randomized controlled trials. Coming up with a protocol is fine, says Kaul, but “you have to do the hard work of doing a randomized control trial to determine if those drugs given in those combinations work or not.”

“When I looked at it, I thought it was actually not very evidence based,” says Michelle Gong, MD, chief of the Division of Critical Care Medicine at Montefiore Health System in New York City. “It is not something I would recommend for my doctors to do outside of a clinical trial.”

The protocol authors push back against the necessity and feasibility of randomized control trials.

There is no time for a randomized control trial right now, says Jose Iglesias, DO, associate professor at Hackensack Meridian School of Medicine at Seton Hall and critical care specialist at Community Medical Center and Jersey Shore University Medical Center in New Jersey. “Time is limited. We’re busy bedside clinicians taking care of patients, and patients who are dying.”

Marik argues there is not equipoise: It wouldn’t be ethical to randomize patients in a placebo group when the physicians are confident the steroids will help. And the protocol is personalized for each patient, making the standardization required for a randomized control trial incredibly difficult, he says. He also cites “the people who are unwilling to accept our results and just think it’s too good to be true.”

Hugh Cassiere, MD, director of critical care medicine at Northwell Health’s North Shore University Hospital in Manhasset, New York, said he finds it “very disturbing that this is being propagated.” In the context of a pandemic in which physicians from other specialties are helping out colleagues in ICUs and might follow the protocol uncritically, he worries, “this could potentially lead to harm.”

“I understand the intention; everybody wants to do something, these patients are so sick and the crisis so sharp that we all want to do something to make patients better,” Gong said. “But as physicians taking care of patients we need to make sure we separate the noise from the evidence.”
 

Peer review

The physicians who reviewed MATH+ for Medscape Medical News differed on which parts of the protocol they support and which parts they would change.

Dexamethasone should be the corticosteroid of choice over methylprednisolone, says Cassiere, because it has now been proven effective in the randomized RECOVERY Trial, which also tested dosing and a timetable for treatment.

But Sam Parnia, MD, PhD, associate professor of medicine and director of critical care and resuscitation research at NYU Langone, thinks methylprednisolone may be effective, and that even higher doses over longer periods of time may stave off recurring pneumonia, based on his experience using the steroid to treat COVID-19 patients in New York.

“What I really like about this protocol is, these guys are very smart, they recommend the need to treat multiple different things at the same time,” says Parnia. COVID-19 is a complex condition, he notes: If physicians are only focused on solving one problem, like hypoxia, patients could still be dying from blood clots.

Despite general concerns about the protocol, Cassiere says he was excited about the inclusion of heparin. Given the extreme levels of clotting seen in COVID-19 patients, he would have included specific D-dimer levels to guide treatment and explored antiplatelet therapies like aspirin. Gong, however, cautioned that she had seen her patients on anticoagulants develop gastrointestinal bleeding, and reiterated the need for clinical evidence. (At least one clinical trial is currently testing the risks and benefits of heparin as an antithrombotic therapy for COVID-19 patients.)

Perhaps the most divisive part of the protocol is the inclusion of ascorbic acid. “That’s the civil war,” says Kory. “It’s the most polarizing medicine.” The authors of the MATH+ protocol were close colleagues before COVID-19 in part because of a mutual research interest in ascorbic acid, he says. Other physicians, including Cassiere, are extremely skeptical that ascorbic acid has any effect, citing recently published studies in the Journal of the American Medical Association that found ascorbic acid ineffective for treating sepsis.

The MATH+ creators say they are working on a literature review of the research behind the protocol, and they plan to write up the observational impacts of the protocol. Marik says he’s not optimistic about getting the findings published in a high-impact journal given the observational nature of the research; the relatively small number of patients treated at hospitals using the protocol (140 patients at Marik’s hospital in Virginia and 180 at Varon’s in Houston, according to Marik); and the vast number of COVID-19 papers being submitted to scientific journals right now.

“This is not a remedy with expensive designer drugs,” Marik said. “No one has any interest in treating patients with cheap, safe, readily available drugs.”

“I hope they’re right if they’re saying this combination of medicines dramatically decreases mortality,” says Taison Bell, MD, director of the medical intensive care unit and assistant professor of medicine at UVA Health in Charlottesville, Virginia.

But physicians have hurt patients in the past with medications they hoped would work, he says. “We have to make sure we’re balancing the risk and the harm with that benefit, and the only way to protect patients from those biases is by doing a randomized controlled trial.”

This article first appeared on Medscape.com.

As COVID-19 cases mounted in Texas in late June, a local Houston news station shadowed Joseph Varon, MD, making rounds in the intensive care unit at United Memorial Medical Center in Houston. An unseen newscaster tells viewers that Varon credits his success against COVID-19 so far to an experimental and “controversial” drug protocol consisting of vitamins, steroids, and blood thinners.

“This is war. There’s no time to double-blind anything,” Varon tells the camera. “This is working. And if it’s working, I’m going to keep on doing it.”

Varon is one of 10 physicians behind the protocol known as MATH+, which in media interviews and congressional testimony they say has worked to treat COVID-19 patients and save lives in their intensive care units across the country. But response to the protocol among other critical care physicians is mixed, with several physicians, in interviews with Medscape Medical News, urging caution because the benefits and relative risks of the combined medications have not been tested in randomized control trials.

From the earliest days of the pandemic, there’s been tension between the need for rigorous scientific study to understand a novel disease, which takes time, and the need to treat seriously ill patients immediately. Some treatments, like hydroxychloroquine, were promoted without randomized clinical trial data and then later were shown to be ineffective or even potentially harmful when tested.

“This pandemic has shown us there’s lots of ideas out there and they need to be tested and a theoretical basis is insufficient,” says Daniel Kaul, MD, a professor of infectious disease at the University of Michigan in Ann Arbor. The ups and downs with hydroxychloroquine offer a sobering example, he says. “I would argue we have an ethical obligation to do randomized controlled trials to see if our treatments work.”
 

Creating MATH+

MATH+ stands for methylprednisolone, ascorbic acid, thiamine, and heparin. The “+” holds a place for additional therapies like vitamin D, zinc, and melatonin. The protocol originated as a variation of the “HAT therapy,” a combination of hydrocortisone, ascorbic acid, and thiamine, which critical care specialist Paul Marik, MD, created for treating critically ill patients with sepsis.

Over a few weeks, the protocol evolved as Marik, chief of the division of pulmonary and critical care medicine at Eastern Virginia Medical School in Norfolk, emailed with a small group of colleagues about treatments and their observations of SARS-CoV-2 in action, swapping in methylprednisolone and adding the anticoagulant heparin.

When Marik and colleagues created the protocol in early March, many healthcare organizations like the World Health Organization (WHO) were advising against steroids for COVID-19 patients. The MATH+ physicians decided they needed to spread a different message, and began publicizing the protocol with a website and a small communications team.

Marik says they tried to get their protocol in front of healthcare organizations – including the WHO, the Centers for Disease Control and Prevention, and the National Institutes of Health – but received no response. Marik went on Newt Gingrich’s podcast to discuss the protocol in the hopes it would make its way to the White House.

Senator Ron Johnson of Wisconsin saw the protocol and invited Pierre Kory, MD, MPA, who practices in Johnson’s home state, to testify remotely in front of the Senate Homeland Security Committee. Kory is a pulmonary critical care specialist about to start a new job at Aurora St. Luke’s Medical Center in Milwaukee.

In his testimony, Kory shared his positive experience using the protocol to treat patients and expressed his dismay that national healthcare organizations came out against the use of corticosteroids for COVID-19 from the early days of the pandemic based on what he called a “tragic error in analysis of medical data.” Although an analysis by national organizations suggested corticosteroids might be dangerous in COVID-19 patients, one of his colleagues came to the opposite conclusion, he said. But these organizations advised supportive care only, and against steroids. “We think that is a fatal and tragic flaw,” Kory said.

“The problem with the protocol early on was that it was heresy,” says Kory, referring to the protocol’s inclusion of corticosteroids before official treatment guidelines. During the height of the pandemic in New York this spring, Kory spent 5 weeks working in the ICU at Mount Sinai Beth Israel in Manhattan. Seeing patients flounder on supportive care, Kory says he used MATH+ successfully during his time in New York, using escalating and pulse doses of corticosteroids to stabilize rapidly deteriorating patients.

The website’s home page initially included an invitation for visitors to donate money to support “getting word of this effective treatment protocol out to physicians and hospitals around the world.” After Medscape Medical News brought up the donation prompt in questions, the physicians decided to remove all calls for donations from the website and social media, communications representative Betsy Ashton said. “Critics are misinterpreting this as some kind of fund-raising operation, when that could hardly be the case,” Ashton said in an email. “They are horrified that anyone would impugn their motives.”

Donations paid for the website designer, webmaster, and her work, Ashton said, and the physicians now have donors who will support publicizing the protocol without online calls for donations. “We have no commercial or vested interest,” Marik said. “I’m not going to make a single cent out of this and it’s obviously very time-consuming.”
 

The basis for the protocol

The protocol is based on common sense, an understanding of scientific literature, and an understanding of COVID-19, Marik says. The website includes links to past research trials and observational studies examining ascorbic acid and thiamine in critically ill patients and early looks at anticoagulants in COVID-19 patients.

They chose methylprednisolone as their corticosteroid based on the expertise of group member G. Umberto Meduri, MD, professor of medicine at the University of Tennessee Health Science Center in Memphis, Tennessee, who had found the steroid effective in treating acute respiratory distress syndrome. On the MATH+ website, the physicians link to multiple observational studies posted on preprint servers in April and May that suggest methylprednisolone helped COVID-19 patients.

“What’s happened with time is all the elements have been validated by scientific studies, which makes this so cool,” says Marik. The RECOVERY Trial results in particular validated the push to use corticosteroids in COVID-19 patients, he says. But that study used a different steroid, dexamethasone, in much smaller doses than what MATH+ recommends. Revised guidance from the Infectious Diseases Society of America recommends dexamethasone for severely ill patients, but says methylprednisolone and prednisone can be used as substitutes at equivalent doses.

Marik and Kory say that mortality rates for COVID-19 patients at their respective hospitals decreased after they began using the protocol. The physicians have been collecting observational data on their patients, but have not yet published any, and do not plan to conduct a randomized trial.

Several physicians who were not involved in the creation of the protocol say the evidence the physicians cite is not robust enough to warrant the promotion of MATH+ and call for randomized controlled trials. Coming up with a protocol is fine, says Kaul, but “you have to do the hard work of doing a randomized control trial to determine if those drugs given in those combinations work or not.”

“When I looked at it, I thought it was actually not very evidence based,” says Michelle Gong, MD, chief of the Division of Critical Care Medicine at Montefiore Health System in New York City. “It is not something I would recommend for my doctors to do outside of a clinical trial.”

The protocol authors push back against the necessity and feasibility of randomized control trials.

There is no time for a randomized control trial right now, says Jose Iglesias, DO, associate professor at Hackensack Meridian School of Medicine at Seton Hall and critical care specialist at Community Medical Center and Jersey Shore University Medical Center in New Jersey. “Time is limited. We’re busy bedside clinicians taking care of patients, and patients who are dying.”

