Pediatrics

For the second time during the 2019-2020 flu season, activity measures have climbed into noteworthy territory.

The proportion of outpatient visits for influenza-like illness (ILI) reached its highest December level, 7.1%, since 2003 and then dropped for 2 weeks. Three weeks of increases since then, however, have the outpatient-visit rate at 6.7% for the week ending Feb. 1, 2020, the Centers for Disease Control and Prevention reported. The baseline rate for the United States is 2.4%.

That rate of 6.7% is already above the highest rates recorded in eight of the last nine flu seasons, and another increase could mean a second, separate trip above 7.0% in the 2019-2020 season – something that has not occurred since national tracking began in 1997, CDC data show.

Those same data also show that, from 1997-1998 to 2018-2019, the United States has spent a total of 11 weeks above the 7.0% mark for ILI-related visits.

Another important measure on the rise, the proportion of respiratory specimens testing positive for influenza, reached a new high for the season, 29.8%, during the week of Feb. 1, the CDC’s influenza division said.

Tests at clinical laboratories also show that predominance is continuing to switch from type B (45.6%) to type A (54.4%), the influenza division noted. Overall predominance for the season, however, continues to favor type B, 59.3% to 40.7%.

The percentage of deaths caused by pneumonia and influenza, which passed the threshold for epidemic of 7.2% back in early January, has been trending downward for the last 3 weeks and was 7.1% as of Feb. 1, according to the influenza division.

ILI-related deaths among children continue to remain high, with a total count of 78 for the season after another 10 deaths were reported during the week ending Feb. 1, the CDC reported. Comparable numbers for the last three seasons are 44 (2018-2019), 97 (2017-2018), and 35 (2016-2017).

The CDC estimates put the total number of ILIs at around 22 million for the season so far, leading to 210,000 hospitalizations. The agency said that it expects to release estimates of vaccine effectiveness later this month.

[email protected]

For the second time during the 2019-2020 flu season, activity measures have climbed into noteworthy territory.

The proportion of outpatient visits for influenza-like illness (ILI) reached its highest December level, 7.1%, since 2003 and then dropped for 2 weeks. Three weeks of increases since then, however, have the outpatient-visit rate at 6.7% for the week ending Feb. 1, 2020, the Centers for Disease Control and Prevention reported. The baseline rate for the United States is 2.4%.

That rate of 6.7% is already above the highest rates recorded in eight of the last nine flu seasons, and another increase could mean a second, separate trip above 7.0% in the 2019-2020 season – something that has not occurred since national tracking began in 1997, CDC data show.

Those same data also show that, from 1997-1998 to 2018-2019, the United States has spent a total of 11 weeks above the 7.0% mark for ILI-related visits.

Another important measure on the rise, the proportion of respiratory specimens testing positive for influenza, reached a new high for the season, 29.8%, during the week of Feb. 1, the CDC’s influenza division said.

Tests at clinical laboratories also show that predominance is continuing to switch from type B (45.6%) to type A (54.4%), the influenza division noted. Overall predominance for the season, however, continues to favor type B, 59.3% to 40.7%.

The percentage of deaths caused by pneumonia and influenza, which passed the threshold for epidemic of 7.2% back in early January, has been trending downward for the last 3 weeks and was 7.1% as of Feb. 1, according to the influenza division.

ILI-related deaths among children continue to remain high, with a total count of 78 for the season after another 10 deaths were reported during the week ending Feb. 1, the CDC reported. Comparable numbers for the last three seasons are 44 (2018-2019), 97 (2017-2018), and 35 (2016-2017).

The CDC estimates put the total number of ILIs at around 22 million for the season so far, leading to 210,000 hospitalizations. The agency said that it expects to release estimates of vaccine effectiveness later this month.

[email protected]

For the second time during the 2019-2020 flu season, activity measures have climbed into noteworthy territory.

The proportion of outpatient visits for influenza-like illness (ILI) reached its highest December level, 7.1%, since 2003 and then dropped for 2 weeks. Three weeks of increases since then, however, have the outpatient-visit rate at 6.7% for the week ending Feb. 1, 2020, the Centers for Disease Control and Prevention reported. The baseline rate for the United States is 2.4%.

That rate of 6.7% is already above the highest rates recorded in eight of the last nine flu seasons, and another increase could mean a second, separate trip above 7.0% in the 2019-2020 season – something that has not occurred since national tracking began in 1997, CDC data show.

Those same data also show that, from 1997-1998 to 2018-2019, the United States has spent a total of 11 weeks above the 7.0% mark for ILI-related visits.

Another important measure on the rise, the proportion of respiratory specimens testing positive for influenza, reached a new high for the season, 29.8%, during the week of Feb. 1, the CDC’s influenza division said.

Tests at clinical laboratories also show that predominance is continuing to switch from type B (45.6%) to type A (54.4%), the influenza division noted. Overall predominance for the season, however, continues to favor type B, 59.3% to 40.7%.

The percentage of deaths caused by pneumonia and influenza, which passed the threshold for epidemic of 7.2% back in early January, has been trending downward for the last 3 weeks and was 7.1% as of Feb. 1, according to the influenza division.

ILI-related deaths among children continue to remain high, with a total count of 78 for the season after another 10 deaths were reported during the week ending Feb. 1, the CDC reported. Comparable numbers for the last three seasons are 44 (2018-2019), 97 (2017-2018), and 35 (2016-2017).

The CDC estimates put the total number of ILIs at around 22 million for the season so far, leading to 210,000 hospitalizations. The agency said that it expects to release estimates of vaccine effectiveness later this month.

[email protected]

BALTIMORE – Abnormal findings on overnight continuous EEG in patients with autism spectrum disorder (ASD) are associated with a significantly increased risk of subsequent epilepsy, according to research presented at the annual meeting of the American Epilepsy Society. In addition, a positive family history of febrile seizures also is associated with an increased risk of epilepsy in this population.

