Pediatrics

Just like exposure to secondhand smoke, exposure to secondhand aerosols from e-cigarettes is associated with an increased risk of asthma exacerbations in children, according to a review of the 11,830 kids with asthma in the 2016 Florida Youth Tobacco survey.

diego_cervo/Thinkstock

Every year, the Florida Department of Health surveys public school children aged 11-17 years about various tobacco issues. In 2016, almost 12% of the asthmatic children in the survey said they vaped. Almost half were exposed to secondhand smoke, and a third reported exposure to secondhand vaping aerosols within the past 30 days. Overall, 21% reported an asthma attack in the past 12 months.

Using data from the Florida survey, the investigators crunched the numbers and found that secondhand aerosol exposure increased the odds of an asthma attack by 27%, independent of exposure to secondhand smoke and whether children smoked or vaped themselves (adjusted odds ratio, 1.27; 95% confidence interval, 1.11-1.47).

“Health professionals may wish to counsel asthmatic youth and their families regarding the potential risks of ENDS [electronic nicotine delivery system] use and exposure to ENDS aerosols.” Providers “may also consider including ENDS aerosol exposure as a possible trigger in asthma self-management/action plans and updating asthma home environment assessments to include exposure to ENDS aerosols,” said investigators led by medical student Jennifer Bayly, a research fellow at the National Institute on Minority Health and Health Disparities in Bethesda, Md.

About 4% of adults in the United States and 11% of high school students vape, and almost 10% of U.S. adolescents reported living with an ENDS user in 2014. Given the data, “it is likely that a substantial number of asthmatic youth are exposed,” the investigators said.

The study adds to a growing body of evidence linking e-cigarettes to asthma. There’s moderate evidence for increased cough and wheezing in adolescents who use e-cigarettes, plus an association with e-cigarette use and increased asthma exacerbations. The new study, however, is likely the first to look specifically at secondhand exposure among asthmatic children. Ingredients in vaping aerosols, including flavorings, propylene glycol, and vegetable glycerin, are physiologically active in the lungs, and may be lung irritants.

Overall, about half of the respondents were female, and two-thirds were 11-13 years old. About a third identified as Hispanic, a third as white, and just over a fifth as black. Three-quarters of the sample lived in large or midsized metropolitan areas, and close to two-thirds in stand-alone homes. Participants were considered exposed to secondhand aerosols if they reported that in the past month they were in a room or car with someone who was vaping.

The work was funded by the National Institutes of Health. The investigators had no disclosures.

aotto@mdedge.com

SOURCE: Bayly JE et al. CHEST®. 2018 Oct 22. doi: 10.1016/j.chest.2018.10.005.

Just like exposure to secondhand smoke, exposure to secondhand aerosols from e-cigarettes is associated with an increased risk of asthma exacerbations in children, according to a review of the 11,830 kids with asthma in the 2016 Florida Youth Tobacco survey.

diego_cervo/Thinkstock

Every year, the Florida Department of Health surveys public school children aged 11-17 years about various tobacco issues. In 2016, almost 12% of the asthmatic children in the survey said they vaped. Almost half were exposed to secondhand smoke, and a third reported exposure to secondhand vaping aerosols within the past 30 days. Overall, 21% reported an asthma attack in the past 12 months.

Using data from the Florida survey, the investigators crunched the numbers and found that secondhand aerosol exposure increased the odds of an asthma attack by 27%, independent of exposure to secondhand smoke and whether children smoked or vaped themselves (adjusted odds ratio, 1.27; 95% confidence interval, 1.11-1.47).

“Health professionals may wish to counsel asthmatic youth and their families regarding the potential risks of ENDS [electronic nicotine delivery system] use and exposure to ENDS aerosols.” Providers “may also consider including ENDS aerosol exposure as a possible trigger in asthma self-management/action plans and updating asthma home environment assessments to include exposure to ENDS aerosols,” said investigators led by medical student Jennifer Bayly, a research fellow at the National Institute on Minority Health and Health Disparities in Bethesda, Md.

About 4% of adults in the United States and 11% of high school students vape, and almost 10% of U.S. adolescents reported living with an ENDS user in 2014. Given the data, “it is likely that a substantial number of asthmatic youth are exposed,” the investigators said.

The study adds to a growing body of evidence linking e-cigarettes to asthma. There’s moderate evidence for increased cough and wheezing in adolescents who use e-cigarettes, plus an association with e-cigarette use and increased asthma exacerbations. The new study, however, is likely the first to look specifically at secondhand exposure among asthmatic children. Ingredients in vaping aerosols, including flavorings, propylene glycol, and vegetable glycerin, are physiologically active in the lungs, and may be lung irritants.

Overall, about half of the respondents were female, and two-thirds were 11-13 years old. About a third identified as Hispanic, a third as white, and just over a fifth as black. Three-quarters of the sample lived in large or midsized metropolitan areas, and close to two-thirds in stand-alone homes. Participants were considered exposed to secondhand aerosols if they reported that in the past month they were in a room or car with someone who was vaping.

The work was funded by the National Institutes of Health. The investigators had no disclosures.

aotto@mdedge.com

SOURCE: Bayly JE et al. CHEST®. 2018 Oct 22. doi: 10.1016/j.chest.2018.10.005.

Just like exposure to secondhand smoke, exposure to secondhand aerosols from e-cigarettes is associated with an increased risk of asthma exacerbations in children, according to a review of the 11,830 kids with asthma in the 2016 Florida Youth Tobacco survey.

diego_cervo/Thinkstock

Every year, the Florida Department of Health surveys public school children aged 11-17 years about various tobacco issues. In 2016, almost 12% of the asthmatic children in the survey said they vaped. Almost half were exposed to secondhand smoke, and a third reported exposure to secondhand vaping aerosols within the past 30 days. Overall, 21% reported an asthma attack in the past 12 months.

Using data from the Florida survey, the investigators crunched the numbers and found that secondhand aerosol exposure increased the odds of an asthma attack by 27%, independent of exposure to secondhand smoke and whether children smoked or vaped themselves (adjusted odds ratio, 1.27; 95% confidence interval, 1.11-1.47).

“Health professionals may wish to counsel asthmatic youth and their families regarding the potential risks of ENDS [electronic nicotine delivery system] use and exposure to ENDS aerosols.” Providers “may also consider including ENDS aerosol exposure as a possible trigger in asthma self-management/action plans and updating asthma home environment assessments to include exposure to ENDS aerosols,” said investigators led by medical student Jennifer Bayly, a research fellow at the National Institute on Minority Health and Health Disparities in Bethesda, Md.

About 4% of adults in the United States and 11% of high school students vape, and almost 10% of U.S. adolescents reported living with an ENDS user in 2014. Given the data, “it is likely that a substantial number of asthmatic youth are exposed,” the investigators said.

The study adds to a growing body of evidence linking e-cigarettes to asthma. There’s moderate evidence for increased cough and wheezing in adolescents who use e-cigarettes, plus an association with e-cigarette use and increased asthma exacerbations. The new study, however, is likely the first to look specifically at secondhand exposure among asthmatic children. Ingredients in vaping aerosols, including flavorings, propylene glycol, and vegetable glycerin, are physiologically active in the lungs, and may be lung irritants.

Overall, about half of the respondents were female, and two-thirds were 11-13 years old. About a third identified as Hispanic, a third as white, and just over a fifth as black. Three-quarters of the sample lived in large or midsized metropolitan areas, and close to two-thirds in stand-alone homes. Participants were considered exposed to secondhand aerosols if they reported that in the past month they were in a room or car with someone who was vaping.

The work was funded by the National Institutes of Health. The investigators had no disclosures.

aotto@mdedge.com

SOURCE: Bayly JE et al. CHEST®. 2018 Oct 22. doi: 10.1016/j.chest.2018.10.005.

Sleep problems in children diagnosed with attention-deficit/hyperactivity disorder are treated with a variety of medications, many off label for sleep and unstudied for safety and effectiveness in children, a study of Medicaid prescriptions has found.

“Sleep disorders coexist with attention-deficit/hyperactivity disorder (ADHD) for many children and are associated with neuropsychiatric, physiologic, and medication-related outcomes,” wrote Tracy Klein, PhD, of Washington State University, Vancouver, and her colleagues. The report is in the Journal of Pediatric Health Care. These patients can have sleep disordered breathing and behavioral issues occurring around bedtime. Known adverse effects of the stimulant and nonstimulant medications used to treat ADHD can include sleep disturbance, delayed circadian rhythm, insomnia, and somnolence. Yet, research on both sleep problems in children with ADHD and prescribing patterns is scanty, according to the investigators.

Dr. Klein and her colleagues conducted a study aimed at identifying the off-label medications being prescribed to potentiate sleep in children with ADHD, and the characteristics of the children and their prescribers. They used 5 years of pharmacy claims for children in Oregon insured through Medicaid and had a provider diagnosis of ADHD during Jan. 1, 2012, to Dec. 31, 2016. The children were aged 3-18 years and the prescriptions measured were the number of 30-day prescriptions. Prescribers were identified by national provider identifier taxonomies (nurse, physician, other prescriber), and classified as either generalist or specialist. The medications were classified as controlled or uncontrolled as determined by Title 21 of the U.S. Controlled Substances Act.

The data yielded 14,567 prescriptions for 2,518 children for a 30-day supply of medication known to potentiate sleep but off-label for children. Children aged 3-11 years comprised about 38% of these patients. Some children were prescribed more than one of these medications. Medications specifically on label for sleep but not indicated for children were not included. Those medications indicated for comorbid conditions and those indicated for ADHD that specifically cause somnolence were excluded.

The uncontrolled medications prescribed in this sample were amitriptyline, doxepin, hydroxyzine, low-dose quetiapine, and trazodone. The controlled medications identified were clonazepam and lorazepam, and a few prescriptions for phenobarbital.

Most of the prescriptions (63.8%) went to older children aged 12-18 years and most prescriptions (66.3%) went to males. The most commonly prescribed noncontrolled medication was trazodone (5,190 prescriptions), followed by hydroxyzine (2,539), and quetiapine (2,402). The most frequently prescribed controlled medication was clonazepam (2,145), followed by lorazepam (534).

Specialist prescribers wrote most of the prescriptions for this patient group, but no differences were found in prescribing patterns between specialists and generalists.

Dr. Klein and her colleagues noted that 871 unique children were prescribed 5,190 30-day−supply prescriptions for trazodone, including 23 children under age 5. Trazodone is a serotonin modulator indicated for the treatment of major depressive disorder, but has not been studied for safety and efficacy in children and has no Food and Drug Administration indication for children. “Hydroxyzine, quetiapine, and amitriptyline also were prescribed for a large number of children, including some for children as young as 3 years, despite lack of approval for use to induce to sleep and increased potential for significant adverse reactions in children,” they wrote.

Dr. Klein suggested that prescribers receive pressure from families to “do something” for their children, who may be disruptive day and night. “Prescribers may be unaware that trazodone, which is commonly used in practice, has never been approved for treatment of insomnia in children or adults. Insurance may not adequately fund other options, such as extensive behavioral therapy,” she stated in an interview. These medications come with some risk for children, Dr. Klein noted.

“Developmentally, [children] may be unable to verbally express the side effects they are feeling and may therefore be subject to a drug to treat a drug side effect, especially if their reaction to it is behavioral.” There is also potential for unanticipated drug interactions between off-label medications prescribed for sleep and drugs prescribed to treat ADHD.

This study has limitations related to the absence of detailed clinical explanatory information found in claims data. Information on adherence to treatment and adverse events, for example, is not contained in claims data. The study does not address the overall rates of sleep disorders in children with ADHD nor the percentage of children with ADHD who are prescribed any medication to potentiate sleep but looks at which off-label drugs are being prescribed, to which children, and by whom.

“Most medications prescribed in this study, used to induce sleep or treat insomnia, have not been studied for safety and efficacy in children, and their use should not be extrapolated from adult studies,” the researchers concluded.

They reported having no disclosures.

tborden@mdedge.com

SOURCE: Klein T et al. J Pediatr Health Care. 2018 Jan 8. doi: 10.1016/j.pedhc.2018.10.002.

Sleep problems in children diagnosed with attention-deficit/hyperactivity disorder are treated with a variety of medications, many off label for sleep and unstudied for safety and effectiveness in children, a study of Medicaid prescriptions has found.

“Sleep disorders coexist with attention-deficit/hyperactivity disorder (ADHD) for many children and are associated with neuropsychiatric, physiologic, and medication-related outcomes,” wrote Tracy Klein, PhD, of Washington State University, Vancouver, and her colleagues. The report is in the Journal of Pediatric Health Care. These patients can have sleep disordered breathing and behavioral issues occurring around bedtime. Known adverse effects of the stimulant and nonstimulant medications used to treat ADHD can include sleep disturbance, delayed circadian rhythm, insomnia, and somnolence. Yet, research on both sleep problems in children with ADHD and prescribing patterns is scanty, according to the investigators.

Dr. Klein and her colleagues conducted a study aimed at identifying the off-label medications being prescribed to potentiate sleep in children with ADHD, and the characteristics of the children and their prescribers. They used 5 years of pharmacy claims for children in Oregon insured through Medicaid and had a provider diagnosis of ADHD during Jan. 1, 2012, to Dec. 31, 2016. The children were aged 3-18 years and the prescriptions measured were the number of 30-day prescriptions. Prescribers were identified by national provider identifier taxonomies (nurse, physician, other prescriber), and classified as either generalist or specialist. The medications were classified as controlled or uncontrolled as determined by Title 21 of the U.S. Controlled Substances Act.

The data yielded 14,567 prescriptions for 2,518 children for a 30-day supply of medication known to potentiate sleep but off-label for children. Children aged 3-11 years comprised about 38% of these patients. Some children were prescribed more than one of these medications. Medications specifically on label for sleep but not indicated for children were not included. Those medications indicated for comorbid conditions and those indicated for ADHD that specifically cause somnolence were excluded.

The uncontrolled medications prescribed in this sample were amitriptyline, doxepin, hydroxyzine, low-dose quetiapine, and trazodone. The controlled medications identified were clonazepam and lorazepam, and a few prescriptions for phenobarbital.

Most of the prescriptions (63.8%) went to older children aged 12-18 years and most prescriptions (66.3%) went to males. The most commonly prescribed noncontrolled medication was trazodone (5,190 prescriptions), followed by hydroxyzine (2,539), and quetiapine (2,402). The most frequently prescribed controlled medication was clonazepam (2,145), followed by lorazepam (534).

Specialist prescribers wrote most of the prescriptions for this patient group, but no differences were found in prescribing patterns between specialists and generalists.

Dr. Klein and her colleagues noted that 871 unique children were prescribed 5,190 30-day−supply prescriptions for trazodone, including 23 children under age 5. Trazodone is a serotonin modulator indicated for the treatment of major depressive disorder, but has not been studied for safety and efficacy in children and has no Food and Drug Administration indication for children. “Hydroxyzine, quetiapine, and amitriptyline also were prescribed for a large number of children, including some for children as young as 3 years, despite lack of approval for use to induce to sleep and increased potential for significant adverse reactions in children,” they wrote.