Marik argues there is not equipoise: It wouldn’t be ethical to randomize patients in a placebo group when the physicians are confident the steroids will help. And the protocol is personalized for each patient, making the standardization required for a randomized control trial incredibly difficult, he says. He also cites “the people who are unwilling to accept our results and just think it’s too good to be true.”

Hugh Cassiere, MD, director of critical care medicine at Northwell Health’s North Shore University Hospital in Manhasset, New York, said he finds it “very disturbing that this is being propagated.” In the context of a pandemic in which physicians from other specialties are helping out colleagues in ICUs and might follow the protocol uncritically, he worries, “this could potentially lead to harm.”

“I understand the intention; everybody wants to do something, these patients are so sick and the crisis so sharp that we all want to do something to make patients better,” Gong said. “But as physicians taking care of patients we need to make sure we separate the noise from the evidence.”
 

Peer review

The physicians who reviewed MATH+ for Medscape Medical News differed on which parts of the protocol they support and which parts they would change.

Dexamethasone should be the corticosteroid of choice over methylprednisolone, says Cassiere, because it has now been proven effective in the randomized RECOVERY Trial, which also tested dosing and a timetable for treatment.

But Sam Parnia, MD, PhD, associate professor of medicine and director of critical care and resuscitation research at NYU Langone, thinks methylprednisolone may be effective, and that even higher doses over longer periods of time may stave off recurring pneumonia, based on his experience using the steroid to treat COVID-19 patients in New York.

“What I really like about this protocol is, these guys are very smart, they recommend the need to treat multiple different things at the same time,” says Parnia. COVID-19 is a complex condition, he notes: If physicians are only focused on solving one problem, like hypoxia, patients could still be dying from blood clots.

Despite general concerns about the protocol, Cassiere says he was excited about the inclusion of heparin. Given the extreme levels of clotting seen in COVID-19 patients, he would have included specific D-dimer levels to guide treatment and explored antiplatelet therapies like aspirin. Gong, however, cautioned that she had seen her patients on anticoagulants develop gastrointestinal bleeding, and reiterated the need for clinical evidence. (At least one clinical trial is currently testing the risks and benefits of heparin as an antithrombotic therapy for COVID-19 patients.)

Perhaps the most divisive part of the protocol is the inclusion of ascorbic acid. “That’s the civil war,” says Kory. “It’s the most polarizing medicine.” The authors of the MATH+ protocol were close colleagues before COVID-19 in part because of a mutual research interest in ascorbic acid, he says. Other physicians, including Cassiere, are extremely skeptical that ascorbic acid has any effect, citing recently published studies in the Journal of the American Medical Association that found ascorbic acid ineffective for treating sepsis.

The MATH+ creators say they are working on a literature review of the research behind the protocol, and they plan to write up the observational impacts of the protocol. Marik says he’s not optimistic about getting the findings published in a high-impact journal given the observational nature of the research; the relatively small number of patients treated at hospitals using the protocol (140 patients at Marik’s hospital in Virginia and 180 at Varon’s in Houston, according to Marik); and the vast number of COVID-19 papers being submitted to scientific journals right now.

“This is not a remedy with expensive designer drugs,” Marik said. “No one has any interest in treating patients with cheap, safe, readily available drugs.”

“I hope they’re right if they’re saying this combination of medicines dramatically decreases mortality,” says Taison Bell, MD, director of the medical intensive care unit and assistant professor of medicine at UVA Health in Charlottesville, Virginia.

But physicians have hurt patients in the past with medications they hoped would work, he says. “We have to make sure we’re balancing the risk and the harm with that benefit, and the only way to protect patients from those biases is by doing a randomized controlled trial.”

This article first appeared on Medscape.com.

As COVID-19 cases mounted in Texas in late June, a local Houston news station shadowed Joseph Varon, MD, making rounds in the intensive care unit at United Memorial Medical Center in Houston. An unseen newscaster tells viewers that Varon credits his success against COVID-19 so far to an experimental and “controversial” drug protocol consisting of vitamins, steroids, and blood thinners.

“This is war. There’s no time to double-blind anything,” Varon tells the camera. “This is working. And if it’s working, I’m going to keep on doing it.”

Varon is one of 10 physicians behind the protocol known as MATH+, which in media interviews and congressional testimony they say has worked to treat COVID-19 patients and save lives in their intensive care units across the country. But response to the protocol among other critical care physicians is mixed, with several physicians, in interviews with Medscape Medical News, urging caution because the benefits and relative risks of the combined medications have not been tested in randomized control trials.

From the earliest days of the pandemic, there’s been tension between the need for rigorous scientific study to understand a novel disease, which takes time, and the need to treat seriously ill patients immediately. Some treatments, like hydroxychloroquine, were promoted without randomized clinical trial data and then later were shown to be ineffective or even potentially harmful when tested.

“This pandemic has shown us there’s lots of ideas out there and they need to be tested and a theoretical basis is insufficient,” says Daniel Kaul, MD, a professor of infectious disease at the University of Michigan in Ann Arbor. The ups and downs with hydroxychloroquine offer a sobering example, he says. “I would argue we have an ethical obligation to do randomized controlled trials to see if our treatments work.”
 

Creating MATH+

MATH+ stands for methylprednisolone, ascorbic acid, thiamine, and heparin. The “+” holds a place for additional therapies like vitamin D, zinc, and melatonin. The protocol originated as a variation of the “HAT therapy,” a combination of hydrocortisone, ascorbic acid, and thiamine, which critical care specialist Paul Marik, MD, created for treating critically ill patients with sepsis.

Over a few weeks, the protocol evolved as Marik, chief of the division of pulmonary and critical care medicine at Eastern Virginia Medical School in Norfolk, emailed with a small group of colleagues about treatments and their observations of SARS-CoV-2 in action, swapping in methylprednisolone and adding the anticoagulant heparin.

When Marik and colleagues created the protocol in early March, many healthcare organizations like the World Health Organization (WHO) were advising against steroids for COVID-19 patients. The MATH+ physicians decided they needed to spread a different message, and began publicizing the protocol with a website and a small communications team.

Marik says they tried to get their protocol in front of healthcare organizations – including the WHO, the Centers for Disease Control and Prevention, and the National Institutes of Health – but received no response. Marik went on Newt Gingrich’s podcast to discuss the protocol in the hopes it would make its way to the White House.

Senator Ron Johnson of Wisconsin saw the protocol and invited Pierre Kory, MD, MPA, who practices in Johnson’s home state, to testify remotely in front of the Senate Homeland Security Committee. Kory is a pulmonary critical care specialist about to start a new job at Aurora St. Luke’s Medical Center in Milwaukee.

In his testimony, Kory shared his positive experience using the protocol to treat patients and expressed his dismay that national healthcare organizations came out against the use of corticosteroids for COVID-19 from the early days of the pandemic based on what he called a “tragic error in analysis of medical data.” Although an analysis by national organizations suggested corticosteroids might be dangerous in COVID-19 patients, one of his colleagues came to the opposite conclusion, he said. But these organizations advised supportive care only, and against steroids. “We think that is a fatal and tragic flaw,” Kory said.

“The problem with the protocol early on was that it was heresy,” says Kory, referring to the protocol’s inclusion of corticosteroids before official treatment guidelines. During the height of the pandemic in New York this spring, Kory spent 5 weeks working in the ICU at Mount Sinai Beth Israel in Manhattan. Seeing patients flounder on supportive care, Kory says he used MATH+ successfully during his time in New York, using escalating and pulse doses of corticosteroids to stabilize rapidly deteriorating patients.

The website’s home page initially included an invitation for visitors to donate money to support “getting word of this effective treatment protocol out to physicians and hospitals around the world.” After Medscape Medical News brought up the donation prompt in questions, the physicians decided to remove all calls for donations from the website and social media, communications representative Betsy Ashton said. “Critics are misinterpreting this as some kind of fund-raising operation, when that could hardly be the case,” Ashton said in an email. “They are horrified that anyone would impugn their motives.”

Donations paid for the website designer, webmaster, and her work, Ashton said, and the physicians now have donors who will support publicizing the protocol without online calls for donations. “We have no commercial or vested interest,” Marik said. “I’m not going to make a single cent out of this and it’s obviously very time-consuming.”
 

The basis for the protocol

The protocol is based on common sense, an understanding of scientific literature, and an understanding of COVID-19, Marik says. The website includes links to past research trials and observational studies examining ascorbic acid and thiamine in critically ill patients and early looks at anticoagulants in COVID-19 patients.

They chose methylprednisolone as their corticosteroid based on the expertise of group member G. Umberto Meduri, MD, professor of medicine at the University of Tennessee Health Science Center in Memphis, Tennessee, who had found the steroid effective in treating acute respiratory distress syndrome. On the MATH+ website, the physicians link to multiple observational studies posted on preprint servers in April and May that suggest methylprednisolone helped COVID-19 patients.

“What’s happened with time is all the elements have been validated by scientific studies, which makes this so cool,” says Marik. The RECOVERY Trial results in particular validated the push to use corticosteroids in COVID-19 patients, he says. But that study used a different steroid, dexamethasone, in much smaller doses than what MATH+ recommends. Revised guidance from the Infectious Diseases Society of America recommends dexamethasone for severely ill patients, but says methylprednisolone and prednisone can be used as substitutes at equivalent doses.

Marik and Kory say that mortality rates for COVID-19 patients at their respective hospitals decreased after they began using the protocol. The physicians have been collecting observational data on their patients, but have not yet published any, and do not plan to conduct a randomized trial.

Several physicians who were not involved in the creation of the protocol say the evidence the physicians cite is not robust enough to warrant the promotion of MATH+ and call for randomized controlled trials. Coming up with a protocol is fine, says Kaul, but “you have to do the hard work of doing a randomized control trial to determine if those drugs given in those combinations work or not.”

“When I looked at it, I thought it was actually not very evidence based,” says Michelle Gong, MD, chief of the Division of Critical Care Medicine at Montefiore Health System in New York City. “It is not something I would recommend for my doctors to do outside of a clinical trial.”

The protocol authors push back against the necessity and feasibility of randomized control trials.

There is no time for a randomized control trial right now, says Jose Iglesias, DO, associate professor at Hackensack Meridian School of Medicine at Seton Hall and critical care specialist at Community Medical Center and Jersey Shore University Medical Center in New Jersey. “Time is limited. We’re busy bedside clinicians taking care of patients, and patients who are dying.”

Marik argues there is not equipoise: It wouldn’t be ethical to randomize patients in a placebo group when the physicians are confident the steroids will help. And the protocol is personalized for each patient, making the standardization required for a randomized control trial incredibly difficult, he says. He also cites “the people who are unwilling to accept our results and just think it’s too good to be true.”

Hugh Cassiere, MD, director of critical care medicine at Northwell Health’s North Shore University Hospital in Manhasset, New York, said he finds it “very disturbing that this is being propagated.” In the context of a pandemic in which physicians from other specialties are helping out colleagues in ICUs and might follow the protocol uncritically, he worries, “this could potentially lead to harm.”

“I understand the intention; everybody wants to do something, these patients are so sick and the crisis so sharp that we all want to do something to make patients better,” Gong said. “But as physicians taking care of patients we need to make sure we separate the noise from the evidence.”
 

Peer review

The physicians who reviewed MATH+ for Medscape Medical News differed on which parts of the protocol they support and which parts they would change.