The literature suggests that the prevalence of epilepsy in patients with ASD ranges from 5% to 40%. This broad range may result from the heterogeneity of epilepsy risk factors among patients with ASD. These risk factors include intellectual disability, age, and syndromic forms of ASD such as tuberous sclerosis complex. Regardless of whether they have epilepsy, approximately 60% of patients with ASD have EEG abnormalities. The prognostic implications of these abnormalities are uncertain.
 

Investigators reviewed patients’ charts retrospectively

Divya Nadkarni, MD, a neurologist at Ronald Reagan UCLA Medical Center in Los Angeles, and colleagues sought to clarify the relationship between risk factors such as EEG abnormalities and subsequent epilepsy in patients with ASD. They retrospectively identified patients who were followed jointly at UCLA and at Pediatric Minds, a neurodevelopmental clinic in Torrance, Calif. Eligible patients had a diagnosis of ASD, based on criteria from DSM-IV, DSM-5, or the Autism Diagnostic Observation Schedule. In addition, patients had overnight, continuous video EEG evaluation and a minimum follow-up of 1 week after EEG. Patients with a history of epilepsy before the initial EEG evaluation were excluded. Dr. Nadkarni and colleagues collected clinical and electrographic data by chart review.

The study’s primary outcome was time to onset of epilepsy. Among the variables that the investigators analyzed were EEG abnormalities, which they defined as focal slowing or generalized or focal epileptiform discharges. The other variables were history of febrile seizures, family history of epilepsy, family history of febrile seizures, and family history of ASD. Dr. Nadkarni and colleagues analyzed the data using the Kaplan–Meier method and Cox proportional hazards models.

In all, 164 patients met the study’s inclusion criteria. The population’s median age at the initial EEG evaluation was 4.5 years. The median follow-up after this evaluation was 2.4 years. The investigators found 63 patients (38.4%) with abnormal EEGs, and 18 patients (11%) subsequently developed epilepsy after a median of 1.9 years.
 

Family history of febrile seizures was associated with time to epilepsy onset

The time to epilepsy onset was associated with abnormalities on the initial overnight continuous EEG. The hazard ratio of epilepsy among patients with EEG abnormalities was 8.0. Approximately one-third of patients with EEG abnormalities developed subsequent epilepsy, compared with approximately 5% of patients without EEG abnormalities, said Dr. Nadkarni.

In addition, time to epilepsy onset was independently associated with a positive family history of febrile seizures. This finding was unexpected, said Dr. Nadkarni. The hazard ratio of epilepsy among patients with a positive family history of febrile seizures was 12.6.

The patient’s own history of febrile seizures was not associated with time to epilepsy onset. One potential explanation for this result is that it is difficult to distinguish between febrile seizure and seizure with fever in the general pediatric population. Making this distinction in children with ASD, who may have atypical febrile seizures, might be still more difficult, said Dr. Nadkarni.
 

Time for guideline updates?

“Statements from the Centers for Disease Control and Prevention, the American Academy of Pediatrics, the American Academy of Neurology, and the Child Neurology Society do not currently recommend routine EEG screening for all children with ASD,” said Dr. Nadkarni. Investigators are suggesting that the guidelines should be reevaluated, however. “Research shows that EEG abnormalities, particularly epileptiform abnormalities, are associated with worse outcome, in terms of developmental and adaptive functioning. EEG endophenotypes in ASD are starting to be elucidated ... That’s one reason to consider EEG screening.” Furthermore, preliminary connectivity research suggests that EEG screening of high-risk siblings of children with ASD may predict the development of ASD.

The small cohort and retrospective design were among the study’s limitations, said Dr. Nadkarni. Some patients were lost to follow-up, and some data were missing from patients’ charts.

“In our opinion, further study – ideally, a prospective, observational cohort study – might be warranted to determine whether overnight continuous EEG monitoring might be useful as a screening tool for epilepsy in patients with ASD,” Dr. Nadkarni concluded.

The study was conducted without external funding, and the investigators had no disclosures.

[email protected]

SOURCE: Nadkarni D et al. AES 2019. Abstract 1.29.

BALTIMORE – Abnormal findings on overnight continuous EEG in patients with autism spectrum disorder (ASD) are associated with a significantly increased risk of subsequent epilepsy, according to research presented at the annual meeting of the American Epilepsy Society. In addition, a positive family history of febrile seizures also is associated with an increased risk of epilepsy in this population.

The literature suggests that the prevalence of epilepsy in patients with ASD ranges from 5% to 40%. This broad range may result from the heterogeneity of epilepsy risk factors among patients with ASD. These risk factors include intellectual disability, age, and syndromic forms of ASD such as tuberous sclerosis complex. Regardless of whether they have epilepsy, approximately 60% of patients with ASD have EEG abnormalities. The prognostic implications of these abnormalities are uncertain.
 

Investigators reviewed patients’ charts retrospectively

Divya Nadkarni, MD, a neurologist at Ronald Reagan UCLA Medical Center in Los Angeles, and colleagues sought to clarify the relationship between risk factors such as EEG abnormalities and subsequent epilepsy in patients with ASD. They retrospectively identified patients who were followed jointly at UCLA and at Pediatric Minds, a neurodevelopmental clinic in Torrance, Calif. Eligible patients had a diagnosis of ASD, based on criteria from DSM-IV, DSM-5, or the Autism Diagnostic Observation Schedule. In addition, patients had overnight, continuous video EEG evaluation and a minimum follow-up of 1 week after EEG. Patients with a history of epilepsy before the initial EEG evaluation were excluded. Dr. Nadkarni and colleagues collected clinical and electrographic data by chart review.