Dr. Klein suggested that prescribers receive pressure from families to “do something” for their children, who may be disruptive day and night. “Prescribers may be unaware that trazodone, which is commonly used in practice, has never been approved for treatment of insomnia in children or adults. Insurance may not adequately fund other options, such as extensive behavioral therapy,” she stated in an interview. These medications come with some risk for children, Dr. Klein noted.

“Developmentally, [children] may be unable to verbally express the side effects they are feeling and may therefore be subject to a drug to treat a drug side effect, especially if their reaction to it is behavioral.” There is also potential for unanticipated drug interactions between off-label medications prescribed for sleep and drugs prescribed to treat ADHD.

This study has limitations related to the absence of detailed clinical explanatory information found in claims data. Information on adherence to treatment and adverse events, for example, is not contained in claims data. The study does not address the overall rates of sleep disorders in children with ADHD nor the percentage of children with ADHD who are prescribed any medication to potentiate sleep but looks at which off-label drugs are being prescribed, to which children, and by whom.

“Most medications prescribed in this study, used to induce sleep or treat insomnia, have not been studied for safety and efficacy in children, and their use should not be extrapolated from adult studies,” the researchers concluded.

They reported having no disclosures.

tborden@mdedge.com

SOURCE: Klein T et al. J Pediatr Health Care. 2018 Jan 8. doi: 10.1016/j.pedhc.2018.10.002.

Sleep problems in children diagnosed with attention-deficit/hyperactivity disorder are treated with a variety of medications, many off label for sleep and unstudied for safety and effectiveness in children, a study of Medicaid prescriptions has found.

“Sleep disorders coexist with attention-deficit/hyperactivity disorder (ADHD) for many children and are associated with neuropsychiatric, physiologic, and medication-related outcomes,” wrote Tracy Klein, PhD, of Washington State University, Vancouver, and her colleagues. The report is in the Journal of Pediatric Health Care. These patients can have sleep disordered breathing and behavioral issues occurring around bedtime. Known adverse effects of the stimulant and nonstimulant medications used to treat ADHD can include sleep disturbance, delayed circadian rhythm, insomnia, and somnolence. Yet, research on both sleep problems in children with ADHD and prescribing patterns is scanty, according to the investigators.

Dr. Klein and her colleagues conducted a study aimed at identifying the off-label medications being prescribed to potentiate sleep in children with ADHD, and the characteristics of the children and their prescribers. They used 5 years of pharmacy claims for children in Oregon insured through Medicaid and had a provider diagnosis of ADHD during Jan. 1, 2012, to Dec. 31, 2016. The children were aged 3-18 years and the prescriptions measured were the number of 30-day prescriptions. Prescribers were identified by national provider identifier taxonomies (nurse, physician, other prescriber), and classified as either generalist or specialist. The medications were classified as controlled or uncontrolled as determined by Title 21 of the U.S. Controlled Substances Act.

The data yielded 14,567 prescriptions for 2,518 children for a 30-day supply of medication known to potentiate sleep but off-label for children. Children aged 3-11 years comprised about 38% of these patients. Some children were prescribed more than one of these medications. Medications specifically on label for sleep but not indicated for children were not included. Those medications indicated for comorbid conditions and those indicated for ADHD that specifically cause somnolence were excluded.

The uncontrolled medications prescribed in this sample were amitriptyline, doxepin, hydroxyzine, low-dose quetiapine, and trazodone. The controlled medications identified were clonazepam and lorazepam, and a few prescriptions for phenobarbital.

Most of the prescriptions (63.8%) went to older children aged 12-18 years and most prescriptions (66.3%) went to males. The most commonly prescribed noncontrolled medication was trazodone (5,190 prescriptions), followed by hydroxyzine (2,539), and quetiapine (2,402). The most frequently prescribed controlled medication was clonazepam (2,145), followed by lorazepam (534).

Specialist prescribers wrote most of the prescriptions for this patient group, but no differences were found in prescribing patterns between specialists and generalists.

Dr. Klein and her colleagues noted that 871 unique children were prescribed 5,190 30-day−supply prescriptions for trazodone, including 23 children under age 5. Trazodone is a serotonin modulator indicated for the treatment of major depressive disorder, but has not been studied for safety and efficacy in children and has no Food and Drug Administration indication for children. “Hydroxyzine, quetiapine, and amitriptyline also were prescribed for a large number of children, including some for children as young as 3 years, despite lack of approval for use to induce to sleep and increased potential for significant adverse reactions in children,” they wrote.

Dr. Klein suggested that prescribers receive pressure from families to “do something” for their children, who may be disruptive day and night. “Prescribers may be unaware that trazodone, which is commonly used in practice, has never been approved for treatment of insomnia in children or adults. Insurance may not adequately fund other options, such as extensive behavioral therapy,” she stated in an interview. These medications come with some risk for children, Dr. Klein noted.

“Developmentally, [children] may be unable to verbally express the side effects they are feeling and may therefore be subject to a drug to treat a drug side effect, especially if their reaction to it is behavioral.” There is also potential for unanticipated drug interactions between off-label medications prescribed for sleep and drugs prescribed to treat ADHD.

This study has limitations related to the absence of detailed clinical explanatory information found in claims data. Information on adherence to treatment and adverse events, for example, is not contained in claims data. The study does not address the overall rates of sleep disorders in children with ADHD nor the percentage of children with ADHD who are prescribed any medication to potentiate sleep but looks at which off-label drugs are being prescribed, to which children, and by whom.

“Most medications prescribed in this study, used to induce sleep or treat insomnia, have not been studied for safety and efficacy in children, and their use should not be extrapolated from adult studies,” the researchers concluded.

They reported having no disclosures.

tborden@mdedge.com

SOURCE: Klein T et al. J Pediatr Health Care. 2018 Jan 8. doi: 10.1016/j.pedhc.2018.10.002.

NEW ORLEANS – The onset of pediatric refractory status epilepticus follows a circadian pattern, according to research presented at the annual meeting of the American Epilepsy Society. The number of episodes is greatest between 10 a.m. and 11 a.m. and smallest between 10 p.m. and 11 p.m.

“Our findings may inform the increase in preventive monitoring, such as video monitoring or seizure-tracking devices for patients,” said Justice Clark, MPH, a program coordinator at Boston Children’s Hospital. “They may also inform chronotherapeutic strategies.”

Research suggests that various types of seizures cluster at different times of the day. Data about the circadian distribution of status epilepticus, however, are limited.

Ms. Clark and colleagues conducted a prospective observational study at 25 hospitals in the United States and Canada from June 2011 to January 2018. Eligible participants were between ages 1 month and 21 years, had focal or generalized convulsive status epilepticus, and had failed to respond to one benzodiazepine and one nonbenzodiazepine antiseizure medication. For patients with more than one episode of refractory status epilepticus during the study, the researchers included only the first episode.

The investigators examined whether the temporal distribution of pediatric refractory status epilepticus onset followed a circadian pattern using a cosinor analysis with a 12-hour cycle. They used the midline-estimating statistic of rhythm (MESOR) technique to estimate the mean number of refractory status epilepticus episodes per hour if onset was evenly distributed. The amplitude in this analysis was the difference in number of episodes per hour between the MESOR and the peak or the MESOR and the trough.

Ms. Clark and her colleagues included 300 patients in their analysis, each of whom had one episode. Approximately 45% of participants were female. The population’s median age was 4.2 years, and the median duration of status epilepticus was 120 minutes.

The MESOR was 12.5 episodes per hour, and the amplitude was 2.4 episodes per hour, indicating that the distribution was not even over 24 hours. The peak number of onsets was between 10 a.m. and 11 a.m., and the trough was between 10 p.m. and 11 p.m.

A secondary analysis examined the circadian distribution of time to treatment with rescue medications. The distribution of time to treatment with the first benzodiazepine did not differ significantly from a uniform distribution. The time to treatment with the first nonbenzodiazepine antiseizure medication, however, was not uniformly distributed. The longest time to treatment occurred between 3 a.m. and 4 a.m., and the shortest time was between 3 p.m. and 4 p.m. “Although fewer refractory status epilepticus episodes occurred at night, the time to antiseizure medication administration was the longest [during that period]. Thus, nighttime refractory status epilepticus episodes may be at higher risk for delayed treatment,” said Ms. Clark. A limitation of this analysis is that it was influenced by outliers, she added.

The Pediatric Epilepsy Research Foundation and the Epilepsy Research Fund supported the study.

egreb@mdedge.com

SOURCE: Clark J et al. AES 2018. Abstract 3.426.

NEW ORLEANS – The onset of pediatric refractory status epilepticus follows a circadian pattern, according to research presented at the annual meeting of the American Epilepsy Society. The number of episodes is greatest between 10 a.m. and 11 a.m. and smallest between 10 p.m. and 11 p.m.

“Our findings may inform the increase in preventive monitoring, such as video monitoring or seizure-tracking devices for patients,” said Justice Clark, MPH, a program coordinator at Boston Children’s Hospital. “They may also inform chronotherapeutic strategies.”

Research suggests that various types of seizures cluster at different times of the day. Data about the circadian distribution of status epilepticus, however, are limited.

Ms. Clark and colleagues conducted a prospective observational study at 25 hospitals in the United States and Canada from June 2011 to January 2018. Eligible participants were between ages 1 month and 21 years, had focal or generalized convulsive status epilepticus, and had failed to respond to one benzodiazepine and one nonbenzodiazepine antiseizure medication. For patients with more than one episode of refractory status epilepticus during the study, the researchers included only the first episode.

The investigators examined whether the temporal distribution of pediatric refractory status epilepticus onset followed a circadian pattern using a cosinor analysis with a 12-hour cycle. They used the midline-estimating statistic of rhythm (MESOR) technique to estimate the mean number of refractory status epilepticus episodes per hour if onset was evenly distributed. The amplitude in this analysis was the difference in number of episodes per hour between the MESOR and the peak or the MESOR and the trough.

Ms. Clark and her colleagues included 300 patients in their analysis, each of whom had one episode. Approximately 45% of participants were female. The population’s median age was 4.2 years, and the median duration of status epilepticus was 120 minutes.

The MESOR was 12.5 episodes per hour, and the amplitude was 2.4 episodes per hour, indicating that the distribution was not even over 24 hours. The peak number of onsets was between 10 a.m. and 11 a.m., and the trough was between 10 p.m. and 11 p.m.

A secondary analysis examined the circadian distribution of time to treatment with rescue medications. The distribution of time to treatment with the first benzodiazepine did not differ significantly from a uniform distribution. The time to treatment with the first nonbenzodiazepine antiseizure medication, however, was not uniformly distributed. The longest time to treatment occurred between 3 a.m. and 4 a.m., and the shortest time was between 3 p.m. and 4 p.m. “Although fewer refractory status epilepticus episodes occurred at night, the time to antiseizure medication administration was the longest [during that period]. Thus, nighttime refractory status epilepticus episodes may be at higher risk for delayed treatment,” said Ms. Clark. A limitation of this analysis is that it was influenced by outliers, she added.

The Pediatric Epilepsy Research Foundation and the Epilepsy Research Fund supported the study.

egreb@mdedge.com

SOURCE: Clark J et al. AES 2018. Abstract 3.426.

NEW ORLEANS – The onset of pediatric refractory status epilepticus follows a circadian pattern, according to research presented at the annual meeting of the American Epilepsy Society. The number of episodes is greatest between 10 a.m. and 11 a.m. and smallest between 10 p.m. and 11 p.m.

“Our findings may inform the increase in preventive monitoring, such as video monitoring or seizure-tracking devices for patients,” said Justice Clark, MPH, a program coordinator at Boston Children’s Hospital. “They may also inform chronotherapeutic strategies.”

Research suggests that various types of seizures cluster at different times of the day. Data about the circadian distribution of status epilepticus, however, are limited.

Ms. Clark and colleagues conducted a prospective observational study at 25 hospitals in the United States and Canada from June 2011 to January 2018. Eligible participants were between ages 1 month and 21 years, had focal or generalized convulsive status epilepticus, and had failed to respond to one benzodiazepine and one nonbenzodiazepine antiseizure medication. For patients with more than one episode of refractory status epilepticus during the study, the researchers included only the first episode.

The investigators examined whether the temporal distribution of pediatric refractory status epilepticus onset followed a circadian pattern using a cosinor analysis with a 12-hour cycle. They used the midline-estimating statistic of rhythm (MESOR) technique to estimate the mean number of refractory status epilepticus episodes per hour if onset was evenly distributed. The amplitude in this analysis was the difference in number of episodes per hour between the MESOR and the peak or the MESOR and the trough.

Ms. Clark and her colleagues included 300 patients in their analysis, each of whom had one episode. Approximately 45% of participants were female. The population’s median age was 4.2 years, and the median duration of status epilepticus was 120 minutes.

The MESOR was 12.5 episodes per hour, and the amplitude was 2.4 episodes per hour, indicating that the distribution was not even over 24 hours. The peak number of onsets was between 10 a.m. and 11 a.m., and the trough was between 10 p.m. and 11 p.m.

A secondary analysis examined the circadian distribution of time to treatment with rescue medications. The distribution of time to treatment with the first benzodiazepine did not differ significantly from a uniform distribution. The time to treatment with the first nonbenzodiazepine antiseizure medication, however, was not uniformly distributed. The longest time to treatment occurred between 3 a.m. and 4 a.m., and the shortest time was between 3 p.m. and 4 p.m. “Although fewer refractory status epilepticus episodes occurred at night, the time to antiseizure medication administration was the longest [during that period]. Thus, nighttime refractory status epilepticus episodes may be at higher risk for delayed treatment,” said Ms. Clark. A limitation of this analysis is that it was influenced by outliers, she added.

The Pediatric Epilepsy Research Foundation and the Epilepsy Research Fund supported the study.

egreb@mdedge.com

SOURCE: Clark J et al. AES 2018. Abstract 3.426.

The definition of warts is variable, largely reflecting their manifold appearance, biologic potential, and public health concerns. One vernacular dictionary defines warts as:

Small, benign growths caused by a vital infection of the skin or mucous membrane. The virus infects the surface layer. The viruses that cause warts are members of the human papilloma virus (HPV) family. Warts are not cancerous but some strains of HPV, usually not associated with warts, have been linked with cancer formation. Warts are contagious from person to person and from one area of the body to another on the same person.¹

The World Health Organization defines warts by their structural components as:

Human papillomavirus (HPV) is a small, non-enveloped deoxyribonucleic acid (DNA) virus that infects skin or mucosal cells. The circular, double-stranded viral genome is approximately 8-kb in length. The genome encodes for 6 early proteins responsible for virus replication and 2 late proteins, L1 and L2, which are the viral structural proteins.²

In pediatric and adolescent dermatology, warts often are defined by their location and morphology; for example, facial warts typically are flat, minimally hyperkeratotic, or filiform, wherein the base is narrow and the lesion is tall, growing at a 90° angle to the surface of the skin. On the arms and legs, warts usually present as round to oval papules with overlying thick hyperkeratosis and/or callosity.^3,4 Common warts usually are flesh colored or lighter, and heavily pigmented lesions should be evaluated dermoscopically for a pigment network and biopsied when pigment is present.⁵

In this article, a successful paradigm for management of pediatric warts is provided with enhanced outcomes based on further insight into the disease course and patient selection.