Dexamethasone should be the corticosteroid of choice over methylprednisolone, says Cassiere, because it has now been proven effective in the randomized RECOVERY Trial, which also tested dosing and a timetable for treatment.

But Sam Parnia, MD, PhD, associate professor of medicine and director of critical care and resuscitation research at NYU Langone, thinks methylprednisolone may be effective, and that even higher doses over longer periods of time may stave off recurring pneumonia, based on his experience using the steroid to treat COVID-19 patients in New York.

“What I really like about this protocol is, these guys are very smart, they recommend the need to treat multiple different things at the same time,” says Parnia. COVID-19 is a complex condition, he notes: If physicians are only focused on solving one problem, like hypoxia, patients could still be dying from blood clots.

Despite general concerns about the protocol, Cassiere says he was excited about the inclusion of heparin. Given the extreme levels of clotting seen in COVID-19 patients, he would have included specific D-dimer levels to guide treatment and explored antiplatelet therapies like aspirin. Gong, however, cautioned that she had seen her patients on anticoagulants develop gastrointestinal bleeding, and reiterated the need for clinical evidence. (At least one clinical trial is currently testing the risks and benefits of heparin as an antithrombotic therapy for COVID-19 patients.)

Perhaps the most divisive part of the protocol is the inclusion of ascorbic acid. “That’s the civil war,” says Kory. “It’s the most polarizing medicine.” The authors of the MATH+ protocol were close colleagues before COVID-19 in part because of a mutual research interest in ascorbic acid, he says. Other physicians, including Cassiere, are extremely skeptical that ascorbic acid has any effect, citing recently published studies in the Journal of the American Medical Association that found ascorbic acid ineffective for treating sepsis.

The MATH+ creators say they are working on a literature review of the research behind the protocol, and they plan to write up the observational impacts of the protocol. Marik says he’s not optimistic about getting the findings published in a high-impact journal given the observational nature of the research; the relatively small number of patients treated at hospitals using the protocol (140 patients at Marik’s hospital in Virginia and 180 at Varon’s in Houston, according to Marik); and the vast number of COVID-19 papers being submitted to scientific journals right now.

“This is not a remedy with expensive designer drugs,” Marik said. “No one has any interest in treating patients with cheap, safe, readily available drugs.”

“I hope they’re right if they’re saying this combination of medicines dramatically decreases mortality,” says Taison Bell, MD, director of the medical intensive care unit and assistant professor of medicine at UVA Health in Charlottesville, Virginia.

But physicians have hurt patients in the past with medications they hoped would work, he says. “We have to make sure we’re balancing the risk and the harm with that benefit, and the only way to protect patients from those biases is by doing a randomized controlled trial.”

This article first appeared on Medscape.com.

A new multicenter trial has yielded conflicting results regarding intranasal insulin’s ability to deliver cognitive and functional benefit for patients with mild cognitive impairment (MCI) and Alzheimer’s disease. The randomized trial of nearly 300 patients showed that, although one insulin administration device produced marked benefit in terms of change in mean score on the Alzheimer Disease Assessment Scale–Cognitive Subscale 12 (ADAS-cog-12) over 12 months, reliability was inconsistent. A second device, used on the majority of patients in the study’s intention-to-treat population, showed no difference in these measures between patients who did and those who did not receive intranasal insulin.

“The primary analysis of the study showed no benefit of intranasal insulin on any measures of cognition or cerebrospinal fluid Alzheimer’s disease biomarkers when using the new device,” said principal investigator Suzanne Craft, PhD.

“But when we looked at our planned secondary analysis with the original device – which has been successful in previous studies – we saw quite a different picture,” added Dr. Craft, director of the Alzheimer’s Disease Research Center at Wake Forest University, Winston-Salem, N.C.

“We found a pronounced benefit with that device, such that after 18 months of administration, participants who had been receiving insulin from the beginning of the study had a large and clinically significant advantage in the primary outcome measure.”

Dr. Craft described the findings as complex. “The primary results were negative,” she added. “But the secondary results replicated those of several earlier studies when we used the same device that was used in those.”

The study was published online June 22 in JAMA Neurology.

Important for brain function

Insulin has been shown to play several important roles in brain function. The hormone is associated with a variety of cognitive functions, including memory. Through its association with vasoreactivity, lipid metabolism, and inflammation, insulin also plays an important role in vascular function.

“In the normal brain in healthy individuals, insulin is very important for synaptic function and viability. Insulin also promotes dendritic growth and facilitates synaptic health. Through this role, it plays an important part in memory,” said Dr. Craft. Given these connections, it is not surprising that reduced insulin levels or activity in brain and cerebrospinal fluid have been documented in some, but not all, studies of Alzheimer’s disease. Markers of insulin resistance also have been detected in both neuronally derived exosomes and brain tissue from adults with Alzheimer’s disease.

In light of the several important roles that insulin plays in the brain – coupled with the evidence connecting dysregulation of brain insulin and AD pathology – restoring brain insulin function may offer therapeutic benefit for adults suffering either Alzheimer’s disease or MCI. “There are a number of ways to do this,” said Dr. Craft. “But one of the approaches that we’ve focused on is providing insulin directly to the brain through intranasal administration. “By doing this, you circumvent potential issues if you administered insulin systemically.”

Previous research has shown that through this mode of administration, insulin can bypass the blood-brain barrier and reach the brain through olfactory and trigeminal perivascular channels, with little effect on peripheral insulin or blood glucose levels.

As previously reported, an earlier pilot study, also conducted by Dr. Craft and her team, showed that 4 months of daily intranasal administration of 20 IU or 40 IU of insulin preserved cognitive performance in individuals with Alzheimer’s disease or MCI.

Deeper dive

In the current investigation, the researchers wanted to broaden these findings in a larger, longer, randomized double-blinded clinical trial. The investigators assessed the efficacy of intranasal insulin on cognition, function, and biomarkers of Alzheimer’s disease, as well as the safety and feasibility of the delivery method. The multicenter trial was conducted from 2014 to 2018 and included 27 sites.

Study participants were between the ages of 55 and 85 years and had been diagnosed with amnestic MCI or Alzheimer’s disease on the basis of National Institute on Aging–Alzheimer Association criteria, a score of 20 or higher on the Mini–Mental State Examination, a clinical dementia rating of 0.5 or 1.0, or a delayed logical memory score within a specified range.

In total, 289 participants were randomly assigned to receive 40 IU of insulin or placebo for 12 months, followed by a 6-month open-label extension phase. The first 49 participants (32 men; mean age, 71.9 years) underwent insulin administration with the same device the investigators used in previous trials.

Of these, 45 completed the blinded phase, and 42 completed the open-label extension. When this device, which uses an electronic nebulizer-like delivery system, proved unreliable, the researchers switched to a second device, which uses a liquid hydrofluoroalkane propellant to deliver a metered dose of insulin through a nose tip without electronic assistance. Device 2 was used for the remaining 240 participants (123 men; mean age, 70.8 years). These patients became the study’s primary intention-to-treat population.

The study’s primary outcome was the mean change in score on the Alzheimer Disease Assessment Scale–Cognitive Subscale 12 (ADAS-cog-12), which was evaluated at 3-month intervals.

Secondary clinical outcomes were assessed at 6-month intervals. These included the mean change in scores for the Alzheimer Disease Cooperative Study Activities of Daily Living Scale for Mild Cognitive Impairment and the Clinical Dementia Rating Scale Sum of Boxes.

Safety and adherence were also assessed during each study visit. Physical and neurologic examinations were performed at baseline and at months 6, 12, and 18.

Of the primary intention-to-treat population of 240 patients, 121 were randomly assigned to receive intranasal insulin. The remaining 119 received placebo and served as controls. The two groups were demographically comparable.

Better cognitive performance

A total of 215 participants completed the blinded phase; 198 participants completed the open-label extension. Discontinuation rates were comparable in both arms. The researchers found no differences between groups with respect to mean change in ADAS-cog-12 score from baseline to month 12 (0.0258 points; 95% confidence interval, –1.771 to 1.822 points; P = .98). The two groups also proved comparable in terms of performance on all other cognitive tests.

The open-label portion yielded similar results. Participants originally assigned to the insulin arm and their counterparts in the placebo arm did not differ with respect to mean score change on the ADAS-cog-12 test (or any other outcome) at either month 15 or 18.

Cerebrospinal fluid insulin levels were unchanged between groups, as were blood glucose and hemoglobin A1c values. Indeed, levels of A-beta42, A-beta40, total tau protein, and tau p-181 were comparable for the patients who received intranasal insulin and those who received placebo.

The most common adverse events were infections, injuries, respiratory disorders, and nervous system disorders, though these did not differ between groups. In addition, there were no differences between groups with respect to severity of adverse events; most were rated as mild.

In contrast with the intention-to-treat population, the study’s secondary analysis – using data from the original administration device – yielded markedly different results. In the blinded phase, patients who received insulin had better ADAS-cog-12 performance at 12 months (−2.81 points; 95% CI, −6.09 to 0.45 points; P = .09) and nominally significant effects at 6 months (−3.78 points; 95% CI, −6.79 to −0.78 points; P = .01).

Device type critical

These effects persisted in the open-label analyses. Patients who received intranasal insulin had superior ADAS-cog-12 scores at month 15 (−5.70 points; 95% CI, −9.62 to −1.79 points; P = .004) and month 18 (−5.78 points; 95% CI, −10.55 to −1.01 points; P = .02), compared with their counterparts who received insulin via the second device. This part of the study also showed that, although individual biomarkers did not differ significantly between the two arms, the ratios of A-beta42 to A-beta40 (P = .01) and A-beta42 to total tau (P = .03) increased with use of the first device. The number, type, and severity of adverse events were comparable between the insulin and placebo groups in this arm of the study.

The mixed results revealed by the trial demonstrate that the device used for intranasal insulin administration is paramount in determining the therapy’s potential efficacy. “Our take-home message is that the device is a very important factor for these studies and that one needs to validate their ability to effectively deliver insulin to the CNS,” said Dr. Craft.

“We were quite confident that the first device was able to do that. On the other hand, the second device has never been tested in that way, and we still don’t know whether or not that device was able to successfully deliver insulin,” she said.

The investigators recognize the need for more research in the field. Such studies, Dr. Craft noted, will utilize administration devices that have been previously verified to have the ability to deliver insulin to the central nervous system. “We’re currently testing several devices,” she noted. “We’re using a protocol where we administer insulin with the devices and then conduct a lumbar puncture about 30 minutes later to verify that it is actually raising insulin levels in the cerebrospinal fluid.”

Not a failure

Commenting on the findings, Samuel E. Gandy, MD, PhD, who was not involved in the study, said the research illustrates the challenge when a new therapy, a new delivery device, and a cohort of cognitively impaired patients collide. “The result is not quite a slam dunk but is also by no means a failure,” commented Dr. Gandy, Mount Sinai Chair in Alzheimer’s Research at Mount Sinai Medical Center, New York.

“One looks forward to future iterations of the Craft et al. approach, wherein the trialists tweak the ligand and/or the delivery schedule and/or the device and/or the disease and/or the disease stage,” Dr. Gandy added. “Another ligand, VGF, also holds promise for intranasal delivery, based on work from Steve Salton, Michelle Ehrlich, and Eric Schadt, all from Mount Sinai. Perhaps the nose knows!”