The study’s primary outcome was time to onset of epilepsy. Among the variables that the investigators analyzed were EEG abnormalities, which they defined as focal slowing or generalized or focal epileptiform discharges. The other variables were history of febrile seizures, family history of epilepsy, family history of febrile seizures, and family history of ASD. Dr. Nadkarni and colleagues analyzed the data using the Kaplan–Meier method and Cox proportional hazards models.

In all, 164 patients met the study’s inclusion criteria. The population’s median age at the initial EEG evaluation was 4.5 years. The median follow-up after this evaluation was 2.4 years. The investigators found 63 patients (38.4%) with abnormal EEGs, and 18 patients (11%) subsequently developed epilepsy after a median of 1.9 years.
 

Family history of febrile seizures was associated with time to epilepsy onset

The time to epilepsy onset was associated with abnormalities on the initial overnight continuous EEG. The hazard ratio of epilepsy among patients with EEG abnormalities was 8.0. Approximately one-third of patients with EEG abnormalities developed subsequent epilepsy, compared with approximately 5% of patients without EEG abnormalities, said Dr. Nadkarni.

In addition, time to epilepsy onset was independently associated with a positive family history of febrile seizures. This finding was unexpected, said Dr. Nadkarni. The hazard ratio of epilepsy among patients with a positive family history of febrile seizures was 12.6.

The patient’s own history of febrile seizures was not associated with time to epilepsy onset. One potential explanation for this result is that it is difficult to distinguish between febrile seizure and seizure with fever in the general pediatric population. Making this distinction in children with ASD, who may have atypical febrile seizures, might be still more difficult, said Dr. Nadkarni.
 

Time for guideline updates?

“Statements from the Centers for Disease Control and Prevention, the American Academy of Pediatrics, the American Academy of Neurology, and the Child Neurology Society do not currently recommend routine EEG screening for all children with ASD,” said Dr. Nadkarni. Investigators are suggesting that the guidelines should be reevaluated, however. “Research shows that EEG abnormalities, particularly epileptiform abnormalities, are associated with worse outcome, in terms of developmental and adaptive functioning. EEG endophenotypes in ASD are starting to be elucidated ... That’s one reason to consider EEG screening.” Furthermore, preliminary connectivity research suggests that EEG screening of high-risk siblings of children with ASD may predict the development of ASD.

The small cohort and retrospective design were among the study’s limitations, said Dr. Nadkarni. Some patients were lost to follow-up, and some data were missing from patients’ charts.

“In our opinion, further study – ideally, a prospective, observational cohort study – might be warranted to determine whether overnight continuous EEG monitoring might be useful as a screening tool for epilepsy in patients with ASD,” Dr. Nadkarni concluded.

The study was conducted without external funding, and the investigators had no disclosures.

[email protected]

SOURCE: Nadkarni D et al. AES 2019. Abstract 1.29.

BALTIMORE – Abnormal findings on overnight continuous EEG in patients with autism spectrum disorder (ASD) are associated with a significantly increased risk of subsequent epilepsy, according to research presented at the annual meeting of the American Epilepsy Society. In addition, a positive family history of febrile seizures also is associated with an increased risk of epilepsy in this population.

The literature suggests that the prevalence of epilepsy in patients with ASD ranges from 5% to 40%. This broad range may result from the heterogeneity of epilepsy risk factors among patients with ASD. These risk factors include intellectual disability, age, and syndromic forms of ASD such as tuberous sclerosis complex. Regardless of whether they have epilepsy, approximately 60% of patients with ASD have EEG abnormalities. The prognostic implications of these abnormalities are uncertain.
 

Investigators reviewed patients’ charts retrospectively

Divya Nadkarni, MD, a neurologist at Ronald Reagan UCLA Medical Center in Los Angeles, and colleagues sought to clarify the relationship between risk factors such as EEG abnormalities and subsequent epilepsy in patients with ASD. They retrospectively identified patients who were followed jointly at UCLA and at Pediatric Minds, a neurodevelopmental clinic in Torrance, Calif. Eligible patients had a diagnosis of ASD, based on criteria from DSM-IV, DSM-5, or the Autism Diagnostic Observation Schedule. In addition, patients had overnight, continuous video EEG evaluation and a minimum follow-up of 1 week after EEG. Patients with a history of epilepsy before the initial EEG evaluation were excluded. Dr. Nadkarni and colleagues collected clinical and electrographic data by chart review.

The study’s primary outcome was time to onset of epilepsy. Among the variables that the investigators analyzed were EEG abnormalities, which they defined as focal slowing or generalized or focal epileptiform discharges. The other variables were history of febrile seizures, family history of epilepsy, family history of febrile seizures, and family history of ASD. Dr. Nadkarni and colleagues analyzed the data using the Kaplan–Meier method and Cox proportional hazards models.

In all, 164 patients met the study’s inclusion criteria. The population’s median age at the initial EEG evaluation was 4.5 years. The median follow-up after this evaluation was 2.4 years. The investigators found 63 patients (38.4%) with abnormal EEGs, and 18 patients (11%) subsequently developed epilepsy after a median of 1.9 years.
 

Family history of febrile seizures was associated with time to epilepsy onset

The time to epilepsy onset was associated with abnormalities on the initial overnight continuous EEG. The hazard ratio of epilepsy among patients with EEG abnormalities was 8.0. Approximately one-third of patients with EEG abnormalities developed subsequent epilepsy, compared with approximately 5% of patients without EEG abnormalities, said Dr. Nadkarni.

In addition, time to epilepsy onset was independently associated with a positive family history of febrile seizures. This finding was unexpected, said Dr. Nadkarni. The hazard ratio of epilepsy among patients with a positive family history of febrile seizures was 12.6.