Epidemiology of Pediatric Warts

There are more than 200 types of human papillomaviruses (HPV), with more than 100 oncogenic types. There is quite a bit of homology by species and genus that contributes to cross-immunity and similar behavior between certain types of HPV. The lifetime incidence of warts is very high. Approximately 30% of children develop a wart.⁶ A review of the 2007 National Health Interview Survey of 9417 children demonstrated a steady increase in prevalence of warts from 1 to 2 years of age to 7 to 8 years of age, with a peak at 9 to 10 years of age and a plateau at 11 to 17 years of age. Warts were most common in non-Hispanic white children and less common in black children.⁷ In an in-person survey of 12,370 individuals aged 18 to 74 years from 5 European countries, warts were the most common physician-diagnosed (27.3%) and self-reported (41.0%) dermatologic condition. Warts are more common in Northern countries (eg, Netherlands, Germany).⁸ Children with atopic dermatitis have a higher risk of developing warts and extracutaneous infections. In one study, children with warts and atopic dermatitis had a higher number of infections and food allergies and higher incidence of asthma and hay fever than either condition alone.⁹

Clinical Presentation of Warts

Warts usually present as common, palmoplantar, flat, or filiform in childhood, but variations by age are common (eFigure). The common and palmoplantar variants often are caused by HPV types 1 and 2.^4,5 In infancy, vertically transmitted HPV infections can cause juvenile-onset respiratory papillomatosis or vertically transmitted condyloma. Juvenile-onset respiratory papillomatosis refers to upper respiratory papillomas that are difficult to eliminate and has been associated with exfoliated cervical cell testing with 18.1% (13/72) typed HPV-positive, which allows neonates to be exposed to HPV in the upper respiratory tract in utero.¹⁰

Vertically transmitted condyloma is a difficult topic. Much data supports the vertical transmission of condyloma as the leading cause of condyloma in small children; however, a reasonable amount of caution is needed in this patient population. In cases suspicious for sexual abuse as well as those presenting in children 4 years and older, formal household evaluation by a sexual abuse clinic and mandatory reporting is needed. Anywhere from 2.6% to 32% of cases of genital warts in children have been reported to be caused by sexual abuse.^11-13 Therefore, most investigators have recommended careful review of the patient’s history and socioeconomic circumstances as well as a thorough physical examination. Mandatory reporting of suspected child sexual abuse is required in suspicious cases. Because HPV type 16 has been found in vertically transmitted cases, concern for long-term oncogenesis exists.^11-13

Adolescents generally present with lesions on the hands and feet. Plantar warts often are caused by HPV types from the alpha genus. Subtypes noted in plantar warts include HPV types 1a, 2, 27, 57, and 65.¹⁴ By 15 years of age, genital HPV becomes a common adolescent infection, persisting into adulthood.¹⁵ When studied, genital HPV often is subclinical or latent and often is preventable through vaccination. High-risk oncogenic alpha-genus HPV types can immortalize human keratinocytes. When HPV types 11, 16, 18, and 31 are compared, HPV-18 has the highest oncogenic potential based on colony-stimulating potential.¹⁶ Vaccination with the 9-valent HPV vaccine is recommended in adolescence due to the concern for exposures to both low-potential (HPV types 6 and 11) and high-potential (HPV types 16 and 18) oncogenic HPV types. Data strongly support the benefit of 9-valent HPV vaccination in the prevention of sexually transmitted HPV in both males and females.¹⁷

Contagion of HPV is easy due to its excellent survival of fomites on surfaces, which generally is how warts are transferred in gym or pool settings where individuals who walk barefoot in changing rooms are almost twice as likely to contract plantar warts (odds ratio, 1.97 [95% CI, 1.39%-2.79%]).¹⁸ In another case series, walking barefoot, using a swimming pool, and having a household contact with warts were the leading risk factors for contraction of warts in children younger than 13 years.¹⁹ Children often transfer warts from site to site as well as to siblings and other close contacts. Skin-to-skin contact is responsible for sexual transmission of warts, and surface transmission occurs via fomites. Entry of the virus often occurs through small breaks in the skin. Other modes of transmission include orogenital.²⁰

Therapeutic Options

Although the nuances of each available treatment for pediatric warts are beyond the scope of this article, the main core of therapy is 1 of 3 approaches: (1) observation, (2) over-the-counter salicylic acid therapy, and (3) in-office cryotherapy. Observation is an affirmed style of therapy for warts, as it is expected that two-thirds of warts will spontaneously resolve in 2 years and three-quarters will resolve in 3 years.^4,5 Condyloma in children has been responsive to therapies such as cryotherapy and imiquimod,¹³ but spontaneous clearance in 5 years has been noted in 76% of children,²¹ which is linked to development of spontaneous immune response in most individuals.

Therapies for pediatric warts are characterized according to 6 major categories: destructive; immune stimulating; immune modulating, including normalization of epithelial growth; irritant; vascular destructive; and nitric oxide releasing (eTable).

Immune-Stimulating Therapies                                                                                                                                                                                                                         
Immune stimulants often are used to treat warts in children and adolescents who have many lesions, a prolonged disease course, disfigurement, and/or subungual localizations, as well as in those who have been treated with multiple destructive methods without success. Topical imiquimod and oral cimetidine are readily available, while squaric acid (at-home or in-office therapy) and intralesional candida antigen can be used in offices that carry these agents. Topical imiquimod has been reported to achieve success in genital warts in children,¹³ with good efficacy in recalcitrant, periungual, and subungual warts when used for up to 16 weeks.³¹ In one randomized clinical trial, imiquimod cream 5% combined with salicylic acid 15% was applied to warts for 6 to 10 hours for 5 consecutive days per week versus cryotherapy with liquid nitrogen every 2 weeks for a maximum of 3 months. At the end of the study period, 81.1% (30/37) of participants treated with imiquimod and salicylic acid showed clearance of their warts versus 67.3% (33/49) of those treated with cryotherapy.³²

Oral cimetidine has been reported to be successful in treating recalcitrant warts in more than 80% of children when dosed at 30 to 40 mg/kg 3 times daily, requiring 6 to 12 weeks to achieve clearance. Side effects of oral cimetidine include many cytochrome P450 interactions; gynecomastia, which limits usage in teenaged males; and stomach upset.³⁰

Treatment of recalcitrant pediatric warts with intralesional candida antigen has been associated with side effects consistent with delayed-type hypersensitivity reactions. Injections should be administered once monthly, with a minimum of 3 cycles if not effective and up to 6 cycles where partial efficacy is noted. In a retrospective review of 220 cases, 70.9% of children showed complete clearance and 16.8% had partial response.³³ However, the treatment may be limited in children by fear of needles.

Squaric acid dibutyl ester is a universal allergen that is not mutagenic on Ames testing and causes milder allergy symptoms than the mutagenic dinitrochlorobenzene and less erythema and pruritus than diphencyclopropenone. Squaric acid dibutyl ester home therapy was evaluated in 61 children with at least one nonfacial wart.³⁴ Application began with squaric acid dibutyl ester in acetone (SADBE) 2% sensitization on the arm followed by at-home application of SADBE 0.2% three to seven times weekly for a minimum of 2 months to determine benefit and for 3 to 4 months as needed; however, average response was 7 weeks. The average complete clearance was 58% and partial clearance was 18%. Side effects included erythema and mild itching as well as urticaria in one case.³⁴ In-office SADBE also has been evaluated in children. In a case series that included 29 children sensitized with SADBE 1% to 2% under occlusion followed by once monthly application of SADBE 0.5% to 5.0% to their warts, 69% clearance and 10% partial clearance was noted after a little more than 4 months of treatment.³⁵ One retrospective review compared combination SADBE, trichloroacetic acid (TCA), and cantharidin both alone and in combination as duos (eg, SADBE and TCA) or trios (SADBE, TCA, and cantharidin).²³ Of the 74 children whose medical charts were reviewed, the addition of pretreatment of warts with TCA 50% prior to in-office sensitization and monthly in-office application of SADBE increased treatment response to 100% with an average 2.45 months of therapy, whereas no enhancement was noted with cantharidin. Therefore, it appears that there may be enhanced immune reactivity when TCA pretreatment of warts is performed.²³

Immune-Modulating Therapies (Including Normalization of Epithelial Growth)
The most novel immunologic therapy for warts is plerixafor, an agent used to treat WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, which has been linked to heterozygous gain of function mutations in the chemokine receptor CXCR4 (located on 2q22). In WHIM syndrome, the mutated CXCR4 is more sensitive to CXCL12 activation. Plerixafor is a selective reversible antagonist that blocks the capacity of the chemokine CXCL12 to sustain the permanent activation of CXCR4.³⁷ Combination therapy with plerixafor and topical imiquimod has resulted in wart improvement in WHIM syndrome patients in a small series.³⁸

Oral isotretinoin has been described to be efficacious over placebo at a dosage of 30 mg daily for 12 weeks and can be used in teenagers but requires standard monitoring.³⁶

Nitric Oxide–Releasing Therapies                                                                                                                                                                                                                         
Nitric oxide release may increase local blood flow, thereby increasing immune response, or may have a primary mechanism of antimicrobial activity, which is why these agents have been investigated for wart treatment. Topical garlic has been described anecdotally as a therapy for thin childhood warts with the putative mechanism being nitric oxide release.⁴² A new investigational drug recently has had phase 2 data published. Berdazimer sodium plus carboxymethyl cellulose hydrogel has demonstrated benefit in adult warts, but data in children is lacking.⁴¹

Therapeutic Ladder for Childhood Warts

The therapeutic ladder (Table) for childhood warts starts with first doing no harm. Although many parents are disturbed by their child’s condition, the natural history of resolution is spontaneous and therefore no therapy is required in many cases. The child and his/her caregivers should be engaged to determine if he/she is emotionally disturbed or uncomfortable with their lesions and to address any fears and concerns that some children may experience (eg, contagion risk, pain with ambulation, ostracism). For example, children with hand warts may report that other children will not hold their hand while in line at school. Prominent facial lesions can be particularly problematic for children due to teasing and bullying.

Conclusion

Warts are a common infection in childhood caused by the ubiquitous HPV virus. Therapeutic options abound, but most cases are either ignored or treated with over-the-counter salicylic acid or in-office cryotherapy. The decision to employ alternative therapeutic options requires agreement by the child, his/her caregiver, and the treating physician and can be tailored to suit the desires and needs of the child. Whether or not therapy is offered, spontaneous clearance is frequently seen in common warts. On the other hand, genital warts are associated with later conversion to malignancies of the genital tract; therefore, encouragement of HPV vaccination is needed in the adolescent population to best ensure long-term genital health.

The definition of warts is variable, largely reflecting their manifold appearance, biologic potential, and public health concerns. One vernacular dictionary defines warts as:

Small, benign growths caused by a vital infection of the skin or mucous membrane. The virus infects the surface layer. The viruses that cause warts are members of the human papilloma virus (HPV) family. Warts are not cancerous but some strains of HPV, usually not associated with warts, have been linked with cancer formation. Warts are contagious from person to person and from one area of the body to another on the same person.¹

The World Health Organization defines warts by their structural components as:

Human papillomavirus (HPV) is a small, non-enveloped deoxyribonucleic acid (DNA) virus that infects skin or mucosal cells. The circular, double-stranded viral genome is approximately 8-kb in length. The genome encodes for 6 early proteins responsible for virus replication and 2 late proteins, L1 and L2, which are the viral structural proteins.²

In pediatric and adolescent dermatology, warts often are defined by their location and morphology; for example, facial warts typically are flat, minimally hyperkeratotic, or filiform, wherein the base is narrow and the lesion is tall, growing at a 90° angle to the surface of the skin. On the arms and legs, warts usually present as round to oval papules with overlying thick hyperkeratosis and/or callosity.^3,4 Common warts usually are flesh colored or lighter, and heavily pigmented lesions should be evaluated dermoscopically for a pigment network and biopsied when pigment is present.⁵

In this article, a successful paradigm for management of pediatric warts is provided with enhanced outcomes based on further insight into the disease course and patient selection.

Epidemiology of Pediatric Warts

There are more than 200 types of human papillomaviruses (HPV), with more than 100 oncogenic types. There is quite a bit of homology by species and genus that contributes to cross-immunity and similar behavior between certain types of HPV. The lifetime incidence of warts is very high. Approximately 30% of children develop a wart.⁶ A review of the 2007 National Health Interview Survey of 9417 children demonstrated a steady increase in prevalence of warts from 1 to 2 years of age to 7 to 8 years of age, with a peak at 9 to 10 years of age and a plateau at 11 to 17 years of age. Warts were most common in non-Hispanic white children and less common in black children.⁷ In an in-person survey of 12,370 individuals aged 18 to 74 years from 5 European countries, warts were the most common physician-diagnosed (27.3%) and self-reported (41.0%) dermatologic condition. Warts are more common in Northern countries (eg, Netherlands, Germany).⁸ Children with atopic dermatitis have a higher risk of developing warts and extracutaneous infections. In one study, children with warts and atopic dermatitis had a higher number of infections and food allergies and higher incidence of asthma and hay fever than either condition alone.⁹

Clinical Presentation of Warts

Warts usually present as common, palmoplantar, flat, or filiform in childhood, but variations by age are common (eFigure). The common and palmoplantar variants often are caused by HPV types 1 and 2.^4,5 In infancy, vertically transmitted HPV infections can cause juvenile-onset respiratory papillomatosis or vertically transmitted condyloma. Juvenile-onset respiratory papillomatosis refers to upper respiratory papillomas that are difficult to eliminate and has been associated with exfoliated cervical cell testing with 18.1% (13/72) typed HPV-positive, which allows neonates to be exposed to HPV in the upper respiratory tract in utero.¹⁰

Vertically transmitted condyloma is a difficult topic. Much data supports the vertical transmission of condyloma as the leading cause of condyloma in small children; however, a reasonable amount of caution is needed in this patient population. In cases suspicious for sexual abuse as well as those presenting in children 4 years and older, formal household evaluation by a sexual abuse clinic and mandatory reporting is needed. Anywhere from 2.6% to 32% of cases of genital warts in children have been reported to be caused by sexual abuse.^11-13 Therefore, most investigators have recommended careful review of the patient’s history and socioeconomic circumstances as well as a thorough physical examination. Mandatory reporting of suspected child sexual abuse is required in suspicious cases. Because HPV type 16 has been found in vertically transmitted cases, concern for long-term oncogenesis exists.^11-13