For Dr. Craft, the potential upside of intranasal insulin for these patients is significant and warrants further investigation. “I understand why people who are not familiar with prior research in this area might be skeptical of our enthusiasm, given the results in the intention-to-treat population,” she said. “But those of us who have been working along with this for a while now, we feel like we’ve got to do the next study. But we need to have a device that we know works,” Dr. Craft added.

“If this is real, then there may be a very large clinical benefit in symptomatic patients, and there’s nothing so far that has really improved symptomatic disease.”

The study was supported by the National Institute on Aging. Eli Lilly provided diluent placebo for the blinded phase and insulin for the open-label phase of the clinical trial at no cost. Dr. Craft received grants from the National Institute on Aging and nonfinancial support from Eli Lilly during the conduct of the study and personal fees from T3D Therapeutics and vTv Therapeutics outside the submitted work.

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

A new multicenter trial has yielded conflicting results regarding intranasal insulin’s ability to deliver cognitive and functional benefit for patients with mild cognitive impairment (MCI) and Alzheimer’s disease. The randomized trial of nearly 300 patients showed that, although one insulin administration device produced marked benefit in terms of change in mean score on the Alzheimer Disease Assessment Scale–Cognitive Subscale 12 (ADAS-cog-12) over 12 months, reliability was inconsistent. A second device, used on the majority of patients in the study’s intention-to-treat population, showed no difference in these measures between patients who did and those who did not receive intranasal insulin.

“The primary analysis of the study showed no benefit of intranasal insulin on any measures of cognition or cerebrospinal fluid Alzheimer’s disease biomarkers when using the new device,” said principal investigator Suzanne Craft, PhD.

“But when we looked at our planned secondary analysis with the original device – which has been successful in previous studies – we saw quite a different picture,” added Dr. Craft, director of the Alzheimer’s Disease Research Center at Wake Forest University, Winston-Salem, N.C.

“We found a pronounced benefit with that device, such that after 18 months of administration, participants who had been receiving insulin from the beginning of the study had a large and clinically significant advantage in the primary outcome measure.”

Dr. Craft described the findings as complex. “The primary results were negative,” she added. “But the secondary results replicated those of several earlier studies when we used the same device that was used in those.”

The study was published online June 22 in JAMA Neurology.

Important for brain function

Insulin has been shown to play several important roles in brain function. The hormone is associated with a variety of cognitive functions, including memory. Through its association with vasoreactivity, lipid metabolism, and inflammation, insulin also plays an important role in vascular function.

“In the normal brain in healthy individuals, insulin is very important for synaptic function and viability. Insulin also promotes dendritic growth and facilitates synaptic health. Through this role, it plays an important part in memory,” said Dr. Craft. Given these connections, it is not surprising that reduced insulin levels or activity in brain and cerebrospinal fluid have been documented in some, but not all, studies of Alzheimer’s disease. Markers of insulin resistance also have been detected in both neuronally derived exosomes and brain tissue from adults with Alzheimer’s disease.

In light of the several important roles that insulin plays in the brain – coupled with the evidence connecting dysregulation of brain insulin and AD pathology – restoring brain insulin function may offer therapeutic benefit for adults suffering either Alzheimer’s disease or MCI. “There are a number of ways to do this,” said Dr. Craft. “But one of the approaches that we’ve focused on is providing insulin directly to the brain through intranasal administration. “By doing this, you circumvent potential issues if you administered insulin systemically.”

Previous research has shown that through this mode of administration, insulin can bypass the blood-brain barrier and reach the brain through olfactory and trigeminal perivascular channels, with little effect on peripheral insulin or blood glucose levels.

As previously reported, an earlier pilot study, also conducted by Dr. Craft and her team, showed that 4 months of daily intranasal administration of 20 IU or 40 IU of insulin preserved cognitive performance in individuals with Alzheimer’s disease or MCI.

Deeper dive

In the current investigation, the researchers wanted to broaden these findings in a larger, longer, randomized double-blinded clinical trial. The investigators assessed the efficacy of intranasal insulin on cognition, function, and biomarkers of Alzheimer’s disease, as well as the safety and feasibility of the delivery method. The multicenter trial was conducted from 2014 to 2018 and included 27 sites.

Study participants were between the ages of 55 and 85 years and had been diagnosed with amnestic MCI or Alzheimer’s disease on the basis of National Institute on Aging–Alzheimer Association criteria, a score of 20 or higher on the Mini–Mental State Examination, a clinical dementia rating of 0.5 or 1.0, or a delayed logical memory score within a specified range.

In total, 289 participants were randomly assigned to receive 40 IU of insulin or placebo for 12 months, followed by a 6-month open-label extension phase. The first 49 participants (32 men; mean age, 71.9 years) underwent insulin administration with the same device the investigators used in previous trials.

Of these, 45 completed the blinded phase, and 42 completed the open-label extension. When this device, which uses an electronic nebulizer-like delivery system, proved unreliable, the researchers switched to a second device, which uses a liquid hydrofluoroalkane propellant to deliver a metered dose of insulin through a nose tip without electronic assistance. Device 2 was used for the remaining 240 participants (123 men; mean age, 70.8 years). These patients became the study’s primary intention-to-treat population.

The study’s primary outcome was the mean change in score on the Alzheimer Disease Assessment Scale–Cognitive Subscale 12 (ADAS-cog-12), which was evaluated at 3-month intervals.

Secondary clinical outcomes were assessed at 6-month intervals. These included the mean change in scores for the Alzheimer Disease Cooperative Study Activities of Daily Living Scale for Mild Cognitive Impairment and the Clinical Dementia Rating Scale Sum of Boxes.

Safety and adherence were also assessed during each study visit. Physical and neurologic examinations were performed at baseline and at months 6, 12, and 18.

Of the primary intention-to-treat population of 240 patients, 121 were randomly assigned to receive intranasal insulin. The remaining 119 received placebo and served as controls. The two groups were demographically comparable.

Better cognitive performance

A total of 215 participants completed the blinded phase; 198 participants completed the open-label extension. Discontinuation rates were comparable in both arms. The researchers found no differences between groups with respect to mean change in ADAS-cog-12 score from baseline to month 12 (0.0258 points; 95% confidence interval, –1.771 to 1.822 points; P = .98). The two groups also proved comparable in terms of performance on all other cognitive tests.

The open-label portion yielded similar results. Participants originally assigned to the insulin arm and their counterparts in the placebo arm did not differ with respect to mean score change on the ADAS-cog-12 test (or any other outcome) at either month 15 or 18.

Cerebrospinal fluid insulin levels were unchanged between groups, as were blood glucose and hemoglobin A1c values. Indeed, levels of A-beta42, A-beta40, total tau protein, and tau p-181 were comparable for the patients who received intranasal insulin and those who received placebo.

The most common adverse events were infections, injuries, respiratory disorders, and nervous system disorders, though these did not differ between groups. In addition, there were no differences between groups with respect to severity of adverse events; most were rated as mild.

In contrast with the intention-to-treat population, the study’s secondary analysis – using data from the original administration device – yielded markedly different results. In the blinded phase, patients who received insulin had better ADAS-cog-12 performance at 12 months (−2.81 points; 95% CI, −6.09 to 0.45 points; P = .09) and nominally significant effects at 6 months (−3.78 points; 95% CI, −6.79 to −0.78 points; P = .01).

Device type critical

These effects persisted in the open-label analyses. Patients who received intranasal insulin had superior ADAS-cog-12 scores at month 15 (−5.70 points; 95% CI, −9.62 to −1.79 points; P = .004) and month 18 (−5.78 points; 95% CI, −10.55 to −1.01 points; P = .02), compared with their counterparts who received insulin via the second device. This part of the study also showed that, although individual biomarkers did not differ significantly between the two arms, the ratios of A-beta42 to A-beta40 (P = .01) and A-beta42 to total tau (P = .03) increased with use of the first device. The number, type, and severity of adverse events were comparable between the insulin and placebo groups in this arm of the study.

The mixed results revealed by the trial demonstrate that the device used for intranasal insulin administration is paramount in determining the therapy’s potential efficacy. “Our take-home message is that the device is a very important factor for these studies and that one needs to validate their ability to effectively deliver insulin to the CNS,” said Dr. Craft.

“We were quite confident that the first device was able to do that. On the other hand, the second device has never been tested in that way, and we still don’t know whether or not that device was able to successfully deliver insulin,” she said.

The investigators recognize the need for more research in the field. Such studies, Dr. Craft noted, will utilize administration devices that have been previously verified to have the ability to deliver insulin to the central nervous system. “We’re currently testing several devices,” she noted. “We’re using a protocol where we administer insulin with the devices and then conduct a lumbar puncture about 30 minutes later to verify that it is actually raising insulin levels in the cerebrospinal fluid.”

Not a failure

Commenting on the findings, Samuel E. Gandy, MD, PhD, who was not involved in the study, said the research illustrates the challenge when a new therapy, a new delivery device, and a cohort of cognitively impaired patients collide. “The result is not quite a slam dunk but is also by no means a failure,” commented Dr. Gandy, Mount Sinai Chair in Alzheimer’s Research at Mount Sinai Medical Center, New York.

“One looks forward to future iterations of the Craft et al. approach, wherein the trialists tweak the ligand and/or the delivery schedule and/or the device and/or the disease and/or the disease stage,” Dr. Gandy added. “Another ligand, VGF, also holds promise for intranasal delivery, based on work from Steve Salton, Michelle Ehrlich, and Eric Schadt, all from Mount Sinai. Perhaps the nose knows!”

For Dr. Craft, the potential upside of intranasal insulin for these patients is significant and warrants further investigation. “I understand why people who are not familiar with prior research in this area might be skeptical of our enthusiasm, given the results in the intention-to-treat population,” she said. “But those of us who have been working along with this for a while now, we feel like we’ve got to do the next study. But we need to have a device that we know works,” Dr. Craft added.

“If this is real, then there may be a very large clinical benefit in symptomatic patients, and there’s nothing so far that has really improved symptomatic disease.”

The study was supported by the National Institute on Aging. Eli Lilly provided diluent placebo for the blinded phase and insulin for the open-label phase of the clinical trial at no cost. Dr. Craft received grants from the National Institute on Aging and nonfinancial support from Eli Lilly during the conduct of the study and personal fees from T3D Therapeutics and vTv Therapeutics outside the submitted work.

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

A new multicenter trial has yielded conflicting results regarding intranasal insulin’s ability to deliver cognitive and functional benefit for patients with mild cognitive impairment (MCI) and Alzheimer’s disease. The randomized trial of nearly 300 patients showed that, although one insulin administration device produced marked benefit in terms of change in mean score on the Alzheimer Disease Assessment Scale–Cognitive Subscale 12 (ADAS-cog-12) over 12 months, reliability was inconsistent. A second device, used on the majority of patients in the study’s intention-to-treat population, showed no difference in these measures between patients who did and those who did not receive intranasal insulin.

“The primary analysis of the study showed no benefit of intranasal insulin on any measures of cognition or cerebrospinal fluid Alzheimer’s disease biomarkers when using the new device,” said principal investigator Suzanne Craft, PhD.

“But when we looked at our planned secondary analysis with the original device – which has been successful in previous studies – we saw quite a different picture,” added Dr. Craft, director of the Alzheimer’s Disease Research Center at Wake Forest University, Winston-Salem, N.C.