The patient’s own history of febrile seizures was not associated with time to epilepsy onset. One potential explanation for this result is that it is difficult to distinguish between febrile seizure and seizure with fever in the general pediatric population. Making this distinction in children with ASD, who may have atypical febrile seizures, might be still more difficult, said Dr. Nadkarni.
 

Time for guideline updates?

“Statements from the Centers for Disease Control and Prevention, the American Academy of Pediatrics, the American Academy of Neurology, and the Child Neurology Society do not currently recommend routine EEG screening for all children with ASD,” said Dr. Nadkarni. Investigators are suggesting that the guidelines should be reevaluated, however. “Research shows that EEG abnormalities, particularly epileptiform abnormalities, are associated with worse outcome, in terms of developmental and adaptive functioning. EEG endophenotypes in ASD are starting to be elucidated ... That’s one reason to consider EEG screening.” Furthermore, preliminary connectivity research suggests that EEG screening of high-risk siblings of children with ASD may predict the development of ASD.

The small cohort and retrospective design were among the study’s limitations, said Dr. Nadkarni. Some patients were lost to follow-up, and some data were missing from patients’ charts.

“In our opinion, further study – ideally, a prospective, observational cohort study – might be warranted to determine whether overnight continuous EEG monitoring might be useful as a screening tool for epilepsy in patients with ASD,” Dr. Nadkarni concluded.

The study was conducted without external funding, and the investigators had no disclosures.

[email protected]

SOURCE: Nadkarni D et al. AES 2019. Abstract 1.29.

ORLANDO – Do you have pediatric patients with atopic dermatitis (AD) flares despite complying with treatment, or those who have a new rash in an unusual area? Consider patch testing to assess whether they have allergic contact dermatitis.

Jeff Craven/MDedge News

“Of the patients who are sent to me by local pediatric dermatologists, 50% of them are positive” for allergens, said Jonathan H. Zippin, MD, PhD, director of the contact, occupational, and photodermatitis service at Cornell University, New York.

Speaking at the ODAC Dermatology, Aesthetic, and Surgical Conference, Dr. Zippin noted the prevalence of allergen sensitization is between 13% and 25% among children who are asymptomatic, while the prevalence of sensitization to at least one allergen among children with suspected allergic contact dermatitis (ACD) is between 25% and 96%. In 2014, a study from the National American Contact Dermatitis Group (NACDG) showed that of 883 children who were patch tested, 56.7% had at least one relevant positive patch test (RPPT) result.

“The take-home message here is that pediatric contact dermatitis is common, much more common than a lot of people realize,” Dr. Zippin said.

He described three common scenarios to keep in mind: a worsening rash, a new rash, and failure of a rash to improve after the patient avoids all of his or her positive allergens.

When a rash worsens, patch testing is likely to offer answers. In an analysis of 1,142 patients with suspected ACD aged 18 years or younger (mean age, 10.5 years; 64% female) in the Pediatric Contact Dermatitis Registry study database, 65% had at least one positive patch test, and 48% had at least 1 RPPT (Dermatitis 2016; 27[5] 293-302).

But not all patch testing is the same: The study also found that 24% of the RPPT cases would have been missed if assessed with the T.R.U.E. TEST compared with extended patch testing. If a T.R.U.E. TEST fails to explain generalized atopic dermatitis, the patient should be sent for more comprehensive testing where available, Dr. Zippin advised.

Pediatric patients also have unique allergens clinicians should consider. In the same study, children had a number of allergens similar to those of adults as reported in previous studies, such as nickel, cobalt, and neomycin. However, propylene glycol and cocamidopropyl betaine were allergens identified as unique to the pediatric population.

Another study looking at the same group of patients found that compared with children who did not have AD, children with AD had 7.4 times higher odds of having an RPPT to cocamidopropyl betaine, 7.6 times higher odds of having an RPPT to parthenolide, 5.3 times higher odds of having an RPPT to tixocortol pivalate, 4.2 times higher odds of having an RPPT to wool alcohols, and 4 times higher odds of having an RPPT to lanolin (JAMA Dermatology 2017;153[8]:765-70).

All of these are components of topical medicaments used to treat AD, “either components of emollients that we recommend, or components of steroids that we recommend,” Dr. Zippin pointed out.

One of these allergens could be the culprit when a child develops a new rash but there are no new apparent changes in products, exposures, and activities. Lanolin, also called wool grease, is used in many skin care products, for example. Dr. Zippin described the case of a 6-year-old girl with a history of AD, who presented with a new rash on her scalp and behind her ears, not explained by any obvious changes to products, exposures, or activities. Subsequent patch testing determined that the rash was caused by baby shampoo, which contained cocamidopropyl betaine, which is used in hypoallergenic products. The rash resolved after a different shampoo was used.

“Sometimes, we really have to be thinking when the rash is getting worse, is there something they’re being exposed to that might be an allergen?” Dr. Zippin said.

In patients who have avoided all their positive allergens but a rash has not improved, clinicians should consider systemic contact dermatitis (SCD). Patients can develop SCD through different types of exposures, including transepidermal, transmucosal, oral, intravenous, subcutaneous, intramuscular, inhalation, and implantation routes.

SCD also has a variety of presentations, including pompholyx/dyshidrosis/vesicular dermatitis, maculopapular eruption, chronic pruritus, exfoliative erythroderma/toxiderma, chronic urticaria, erythema multiforme and vasculitis, hyperkeratotic papules of the elbows, acute generalized exanthematous pustulosis, and pruritus ani, according to Dr. Zippin.

SCD should be considered when a patient has a positive patch test to an allergen that is known to cause SCD, and does not clear after avoiding cutaneous exposure to the allergen, Dr. Zippin advised.