Adolescents generally present with lesions on the hands and feet. Plantar warts often are caused by HPV types from the alpha genus. Subtypes noted in plantar warts include HPV types 1a, 2, 27, 57, and 65.¹⁴ By 15 years of age, genital HPV becomes a common adolescent infection, persisting into adulthood.¹⁵ When studied, genital HPV often is subclinical or latent and often is preventable through vaccination. High-risk oncogenic alpha-genus HPV types can immortalize human keratinocytes. When HPV types 11, 16, 18, and 31 are compared, HPV-18 has the highest oncogenic potential based on colony-stimulating potential.¹⁶ Vaccination with the 9-valent HPV vaccine is recommended in adolescence due to the concern for exposures to both low-potential (HPV types 6 and 11) and high-potential (HPV types 16 and 18) oncogenic HPV types. Data strongly support the benefit of 9-valent HPV vaccination in the prevention of sexually transmitted HPV in both males and females.¹⁷

Contagion of HPV is easy due to its excellent survival of fomites on surfaces, which generally is how warts are transferred in gym or pool settings where individuals who walk barefoot in changing rooms are almost twice as likely to contract plantar warts (odds ratio, 1.97 [95% CI, 1.39%-2.79%]).¹⁸ In another case series, walking barefoot, using a swimming pool, and having a household contact with warts were the leading risk factors for contraction of warts in children younger than 13 years.¹⁹ Children often transfer warts from site to site as well as to siblings and other close contacts. Skin-to-skin contact is responsible for sexual transmission of warts, and surface transmission occurs via fomites. Entry of the virus often occurs through small breaks in the skin. Other modes of transmission include orogenital.²⁰

Therapeutic Options

Although the nuances of each available treatment for pediatric warts are beyond the scope of this article, the main core of therapy is 1 of 3 approaches: (1) observation, (2) over-the-counter salicylic acid therapy, and (3) in-office cryotherapy. Observation is an affirmed style of therapy for warts, as it is expected that two-thirds of warts will spontaneously resolve in 2 years and three-quarters will resolve in 3 years.^4,5 Condyloma in children has been responsive to therapies such as cryotherapy and imiquimod,¹³ but spontaneous clearance in 5 years has been noted in 76% of children,²¹ which is linked to development of spontaneous immune response in most individuals.

Therapies for pediatric warts are characterized according to 6 major categories: destructive; immune stimulating; immune modulating, including normalization of epithelial growth; irritant; vascular destructive; and nitric oxide releasing (eTable).

Immune-Stimulating Therapies                                                                                                                                                                                                                         
Immune stimulants often are used to treat warts in children and adolescents who have many lesions, a prolonged disease course, disfigurement, and/or subungual localizations, as well as in those who have been treated with multiple destructive methods without success. Topical imiquimod and oral cimetidine are readily available, while squaric acid (at-home or in-office therapy) and intralesional candida antigen can be used in offices that carry these agents. Topical imiquimod has been reported to achieve success in genital warts in children,¹³ with good efficacy in recalcitrant, periungual, and subungual warts when used for up to 16 weeks.³¹ In one randomized clinical trial, imiquimod cream 5% combined with salicylic acid 15% was applied to warts for 6 to 10 hours for 5 consecutive days per week versus cryotherapy with liquid nitrogen every 2 weeks for a maximum of 3 months. At the end of the study period, 81.1% (30/37) of participants treated with imiquimod and salicylic acid showed clearance of their warts versus 67.3% (33/49) of those treated with cryotherapy.³²

Oral cimetidine has been reported to be successful in treating recalcitrant warts in more than 80% of children when dosed at 30 to 40 mg/kg 3 times daily, requiring 6 to 12 weeks to achieve clearance. Side effects of oral cimetidine include many cytochrome P450 interactions; gynecomastia, which limits usage in teenaged males; and stomach upset.³⁰

Treatment of recalcitrant pediatric warts with intralesional candida antigen has been associated with side effects consistent with delayed-type hypersensitivity reactions. Injections should be administered once monthly, with a minimum of 3 cycles if not effective and up to 6 cycles where partial efficacy is noted. In a retrospective review of 220 cases, 70.9% of children showed complete clearance and 16.8% had partial response.³³ However, the treatment may be limited in children by fear of needles.

Squaric acid dibutyl ester is a universal allergen that is not mutagenic on Ames testing and causes milder allergy symptoms than the mutagenic dinitrochlorobenzene and less erythema and pruritus than diphencyclopropenone. Squaric acid dibutyl ester home therapy was evaluated in 61 children with at least one nonfacial wart.³⁴ Application began with squaric acid dibutyl ester in acetone (SADBE) 2% sensitization on the arm followed by at-home application of SADBE 0.2% three to seven times weekly for a minimum of 2 months to determine benefit and for 3 to 4 months as needed; however, average response was 7 weeks. The average complete clearance was 58% and partial clearance was 18%. Side effects included erythema and mild itching as well as urticaria in one case.³⁴ In-office SADBE also has been evaluated in children. In a case series that included 29 children sensitized with SADBE 1% to 2% under occlusion followed by once monthly application of SADBE 0.5% to 5.0% to their warts, 69% clearance and 10% partial clearance was noted after a little more than 4 months of treatment.³⁵ One retrospective review compared combination SADBE, trichloroacetic acid (TCA), and cantharidin both alone and in combination as duos (eg, SADBE and TCA) or trios (SADBE, TCA, and cantharidin).²³ Of the 74 children whose medical charts were reviewed, the addition of pretreatment of warts with TCA 50% prior to in-office sensitization and monthly in-office application of SADBE increased treatment response to 100% with an average 2.45 months of therapy, whereas no enhancement was noted with cantharidin. Therefore, it appears that there may be enhanced immune reactivity when TCA pretreatment of warts is performed.²³

Immune-Modulating Therapies (Including Normalization of Epithelial Growth)
The most novel immunologic therapy for warts is plerixafor, an agent used to treat WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, which has been linked to heterozygous gain of function mutations in the chemokine receptor CXCR4 (located on 2q22). In WHIM syndrome, the mutated CXCR4 is more sensitive to CXCL12 activation. Plerixafor is a selective reversible antagonist that blocks the capacity of the chemokine CXCL12 to sustain the permanent activation of CXCR4.³⁷ Combination therapy with plerixafor and topical imiquimod has resulted in wart improvement in WHIM syndrome patients in a small series.³⁸

Oral isotretinoin has been described to be efficacious over placebo at a dosage of 30 mg daily for 12 weeks and can be used in teenagers but requires standard monitoring.³⁶

Nitric Oxide–Releasing Therapies                                                                                                                                                                                                                         
Nitric oxide release may increase local blood flow, thereby increasing immune response, or may have a primary mechanism of antimicrobial activity, which is why these agents have been investigated for wart treatment. Topical garlic has been described anecdotally as a therapy for thin childhood warts with the putative mechanism being nitric oxide release.⁴² A new investigational drug recently has had phase 2 data published. Berdazimer sodium plus carboxymethyl cellulose hydrogel has demonstrated benefit in adult warts, but data in children is lacking.⁴¹

Therapeutic Ladder for Childhood Warts

The therapeutic ladder (Table) for childhood warts starts with first doing no harm. Although many parents are disturbed by their child’s condition, the natural history of resolution is spontaneous and therefore no therapy is required in many cases. The child and his/her caregivers should be engaged to determine if he/she is emotionally disturbed or uncomfortable with their lesions and to address any fears and concerns that some children may experience (eg, contagion risk, pain with ambulation, ostracism). For example, children with hand warts may report that other children will not hold their hand while in line at school. Prominent facial lesions can be particularly problematic for children due to teasing and bullying.

Conclusion

Warts are a common infection in childhood caused by the ubiquitous HPV virus. Therapeutic options abound, but most cases are either ignored or treated with over-the-counter salicylic acid or in-office cryotherapy. The decision to employ alternative therapeutic options requires agreement by the child, his/her caregiver, and the treating physician and can be tailored to suit the desires and needs of the child. Whether or not therapy is offered, spontaneous clearance is frequently seen in common warts. On the other hand, genital warts are associated with later conversion to malignancies of the genital tract; therefore, encouragement of HPV vaccination is needed in the adolescent population to best ensure long-term genital health.

The definition of warts is variable, largely reflecting their manifold appearance, biologic potential, and public health concerns. One vernacular dictionary defines warts as:

Small, benign growths caused by a vital infection of the skin or mucous membrane. The virus infects the surface layer. The viruses that cause warts are members of the human papilloma virus (HPV) family. Warts are not cancerous but some strains of HPV, usually not associated with warts, have been linked with cancer formation. Warts are contagious from person to person and from one area of the body to another on the same person.¹

The World Health Organization defines warts by their structural components as:

Human papillomavirus (HPV) is a small, non-enveloped deoxyribonucleic acid (DNA) virus that infects skin or mucosal cells. The circular, double-stranded viral genome is approximately 8-kb in length. The genome encodes for 6 early proteins responsible for virus replication and 2 late proteins, L1 and L2, which are the viral structural proteins.²

In pediatric and adolescent dermatology, warts often are defined by their location and morphology; for example, facial warts typically are flat, minimally hyperkeratotic, or filiform, wherein the base is narrow and the lesion is tall, growing at a 90° angle to the surface of the skin. On the arms and legs, warts usually present as round to oval papules with overlying thick hyperkeratosis and/or callosity.^3,4 Common warts usually are flesh colored or lighter, and heavily pigmented lesions should be evaluated dermoscopically for a pigment network and biopsied when pigment is present.⁵

In this article, a successful paradigm for management of pediatric warts is provided with enhanced outcomes based on further insight into the disease course and patient selection.

Epidemiology of Pediatric Warts

There are more than 200 types of human papillomaviruses (HPV), with more than 100 oncogenic types. There is quite a bit of homology by species and genus that contributes to cross-immunity and similar behavior between certain types of HPV. The lifetime incidence of warts is very high. Approximately 30% of children develop a wart.⁶ A review of the 2007 National Health Interview Survey of 9417 children demonstrated a steady increase in prevalence of warts from 1 to 2 years of age to 7 to 8 years of age, with a peak at 9 to 10 years of age and a plateau at 11 to 17 years of age. Warts were most common in non-Hispanic white children and less common in black children.⁷ In an in-person survey of 12,370 individuals aged 18 to 74 years from 5 European countries, warts were the most common physician-diagnosed (27.3%) and self-reported (41.0%) dermatologic condition. Warts are more common in Northern countries (eg, Netherlands, Germany).⁸ Children with atopic dermatitis have a higher risk of developing warts and extracutaneous infections. In one study, children with warts and atopic dermatitis had a higher number of infections and food allergies and higher incidence of asthma and hay fever than either condition alone.⁹

Clinical Presentation of Warts

Warts usually present as common, palmoplantar, flat, or filiform in childhood, but variations by age are common (eFigure). The common and palmoplantar variants often are caused by HPV types 1 and 2.^4,5 In infancy, vertically transmitted HPV infections can cause juvenile-onset respiratory papillomatosis or vertically transmitted condyloma. Juvenile-onset respiratory papillomatosis refers to upper respiratory papillomas that are difficult to eliminate and has been associated with exfoliated cervical cell testing with 18.1% (13/72) typed HPV-positive, which allows neonates to be exposed to HPV in the upper respiratory tract in utero.¹⁰

Vertically transmitted condyloma is a difficult topic. Much data supports the vertical transmission of condyloma as the leading cause of condyloma in small children; however, a reasonable amount of caution is needed in this patient population. In cases suspicious for sexual abuse as well as those presenting in children 4 years and older, formal household evaluation by a sexual abuse clinic and mandatory reporting is needed. Anywhere from 2.6% to 32% of cases of genital warts in children have been reported to be caused by sexual abuse.^11-13 Therefore, most investigators have recommended careful review of the patient’s history and socioeconomic circumstances as well as a thorough physical examination. Mandatory reporting of suspected child sexual abuse is required in suspicious cases. Because HPV type 16 has been found in vertically transmitted cases, concern for long-term oncogenesis exists.^11-13

Adolescents generally present with lesions on the hands and feet. Plantar warts often are caused by HPV types from the alpha genus. Subtypes noted in plantar warts include HPV types 1a, 2, 27, 57, and 65.¹⁴ By 15 years of age, genital HPV becomes a common adolescent infection, persisting into adulthood.¹⁵ When studied, genital HPV often is subclinical or latent and often is preventable through vaccination. High-risk oncogenic alpha-genus HPV types can immortalize human keratinocytes. When HPV types 11, 16, 18, and 31 are compared, HPV-18 has the highest oncogenic potential based on colony-stimulating potential.¹⁶ Vaccination with the 9-valent HPV vaccine is recommended in adolescence due to the concern for exposures to both low-potential (HPV types 6 and 11) and high-potential (HPV types 16 and 18) oncogenic HPV types. Data strongly support the benefit of 9-valent HPV vaccination in the prevention of sexually transmitted HPV in both males and females.¹⁷

Contagion of HPV is easy due to its excellent survival of fomites on surfaces, which generally is how warts are transferred in gym or pool settings where individuals who walk barefoot in changing rooms are almost twice as likely to contract plantar warts (odds ratio, 1.97 [95% CI, 1.39%-2.79%]).¹⁸ In another case series, walking barefoot, using a swimming pool, and having a household contact with warts were the leading risk factors for contraction of warts in children younger than 13 years.¹⁹ Children often transfer warts from site to site as well as to siblings and other close contacts. Skin-to-skin contact is responsible for sexual transmission of warts, and surface transmission occurs via fomites. Entry of the virus often occurs through small breaks in the skin. Other modes of transmission include orogenital.²⁰

Therapeutic Options

Although the nuances of each available treatment for pediatric warts are beyond the scope of this article, the main core of therapy is 1 of 3 approaches: (1) observation, (2) over-the-counter salicylic acid therapy, and (3) in-office cryotherapy. Observation is an affirmed style of therapy for warts, as it is expected that two-thirds of warts will spontaneously resolve in 2 years and three-quarters will resolve in 3 years.^4,5 Condyloma in children has been responsive to therapies such as cryotherapy and imiquimod,¹³ but spontaneous clearance in 5 years has been noted in 76% of children,²¹ which is linked to development of spontaneous immune response in most individuals.

Therapies for pediatric warts are characterized according to 6 major categories: destructive; immune stimulating; immune modulating, including normalization of epithelial growth; irritant; vascular destructive; and nitric oxide releasing (eTable).