“We found a pronounced benefit with that device, such that after 18 months of administration, participants who had been receiving insulin from the beginning of the study had a large and clinically significant advantage in the primary outcome measure.”

Dr. Craft described the findings as complex. “The primary results were negative,” she added. “But the secondary results replicated those of several earlier studies when we used the same device that was used in those.”

The study was published online June 22 in JAMA Neurology.

Important for brain function

Insulin has been shown to play several important roles in brain function. The hormone is associated with a variety of cognitive functions, including memory. Through its association with vasoreactivity, lipid metabolism, and inflammation, insulin also plays an important role in vascular function.

“In the normal brain in healthy individuals, insulin is very important for synaptic function and viability. Insulin also promotes dendritic growth and facilitates synaptic health. Through this role, it plays an important part in memory,” said Dr. Craft. Given these connections, it is not surprising that reduced insulin levels or activity in brain and cerebrospinal fluid have been documented in some, but not all, studies of Alzheimer’s disease. Markers of insulin resistance also have been detected in both neuronally derived exosomes and brain tissue from adults with Alzheimer’s disease.

In light of the several important roles that insulin plays in the brain – coupled with the evidence connecting dysregulation of brain insulin and AD pathology – restoring brain insulin function may offer therapeutic benefit for adults suffering either Alzheimer’s disease or MCI. “There are a number of ways to do this,” said Dr. Craft. “But one of the approaches that we’ve focused on is providing insulin directly to the brain through intranasal administration. “By doing this, you circumvent potential issues if you administered insulin systemically.”

Previous research has shown that through this mode of administration, insulin can bypass the blood-brain barrier and reach the brain through olfactory and trigeminal perivascular channels, with little effect on peripheral insulin or blood glucose levels.

As previously reported, an earlier pilot study, also conducted by Dr. Craft and her team, showed that 4 months of daily intranasal administration of 20 IU or 40 IU of insulin preserved cognitive performance in individuals with Alzheimer’s disease or MCI.

Deeper dive

In the current investigation, the researchers wanted to broaden these findings in a larger, longer, randomized double-blinded clinical trial. The investigators assessed the efficacy of intranasal insulin on cognition, function, and biomarkers of Alzheimer’s disease, as well as the safety and feasibility of the delivery method. The multicenter trial was conducted from 2014 to 2018 and included 27 sites.

Study participants were between the ages of 55 and 85 years and had been diagnosed with amnestic MCI or Alzheimer’s disease on the basis of National Institute on Aging–Alzheimer Association criteria, a score of 20 or higher on the Mini–Mental State Examination, a clinical dementia rating of 0.5 or 1.0, or a delayed logical memory score within a specified range.

In total, 289 participants were randomly assigned to receive 40 IU of insulin or placebo for 12 months, followed by a 6-month open-label extension phase. The first 49 participants (32 men; mean age, 71.9 years) underwent insulin administration with the same device the investigators used in previous trials.

Of these, 45 completed the blinded phase, and 42 completed the open-label extension. When this device, which uses an electronic nebulizer-like delivery system, proved unreliable, the researchers switched to a second device, which uses a liquid hydrofluoroalkane propellant to deliver a metered dose of insulin through a nose tip without electronic assistance. Device 2 was used for the remaining 240 participants (123 men; mean age, 70.8 years). These patients became the study’s primary intention-to-treat population.

The study’s primary outcome was the mean change in score on the Alzheimer Disease Assessment Scale–Cognitive Subscale 12 (ADAS-cog-12), which was evaluated at 3-month intervals.

Secondary clinical outcomes were assessed at 6-month intervals. These included the mean change in scores for the Alzheimer Disease Cooperative Study Activities of Daily Living Scale for Mild Cognitive Impairment and the Clinical Dementia Rating Scale Sum of Boxes.

Safety and adherence were also assessed during each study visit. Physical and neurologic examinations were performed at baseline and at months 6, 12, and 18.

Of the primary intention-to-treat population of 240 patients, 121 were randomly assigned to receive intranasal insulin. The remaining 119 received placebo and served as controls. The two groups were demographically comparable.

Better cognitive performance

A total of 215 participants completed the blinded phase; 198 participants completed the open-label extension. Discontinuation rates were comparable in both arms. The researchers found no differences between groups with respect to mean change in ADAS-cog-12 score from baseline to month 12 (0.0258 points; 95% confidence interval, –1.771 to 1.822 points; P = .98). The two groups also proved comparable in terms of performance on all other cognitive tests.

The open-label portion yielded similar results. Participants originally assigned to the insulin arm and their counterparts in the placebo arm did not differ with respect to mean score change on the ADAS-cog-12 test (or any other outcome) at either month 15 or 18.

Cerebrospinal fluid insulin levels were unchanged between groups, as were blood glucose and hemoglobin A1c values. Indeed, levels of A-beta42, A-beta40, total tau protein, and tau p-181 were comparable for the patients who received intranasal insulin and those who received placebo.

The most common adverse events were infections, injuries, respiratory disorders, and nervous system disorders, though these did not differ between groups. In addition, there were no differences between groups with respect to severity of adverse events; most were rated as mild.

In contrast with the intention-to-treat population, the study’s secondary analysis – using data from the original administration device – yielded markedly different results. In the blinded phase, patients who received insulin had better ADAS-cog-12 performance at 12 months (−2.81 points; 95% CI, −6.09 to 0.45 points; P = .09) and nominally significant effects at 6 months (−3.78 points; 95% CI, −6.79 to −0.78 points; P = .01).

Device type critical

These effects persisted in the open-label analyses. Patients who received intranasal insulin had superior ADAS-cog-12 scores at month 15 (−5.70 points; 95% CI, −9.62 to −1.79 points; P = .004) and month 18 (−5.78 points; 95% CI, −10.55 to −1.01 points; P = .02), compared with their counterparts who received insulin via the second device. This part of the study also showed that, although individual biomarkers did not differ significantly between the two arms, the ratios of A-beta42 to A-beta40 (P = .01) and A-beta42 to total tau (P = .03) increased with use of the first device. The number, type, and severity of adverse events were comparable between the insulin and placebo groups in this arm of the study.

The mixed results revealed by the trial demonstrate that the device used for intranasal insulin administration is paramount in determining the therapy’s potential efficacy. “Our take-home message is that the device is a very important factor for these studies and that one needs to validate their ability to effectively deliver insulin to the CNS,” said Dr. Craft.

“We were quite confident that the first device was able to do that. On the other hand, the second device has never been tested in that way, and we still don’t know whether or not that device was able to successfully deliver insulin,” she said.

The investigators recognize the need for more research in the field. Such studies, Dr. Craft noted, will utilize administration devices that have been previously verified to have the ability to deliver insulin to the central nervous system. “We’re currently testing several devices,” she noted. “We’re using a protocol where we administer insulin with the devices and then conduct a lumbar puncture about 30 minutes later to verify that it is actually raising insulin levels in the cerebrospinal fluid.”

Not a failure

Commenting on the findings, Samuel E. Gandy, MD, PhD, who was not involved in the study, said the research illustrates the challenge when a new therapy, a new delivery device, and a cohort of cognitively impaired patients collide. “The result is not quite a slam dunk but is also by no means a failure,” commented Dr. Gandy, Mount Sinai Chair in Alzheimer’s Research at Mount Sinai Medical Center, New York.

“One looks forward to future iterations of the Craft et al. approach, wherein the trialists tweak the ligand and/or the delivery schedule and/or the device and/or the disease and/or the disease stage,” Dr. Gandy added. “Another ligand, VGF, also holds promise for intranasal delivery, based on work from Steve Salton, Michelle Ehrlich, and Eric Schadt, all from Mount Sinai. Perhaps the nose knows!”

For Dr. Craft, the potential upside of intranasal insulin for these patients is significant and warrants further investigation. “I understand why people who are not familiar with prior research in this area might be skeptical of our enthusiasm, given the results in the intention-to-treat population,” she said. “But those of us who have been working along with this for a while now, we feel like we’ve got to do the next study. But we need to have a device that we know works,” Dr. Craft added.

“If this is real, then there may be a very large clinical benefit in symptomatic patients, and there’s nothing so far that has really improved symptomatic disease.”

The study was supported by the National Institute on Aging. Eli Lilly provided diluent placebo for the blinded phase and insulin for the open-label phase of the clinical trial at no cost. Dr. Craft received grants from the National Institute on Aging and nonfinancial support from Eli Lilly during the conduct of the study and personal fees from T3D Therapeutics and vTv Therapeutics outside the submitted work.

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

The conventional treatment mainstays for pemphigus are problematic during the COVID-19 pandemic, and a shift in disease management strategy is in order, Dedee F. Murrell, MD, said at the virtual annual meeting of the American Academy of Dermatology.

Together with physicians from the Mayo Clinic, Alexandria (Egypt) University, and Tehran (Iran) University, she recently published updated expert guidance for treatment of this severe, potentially fatal mucocutaneous autoimmune blistering disease, in a letter to the editor in the Journal of the American Academy of Dermatology. She presented some of the key recommendations at AAD 2020.

First off, rituximab (Rituxan), the only Food and Drug Administration–approved medication for moderate to severe pemphigus vulgaris and a biologic considered first-line therapy prepandemic, is ill-advised during the COVID-19 era. Its mechanism of benefit is through B-cell depletion. This is an irreversible effect, and reconstitution of B-cell immunity takes 6-12 months. The absence of this immunologic protection for such a long time poses potentially serious problems for pemphigus patients who become infected with SARS-CoV-2.

Also, the opportunity to administer intravenous infusions of the biologic becomes unpredictable during pandemic surges, when limitations on nonemergent medical care may be necessary, noted Dr. Murrell, professor of dermatology at the University of New South Wales and head of dermatology at St. George University Hospital, both in Sydney.

“We have taken the approach of postponing rituximab infusions temporarily, with the aim of delaying peak patient immunosuppression during peak COVID-19 incidence to reduce the risk of adverse outcomes,” Dr. Murrell and coauthors wrote in the letter (J Am Acad Dermatol. 2020 Jun;82[6]:e235-6).

The other traditional go-to therapy for pemphigus is corticosteroids. They’re effective, fast acting, and relatively inexpensive. But their nonselective immunosuppressive action boosts infection risk in general, and more specifically it increases the risk of developing severe forms of COVID-19 should a patient become infected with SARS-CoV-2.

“A basic therapeutic principle with particular importance during the pandemic is that glucocorticoids and steroid-sparing immunosuppressive agents, such as azathioprine and mycophenolate mofetil, should be tapered to the lowest effective dose. In active COVID-19 infection, immunosuppressive steroid-sparing medications should be discontinued when possible, although glucocorticoid cessation often cannot be considered due to risk for adrenal insufficiency,” the authors continued.

“Effective as adjuvant treatment in both pemphigus and COVID-19,intravenous immunoglobulin supports immunity and therefore may be useful in this setting,” they wrote. It’s not immunosuppressive, and, they noted, there’s good-quality evidence from a Japanese randomized, double-blind, controlled trial that a 5-day course of intravenous immunoglobulin is effective therapy for pemphigus (J Am Acad Dermatol. 2009 Apr;60[4]:595-603).