Patients will most often develop SCD from plants and herbs, Dr. Zippin noted. Chrysanthemums and chamomile tea are common culprits for compositae allergy and can trigger SCD; other causes are Anacardiaceae, Balsam of Peru, and propolis. Metals (nickel, cobalt, gold, and chromium), medications (aminoglycosides, corticosteroids, and ethylenediamine), and other sources (formaldehyde, propylene glycol in frozen foods, gallates, and methylisothiazolinone) can cause SCD as well.

Methylisothiazolinone in particular is a very common sensitizer, Dr. Zippin said. “If you have a patient who is positive to this, it’s almost always the cause of their problem.”

Balsam of Peru is in a number of different foods, and patients who need to follow a diet free of Balsam of Peru should avoid a long list of foods including citrus; bakery goods; Danish pastry; candy; gum; spices such as cinnamon, cloves, vanilla, curry, allspice, anise, and ginger; spicy condiments such as ketchup, chili sauce, barbecue sauce; chili, pizza, and foods with red sauces; tomatoes; pickles; alcohol (wine, beer, gin, vermouth); tea (perfumed or flavored); tobacco; chocolate and ice cream; and soft drinks (cola or spiced soft drinks).

Patients starting a nickel-free diet should avoid soy, peanuts and other nuts, legumes, chocolate, cocoa, oats, fish, and whole wheat flours. Any elimination diet should last for 3 months but should at least be tried for 3-4 weeks, with gradual reintroduction of foods suspected as triggers once per week. Any type I allergies that are discovered or suspected can be referred to an allergist for allergen challenge and desensitization therapy.

For more information, Dr. Zippin recommended the American Contact Dermatitis Society website for more information.

Dr. Zippin reported that he is the founder and holds stock options at CEP Biotech; is on the medical advisory board and receives stock options from YouV Labs., is a paid consultant and performs industry-sponsored research for Pfizer, receives stock options from Regeneron, and is on the medical advisory board for Hoth Therapeutics Inc. He is on the board of directors for the American Contact Dermatitis Society.

ORLANDO – Do you have pediatric patients with atopic dermatitis (AD) flares despite complying with treatment, or those who have a new rash in an unusual area? Consider patch testing to assess whether they have allergic contact dermatitis.

Jeff Craven/MDedge News

“Of the patients who are sent to me by local pediatric dermatologists, 50% of them are positive” for allergens, said Jonathan H. Zippin, MD, PhD, director of the contact, occupational, and photodermatitis service at Cornell University, New York.

Speaking at the ODAC Dermatology, Aesthetic, and Surgical Conference, Dr. Zippin noted the prevalence of allergen sensitization is between 13% and 25% among children who are asymptomatic, while the prevalence of sensitization to at least one allergen among children with suspected allergic contact dermatitis (ACD) is between 25% and 96%. In 2014, a study from the National American Contact Dermatitis Group (NACDG) showed that of 883 children who were patch tested, 56.7% had at least one relevant positive patch test (RPPT) result.

“The take-home message here is that pediatric contact dermatitis is common, much more common than a lot of people realize,” Dr. Zippin said.

He described three common scenarios to keep in mind: a worsening rash, a new rash, and failure of a rash to improve after the patient avoids all of his or her positive allergens.

When a rash worsens, patch testing is likely to offer answers. In an analysis of 1,142 patients with suspected ACD aged 18 years or younger (mean age, 10.5 years; 64% female) in the Pediatric Contact Dermatitis Registry study database, 65% had at least one positive patch test, and 48% had at least 1 RPPT (Dermatitis 2016; 27[5] 293-302).

But not all patch testing is the same: The study also found that 24% of the RPPT cases would have been missed if assessed with the T.R.U.E. TEST compared with extended patch testing. If a T.R.U.E. TEST fails to explain generalized atopic dermatitis, the patient should be sent for more comprehensive testing where available, Dr. Zippin advised.

Pediatric patients also have unique allergens clinicians should consider. In the same study, children had a number of allergens similar to those of adults as reported in previous studies, such as nickel, cobalt, and neomycin. However, propylene glycol and cocamidopropyl betaine were allergens identified as unique to the pediatric population.

Another study looking at the same group of patients found that compared with children who did not have AD, children with AD had 7.4 times higher odds of having an RPPT to cocamidopropyl betaine, 7.6 times higher odds of having an RPPT to parthenolide, 5.3 times higher odds of having an RPPT to tixocortol pivalate, 4.2 times higher odds of having an RPPT to wool alcohols, and 4 times higher odds of having an RPPT to lanolin (JAMA Dermatology 2017;153[8]:765-70).

All of these are components of topical medicaments used to treat AD, “either components of emollients that we recommend, or components of steroids that we recommend,” Dr. Zippin pointed out.

One of these allergens could be the culprit when a child develops a new rash but there are no new apparent changes in products, exposures, and activities. Lanolin, also called wool grease, is used in many skin care products, for example. Dr. Zippin described the case of a 6-year-old girl with a history of AD, who presented with a new rash on her scalp and behind her ears, not explained by any obvious changes to products, exposures, or activities. Subsequent patch testing determined that the rash was caused by baby shampoo, which contained cocamidopropyl betaine, which is used in hypoallergenic products. The rash resolved after a different shampoo was used.

“Sometimes, we really have to be thinking when the rash is getting worse, is there something they’re being exposed to that might be an allergen?” Dr. Zippin said.

In patients who have avoided all their positive allergens but a rash has not improved, clinicians should consider systemic contact dermatitis (SCD). Patients can develop SCD through different types of exposures, including transepidermal, transmucosal, oral, intravenous, subcutaneous, intramuscular, inhalation, and implantation routes.