Immune-Stimulating Therapies                                                                                                                                                                                                                         
Immune stimulants often are used to treat warts in children and adolescents who have many lesions, a prolonged disease course, disfigurement, and/or subungual localizations, as well as in those who have been treated with multiple destructive methods without success. Topical imiquimod and oral cimetidine are readily available, while squaric acid (at-home or in-office therapy) and intralesional candida antigen can be used in offices that carry these agents. Topical imiquimod has been reported to achieve success in genital warts in children,¹³ with good efficacy in recalcitrant, periungual, and subungual warts when used for up to 16 weeks.³¹ In one randomized clinical trial, imiquimod cream 5% combined with salicylic acid 15% was applied to warts for 6 to 10 hours for 5 consecutive days per week versus cryotherapy with liquid nitrogen every 2 weeks for a maximum of 3 months. At the end of the study period, 81.1% (30/37) of participants treated with imiquimod and salicylic acid showed clearance of their warts versus 67.3% (33/49) of those treated with cryotherapy.³²

Oral cimetidine has been reported to be successful in treating recalcitrant warts in more than 80% of children when dosed at 30 to 40 mg/kg 3 times daily, requiring 6 to 12 weeks to achieve clearance. Side effects of oral cimetidine include many cytochrome P450 interactions; gynecomastia, which limits usage in teenaged males; and stomach upset.³⁰

Treatment of recalcitrant pediatric warts with intralesional candida antigen has been associated with side effects consistent with delayed-type hypersensitivity reactions. Injections should be administered once monthly, with a minimum of 3 cycles if not effective and up to 6 cycles where partial efficacy is noted. In a retrospective review of 220 cases, 70.9% of children showed complete clearance and 16.8% had partial response.³³ However, the treatment may be limited in children by fear of needles.

Squaric acid dibutyl ester is a universal allergen that is not mutagenic on Ames testing and causes milder allergy symptoms than the mutagenic dinitrochlorobenzene and less erythema and pruritus than diphencyclopropenone. Squaric acid dibutyl ester home therapy was evaluated in 61 children with at least one nonfacial wart.³⁴ Application began with squaric acid dibutyl ester in acetone (SADBE) 2% sensitization on the arm followed by at-home application of SADBE 0.2% three to seven times weekly for a minimum of 2 months to determine benefit and for 3 to 4 months as needed; however, average response was 7 weeks. The average complete clearance was 58% and partial clearance was 18%. Side effects included erythema and mild itching as well as urticaria in one case.³⁴ In-office SADBE also has been evaluated in children. In a case series that included 29 children sensitized with SADBE 1% to 2% under occlusion followed by once monthly application of SADBE 0.5% to 5.0% to their warts, 69% clearance and 10% partial clearance was noted after a little more than 4 months of treatment.³⁵ One retrospective review compared combination SADBE, trichloroacetic acid (TCA), and cantharidin both alone and in combination as duos (eg, SADBE and TCA) or trios (SADBE, TCA, and cantharidin).²³ Of the 74 children whose medical charts were reviewed, the addition of pretreatment of warts with TCA 50% prior to in-office sensitization and monthly in-office application of SADBE increased treatment response to 100% with an average 2.45 months of therapy, whereas no enhancement was noted with cantharidin. Therefore, it appears that there may be enhanced immune reactivity when TCA pretreatment of warts is performed.²³

Immune-Modulating Therapies (Including Normalization of Epithelial Growth)
The most novel immunologic therapy for warts is plerixafor, an agent used to treat WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, which has been linked to heterozygous gain of function mutations in the chemokine receptor CXCR4 (located on 2q22). In WHIM syndrome, the mutated CXCR4 is more sensitive to CXCL12 activation. Plerixafor is a selective reversible antagonist that blocks the capacity of the chemokine CXCL12 to sustain the permanent activation of CXCR4.³⁷ Combination therapy with plerixafor and topical imiquimod has resulted in wart improvement in WHIM syndrome patients in a small series.³⁸

Oral isotretinoin has been described to be efficacious over placebo at a dosage of 30 mg daily for 12 weeks and can be used in teenagers but requires standard monitoring.³⁶

Nitric Oxide–Releasing Therapies                                                                                                                                                                                                                         
Nitric oxide release may increase local blood flow, thereby increasing immune response, or may have a primary mechanism of antimicrobial activity, which is why these agents have been investigated for wart treatment. Topical garlic has been described anecdotally as a therapy for thin childhood warts with the putative mechanism being nitric oxide release.⁴² A new investigational drug recently has had phase 2 data published. Berdazimer sodium plus carboxymethyl cellulose hydrogel has demonstrated benefit in adult warts, but data in children is lacking.⁴¹

Therapeutic Ladder for Childhood Warts

The therapeutic ladder (Table) for childhood warts starts with first doing no harm. Although many parents are disturbed by their child’s condition, the natural history of resolution is spontaneous and therefore no therapy is required in many cases. The child and his/her caregivers should be engaged to determine if he/she is emotionally disturbed or uncomfortable with their lesions and to address any fears and concerns that some children may experience (eg, contagion risk, pain with ambulation, ostracism). For example, children with hand warts may report that other children will not hold their hand while in line at school. Prominent facial lesions can be particularly problematic for children due to teasing and bullying.

Conclusion

Warts are a common infection in childhood caused by the ubiquitous HPV virus. Therapeutic options abound, but most cases are either ignored or treated with over-the-counter salicylic acid or in-office cryotherapy. The decision to employ alternative therapeutic options requires agreement by the child, his/her caregiver, and the treating physician and can be tailored to suit the desires and needs of the child. Whether or not therapy is offered, spontaneous clearance is frequently seen in common warts. On the other hand, genital warts are associated with later conversion to malignancies of the genital tract; therefore, encouragement of HPV vaccination is needed in the adolescent population to best ensure long-term genital health.

The live attenuated influenza vaccine was less effective against the influenza A/H1N1pdm09 virus in children and adolescents across multiple influenza seasons between 2013 and 2016, compared with the inactivated influenza vaccine, according to research published in the journal Pediatrics.

Louise A. Koenig/MDedge News

Jessie R. Chung, MPH, from the influenza division at the Centers for Disease Control and Prevention in Atlanta, and her colleagues performed an analysis of five different studies where vaccine effectiveness (VE) was examined for quadrivalent live attenuated vaccine (LAIV4) and inactivated influenza vaccine (IIV) in children and adolescents aged 2-17 years from 42 states.

The analysis included data from the U.S. Influenza Vaccine Effectiveness Network (6,793 patients), a study from the Louisiana State University Health Sciences Center (3,822 patients), the Influenza Clinical Investigation for Children (3,521 patients), Department of Defense Global, Laboratory-based, Influenza Surveillance Program (1,935 patients), and the Influenza Incidence Surveillance Project (1,102 patients) between the periods of 2013-2014 and 2015-2016. The researchers sourced current and previous season vaccination history from electronic medical records and immunization registries.

Of patients who were vaccinated across all seasons, there was 67% effectiveness against influenza A/H1N1pdm09 (95% confidence interval, 62%-72%) for those who received the IIV and 20% (95% CI, −6%-39%) for LAIV4. Among patients who received the LAIV4 vaccination, there was a significantly higher likelihood of developing influenza A/H1N1pdm09 (odds ratio, 2.66; 95% CI, 2.06-3.44) compared with patients who received the IIV vaccination.

With regard to other strains, there was similar effectiveness against influenza A/H3N2 and influenza B with LAIV4 and IIV vaccinations.

“In contrast to findings of reduced LAIV4 effectiveness against influenza A/H1N1pdm09 viruses, our results suggest a possible but nonsignificant benefit of LAIV4 over IIV against influenza B viruses, which has been described previously,” the investigators wrote.

Limitations of the study included having data only one season prior to enrollment and little available demographic information beyond age, gender, and geographic location.

The Influenza Clinical Investigation for Children was funded by MedImmune, a member of the AstraZeneca Group. Two of the researchers are employees of AstraZeneca. The other authors reported having no conflicts of interest. The U.S. Influenza Vaccine Effectiveness Network was supported by the CDC through cooperative agreements with the University of Michigan, Kaiser Permanente Washington Health Research Institute, Marshfield Clinic Research Institute, University of Pittsburgh, and Baylor Scott & White Health. At the University of Pittsburgh, the project also was supported by the National Institutes of Health.

SOURCE: Chung JR et al. Pediatrics. 2018. doi: 10.1542/peds.2018-2094.

The live attenuated influenza vaccine was less effective against the influenza A/H1N1pdm09 virus in children and adolescents across multiple influenza seasons between 2013 and 2016, compared with the inactivated influenza vaccine, according to research published in the journal Pediatrics.

Louise A. Koenig/MDedge News

Jessie R. Chung, MPH, from the influenza division at the Centers for Disease Control and Prevention in Atlanta, and her colleagues performed an analysis of five different studies where vaccine effectiveness (VE) was examined for quadrivalent live attenuated vaccine (LAIV4) and inactivated influenza vaccine (IIV) in children and adolescents aged 2-17 years from 42 states.

The analysis included data from the U.S. Influenza Vaccine Effectiveness Network (6,793 patients), a study from the Louisiana State University Health Sciences Center (3,822 patients), the Influenza Clinical Investigation for Children (3,521 patients), Department of Defense Global, Laboratory-based, Influenza Surveillance Program (1,935 patients), and the Influenza Incidence Surveillance Project (1,102 patients) between the periods of 2013-2014 and 2015-2016. The researchers sourced current and previous season vaccination history from electronic medical records and immunization registries.

Of patients who were vaccinated across all seasons, there was 67% effectiveness against influenza A/H1N1pdm09 (95% confidence interval, 62%-72%) for those who received the IIV and 20% (95% CI, −6%-39%) for LAIV4. Among patients who received the LAIV4 vaccination, there was a significantly higher likelihood of developing influenza A/H1N1pdm09 (odds ratio, 2.66; 95% CI, 2.06-3.44) compared with patients who received the IIV vaccination.

With regard to other strains, there was similar effectiveness against influenza A/H3N2 and influenza B with LAIV4 and IIV vaccinations.

“In contrast to findings of reduced LAIV4 effectiveness against influenza A/H1N1pdm09 viruses, our results suggest a possible but nonsignificant benefit of LAIV4 over IIV against influenza B viruses, which has been described previously,” the investigators wrote.

Limitations of the study included having data only one season prior to enrollment and little available demographic information beyond age, gender, and geographic location.

The Influenza Clinical Investigation for Children was funded by MedImmune, a member of the AstraZeneca Group. Two of the researchers are employees of AstraZeneca. The other authors reported having no conflicts of interest. The U.S. Influenza Vaccine Effectiveness Network was supported by the CDC through cooperative agreements with the University of Michigan, Kaiser Permanente Washington Health Research Institute, Marshfield Clinic Research Institute, University of Pittsburgh, and Baylor Scott & White Health. At the University of Pittsburgh, the project also was supported by the National Institutes of Health.

SOURCE: Chung JR et al. Pediatrics. 2018. doi: 10.1542/peds.2018-2094.

The live attenuated influenza vaccine was less effective against the influenza A/H1N1pdm09 virus in children and adolescents across multiple influenza seasons between 2013 and 2016, compared with the inactivated influenza vaccine, according to research published in the journal Pediatrics.

Louise A. Koenig/MDedge News

Jessie R. Chung, MPH, from the influenza division at the Centers for Disease Control and Prevention in Atlanta, and her colleagues performed an analysis of five different studies where vaccine effectiveness (VE) was examined for quadrivalent live attenuated vaccine (LAIV4) and inactivated influenza vaccine (IIV) in children and adolescents aged 2-17 years from 42 states.

The analysis included data from the U.S. Influenza Vaccine Effectiveness Network (6,793 patients), a study from the Louisiana State University Health Sciences Center (3,822 patients), the Influenza Clinical Investigation for Children (3,521 patients), Department of Defense Global, Laboratory-based, Influenza Surveillance Program (1,935 patients), and the Influenza Incidence Surveillance Project (1,102 patients) between the periods of 2013-2014 and 2015-2016. The researchers sourced current and previous season vaccination history from electronic medical records and immunization registries.

Of patients who were vaccinated across all seasons, there was 67% effectiveness against influenza A/H1N1pdm09 (95% confidence interval, 62%-72%) for those who received the IIV and 20% (95% CI, −6%-39%) for LAIV4. Among patients who received the LAIV4 vaccination, there was a significantly higher likelihood of developing influenza A/H1N1pdm09 (odds ratio, 2.66; 95% CI, 2.06-3.44) compared with patients who received the IIV vaccination.

With regard to other strains, there was similar effectiveness against influenza A/H3N2 and influenza B with LAIV4 and IIV vaccinations.

“In contrast to findings of reduced LAIV4 effectiveness against influenza A/H1N1pdm09 viruses, our results suggest a possible but nonsignificant benefit of LAIV4 over IIV against influenza B viruses, which has been described previously,” the investigators wrote.

Limitations of the study included having data only one season prior to enrollment and little available demographic information beyond age, gender, and geographic location.

The Influenza Clinical Investigation for Children was funded by MedImmune, a member of the AstraZeneca Group. Two of the researchers are employees of AstraZeneca. The other authors reported having no conflicts of interest. The U.S. Influenza Vaccine Effectiveness Network was supported by the CDC through cooperative agreements with the University of Michigan, Kaiser Permanente Washington Health Research Institute, Marshfield Clinic Research Institute, University of Pittsburgh, and Baylor Scott & White Health. At the University of Pittsburgh, the project also was supported by the National Institutes of Health.

SOURCE: Chung JR et al. Pediatrics. 2018. doi: 10.1542/peds.2018-2094.

Children in military families face unique challenges and stressors related to deployment and frequent relocation. However, these children also have access to an array of services of which civilian pediatricians and other care providers may be unaware.

Senior Airman Kaylee Clark/U.S. Air Force

New guidance from the American Academy of Pediatrics’ Section on Uniformed Services details needs, challenges, and opportunities for military-connected children and points clinicians to resources for these families.

For clinicians who care for military-connected children, key suggestions outlined in the report include attainment of cultural competency; this begins with simply asking about the military status of families, wrote Cmdr. Chadley R. Huebner, MD, MPH, the lead author of the report published in Pediatrics.

A Veteran’s Affairs Community Provider Toolkit gives good grounding in military culture, he added.

The behavioral and emotional screening recommended by the AAP as part of routine pediatric practice also will provide clinicians with valuable information to help guide care of military-connected children; asking about prior or current parental military service and deployment also will help guide care.

Up to half of children in military families receive care in civilian settings, according to Dr. Huebner. “Many children in military families live in settings remote from a military community, and civilian health providers are faced with caring for military children in their practices.”

Dr. Huebner, an active duty commander in the U.S. Navy, led the revision of a 2013 report on the health and mental health needs of children in U.S. military families.

The broad category of military-connected children includes not just the estimated 1.3 million children of active duty service members, but also children of 818,000 National Guard and Reserve members and more than 2 million military retirees. All told, about 4 million children are in military-connected families, with about a third of these aged 5 years or younger.

In an era where the United States has been involved in multiple conflicts, deployment is the best-known stressor for military families. “The stressors associated with deployment, including prolonged family separation, potential injury or death of a service member, and traumatic experiences, can have a cumulative negative effect on the entire family unit,” wrote Dr. Huebner.