Moreover, intravenous immunoglobulin is also reportedly effective in severe COVID-19 (Open Forum Infect Dis. 2020 Mar 21. doi: 10.1093/ofid/ofaa102.).

Another option is to consider enrolling a patient with moderate or severe pemphigus vulgaris or foliaceus in the ongoing pivotal phase 3, international, double-blind, placebo-controlled PEGASUS trial of rilzabrutinib, a promising oral reversible Bruton tyrosine kinase inhibitor. The medication has a short half-life and a self-limited immunomodulatory effect. Moreover, the trial is set up for remote patient visits on an outpatient basis via teledermatology, so the 65-week study can continue despite the pandemic. Both newly diagnosed and relapsing patients are eligible for the trial, headed by Dr. Murrell. At AAD 2020 she reported encouraging results from a phase 2b trial of rilzabrutinib.

She is a consultant to Principia Biopharma, sponsor of the PEGASUS trial, and has received institutional research grants from numerous pharmaceutical companies.

[email protected]

The conventional treatment mainstays for pemphigus are problematic during the COVID-19 pandemic, and a shift in disease management strategy is in order, Dedee F. Murrell, MD, said at the virtual annual meeting of the American Academy of Dermatology.

Together with physicians from the Mayo Clinic, Alexandria (Egypt) University, and Tehran (Iran) University, she recently published updated expert guidance for treatment of this severe, potentially fatal mucocutaneous autoimmune blistering disease, in a letter to the editor in the Journal of the American Academy of Dermatology. She presented some of the key recommendations at AAD 2020.

First off, rituximab (Rituxan), the only Food and Drug Administration–approved medication for moderate to severe pemphigus vulgaris and a biologic considered first-line therapy prepandemic, is ill-advised during the COVID-19 era. Its mechanism of benefit is through B-cell depletion. This is an irreversible effect, and reconstitution of B-cell immunity takes 6-12 months. The absence of this immunologic protection for such a long time poses potentially serious problems for pemphigus patients who become infected with SARS-CoV-2.

Also, the opportunity to administer intravenous infusions of the biologic becomes unpredictable during pandemic surges, when limitations on nonemergent medical care may be necessary, noted Dr. Murrell, professor of dermatology at the University of New South Wales and head of dermatology at St. George University Hospital, both in Sydney.

“We have taken the approach of postponing rituximab infusions temporarily, with the aim of delaying peak patient immunosuppression during peak COVID-19 incidence to reduce the risk of adverse outcomes,” Dr. Murrell and coauthors wrote in the letter (J Am Acad Dermatol. 2020 Jun;82[6]:e235-6).

The other traditional go-to therapy for pemphigus is corticosteroids. They’re effective, fast acting, and relatively inexpensive. But their nonselective immunosuppressive action boosts infection risk in general, and more specifically it increases the risk of developing severe forms of COVID-19 should a patient become infected with SARS-CoV-2.

“A basic therapeutic principle with particular importance during the pandemic is that glucocorticoids and steroid-sparing immunosuppressive agents, such as azathioprine and mycophenolate mofetil, should be tapered to the lowest effective dose. In active COVID-19 infection, immunosuppressive steroid-sparing medications should be discontinued when possible, although glucocorticoid cessation often cannot be considered due to risk for adrenal insufficiency,” the authors continued.

“Effective as adjuvant treatment in both pemphigus and COVID-19,intravenous immunoglobulin supports immunity and therefore may be useful in this setting,” they wrote. It’s not immunosuppressive, and, they noted, there’s good-quality evidence from a Japanese randomized, double-blind, controlled trial that a 5-day course of intravenous immunoglobulin is effective therapy for pemphigus (J Am Acad Dermatol. 2009 Apr;60[4]:595-603).

Moreover, intravenous immunoglobulin is also reportedly effective in severe COVID-19 (Open Forum Infect Dis. 2020 Mar 21. doi: 10.1093/ofid/ofaa102.).

Another option is to consider enrolling a patient with moderate or severe pemphigus vulgaris or foliaceus in the ongoing pivotal phase 3, international, double-blind, placebo-controlled PEGASUS trial of rilzabrutinib, a promising oral reversible Bruton tyrosine kinase inhibitor. The medication has a short half-life and a self-limited immunomodulatory effect. Moreover, the trial is set up for remote patient visits on an outpatient basis via teledermatology, so the 65-week study can continue despite the pandemic. Both newly diagnosed and relapsing patients are eligible for the trial, headed by Dr. Murrell. At AAD 2020 she reported encouraging results from a phase 2b trial of rilzabrutinib.

She is a consultant to Principia Biopharma, sponsor of the PEGASUS trial, and has received institutional research grants from numerous pharmaceutical companies.

[email protected]

The conventional treatment mainstays for pemphigus are problematic during the COVID-19 pandemic, and a shift in disease management strategy is in order, Dedee F. Murrell, MD, said at the virtual annual meeting of the American Academy of Dermatology.

Together with physicians from the Mayo Clinic, Alexandria (Egypt) University, and Tehran (Iran) University, she recently published updated expert guidance for treatment of this severe, potentially fatal mucocutaneous autoimmune blistering disease, in a letter to the editor in the Journal of the American Academy of Dermatology. She presented some of the key recommendations at AAD 2020.

First off, rituximab (Rituxan), the only Food and Drug Administration–approved medication for moderate to severe pemphigus vulgaris and a biologic considered first-line therapy prepandemic, is ill-advised during the COVID-19 era. Its mechanism of benefit is through B-cell depletion. This is an irreversible effect, and reconstitution of B-cell immunity takes 6-12 months. The absence of this immunologic protection for such a long time poses potentially serious problems for pemphigus patients who become infected with SARS-CoV-2.

Also, the opportunity to administer intravenous infusions of the biologic becomes unpredictable during pandemic surges, when limitations on nonemergent medical care may be necessary, noted Dr. Murrell, professor of dermatology at the University of New South Wales and head of dermatology at St. George University Hospital, both in Sydney.

“We have taken the approach of postponing rituximab infusions temporarily, with the aim of delaying peak patient immunosuppression during peak COVID-19 incidence to reduce the risk of adverse outcomes,” Dr. Murrell and coauthors wrote in the letter (J Am Acad Dermatol. 2020 Jun;82[6]:e235-6).

The other traditional go-to therapy for pemphigus is corticosteroids. They’re effective, fast acting, and relatively inexpensive. But their nonselective immunosuppressive action boosts infection risk in general, and more specifically it increases the risk of developing severe forms of COVID-19 should a patient become infected with SARS-CoV-2.

“A basic therapeutic principle with particular importance during the pandemic is that glucocorticoids and steroid-sparing immunosuppressive agents, such as azathioprine and mycophenolate mofetil, should be tapered to the lowest effective dose. In active COVID-19 infection, immunosuppressive steroid-sparing medications should be discontinued when possible, although glucocorticoid cessation often cannot be considered due to risk for adrenal insufficiency,” the authors continued.

“Effective as adjuvant treatment in both pemphigus and COVID-19,intravenous immunoglobulin supports immunity and therefore may be useful in this setting,” they wrote. It’s not immunosuppressive, and, they noted, there’s good-quality evidence from a Japanese randomized, double-blind, controlled trial that a 5-day course of intravenous immunoglobulin is effective therapy for pemphigus (J Am Acad Dermatol. 2009 Apr;60[4]:595-603).

Moreover, intravenous immunoglobulin is also reportedly effective in severe COVID-19 (Open Forum Infect Dis. 2020 Mar 21. doi: 10.1093/ofid/ofaa102.).

Another option is to consider enrolling a patient with moderate or severe pemphigus vulgaris or foliaceus in the ongoing pivotal phase 3, international, double-blind, placebo-controlled PEGASUS trial of rilzabrutinib, a promising oral reversible Bruton tyrosine kinase inhibitor. The medication has a short half-life and a self-limited immunomodulatory effect. Moreover, the trial is set up for remote patient visits on an outpatient basis via teledermatology, so the 65-week study can continue despite the pandemic. Both newly diagnosed and relapsing patients are eligible for the trial, headed by Dr. Murrell. At AAD 2020 she reported encouraging results from a phase 2b trial of rilzabrutinib.

She is a consultant to Principia Biopharma, sponsor of the PEGASUS trial, and has received institutional research grants from numerous pharmaceutical companies.

[email protected]

In 2015, I proposed virtual care for the division of adolescent medicine, to the administration of our Midwestern children and adolescent hospital; they gladly listened and accepted a copy of the resources I provided. Virtual care was acknowledged to be the future direction of our and other organizations.

AJ_Watt/E+

Four years later, virtual visits were introduced in the pediatric urgent care, but with little usability as families were slow to adopt this new form of medicine. Fast forward to the COVID-19 crisis in March 2020, and virtual medicine was the only option to meet the needs of patients and to stop the economic consequences. Unfortunately, the expedited rollout at our and many other hospitals may have resulted in limited program development and a lack of shared best practices.

Since March 2020, both patients and medical providers have accepted virtual care, but we now have an opportunity to review some of the limitations to offering virtual care. Work in primary care centers may see limitations using virtual medicine to meet the needs of all patients. Take into consideration the ability to offer confidential care. Confidential care has been a challenge virtually. For example, while completing a virtual visit with a 19-year-old female, it was apparent she was not alone and when asked a benign question the commotion in the background told the real story. The young woman began to laugh and said, “That was my dad running out of the room.” Despite requesting that parents leave the call, they can be heard within earshot of the caller.

Innovation is essential, and televisits are evolving, using tools such as sticky notes embedded in the computer (virtual note cards to ask confidential questions). On a televisit, written words appear backwards on the video, requiring written questions to be mirror images. When asking questions meant to be confidential, we have used note cards with a question mark. Verbal directions asking the adolescent to give a thumbs up or down to answer the question are required to maintain privacy from others in the room. If the patient responds thumbs up, this leads to additional questions with note cards. Although not ideal, this process gets to the answers, and the adolescent can disclose confidential information without concern about being overheard. Child abuse and neglect professionals have found similar challenges talking to caregivers or children as they are uncertain if others in the home are out of the screen but listening to the questions or prompting responses.

Obtaining vitals may be restricted and picking up hypertension or changes in weight has been limited to face to face visits. To continue to provide virtual care will require screening stations. I foresee a kiosk at the grocery or drugstore with a computer and the ability to obtain vitals or portions of an exam such as heart and lung evaluations. Patients could go at their convenience and the results could be sent to their providers. Technology already exists to use a cell phone to take photos of a toddler’s sore ear drum, and to obtain basic pulse oximetry and ECG, but these have a cost and may be available only to those able to afford these tools.

Billing issues have developed when patients go to a lab on the same day as a virtual visit. Completing a virtual visit for a sore throat thought to be streptococcal pharyngitis should not be finalized without access to a streptococcal throat swab. Until families have home kits to evaluate for strep throat, the families must bring the patient to a clinic or lab to obtain a pharyngeal culture. Furthermore, insurance reimbursement standards will need to be set for ongoing virtual health to become a sustainable option.

Workflows have been disrupted by balancing face to face visits with virtual visits. Unless the virtual visit has been set up for the medical team to access immediately, there are delays accessing the virtual platform, resulting in unnecessary gaps in care. Arranging schedules to separate face to face visits from virtual visits offers more efficiency. Creating a block of virtual visits separated from face-to-face visits or assigning providers to virtual-only schedules may be the best option for an efficient clinic flow. Telemedicine visit templates may need to be created as virtual visits become standard practice.