SCD also has a variety of presentations, including pompholyx/dyshidrosis/vesicular dermatitis, maculopapular eruption, chronic pruritus, exfoliative erythroderma/toxiderma, chronic urticaria, erythema multiforme and vasculitis, hyperkeratotic papules of the elbows, acute generalized exanthematous pustulosis, and pruritus ani, according to Dr. Zippin.

SCD should be considered when a patient has a positive patch test to an allergen that is known to cause SCD, and does not clear after avoiding cutaneous exposure to the allergen, Dr. Zippin advised.

Patients will most often develop SCD from plants and herbs, Dr. Zippin noted. Chrysanthemums and chamomile tea are common culprits for compositae allergy and can trigger SCD; other causes are Anacardiaceae, Balsam of Peru, and propolis. Metals (nickel, cobalt, gold, and chromium), medications (aminoglycosides, corticosteroids, and ethylenediamine), and other sources (formaldehyde, propylene glycol in frozen foods, gallates, and methylisothiazolinone) can cause SCD as well.

Methylisothiazolinone in particular is a very common sensitizer, Dr. Zippin said. “If you have a patient who is positive to this, it’s almost always the cause of their problem.”

Balsam of Peru is in a number of different foods, and patients who need to follow a diet free of Balsam of Peru should avoid a long list of foods including citrus; bakery goods; Danish pastry; candy; gum; spices such as cinnamon, cloves, vanilla, curry, allspice, anise, and ginger; spicy condiments such as ketchup, chili sauce, barbecue sauce; chili, pizza, and foods with red sauces; tomatoes; pickles; alcohol (wine, beer, gin, vermouth); tea (perfumed or flavored); tobacco; chocolate and ice cream; and soft drinks (cola or spiced soft drinks).

Patients starting a nickel-free diet should avoid soy, peanuts and other nuts, legumes, chocolate, cocoa, oats, fish, and whole wheat flours. Any elimination diet should last for 3 months but should at least be tried for 3-4 weeks, with gradual reintroduction of foods suspected as triggers once per week. Any type I allergies that are discovered or suspected can be referred to an allergist for allergen challenge and desensitization therapy.

For more information, Dr. Zippin recommended the American Contact Dermatitis Society website for more information.

Dr. Zippin reported that he is the founder and holds stock options at CEP Biotech; is on the medical advisory board and receives stock options from YouV Labs., is a paid consultant and performs industry-sponsored research for Pfizer, receives stock options from Regeneron, and is on the medical advisory board for Hoth Therapeutics Inc. He is on the board of directors for the American Contact Dermatitis Society.

ORLANDO – Do you have pediatric patients with atopic dermatitis (AD) flares despite complying with treatment, or those who have a new rash in an unusual area? Consider patch testing to assess whether they have allergic contact dermatitis.

Jeff Craven/MDedge News

“Of the patients who are sent to me by local pediatric dermatologists, 50% of them are positive” for allergens, said Jonathan H. Zippin, MD, PhD, director of the contact, occupational, and photodermatitis service at Cornell University, New York.

Speaking at the ODAC Dermatology, Aesthetic, and Surgical Conference, Dr. Zippin noted the prevalence of allergen sensitization is between 13% and 25% among children who are asymptomatic, while the prevalence of sensitization to at least one allergen among children with suspected allergic contact dermatitis (ACD) is between 25% and 96%. In 2014, a study from the National American Contact Dermatitis Group (NACDG) showed that of 883 children who were patch tested, 56.7% had at least one relevant positive patch test (RPPT) result.

“The take-home message here is that pediatric contact dermatitis is common, much more common than a lot of people realize,” Dr. Zippin said.

He described three common scenarios to keep in mind: a worsening rash, a new rash, and failure of a rash to improve after the patient avoids all of his or her positive allergens.

When a rash worsens, patch testing is likely to offer answers. In an analysis of 1,142 patients with suspected ACD aged 18 years or younger (mean age, 10.5 years; 64% female) in the Pediatric Contact Dermatitis Registry study database, 65% had at least one positive patch test, and 48% had at least 1 RPPT (Dermatitis 2016; 27[5] 293-302).

But not all patch testing is the same: The study also found that 24% of the RPPT cases would have been missed if assessed with the T.R.U.E. TEST compared with extended patch testing. If a T.R.U.E. TEST fails to explain generalized atopic dermatitis, the patient should be sent for more comprehensive testing where available, Dr. Zippin advised.

Pediatric patients also have unique allergens clinicians should consider. In the same study, children had a number of allergens similar to those of adults as reported in previous studies, such as nickel, cobalt, and neomycin. However, propylene glycol and cocamidopropyl betaine were allergens identified as unique to the pediatric population.

Another study looking at the same group of patients found that compared with children who did not have AD, children with AD had 7.4 times higher odds of having an RPPT to cocamidopropyl betaine, 7.6 times higher odds of having an RPPT to parthenolide, 5.3 times higher odds of having an RPPT to tixocortol pivalate, 4.2 times higher odds of having an RPPT to wool alcohols, and 4 times higher odds of having an RPPT to lanolin (JAMA Dermatology 2017;153[8]:765-70).

All of these are components of topical medicaments used to treat AD, “either components of emollients that we recommend, or components of steroids that we recommend,” Dr. Zippin pointed out.

One of these allergens could be the culprit when a child develops a new rash but there are no new apparent changes in products, exposures, and activities. Lanolin, also called wool grease, is used in many skin care products, for example. Dr. Zippin described the case of a 6-year-old girl with a history of AD, who presented with a new rash on her scalp and behind her ears, not explained by any obvious changes to products, exposures, or activities. Subsequent patch testing determined that the rash was caused by baby shampoo, which contained cocamidopropyl betaine, which is used in hypoallergenic products. The rash resolved after a different shampoo was used.