Even in young children aged 8 years and under, mental and behavioral health visits increase during deployment; older children experience more psychosocial morbidity as parental stress increases, an effect that can be mitigated by military support systems. Much existing research focuses on “the immediate effects of wartime deployment, and more longitudinal studies are needed to assess the long-term effects,” he wrote.

Still, neglect and child maltreatment increase in military families that have experienced deployment, with the risk increasing at the time of redeployment.

In addition to the known family stresses of deployment, children in military families face frequent relocation, with transitions occurring every 2-4 years and an average of nine schools attended by high school graduation, according to government data cited by Dr. Huebner.

Relocation within the past year is associated with increased use of mental health services, and adolescents in this group saw more psychiatric hospitalizations and ED visits. However, increased resilience among children in military families has been seen in some studies, with frequent relocation associated with fewer problems in school and a positive attitude about the changes associated with moves.

And families turn to each other for support with frequent moves. “Because families often move away from extended family support, they often refer to the military community as a surrogate family that provides a support network,” wrote Dr. Huebner.

Reservists don’t relocate as frequently as active duty service members but are more likely to live in areas without military resources, and their children’s peers, teachers, and caregivers may not be aware of the special challenges of military life. Similar isolation may occur when veterans make the transition to civilian life, with changes in eligibility for and access to military services and benefits.

Military programs can help

Military families, their children, and care providers and educators can turn to the military for help in many areas, whether families are receiving mental and physical health care through the military or from civilian facilities.

A key resource for neglect and abuse prevention is the military’s Family Advocacy Program (FAP), which engages families by means of workshops and other support programs. When child maltreatment is alleged, FAP also conducts its own investigation, so health care professionals should include the local FAP office in the reporting process when there are concerns.

For new parents, home visits and other support programs are available through the New Parent Support program, which will connect families to resources within the community and the Department of Defense (DOD).

Families living near or on military facilities may access DOD-sponsored infant and preschool child development programs, as well as school-aged care programs; subsidies for civilian childcare are also available. Although these programs constitute the country’s largest employer-sponsored childcare program, they serve just a small minority of military families, noted Dr. Huebner, citing a 2008 study by RAND.

DOD schools are attended by 72,000 students, but DOD resources stretch into civilian schools: School liaison offices assist civilian schools and military families located near military installations, and grant funding helps the DOD partner with civilian schools serving military-connected children.

Turning to health care, the military health system provides care globally to service members, retirees, and their families. Tricare is a single-payer, government-managed insurance program that is managed through regional contracts; some care is also delivered through the centralized Military Health System.

Whether Tricare participants receive care at military facilities or from civilian network providers, they generally do not have out-of-pocket costs unless they enroll in the Tricare Select program, a fee-for-service plan that involved cost sharing with deductibles. A link to information about how to connect patients to a Tricare provider or how to become on is available in the full report in Pediatrics.

About 20% of military-connected children have special health care needs and may receive specialty care through civilian providers. To help these families navigate multiple systems of care, the DOD provides a publication called Special Needs Tool Kit: Birth to 18. This toolkit guides families through early intervention and special education, and also provides military-specific information about relocation, Tricare benefits, and military support services.

A program available to all family members with special education or chronic medical needs is the Exceptional Family Members Program (EFMP). Children with autism spectrum disorders and ADHD, for example, are eligible for EFMP enrollment.

Additional supplemental benefits, with rank-adjusted sliding fees, are available for children with serious developmental and physical problems; children with autism spectrum disorders are eligible for additional therapy through an autism care demonstration program.

Forms to document chronic medical conditions (DD Form 2792) and special educational needs, if needed (DD Form 2791-1), are required for EFMP enrollment, which is mandatory for children of active duty personnel. Guidance for completing the forms can be found at www.militaryonesource.mil.

When overseas posts are imminent, clinicians should know that certain medical conditions may disqualify children from accompanying their service member parent. Overseas screening coordinators within the military medical system serve as the point of contact for the family and pediatrician in such circumstances, and clinicians can help families by providing appropriate documentation early in the process.

In addition to attaining military cultural competence, being aware of resources available to military families, and working closely with school personnel to support military-connected children, local and national advocacy efforts can make a difference, noted Dr. Huebner. And in all cases, “health care professional, schools, and communities should proactively reach out to military families.”

Dr. Huebner reported no conflicts of interest and no outside sources of funding. The full report contains hyperlinks to all resources named.

SOURCE: Huebner CR. Pediatrics. 2019;143(1):e20183258.

Children in military families face unique challenges and stressors related to deployment and frequent relocation. However, these children also have access to an array of services of which civilian pediatricians and other care providers may be unaware.

Senior Airman Kaylee Clark/U.S. Air Force

New guidance from the American Academy of Pediatrics’ Section on Uniformed Services details needs, challenges, and opportunities for military-connected children and points clinicians to resources for these families.

For clinicians who care for military-connected children, key suggestions outlined in the report include attainment of cultural competency; this begins with simply asking about the military status of families, wrote Cmdr. Chadley R. Huebner, MD, MPH, the lead author of the report published in Pediatrics.

A Veteran’s Affairs Community Provider Toolkit gives good grounding in military culture, he added.

The behavioral and emotional screening recommended by the AAP as part of routine pediatric practice also will provide clinicians with valuable information to help guide care of military-connected children; asking about prior or current parental military service and deployment also will help guide care.

Up to half of children in military families receive care in civilian settings, according to Dr. Huebner. “Many children in military families live in settings remote from a military community, and civilian health providers are faced with caring for military children in their practices.”

Dr. Huebner, an active duty commander in the U.S. Navy, led the revision of a 2013 report on the health and mental health needs of children in U.S. military families.

The broad category of military-connected children includes not just the estimated 1.3 million children of active duty service members, but also children of 818,000 National Guard and Reserve members and more than 2 million military retirees. All told, about 4 million children are in military-connected families, with about a third of these aged 5 years or younger.

In an era where the United States has been involved in multiple conflicts, deployment is the best-known stressor for military families. “The stressors associated with deployment, including prolonged family separation, potential injury or death of a service member, and traumatic experiences, can have a cumulative negative effect on the entire family unit,” wrote Dr. Huebner.

Even in young children aged 8 years and under, mental and behavioral health visits increase during deployment; older children experience more psychosocial morbidity as parental stress increases, an effect that can be mitigated by military support systems. Much existing research focuses on “the immediate effects of wartime deployment, and more longitudinal studies are needed to assess the long-term effects,” he wrote.

Still, neglect and child maltreatment increase in military families that have experienced deployment, with the risk increasing at the time of redeployment.

In addition to the known family stresses of deployment, children in military families face frequent relocation, with transitions occurring every 2-4 years and an average of nine schools attended by high school graduation, according to government data cited by Dr. Huebner.

Relocation within the past year is associated with increased use of mental health services, and adolescents in this group saw more psychiatric hospitalizations and ED visits. However, increased resilience among children in military families has been seen in some studies, with frequent relocation associated with fewer problems in school and a positive attitude about the changes associated with moves.

And families turn to each other for support with frequent moves. “Because families often move away from extended family support, they often refer to the military community as a surrogate family that provides a support network,” wrote Dr. Huebner.

Reservists don’t relocate as frequently as active duty service members but are more likely to live in areas without military resources, and their children’s peers, teachers, and caregivers may not be aware of the special challenges of military life. Similar isolation may occur when veterans make the transition to civilian life, with changes in eligibility for and access to military services and benefits.

Military programs can help

Military families, their children, and care providers and educators can turn to the military for help in many areas, whether families are receiving mental and physical health care through the military or from civilian facilities.

A key resource for neglect and abuse prevention is the military’s Family Advocacy Program (FAP), which engages families by means of workshops and other support programs. When child maltreatment is alleged, FAP also conducts its own investigation, so health care professionals should include the local FAP office in the reporting process when there are concerns.

For new parents, home visits and other support programs are available through the New Parent Support program, which will connect families to resources within the community and the Department of Defense (DOD).

Families living near or on military facilities may access DOD-sponsored infant and preschool child development programs, as well as school-aged care programs; subsidies for civilian childcare are also available. Although these programs constitute the country’s largest employer-sponsored childcare program, they serve just a small minority of military families, noted Dr. Huebner, citing a 2008 study by RAND.

DOD schools are attended by 72,000 students, but DOD resources stretch into civilian schools: School liaison offices assist civilian schools and military families located near military installations, and grant funding helps the DOD partner with civilian schools serving military-connected children.

Turning to health care, the military health system provides care globally to service members, retirees, and their families. Tricare is a single-payer, government-managed insurance program that is managed through regional contracts; some care is also delivered through the centralized Military Health System.

Whether Tricare participants receive care at military facilities or from civilian network providers, they generally do not have out-of-pocket costs unless they enroll in the Tricare Select program, a fee-for-service plan that involved cost sharing with deductibles. A link to information about how to connect patients to a Tricare provider or how to become on is available in the full report in Pediatrics.

About 20% of military-connected children have special health care needs and may receive specialty care through civilian providers. To help these families navigate multiple systems of care, the DOD provides a publication called Special Needs Tool Kit: Birth to 18. This toolkit guides families through early intervention and special education, and also provides military-specific information about relocation, Tricare benefits, and military support services.

A program available to all family members with special education or chronic medical needs is the Exceptional Family Members Program (EFMP). Children with autism spectrum disorders and ADHD, for example, are eligible for EFMP enrollment.

Additional supplemental benefits, with rank-adjusted sliding fees, are available for children with serious developmental and physical problems; children with autism spectrum disorders are eligible for additional therapy through an autism care demonstration program.

Forms to document chronic medical conditions (DD Form 2792) and special educational needs, if needed (DD Form 2791-1), are required for EFMP enrollment, which is mandatory for children of active duty personnel. Guidance for completing the forms can be found at www.militaryonesource.mil.

When overseas posts are imminent, clinicians should know that certain medical conditions may disqualify children from accompanying their service member parent. Overseas screening coordinators within the military medical system serve as the point of contact for the family and pediatrician in such circumstances, and clinicians can help families by providing appropriate documentation early in the process.

In addition to attaining military cultural competence, being aware of resources available to military families, and working closely with school personnel to support military-connected children, local and national advocacy efforts can make a difference, noted Dr. Huebner. And in all cases, “health care professional, schools, and communities should proactively reach out to military families.”

Dr. Huebner reported no conflicts of interest and no outside sources of funding. The full report contains hyperlinks to all resources named.

SOURCE: Huebner CR. Pediatrics. 2019;143(1):e20183258.

Children in military families face unique challenges and stressors related to deployment and frequent relocation. However, these children also have access to an array of services of which civilian pediatricians and other care providers may be unaware.

Senior Airman Kaylee Clark/U.S. Air Force

New guidance from the American Academy of Pediatrics’ Section on Uniformed Services details needs, challenges, and opportunities for military-connected children and points clinicians to resources for these families.

For clinicians who care for military-connected children, key suggestions outlined in the report include attainment of cultural competency; this begins with simply asking about the military status of families, wrote Cmdr. Chadley R. Huebner, MD, MPH, the lead author of the report published in Pediatrics.

A Veteran’s Affairs Community Provider Toolkit gives good grounding in military culture, he added.

The behavioral and emotional screening recommended by the AAP as part of routine pediatric practice also will provide clinicians with valuable information to help guide care of military-connected children; asking about prior or current parental military service and deployment also will help guide care.

Up to half of children in military families receive care in civilian settings, according to Dr. Huebner. “Many children in military families live in settings remote from a military community, and civilian health providers are faced with caring for military children in their practices.”

Dr. Huebner, an active duty commander in the U.S. Navy, led the revision of a 2013 report on the health and mental health needs of children in U.S. military families.

The broad category of military-connected children includes not just the estimated 1.3 million children of active duty service members, but also children of 818,000 National Guard and Reserve members and more than 2 million military retirees. All told, about 4 million children are in military-connected families, with about a third of these aged 5 years or younger.

In an era where the United States has been involved in multiple conflicts, deployment is the best-known stressor for military families. “The stressors associated with deployment, including prolonged family separation, potential injury or death of a service member, and traumatic experiences, can have a cumulative negative effect on the entire family unit,” wrote Dr. Huebner.

Even in young children aged 8 years and under, mental and behavioral health visits increase during deployment; older children experience more psychosocial morbidity as parental stress increases, an effect that can be mitigated by military support systems. Much existing research focuses on “the immediate effects of wartime deployment, and more longitudinal studies are needed to assess the long-term effects,” he wrote.

Still, neglect and child maltreatment increase in military families that have experienced deployment, with the risk increasing at the time of redeployment.

In addition to the known family stresses of deployment, children in military families face frequent relocation, with transitions occurring every 2-4 years and an average of nine schools attended by high school graduation, according to government data cited by Dr. Huebner.

Relocation within the past year is associated with increased use of mental health services, and adolescents in this group saw more psychiatric hospitalizations and ED visits. However, increased resilience among children in military families has been seen in some studies, with frequent relocation associated with fewer problems in school and a positive attitude about the changes associated with moves.

And families turn to each other for support with frequent moves. “Because families often move away from extended family support, they often refer to the military community as a surrogate family that provides a support network,” wrote Dr. Huebner.

Reservists don’t relocate as frequently as active duty service members but are more likely to live in areas without military resources, and their children’s peers, teachers, and caregivers may not be aware of the special challenges of military life. Similar isolation may occur when veterans make the transition to civilian life, with changes in eligibility for and access to military services and benefits.

Military programs can help

Military families, their children, and care providers and educators can turn to the military for help in many areas, whether families are receiving mental and physical health care through the military or from civilian facilities.

A key resource for neglect and abuse prevention is the military’s Family Advocacy Program (FAP), which engages families by means of workshops and other support programs. When child maltreatment is alleged, FAP also conducts its own investigation, so health care professionals should include the local FAP office in the reporting process when there are concerns.

For new parents, home visits and other support programs are available through the New Parent Support program, which will connect families to resources within the community and the Department of Defense (DOD).

Families living near or on military facilities may access DOD-sponsored infant and preschool child development programs, as well as school-aged care programs; subsidies for civilian childcare are also available. Although these programs constitute the country’s largest employer-sponsored childcare program, they serve just a small minority of military families, noted Dr. Huebner, citing a 2008 study by RAND.

DOD schools are attended by 72,000 students, but DOD resources stretch into civilian schools: School liaison offices assist civilian schools and military families located near military installations, and grant funding helps the DOD partner with civilian schools serving military-connected children.

Turning to health care, the military health system provides care globally to service members, retirees, and their families. Tricare is a single-payer, government-managed insurance program that is managed through regional contracts; some care is also delivered through the centralized Military Health System.

Whether Tricare participants receive care at military facilities or from civilian network providers, they generally do not have out-of-pocket costs unless they enroll in the Tricare Select program, a fee-for-service plan that involved cost sharing with deductibles. A link to information about how to connect patients to a Tricare provider or how to become on is available in the full report in Pediatrics.