At present, virtual visits can only be offered to English-speaking patients. The inability to offer translators limits access to a small number of patients. Given COVID-19’s impact on the underserved communities, having a safe resource to reach these patients has been limited, leaving face-to-face visits as their only option. Requiring a face-to-face visit during peak illness has placed patients at risk. They have refused health care as opposed to exposure to the illness in health care settings.

We have innovative opportunities to create a new health care system. Despite the initial struggles with the adoption of virtual care, patients and providers have begun embracing the technology. Best practices and shared resources will be required to have a successful system before brick and mortar organizations can be reduced or insurance companies create their own health care systems which can branch across state lines.
 

Ms. Thew is the medical director of the department of adolescent medicine at Children’s Wisconsin in Milwaukee. She said she had no relevant financial disclosures. Email her at [email protected].

The article was updated 7/17/2020.

In 2015, I proposed virtual care for the division of adolescent medicine, to the administration of our Midwestern children and adolescent hospital; they gladly listened and accepted a copy of the resources I provided. Virtual care was acknowledged to be the future direction of our and other organizations.

AJ_Watt/E+

Four years later, virtual visits were introduced in the pediatric urgent care, but with little usability as families were slow to adopt this new form of medicine. Fast forward to the COVID-19 crisis in March 2020, and virtual medicine was the only option to meet the needs of patients and to stop the economic consequences. Unfortunately, the expedited rollout at our and many other hospitals may have resulted in limited program development and a lack of shared best practices.

Since March 2020, both patients and medical providers have accepted virtual care, but we now have an opportunity to review some of the limitations to offering virtual care. Work in primary care centers may see limitations using virtual medicine to meet the needs of all patients. Take into consideration the ability to offer confidential care. Confidential care has been a challenge virtually. For example, while completing a virtual visit with a 19-year-old female, it was apparent she was not alone and when asked a benign question the commotion in the background told the real story. The young woman began to laugh and said, “That was my dad running out of the room.” Despite requesting that parents leave the call, they can be heard within earshot of the caller.

Innovation is essential, and televisits are evolving, using tools such as sticky notes embedded in the computer (virtual note cards to ask confidential questions). On a televisit, written words appear backwards on the video, requiring written questions to be mirror images. When asking questions meant to be confidential, we have used note cards with a question mark. Verbal directions asking the adolescent to give a thumbs up or down to answer the question are required to maintain privacy from others in the room. If the patient responds thumbs up, this leads to additional questions with note cards. Although not ideal, this process gets to the answers, and the adolescent can disclose confidential information without concern about being overheard. Child abuse and neglect professionals have found similar challenges talking to caregivers or children as they are uncertain if others in the home are out of the screen but listening to the questions or prompting responses.

Obtaining vitals may be restricted and picking up hypertension or changes in weight has been limited to face to face visits. To continue to provide virtual care will require screening stations. I foresee a kiosk at the grocery or drugstore with a computer and the ability to obtain vitals or portions of an exam such as heart and lung evaluations. Patients could go at their convenience and the results could be sent to their providers. Technology already exists to use a cell phone to take photos of a toddler’s sore ear drum, and to obtain basic pulse oximetry and ECG, but these have a cost and may be available only to those able to afford these tools.

Billing issues have developed when patients go to a lab on the same day as a virtual visit. Completing a virtual visit for a sore throat thought to be streptococcal pharyngitis should not be finalized without access to a streptococcal throat swab. Until families have home kits to evaluate for strep throat, the families must bring the patient to a clinic or lab to obtain a pharyngeal culture. Furthermore, insurance reimbursement standards will need to be set for ongoing virtual health to become a sustainable option.

Workflows have been disrupted by balancing face to face visits with virtual visits. Unless the virtual visit has been set up for the medical team to access immediately, there are delays accessing the virtual platform, resulting in unnecessary gaps in care. Arranging schedules to separate face to face visits from virtual visits offers more efficiency. Creating a block of virtual visits separated from face-to-face visits or assigning providers to virtual-only schedules may be the best option for an efficient clinic flow. Telemedicine visit templates may need to be created as virtual visits become standard practice.

At present, virtual visits can only be offered to English-speaking patients. The inability to offer translators limits access to a small number of patients. Given COVID-19’s impact on the underserved communities, having a safe resource to reach these patients has been limited, leaving face-to-face visits as their only option. Requiring a face-to-face visit during peak illness has placed patients at risk. They have refused health care as opposed to exposure to the illness in health care settings.

We have innovative opportunities to create a new health care system. Despite the initial struggles with the adoption of virtual care, patients and providers have begun embracing the technology. Best practices and shared resources will be required to have a successful system before brick and mortar organizations can be reduced or insurance companies create their own health care systems which can branch across state lines.
 

Ms. Thew is the medical director of the department of adolescent medicine at Children’s Wisconsin in Milwaukee. She said she had no relevant financial disclosures. Email her at [email protected].

The article was updated 7/17/2020.

In 2015, I proposed virtual care for the division of adolescent medicine, to the administration of our Midwestern children and adolescent hospital; they gladly listened and accepted a copy of the resources I provided. Virtual care was acknowledged to be the future direction of our and other organizations.

AJ_Watt/E+

Four years later, virtual visits were introduced in the pediatric urgent care, but with little usability as families were slow to adopt this new form of medicine. Fast forward to the COVID-19 crisis in March 2020, and virtual medicine was the only option to meet the needs of patients and to stop the economic consequences. Unfortunately, the expedited rollout at our and many other hospitals may have resulted in limited program development and a lack of shared best practices.

Since March 2020, both patients and medical providers have accepted virtual care, but we now have an opportunity to review some of the limitations to offering virtual care. Work in primary care centers may see limitations using virtual medicine to meet the needs of all patients. Take into consideration the ability to offer confidential care. Confidential care has been a challenge virtually. For example, while completing a virtual visit with a 19-year-old female, it was apparent she was not alone and when asked a benign question the commotion in the background told the real story. The young woman began to laugh and said, “That was my dad running out of the room.” Despite requesting that parents leave the call, they can be heard within earshot of the caller.

Innovation is essential, and televisits are evolving, using tools such as sticky notes embedded in the computer (virtual note cards to ask confidential questions). On a televisit, written words appear backwards on the video, requiring written questions to be mirror images. When asking questions meant to be confidential, we have used note cards with a question mark. Verbal directions asking the adolescent to give a thumbs up or down to answer the question are required to maintain privacy from others in the room. If the patient responds thumbs up, this leads to additional questions with note cards. Although not ideal, this process gets to the answers, and the adolescent can disclose confidential information without concern about being overheard. Child abuse and neglect professionals have found similar challenges talking to caregivers or children as they are uncertain if others in the home are out of the screen but listening to the questions or prompting responses.

Obtaining vitals may be restricted and picking up hypertension or changes in weight has been limited to face to face visits. To continue to provide virtual care will require screening stations. I foresee a kiosk at the grocery or drugstore with a computer and the ability to obtain vitals or portions of an exam such as heart and lung evaluations. Patients could go at their convenience and the results could be sent to their providers. Technology already exists to use a cell phone to take photos of a toddler’s sore ear drum, and to obtain basic pulse oximetry and ECG, but these have a cost and may be available only to those able to afford these tools.

Billing issues have developed when patients go to a lab on the same day as a virtual visit. Completing a virtual visit for a sore throat thought to be streptococcal pharyngitis should not be finalized without access to a streptococcal throat swab. Until families have home kits to evaluate for strep throat, the families must bring the patient to a clinic or lab to obtain a pharyngeal culture. Furthermore, insurance reimbursement standards will need to be set for ongoing virtual health to become a sustainable option.

Workflows have been disrupted by balancing face to face visits with virtual visits. Unless the virtual visit has been set up for the medical team to access immediately, there are delays accessing the virtual platform, resulting in unnecessary gaps in care. Arranging schedules to separate face to face visits from virtual visits offers more efficiency. Creating a block of virtual visits separated from face-to-face visits or assigning providers to virtual-only schedules may be the best option for an efficient clinic flow. Telemedicine visit templates may need to be created as virtual visits become standard practice.

At present, virtual visits can only be offered to English-speaking patients. The inability to offer translators limits access to a small number of patients. Given COVID-19’s impact on the underserved communities, having a safe resource to reach these patients has been limited, leaving face-to-face visits as their only option. Requiring a face-to-face visit during peak illness has placed patients at risk. They have refused health care as opposed to exposure to the illness in health care settings.

We have innovative opportunities to create a new health care system. Despite the initial struggles with the adoption of virtual care, patients and providers have begun embracing the technology. Best practices and shared resources will be required to have a successful system before brick and mortar organizations can be reduced or insurance companies create their own health care systems which can branch across state lines.
 

Ms. Thew is the medical director of the department of adolescent medicine at Children’s Wisconsin in Milwaukee. She said she had no relevant financial disclosures. Email her at [email protected].

The article was updated 7/17/2020.

Microcephaly may be the hallmark of congenital Zika virus syndrome, but neurologic abnormalities also are common in normocephalic children exposed to the virus in utero, according to data from a large pediatric referral center in Rio de Janeiro.

CDC/ Cynthia Goldsmith

The retrospective analysis demonstrated that there is a “spectrum of clinical manifestations” in children with congenital Zika virus syndrome, including those who “had initially been perceived as developing normally based on [head circumference],” Jessica S. Cranston, a medical student at the University of California, Los Angeles, and associates wrote in JAMA Network Open.

Previous studies have described the poor clinical outcomes in Zika virus–exposed infants with microcephaly, but the current analysis evaluated head circumference (HC) as a continuous variable and stratified outcomes according to the presence or absence of microcephaly, they explained.

In the cohort of 215 children referred to Instituto Fernandes Figueira who had laboratory-confirmed antenatal Zika virus exposure, 53 had microcephaly (cephalic perimeter z score of less than –2 standard deviations) and 162 were normocephalic, the investigators said.

The children were evaluated monthly for the first 6 months of life and then every 3 months. Neurodevelopmental evaluation with the Bayley Scales of Infant and Toddler Development, Third Edition, between 6 months and 3 years of age showed that all of those with microcephaly had abnormal neuromotor findings. All but two of the children with microcephaly had abnormal neuroimaging results, and 38 (72%) had failure to thrive, they reported.

Among the children with normocephaly at birth, 68% had abnormal neurologic findings, including hyperreflexia (27%), abnormal tone (39%), and other congenital neuromotor signs (42%). Results of neuroimaging results, primarily in the form of transfontanelle ultrasonography, were abnormal in 29% of children with normocephaly.

“Infants with a larger birth HC, within the normocephalic range (±2 SDs), had higher overall neurodevelopmental scores on the Bayley-III assessment,” Sarah B. Mulkey, MD, PhD, said in an invited commentary, “whereas infants with a smaller birth HC within the normocephalic range had lower scores in the domains of cognitive and language functions.”

If HC measurements could be combined with early neurologic data such as the results of neuroimaging or a neurological exam, she suggested, it might provide “a practical tool to help determine risk for adverse clinical outcomes in a [Zika virus–]exposed infant at birth that can be widely used in a variety of follow-up settings.”