“Sometimes, we really have to be thinking when the rash is getting worse, is there something they’re being exposed to that might be an allergen?” Dr. Zippin said.

In patients who have avoided all their positive allergens but a rash has not improved, clinicians should consider systemic contact dermatitis (SCD). Patients can develop SCD through different types of exposures, including transepidermal, transmucosal, oral, intravenous, subcutaneous, intramuscular, inhalation, and implantation routes.

SCD also has a variety of presentations, including pompholyx/dyshidrosis/vesicular dermatitis, maculopapular eruption, chronic pruritus, exfoliative erythroderma/toxiderma, chronic urticaria, erythema multiforme and vasculitis, hyperkeratotic papules of the elbows, acute generalized exanthematous pustulosis, and pruritus ani, according to Dr. Zippin.

SCD should be considered when a patient has a positive patch test to an allergen that is known to cause SCD, and does not clear after avoiding cutaneous exposure to the allergen, Dr. Zippin advised.

Patients will most often develop SCD from plants and herbs, Dr. Zippin noted. Chrysanthemums and chamomile tea are common culprits for compositae allergy and can trigger SCD; other causes are Anacardiaceae, Balsam of Peru, and propolis. Metals (nickel, cobalt, gold, and chromium), medications (aminoglycosides, corticosteroids, and ethylenediamine), and other sources (formaldehyde, propylene glycol in frozen foods, gallates, and methylisothiazolinone) can cause SCD as well.

Methylisothiazolinone in particular is a very common sensitizer, Dr. Zippin said. “If you have a patient who is positive to this, it’s almost always the cause of their problem.”

Balsam of Peru is in a number of different foods, and patients who need to follow a diet free of Balsam of Peru should avoid a long list of foods including citrus; bakery goods; Danish pastry; candy; gum; spices such as cinnamon, cloves, vanilla, curry, allspice, anise, and ginger; spicy condiments such as ketchup, chili sauce, barbecue sauce; chili, pizza, and foods with red sauces; tomatoes; pickles; alcohol (wine, beer, gin, vermouth); tea (perfumed or flavored); tobacco; chocolate and ice cream; and soft drinks (cola or spiced soft drinks).

Patients starting a nickel-free diet should avoid soy, peanuts and other nuts, legumes, chocolate, cocoa, oats, fish, and whole wheat flours. Any elimination diet should last for 3 months but should at least be tried for 3-4 weeks, with gradual reintroduction of foods suspected as triggers once per week. Any type I allergies that are discovered or suspected can be referred to an allergist for allergen challenge and desensitization therapy.

For more information, Dr. Zippin recommended the American Contact Dermatitis Society website for more information.

Dr. Zippin reported that he is the founder and holds stock options at CEP Biotech; is on the medical advisory board and receives stock options from YouV Labs., is a paid consultant and performs industry-sponsored research for Pfizer, receives stock options from Regeneron, and is on the medical advisory board for Hoth Therapeutics Inc. He is on the board of directors for the American Contact Dermatitis Society.

Despite expert recommendations promoting room-sharing but not bed-sharing for the first 6 months of life, most mothers don’t follow this advice, according to a recent nationally representative study.

Stanislav Fridkin/iStockphoto.com

Of 3,260 mothers surveyed, 59% of mothers said that they intended to room-share without bed-sharing, but only 45% practiced – and also had the intent to practice – room-sharing without bed-sharing. Of the 41% who said that they did not intend to bed-share, 24% actually did intend to practice at least some bed-sharing with their infants, who were all aged 2-6 months at the time of survey administration.

Mothers who were African American and those who were breastfeeding exclusively were most likely to report that they intended to bed-share, reported Ann Kellams, MD, of the department of pediatrics at the University of Virginia,Charlottesville, and coauthors. Mothers who were exclusively breastfeeding had a nearly threefold higher rate of intending to bed-share than mothers whose infants were fed formula.

How mothers perceived social norms about bed- and room-sharing practices also plays a role. Women who considered that social norms supported bed-sharing and discouraged room-sharing had almost 200 times the odds of intending to bed-share, compared with those who perceived that social norms supported room-sharing without bed-sharing.

Conversely, being advised by a doctor to follow the American Academy of Pediatrics–recommended practice of room-sharing without bed-sharing made it less likely that mothers would plan to share a bed with their infant (adjusted odds ratio, 0.56). Yet women who intended to room-share without bed-sharing but who actually did bed-share some of the time, their doctor’s advice to room-share only had no impact (aOR, 1.01).

The investigators noted that, “although other studies have investigated factors influencing maternal decisions, no studies to date have examined maternal intention regarding sleep location and what factors influence intention.”

The Study of Attitudes and Factors Effecting Infant Care drew from 32 U.S. hospitals, and asked mothers about feeding and care practices, including the infant’s usual sleep locations and all sleep locations over the 2 weeks preceding the survey. Additionally, the survey asked about future intent for sleeping practices, looking ahead to the next 2 weeks.

The survey design and the analysis performed in the study were based on the theory of planned behavior (TPB), “which hypothesizes that attitudes, subjective social norms, and perceptions about control over behavior impact one’s intention, which leads to actual behavior,” explained Dr. Kellams and coinvestigators. They reported that they had previously used TPB to analyze mothers’ intentions and actions regarding supine sleep position for infants, finding that a variety of behavioral and social facets accounted for by TPB affected maternal intention and decision making.

Additionally, the study’s design captured partial-night bed-sharing, where an infant may start the night in a separate bed but be brought to bed for feeding or comforting, then share a bed with the mother for the remainder of the night. “Unintended bed-sharing may explain our finding that there is frequent inconsistency between those whose near-future intention is to room-share without bed-sharing but whose actual practice includes bed-sharing,” the authors wrote.