About 20% of military-connected children have special health care needs and may receive specialty care through civilian providers. To help these families navigate multiple systems of care, the DOD provides a publication called Special Needs Tool Kit: Birth to 18. This toolkit guides families through early intervention and special education, and also provides military-specific information about relocation, Tricare benefits, and military support services.

A program available to all family members with special education or chronic medical needs is the Exceptional Family Members Program (EFMP). Children with autism spectrum disorders and ADHD, for example, are eligible for EFMP enrollment.

Additional supplemental benefits, with rank-adjusted sliding fees, are available for children with serious developmental and physical problems; children with autism spectrum disorders are eligible for additional therapy through an autism care demonstration program.

Forms to document chronic medical conditions (DD Form 2792) and special educational needs, if needed (DD Form 2791-1), are required for EFMP enrollment, which is mandatory for children of active duty personnel. Guidance for completing the forms can be found at www.militaryonesource.mil.

When overseas posts are imminent, clinicians should know that certain medical conditions may disqualify children from accompanying their service member parent. Overseas screening coordinators within the military medical system serve as the point of contact for the family and pediatrician in such circumstances, and clinicians can help families by providing appropriate documentation early in the process.

In addition to attaining military cultural competence, being aware of resources available to military families, and working closely with school personnel to support military-connected children, local and national advocacy efforts can make a difference, noted Dr. Huebner. And in all cases, “health care professional, schools, and communities should proactively reach out to military families.”

Dr. Huebner reported no conflicts of interest and no outside sources of funding. The full report contains hyperlinks to all resources named.

SOURCE: Huebner CR. Pediatrics. 2019;143(1):e20183258.

Here are 5 articles from the January issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Can ultrasound screening improve survival in ovarian cancer?

To take the posttest, go to: https://bit.ly/2Vtuc8F
Expires October 17, 2019

2. Higher BMI associated with greater loss of gray matter volume in MS

To take the posttest, go to: https://bit.ly/2ArvFDp
Expires October 29, 2019

3. Psoriasis adds to increased risk of cardiovascular procedures, surgery in patients with hypertension

To take the posttest, go to: https://bit.ly/2sbnkiS
Expires October 31, 2019

4. Fever, intestinal symptoms may delay diagnosis of Kawasaki disease in children

To take the posttest, go to: https://bit.ly/2RdPoBi
Expires October 31, 2019

5. Rate of STIs is rising, and many U.S. teens are sexually active

To take the posttest, go to: https://bit.ly/2CPuYFW
Expires November 8, 2019

Here are 5 articles from the January issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Can ultrasound screening improve survival in ovarian cancer?

To take the posttest, go to: https://bit.ly/2Vtuc8F
Expires October 17, 2019

2. Higher BMI associated with greater loss of gray matter volume in MS

To take the posttest, go to: https://bit.ly/2ArvFDp
Expires October 29, 2019

3. Psoriasis adds to increased risk of cardiovascular procedures, surgery in patients with hypertension

To take the posttest, go to: https://bit.ly/2sbnkiS
Expires October 31, 2019

4. Fever, intestinal symptoms may delay diagnosis of Kawasaki disease in children

To take the posttest, go to: https://bit.ly/2RdPoBi
Expires October 31, 2019

5. Rate of STIs is rising, and many U.S. teens are sexually active

To take the posttest, go to: https://bit.ly/2CPuYFW
Expires November 8, 2019

Here are 5 articles from the January issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Can ultrasound screening improve survival in ovarian cancer?

To take the posttest, go to: https://bit.ly/2Vtuc8F
Expires October 17, 2019

2. Higher BMI associated with greater loss of gray matter volume in MS

To take the posttest, go to: https://bit.ly/2ArvFDp
Expires October 29, 2019

3. Psoriasis adds to increased risk of cardiovascular procedures, surgery in patients with hypertension

To take the posttest, go to: https://bit.ly/2sbnkiS
Expires October 31, 2019

4. Fever, intestinal symptoms may delay diagnosis of Kawasaki disease in children

To take the posttest, go to: https://bit.ly/2RdPoBi
Expires October 31, 2019

5. Rate of STIs is rising, and many U.S. teens are sexually active

To take the posttest, go to: https://bit.ly/2CPuYFW
Expires November 8, 2019

SAN DIEGO – Research into hundreds of babies with Down syndrome is providing valuable insight into the genetic roots of leukemia and offering a route to identify newborns at high risk.

“We can now identify children at high risk of developing myeloid leukemia within 4 years” through blood or genetic tests, Irene Roberts, MD, a pediatric hematologist at the University of Oxford’s (England) MRC Weatherall Institute of Molecular Medicine, said at the annual meeting of the American Society of Hematology.

About 2%-3% of children with Down syndrome will develop acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML), according to the National Cancer Institute, rates that are much higher than in the general population.

Research suggests that among children aged 0-4 years with Down syndrome, the standardized incidence ratio (SIR) of AML is 114, compared with other children, Dr. Roberts said. The SIR of ALL is 27 in children aged 1-4 years, she said.

For people with Down syndrome aged 0-60 years, the SIRs are 12 and 13 in AML and ALL, respectively, she said.

In her presentation, Dr. Roberts focused on AML that appears before age 4 years and is preceded by a neonatal preleukemia – transient abnormal myelopoiesis (TAM) – that only occurs in Down syndrome. In most cases, TAM, which occurs with GATA1 mutations, resolves on its own after birth, she said. But in others, the GATA1 mutations continue and cause AML to develop.

Dr. Roberts highlighted her institution’s Oxford Down Syndrome Cohort Study and offered an update to a 2013 report (Blood. 2013 Dec 5;122[24]:3908–17). The study recruited 471 neonates with Down syndrome and followed them for up to 4 years: 341 with no GATA1 mutation and 130 (28%) with the mutation. Dr. Roberts called the latter number a “very high frequency.”

Of those with the mutation, 7 patients (5%) developed AML at a median age of 16 months. None of those without the mutation developed AML.

Also, among the 130 neonates with the mutation, 42% were considered to have “clinical” TAM (more than 10% blasts) and 58% were considered to have “silent” TAM (fewer than 10% blasts).

“We predicted that these babies with clinical TAM would have more severe clinical disease ... and that in fact turned out to be the case,” Dr. Roberts said.

Why is the GATA1 mutation so significant? Research suggests that platelet production is abnormal in neonates with Down syndrome, compared with neonates without it, regardless of whether they have the mutation, Dr. Roberts said.

The mutation doesn’t reduce further platelet count, but does disrupt megakaryopoiesis – the process of the production of platelets. As a result, giant platelets and megakaryocyte fragments are more common, she explained.

Moving forward, research data can be used to identify which children are most at risk, Dr. Roberts said. Newborns with Down syndrome are more likely to survive without leukemia if they have silent TAM, compared with those who have clinical TAM, and if they have an estimated variant allele frequency above 15%, according to findings from the Oxford study.

Children at high risk of AML before age 4 years can be identified by analyzing the percentage of blasts on a smear and/or by analyzing mutation of GATA1, according to Dr. Roberts. However, this cannot be accomplished by the use of a complete blood count (CBC) test, she said, which is used to check for leukemia.

Dr. Roberts called for the development of more guidelines for screening newborns with Down syndrome for leukemia risk. The British Society for Haematology issued testing guidelines, coauthored by Dr. Roberts, in 2018 (Br J Haematol. 2018 Jul;182[2]:200-11).

Dr. Roberts reported having no financial disclosures.

SAN DIEGO – Research into hundreds of babies with Down syndrome is providing valuable insight into the genetic roots of leukemia and offering a route to identify newborns at high risk.

“We can now identify children at high risk of developing myeloid leukemia within 4 years” through blood or genetic tests, Irene Roberts, MD, a pediatric hematologist at the University of Oxford’s (England) MRC Weatherall Institute of Molecular Medicine, said at the annual meeting of the American Society of Hematology.

About 2%-3% of children with Down syndrome will develop acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML), according to the National Cancer Institute, rates that are much higher than in the general population.

Research suggests that among children aged 0-4 years with Down syndrome, the standardized incidence ratio (SIR) of AML is 114, compared with other children, Dr. Roberts said. The SIR of ALL is 27 in children aged 1-4 years, she said.

For people with Down syndrome aged 0-60 years, the SIRs are 12 and 13 in AML and ALL, respectively, she said.

In her presentation, Dr. Roberts focused on AML that appears before age 4 years and is preceded by a neonatal preleukemia – transient abnormal myelopoiesis (TAM) – that only occurs in Down syndrome. In most cases, TAM, which occurs with GATA1 mutations, resolves on its own after birth, she said. But in others, the GATA1 mutations continue and cause AML to develop.

Dr. Roberts highlighted her institution’s Oxford Down Syndrome Cohort Study and offered an update to a 2013 report (Blood. 2013 Dec 5;122[24]:3908–17). The study recruited 471 neonates with Down syndrome and followed them for up to 4 years: 341 with no GATA1 mutation and 130 (28%) with the mutation. Dr. Roberts called the latter number a “very high frequency.”

Of those with the mutation, 7 patients (5%) developed AML at a median age of 16 months. None of those without the mutation developed AML.

Also, among the 130 neonates with the mutation, 42% were considered to have “clinical” TAM (more than 10% blasts) and 58% were considered to have “silent” TAM (fewer than 10% blasts).

“We predicted that these babies with clinical TAM would have more severe clinical disease ... and that in fact turned out to be the case,” Dr. Roberts said.

Why is the GATA1 mutation so significant? Research suggests that platelet production is abnormal in neonates with Down syndrome, compared with neonates without it, regardless of whether they have the mutation, Dr. Roberts said.

The mutation doesn’t reduce further platelet count, but does disrupt megakaryopoiesis – the process of the production of platelets. As a result, giant platelets and megakaryocyte fragments are more common, she explained.

Moving forward, research data can be used to identify which children are most at risk, Dr. Roberts said. Newborns with Down syndrome are more likely to survive without leukemia if they have silent TAM, compared with those who have clinical TAM, and if they have an estimated variant allele frequency above 15%, according to findings from the Oxford study.

Children at high risk of AML before age 4 years can be identified by analyzing the percentage of blasts on a smear and/or by analyzing mutation of GATA1, according to Dr. Roberts. However, this cannot be accomplished by the use of a complete blood count (CBC) test, she said, which is used to check for leukemia.

Dr. Roberts called for the development of more guidelines for screening newborns with Down syndrome for leukemia risk. The British Society for Haematology issued testing guidelines, coauthored by Dr. Roberts, in 2018 (Br J Haematol. 2018 Jul;182[2]:200-11).

Dr. Roberts reported having no financial disclosures.

SAN DIEGO – Research into hundreds of babies with Down syndrome is providing valuable insight into the genetic roots of leukemia and offering a route to identify newborns at high risk.

“We can now identify children at high risk of developing myeloid leukemia within 4 years” through blood or genetic tests, Irene Roberts, MD, a pediatric hematologist at the University of Oxford’s (England) MRC Weatherall Institute of Molecular Medicine, said at the annual meeting of the American Society of Hematology.

About 2%-3% of children with Down syndrome will develop acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML), according to the National Cancer Institute, rates that are much higher than in the general population.

Research suggests that among children aged 0-4 years with Down syndrome, the standardized incidence ratio (SIR) of AML is 114, compared with other children, Dr. Roberts said. The SIR of ALL is 27 in children aged 1-4 years, she said.

For people with Down syndrome aged 0-60 years, the SIRs are 12 and 13 in AML and ALL, respectively, she said.

In her presentation, Dr. Roberts focused on AML that appears before age 4 years and is preceded by a neonatal preleukemia – transient abnormal myelopoiesis (TAM) – that only occurs in Down syndrome. In most cases, TAM, which occurs with GATA1 mutations, resolves on its own after birth, she said. But in others, the GATA1 mutations continue and cause AML to develop.

Dr. Roberts highlighted her institution’s Oxford Down Syndrome Cohort Study and offered an update to a 2013 report (Blood. 2013 Dec 5;122[24]:3908–17). The study recruited 471 neonates with Down syndrome and followed them for up to 4 years: 341 with no GATA1 mutation and 130 (28%) with the mutation. Dr. Roberts called the latter number a “very high frequency.”

Of those with the mutation, 7 patients (5%) developed AML at a median age of 16 months. None of those without the mutation developed AML.

Also, among the 130 neonates with the mutation, 42% were considered to have “clinical” TAM (more than 10% blasts) and 58% were considered to have “silent” TAM (fewer than 10% blasts).

“We predicted that these babies with clinical TAM would have more severe clinical disease ... and that in fact turned out to be the case,” Dr. Roberts said.

Why is the GATA1 mutation so significant? Research suggests that platelet production is abnormal in neonates with Down syndrome, compared with neonates without it, regardless of whether they have the mutation, Dr. Roberts said.

The mutation doesn’t reduce further platelet count, but does disrupt megakaryopoiesis – the process of the production of platelets. As a result, giant platelets and megakaryocyte fragments are more common, she explained.

Moving forward, research data can be used to identify which children are most at risk, Dr. Roberts said. Newborns with Down syndrome are more likely to survive without leukemia if they have silent TAM, compared with those who have clinical TAM, and if they have an estimated variant allele frequency above 15%, according to findings from the Oxford study.

Children at high risk of AML before age 4 years can be identified by analyzing the percentage of blasts on a smear and/or by analyzing mutation of GATA1, according to Dr. Roberts. However, this cannot be accomplished by the use of a complete blood count (CBC) test, she said, which is used to check for leukemia.

Dr. Roberts called for the development of more guidelines for screening newborns with Down syndrome for leukemia risk. The British Society for Haematology issued testing guidelines, coauthored by Dr. Roberts, in 2018 (Br J Haematol. 2018 Jul;182[2]:200-11).

Dr. Roberts reported having no financial disclosures.

LOS ANGELES – New ways to preserve beta cell function in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes mellitus are needed, because neither metformin alone nor metformin plus glargine are making a dent.

Doug Brunk/MDedge News

At the same time, the SEARCH for Diabetes in Youth trial showed that the incidence of T2DM in U.S. youth continues to rise, especially among Native Americans and non-Hispanic blacks (P less than .001 for both associations; N Engl J Med. 2017;376:1419-29). In addition, the earlier Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed that rapid treatment failure in youth-onset T2DM was associated with loss of beta cell function (N Engl J Med. 2012;366:2247-56).

“Early treatment of youth with impaired glucose tolerance or type 2 diabetes may require other medications alone or in combination or for longer periods of time to combat the severe insulin resistance of puberty and arrest progressive loss of beta cell function,” Sonia Caprio, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.

She based her remarks on a review of the recently completed multicenter Restoring Insulin Secretion (RISE) Pediatric Medication Study, (Diabetes Care 2018;41[8]:1717-25). It set out to answer the following question: In adolescents with impaired glucose tolerance or recently diagnosed T2DM, can beta cell function be preserved or improved during 12 months of active treatment and maintained for 3 months following the withdrawal of therapy?