In nutritional assessments performed for 143 children with normocephaly, 51% had failure to thrive “because of neurologic repercussions leading to poor feeding,” Ms. Cranston and associates wrote, adding that 15 of the 73 (21%) infants with normocephaly and failure to thrive developed secondary microcephaly.

Altogether, 17 of the 162 (10.5%) children with normocephaly developed microcephaly during the follow-up, with the reverse – microcephaly resolving in infants who were microcephalic at birth – occurring in 4 of the 53 (7.5%) affected infants, indicating that “head circumference was not static,” they said.

“The trajectory of head growth is critical,” said Dr. Mulkey of the Prenatal Pediatrics Institute at Children’s National Hospital in Washington. “The neurologic outcome of a child who develops postnatal microcephaly would be very concerning compared with an infant who is born with normocephaly and maintains a steady HC percentile over time.”

HC is just one piece of the puzzle, however, since children with Zika virus syndrome may exhibit “a variety of manifestations and outcomes.” This lack of certainty suggests that “careful monitoring and evaluation of children with suspected exposure is essential for ensuring early detection of possible disabilities and referral to interventional services,” the investigators wrote.

The findings of this study “are both highly statistically significant and clinically significant,”said Kevin T. Powell, MD, PhD, a pediatric hospitalist and clinical ethics consultant living in St. Louis who was not associated with the study.

“While outcomes at birth are dichotomized into those with and without microcephaly, the developmental outcomes measured at 3 years of age are on a spectrum. ... Those with microcephaly tend to be more severely affected, but many infants with small but normal-sized heads are also mild to moderately impacted. The flip side is that 64% of infected babies ended up with average or better development” based on Bayley-III evaluations, said Dr. Powell, who is a member of the Pediatric News editorial advisory board.

The study was funded by grants from the National Institute of Allergy and Infectious Diseases, the National Eye Institute, and the Thrasher Foundation and by awards from Brazil’s National Council of Scientific and Technological Development; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro. Individual investigators received fees and grants from these and other organizations.

Dr. Mulkey received a contract from the Centers for Disease Control and Prevention for technical expertise for Zika virus studies and received support for Zika studies from the Thrasher Research Fund. Dr. Powell had no relevant financial disclosures.

[email protected]

SOURCE: Cranston JS et al. JAMA Netw Open. 2020 July 7;3(7):e209303.

Microcephaly may be the hallmark of congenital Zika virus syndrome, but neurologic abnormalities also are common in normocephalic children exposed to the virus in utero, according to data from a large pediatric referral center in Rio de Janeiro.

CDC/ Cynthia Goldsmith

The retrospective analysis demonstrated that there is a “spectrum of clinical manifestations” in children with congenital Zika virus syndrome, including those who “had initially been perceived as developing normally based on [head circumference],” Jessica S. Cranston, a medical student at the University of California, Los Angeles, and associates wrote in JAMA Network Open.

Previous studies have described the poor clinical outcomes in Zika virus–exposed infants with microcephaly, but the current analysis evaluated head circumference (HC) as a continuous variable and stratified outcomes according to the presence or absence of microcephaly, they explained.

In the cohort of 215 children referred to Instituto Fernandes Figueira who had laboratory-confirmed antenatal Zika virus exposure, 53 had microcephaly (cephalic perimeter z score of less than –2 standard deviations) and 162 were normocephalic, the investigators said.

The children were evaluated monthly for the first 6 months of life and then every 3 months. Neurodevelopmental evaluation with the Bayley Scales of Infant and Toddler Development, Third Edition, between 6 months and 3 years of age showed that all of those with microcephaly had abnormal neuromotor findings. All but two of the children with microcephaly had abnormal neuroimaging results, and 38 (72%) had failure to thrive, they reported.

Among the children with normocephaly at birth, 68% had abnormal neurologic findings, including hyperreflexia (27%), abnormal tone (39%), and other congenital neuromotor signs (42%). Results of neuroimaging results, primarily in the form of transfontanelle ultrasonography, were abnormal in 29% of children with normocephaly.

“Infants with a larger birth HC, within the normocephalic range (±2 SDs), had higher overall neurodevelopmental scores on the Bayley-III assessment,” Sarah B. Mulkey, MD, PhD, said in an invited commentary, “whereas infants with a smaller birth HC within the normocephalic range had lower scores in the domains of cognitive and language functions.”

If HC measurements could be combined with early neurologic data such as the results of neuroimaging or a neurological exam, she suggested, it might provide “a practical tool to help determine risk for adverse clinical outcomes in a [Zika virus–]exposed infant at birth that can be widely used in a variety of follow-up settings.”

In nutritional assessments performed for 143 children with normocephaly, 51% had failure to thrive “because of neurologic repercussions leading to poor feeding,” Ms. Cranston and associates wrote, adding that 15 of the 73 (21%) infants with normocephaly and failure to thrive developed secondary microcephaly.

Altogether, 17 of the 162 (10.5%) children with normocephaly developed microcephaly during the follow-up, with the reverse – microcephaly resolving in infants who were microcephalic at birth – occurring in 4 of the 53 (7.5%) affected infants, indicating that “head circumference was not static,” they said.

“The trajectory of head growth is critical,” said Dr. Mulkey of the Prenatal Pediatrics Institute at Children’s National Hospital in Washington. “The neurologic outcome of a child who develops postnatal microcephaly would be very concerning compared with an infant who is born with normocephaly and maintains a steady HC percentile over time.”

HC is just one piece of the puzzle, however, since children with Zika virus syndrome may exhibit “a variety of manifestations and outcomes.” This lack of certainty suggests that “careful monitoring and evaluation of children with suspected exposure is essential for ensuring early detection of possible disabilities and referral to interventional services,” the investigators wrote.

The findings of this study “are both highly statistically significant and clinically significant,”said Kevin T. Powell, MD, PhD, a pediatric hospitalist and clinical ethics consultant living in St. Louis who was not associated with the study.

“While outcomes at birth are dichotomized into those with and without microcephaly, the developmental outcomes measured at 3 years of age are on a spectrum. ... Those with microcephaly tend to be more severely affected, but many infants with small but normal-sized heads are also mild to moderately impacted. The flip side is that 64% of infected babies ended up with average or better development” based on Bayley-III evaluations, said Dr. Powell, who is a member of the Pediatric News editorial advisory board.

The study was funded by grants from the National Institute of Allergy and Infectious Diseases, the National Eye Institute, and the Thrasher Foundation and by awards from Brazil’s National Council of Scientific and Technological Development; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro. Individual investigators received fees and grants from these and other organizations.

Dr. Mulkey received a contract from the Centers for Disease Control and Prevention for technical expertise for Zika virus studies and received support for Zika studies from the Thrasher Research Fund. Dr. Powell had no relevant financial disclosures.

[email protected]

SOURCE: Cranston JS et al. JAMA Netw Open. 2020 July 7;3(7):e209303.

Microcephaly may be the hallmark of congenital Zika virus syndrome, but neurologic abnormalities also are common in normocephalic children exposed to the virus in utero, according to data from a large pediatric referral center in Rio de Janeiro.

CDC/ Cynthia Goldsmith

The retrospective analysis demonstrated that there is a “spectrum of clinical manifestations” in children with congenital Zika virus syndrome, including those who “had initially been perceived as developing normally based on [head circumference],” Jessica S. Cranston, a medical student at the University of California, Los Angeles, and associates wrote in JAMA Network Open.

Previous studies have described the poor clinical outcomes in Zika virus–exposed infants with microcephaly, but the current analysis evaluated head circumference (HC) as a continuous variable and stratified outcomes according to the presence or absence of microcephaly, they explained.

In the cohort of 215 children referred to Instituto Fernandes Figueira who had laboratory-confirmed antenatal Zika virus exposure, 53 had microcephaly (cephalic perimeter z score of less than –2 standard deviations) and 162 were normocephalic, the investigators said.

The children were evaluated monthly for the first 6 months of life and then every 3 months. Neurodevelopmental evaluation with the Bayley Scales of Infant and Toddler Development, Third Edition, between 6 months and 3 years of age showed that all of those with microcephaly had abnormal neuromotor findings. All but two of the children with microcephaly had abnormal neuroimaging results, and 38 (72%) had failure to thrive, they reported.

Among the children with normocephaly at birth, 68% had abnormal neurologic findings, including hyperreflexia (27%), abnormal tone (39%), and other congenital neuromotor signs (42%). Results of neuroimaging results, primarily in the form of transfontanelle ultrasonography, were abnormal in 29% of children with normocephaly.

“Infants with a larger birth HC, within the normocephalic range (±2 SDs), had higher overall neurodevelopmental scores on the Bayley-III assessment,” Sarah B. Mulkey, MD, PhD, said in an invited commentary, “whereas infants with a smaller birth HC within the normocephalic range had lower scores in the domains of cognitive and language functions.”

If HC measurements could be combined with early neurologic data such as the results of neuroimaging or a neurological exam, she suggested, it might provide “a practical tool to help determine risk for adverse clinical outcomes in a [Zika virus–]exposed infant at birth that can be widely used in a variety of follow-up settings.”

In nutritional assessments performed for 143 children with normocephaly, 51% had failure to thrive “because of neurologic repercussions leading to poor feeding,” Ms. Cranston and associates wrote, adding that 15 of the 73 (21%) infants with normocephaly and failure to thrive developed secondary microcephaly.

Altogether, 17 of the 162 (10.5%) children with normocephaly developed microcephaly during the follow-up, with the reverse – microcephaly resolving in infants who were microcephalic at birth – occurring in 4 of the 53 (7.5%) affected infants, indicating that “head circumference was not static,” they said.

“The trajectory of head growth is critical,” said Dr. Mulkey of the Prenatal Pediatrics Institute at Children’s National Hospital in Washington. “The neurologic outcome of a child who develops postnatal microcephaly would be very concerning compared with an infant who is born with normocephaly and maintains a steady HC percentile over time.”

HC is just one piece of the puzzle, however, since children with Zika virus syndrome may exhibit “a variety of manifestations and outcomes.” This lack of certainty suggests that “careful monitoring and evaluation of children with suspected exposure is essential for ensuring early detection of possible disabilities and referral to interventional services,” the investigators wrote.

The findings of this study “are both highly statistically significant and clinically significant,”said Kevin T. Powell, MD, PhD, a pediatric hospitalist and clinical ethics consultant living in St. Louis who was not associated with the study.

“While outcomes at birth are dichotomized into those with and without microcephaly, the developmental outcomes measured at 3 years of age are on a spectrum. ... Those with microcephaly tend to be more severely affected, but many infants with small but normal-sized heads are also mild to moderately impacted. The flip side is that 64% of infected babies ended up with average or better development” based on Bayley-III evaluations, said Dr. Powell, who is a member of the Pediatric News editorial advisory board.

The study was funded by grants from the National Institute of Allergy and Infectious Diseases, the National Eye Institute, and the Thrasher Foundation and by awards from Brazil’s National Council of Scientific and Technological Development; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro. Individual investigators received fees and grants from these and other organizations.

Dr. Mulkey received a contract from the Centers for Disease Control and Prevention for technical expertise for Zika virus studies and received support for Zika studies from the Thrasher Research Fund. Dr. Powell had no relevant financial disclosures.

[email protected]

SOURCE: Cranston JS et al. JAMA Netw Open. 2020 July 7;3(7):e209303.