To find out, Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., and her colleagues enrolled 91 youth who were randomized to one of two treatment arms: metformin alone titrated over 4 weeks from 500 mg/day to a 1,000 mg twice daily dose (modified if necessary due to GI symptoms), or to glargine followed by metformin. This group received once-daily insulin glargine, titrated twice weekly over 1 month based on daily self-monitoring of blood glucose to a goal of 80-90 mg/dL. Glargine was discontinued after 3 months and metformin was titrated. Beta-cell function (insulin sensitivity paired with beta-cell responses) was assessed by the two-step hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). All clinical data were collected 3 months after discontinuation of active treatment.

Dr. Caprio described the two-step hyperglycemic clamp as “a robust approach to quantification of insulin sensitivity and beta-cell responses to both glucose and the nonglucose secretagogue arginine. It provides mechanistic insights into how the tested interventions affected two key metabolic defects of type 2 diabetes: insulin sensitivity and beta cell responses.”

The mean age of patients was 14 years, 71% were female, their mean body mass index was 37 kg/m². The researchers observed no significant differences between treatment groups at baseline, 12 months, or 15 months in beta cell function, BMI percentile, hemoglobin A_1c, fasting glucose, or oral glucose tolerance test 2-hour glucose results. In both treatment groups, clamp-measured beta cell function was significantly lower at 12 and 15 months, compared with baseline. HbA_1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.

“These findings are discouraging,” Dr. Caprio said. “They contrast with previous studies in adults showing an improvement in beta cell function with metformin or insulin for type 2 diabetes prevention and treatment.” Results of the RISE Pediatric Medication Study “call for further studies to better understand the physiology underlying beta cell dysfunction in youth to identify effective treatment options. Better approaches to prevent and treat obesity in youth are critically needed.”

Dr. Caprio reported having no disclosures.

dbrunk@mdedge.com

LOS ANGELES – New ways to preserve beta cell function in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes mellitus are needed, because neither metformin alone nor metformin plus glargine are making a dent.

Doug Brunk/MDedge News

At the same time, the SEARCH for Diabetes in Youth trial showed that the incidence of T2DM in U.S. youth continues to rise, especially among Native Americans and non-Hispanic blacks (P less than .001 for both associations; N Engl J Med. 2017;376:1419-29). In addition, the earlier Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed that rapid treatment failure in youth-onset T2DM was associated with loss of beta cell function (N Engl J Med. 2012;366:2247-56).

“Early treatment of youth with impaired glucose tolerance or type 2 diabetes may require other medications alone or in combination or for longer periods of time to combat the severe insulin resistance of puberty and arrest progressive loss of beta cell function,” Sonia Caprio, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.

She based her remarks on a review of the recently completed multicenter Restoring Insulin Secretion (RISE) Pediatric Medication Study, (Diabetes Care 2018;41[8]:1717-25). It set out to answer the following question: In adolescents with impaired glucose tolerance or recently diagnosed T2DM, can beta cell function be preserved or improved during 12 months of active treatment and maintained for 3 months following the withdrawal of therapy?

To find out, Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., and her colleagues enrolled 91 youth who were randomized to one of two treatment arms: metformin alone titrated over 4 weeks from 500 mg/day to a 1,000 mg twice daily dose (modified if necessary due to GI symptoms), or to glargine followed by metformin. This group received once-daily insulin glargine, titrated twice weekly over 1 month based on daily self-monitoring of blood glucose to a goal of 80-90 mg/dL. Glargine was discontinued after 3 months and metformin was titrated. Beta-cell function (insulin sensitivity paired with beta-cell responses) was assessed by the two-step hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). All clinical data were collected 3 months after discontinuation of active treatment.

Dr. Caprio described the two-step hyperglycemic clamp as “a robust approach to quantification of insulin sensitivity and beta-cell responses to both glucose and the nonglucose secretagogue arginine. It provides mechanistic insights into how the tested interventions affected two key metabolic defects of type 2 diabetes: insulin sensitivity and beta cell responses.”

The mean age of patients was 14 years, 71% were female, their mean body mass index was 37 kg/m². The researchers observed no significant differences between treatment groups at baseline, 12 months, or 15 months in beta cell function, BMI percentile, hemoglobin A_1c, fasting glucose, or oral glucose tolerance test 2-hour glucose results. In both treatment groups, clamp-measured beta cell function was significantly lower at 12 and 15 months, compared with baseline. HbA_1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.

“These findings are discouraging,” Dr. Caprio said. “They contrast with previous studies in adults showing an improvement in beta cell function with metformin or insulin for type 2 diabetes prevention and treatment.” Results of the RISE Pediatric Medication Study “call for further studies to better understand the physiology underlying beta cell dysfunction in youth to identify effective treatment options. Better approaches to prevent and treat obesity in youth are critically needed.”

Dr. Caprio reported having no disclosures.

dbrunk@mdedge.com

LOS ANGELES – New ways to preserve beta cell function in youth with impaired glucose tolerance or recently diagnosed type 2 diabetes mellitus are needed, because neither metformin alone nor metformin plus glargine are making a dent.

Doug Brunk/MDedge News

At the same time, the SEARCH for Diabetes in Youth trial showed that the incidence of T2DM in U.S. youth continues to rise, especially among Native Americans and non-Hispanic blacks (P less than .001 for both associations; N Engl J Med. 2017;376:1419-29). In addition, the earlier Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed that rapid treatment failure in youth-onset T2DM was associated with loss of beta cell function (N Engl J Med. 2012;366:2247-56).

“Early treatment of youth with impaired glucose tolerance or type 2 diabetes may require other medications alone or in combination or for longer periods of time to combat the severe insulin resistance of puberty and arrest progressive loss of beta cell function,” Sonia Caprio, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.

She based her remarks on a review of the recently completed multicenter Restoring Insulin Secretion (RISE) Pediatric Medication Study, (Diabetes Care 2018;41[8]:1717-25). It set out to answer the following question: In adolescents with impaired glucose tolerance or recently diagnosed T2DM, can beta cell function be preserved or improved during 12 months of active treatment and maintained for 3 months following the withdrawal of therapy?

To find out, Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., and her colleagues enrolled 91 youth who were randomized to one of two treatment arms: metformin alone titrated over 4 weeks from 500 mg/day to a 1,000 mg twice daily dose (modified if necessary due to GI symptoms), or to glargine followed by metformin. This group received once-daily insulin glargine, titrated twice weekly over 1 month based on daily self-monitoring of blood glucose to a goal of 80-90 mg/dL. Glargine was discontinued after 3 months and metformin was titrated. Beta-cell function (insulin sensitivity paired with beta-cell responses) was assessed by the two-step hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). All clinical data were collected 3 months after discontinuation of active treatment.

Dr. Caprio described the two-step hyperglycemic clamp as “a robust approach to quantification of insulin sensitivity and beta-cell responses to both glucose and the nonglucose secretagogue arginine. It provides mechanistic insights into how the tested interventions affected two key metabolic defects of type 2 diabetes: insulin sensitivity and beta cell responses.”

The mean age of patients was 14 years, 71% were female, their mean body mass index was 37 kg/m². The researchers observed no significant differences between treatment groups at baseline, 12 months, or 15 months in beta cell function, BMI percentile, hemoglobin A_1c, fasting glucose, or oral glucose tolerance test 2-hour glucose results. In both treatment groups, clamp-measured beta cell function was significantly lower at 12 and 15 months, compared with baseline. HbA_1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.

“These findings are discouraging,” Dr. Caprio said. “They contrast with previous studies in adults showing an improvement in beta cell function with metformin or insulin for type 2 diabetes prevention and treatment.” Results of the RISE Pediatric Medication Study “call for further studies to better understand the physiology underlying beta cell dysfunction in youth to identify effective treatment options. Better approaches to prevent and treat obesity in youth are critically needed.”

Dr. Caprio reported having no disclosures.

dbrunk@mdedge.com

Children exposed to valproate in utero were 48% more likely to be diagnosed with ADHD when compared with unexposed children in a population-based cohort study of more than 900,000 children in Denmark.

Antiepileptic drug exposure is associated with an increased risk of various congenital malformations, but its role in the development of ADHD in children has not been well documented, first author Jakob Christensen, MD, PhD, DrMedSci, of Aarhus (Denmark) University Hospital, and his colleagues wrote in their paper, published online Jan. 4 in JAMA Network Open.

The researchers identified 913,302 singleton births in Denmark from 1997 through 2011, with children followed through 2015.

Overall, children who were prenatally exposed to valproate had a 48% increased risk of ADHD. Antiepileptic drug exposure was defined as 30 days before the estimated day of conception to the day of birth, and included valproate, clobazam, and other antiepileptic drugs. The average age of the children at the study’s end was 10 years, and approximately half were male.

A total of 580 children were exposed to valproate in utero; of these, 8.4% were later diagnosed with ADHD, compared with 3.2% of 912,722 children who were not exposed to valproate. In addition, the absolute 15-year risk of ADHD was 11% in valproate-exposed children vs. 4.6% in unexposed children. No significant associations appeared between ADHD and other antiepileptic drugs.

The study findings were limited by several factors, including the contraindication of valproate for use in pregnancy, which may mean that the women taking valproate had more severe disease, the researchers noted.

“Due to the observational nature of this study, we cannot rule out that the observed risk increase for ADHD is at least in part explained by the mother’s health condition that triggered the prescription of valproate during pregnancy,” they said. Other limitations included a lack of data on the exact amounts of valproate taken during pregnancy and the potential impact of nonepilepsy medications, they noted.

However, the results were strengthened by the large size and population-based cohort, and support warnings by professional medical organizations against valproate use in pregnancy, the researchers said. “As randomized clinical trials of valproate use during pregnancy are neither feasible nor ethical, our study provides clinical information on the risk of ADHD associated with valproate use during pregnancy,” they concluded.

The study was supported by grants to various authors from the Danish Epilepsy Association Central Denmark Region, the Aarhus University Research Foundation, the Lundbeck Foundation, the National Institutes of Health, the Novo Nordisk Foundation, and the European Commission.

SOURCE: Christensen J et al. JAMA Network Open. 2019;2(1):e186606. doi: 10.1001/jamanetworkopen.2018.6606.

Children exposed to valproate in utero were 48% more likely to be diagnosed with ADHD when compared with unexposed children in a population-based cohort study of more than 900,000 children in Denmark.

Antiepileptic drug exposure is associated with an increased risk of various congenital malformations, but its role in the development of ADHD in children has not been well documented, first author Jakob Christensen, MD, PhD, DrMedSci, of Aarhus (Denmark) University Hospital, and his colleagues wrote in their paper, published online Jan. 4 in JAMA Network Open.

The researchers identified 913,302 singleton births in Denmark from 1997 through 2011, with children followed through 2015.

Overall, children who were prenatally exposed to valproate had a 48% increased risk of ADHD. Antiepileptic drug exposure was defined as 30 days before the estimated day of conception to the day of birth, and included valproate, clobazam, and other antiepileptic drugs. The average age of the children at the study’s end was 10 years, and approximately half were male.

A total of 580 children were exposed to valproate in utero; of these, 8.4% were later diagnosed with ADHD, compared with 3.2% of 912,722 children who were not exposed to valproate. In addition, the absolute 15-year risk of ADHD was 11% in valproate-exposed children vs. 4.6% in unexposed children. No significant associations appeared between ADHD and other antiepileptic drugs.

The study findings were limited by several factors, including the contraindication of valproate for use in pregnancy, which may mean that the women taking valproate had more severe disease, the researchers noted.

“Due to the observational nature of this study, we cannot rule out that the observed risk increase for ADHD is at least in part explained by the mother’s health condition that triggered the prescription of valproate during pregnancy,” they said. Other limitations included a lack of data on the exact amounts of valproate taken during pregnancy and the potential impact of nonepilepsy medications, they noted.

However, the results were strengthened by the large size and population-based cohort, and support warnings by professional medical organizations against valproate use in pregnancy, the researchers said. “As randomized clinical trials of valproate use during pregnancy are neither feasible nor ethical, our study provides clinical information on the risk of ADHD associated with valproate use during pregnancy,” they concluded.

The study was supported by grants to various authors from the Danish Epilepsy Association Central Denmark Region, the Aarhus University Research Foundation, the Lundbeck Foundation, the National Institutes of Health, the Novo Nordisk Foundation, and the European Commission.

SOURCE: Christensen J et al. JAMA Network Open. 2019;2(1):e186606. doi: 10.1001/jamanetworkopen.2018.6606.

Children exposed to valproate in utero were 48% more likely to be diagnosed with ADHD when compared with unexposed children in a population-based cohort study of more than 900,000 children in Denmark.

Antiepileptic drug exposure is associated with an increased risk of various congenital malformations, but its role in the development of ADHD in children has not been well documented, first author Jakob Christensen, MD, PhD, DrMedSci, of Aarhus (Denmark) University Hospital, and his colleagues wrote in their paper, published online Jan. 4 in JAMA Network Open.

The researchers identified 913,302 singleton births in Denmark from 1997 through 2011, with children followed through 2015.

Overall, children who were prenatally exposed to valproate had a 48% increased risk of ADHD. Antiepileptic drug exposure was defined as 30 days before the estimated day of conception to the day of birth, and included valproate, clobazam, and other antiepileptic drugs. The average age of the children at the study’s end was 10 years, and approximately half were male.

A total of 580 children were exposed to valproate in utero; of these, 8.4% were later diagnosed with ADHD, compared with 3.2% of 912,722 children who were not exposed to valproate. In addition, the absolute 15-year risk of ADHD was 11% in valproate-exposed children vs. 4.6% in unexposed children. No significant associations appeared between ADHD and other antiepileptic drugs.

The study findings were limited by several factors, including the contraindication of valproate for use in pregnancy, which may mean that the women taking valproate had more severe disease, the researchers noted.

“Due to the observational nature of this study, we cannot rule out that the observed risk increase for ADHD is at least in part explained by the mother’s health condition that triggered the prescription of valproate during pregnancy,” they said. Other limitations included a lack of data on the exact amounts of valproate taken during pregnancy and the potential impact of nonepilepsy medications, they noted.

However, the results were strengthened by the large size and population-based cohort, and support warnings by professional medical organizations against valproate use in pregnancy, the researchers said. “As randomized clinical trials of valproate use during pregnancy are neither feasible nor ethical, our study provides clinical information on the risk of ADHD associated with valproate use during pregnancy,” they concluded.

The study was supported by grants to various authors from the Danish Epilepsy Association Central Denmark Region, the Aarhus University Research Foundation, the Lundbeck Foundation, the National Institutes of Health, the Novo Nordisk Foundation, and the European Commission.

SOURCE: Christensen J et al. JAMA Network Open. 2019;2(1):e186606. doi: 10.1001/jamanetworkopen.2018.6606.