“Attitudes, social norms, and doctor advice are associated with infant sleep location and may be potential targets for educational interventions,” concluded Dr. Kellams and coinvestigators.

Dr. Kellams and associates reported no relevant financial disclosures. The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health.

[email protected]

SOURCE: Kellams A et al. Pediatrics. 2020 Feb 7;145(3):e20191523.

Despite expert recommendations promoting room-sharing but not bed-sharing for the first 6 months of life, most mothers don’t follow this advice, according to a recent nationally representative study.

Stanislav Fridkin/iStockphoto.com

Of 3,260 mothers surveyed, 59% of mothers said that they intended to room-share without bed-sharing, but only 45% practiced – and also had the intent to practice – room-sharing without bed-sharing. Of the 41% who said that they did not intend to bed-share, 24% actually did intend to practice at least some bed-sharing with their infants, who were all aged 2-6 months at the time of survey administration.

Mothers who were African American and those who were breastfeeding exclusively were most likely to report that they intended to bed-share, reported Ann Kellams, MD, of the department of pediatrics at the University of Virginia,Charlottesville, and coauthors. Mothers who were exclusively breastfeeding had a nearly threefold higher rate of intending to bed-share than mothers whose infants were fed formula.

How mothers perceived social norms about bed- and room-sharing practices also plays a role. Women who considered that social norms supported bed-sharing and discouraged room-sharing had almost 200 times the odds of intending to bed-share, compared with those who perceived that social norms supported room-sharing without bed-sharing.

Conversely, being advised by a doctor to follow the American Academy of Pediatrics–recommended practice of room-sharing without bed-sharing made it less likely that mothers would plan to share a bed with their infant (adjusted odds ratio, 0.56). Yet women who intended to room-share without bed-sharing but who actually did bed-share some of the time, their doctor’s advice to room-share only had no impact (aOR, 1.01).

The investigators noted that, “although other studies have investigated factors influencing maternal decisions, no studies to date have examined maternal intention regarding sleep location and what factors influence intention.”

The Study of Attitudes and Factors Effecting Infant Care drew from 32 U.S. hospitals, and asked mothers about feeding and care practices, including the infant’s usual sleep locations and all sleep locations over the 2 weeks preceding the survey. Additionally, the survey asked about future intent for sleeping practices, looking ahead to the next 2 weeks.

The survey design and the analysis performed in the study were based on the theory of planned behavior (TPB), “which hypothesizes that attitudes, subjective social norms, and perceptions about control over behavior impact one’s intention, which leads to actual behavior,” explained Dr. Kellams and coinvestigators. They reported that they had previously used TPB to analyze mothers’ intentions and actions regarding supine sleep position for infants, finding that a variety of behavioral and social facets accounted for by TPB affected maternal intention and decision making.

Additionally, the study’s design captured partial-night bed-sharing, where an infant may start the night in a separate bed but be brought to bed for feeding or comforting, then share a bed with the mother for the remainder of the night. “Unintended bed-sharing may explain our finding that there is frequent inconsistency between those whose near-future intention is to room-share without bed-sharing but whose actual practice includes bed-sharing,” the authors wrote.

“Attitudes, social norms, and doctor advice are associated with infant sleep location and may be potential targets for educational interventions,” concluded Dr. Kellams and coinvestigators.

Dr. Kellams and associates reported no relevant financial disclosures. The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health.

[email protected]

SOURCE: Kellams A et al. Pediatrics. 2020 Feb 7;145(3):e20191523.

Despite expert recommendations promoting room-sharing but not bed-sharing for the first 6 months of life, most mothers don’t follow this advice, according to a recent nationally representative study.

Stanislav Fridkin/iStockphoto.com

Of 3,260 mothers surveyed, 59% of mothers said that they intended to room-share without bed-sharing, but only 45% practiced – and also had the intent to practice – room-sharing without bed-sharing. Of the 41% who said that they did not intend to bed-share, 24% actually did intend to practice at least some bed-sharing with their infants, who were all aged 2-6 months at the time of survey administration.

Mothers who were African American and those who were breastfeeding exclusively were most likely to report that they intended to bed-share, reported Ann Kellams, MD, of the department of pediatrics at the University of Virginia,Charlottesville, and coauthors. Mothers who were exclusively breastfeeding had a nearly threefold higher rate of intending to bed-share than mothers whose infants were fed formula.

How mothers perceived social norms about bed- and room-sharing practices also plays a role. Women who considered that social norms supported bed-sharing and discouraged room-sharing had almost 200 times the odds of intending to bed-share, compared with those who perceived that social norms supported room-sharing without bed-sharing.

Conversely, being advised by a doctor to follow the American Academy of Pediatrics–recommended practice of room-sharing without bed-sharing made it less likely that mothers would plan to share a bed with their infant (adjusted odds ratio, 0.56). Yet women who intended to room-share without bed-sharing but who actually did bed-share some of the time, their doctor’s advice to room-share only had no impact (aOR, 1.01).

The investigators noted that, “although other studies have investigated factors influencing maternal decisions, no studies to date have examined maternal intention regarding sleep location and what factors influence intention.”

The Study of Attitudes and Factors Effecting Infant Care drew from 32 U.S. hospitals, and asked mothers about feeding and care practices, including the infant’s usual sleep locations and all sleep locations over the 2 weeks preceding the survey. Additionally, the survey asked about future intent for sleeping practices, looking ahead to the next 2 weeks.

The survey design and the analysis performed in the study were based on the theory of planned behavior (TPB), “which hypothesizes that attitudes, subjective social norms, and perceptions about control over behavior impact one’s intention, which leads to actual behavior,” explained Dr. Kellams and coinvestigators. They reported that they had previously used TPB to analyze mothers’ intentions and actions regarding supine sleep position for infants, finding that a variety of behavioral and social facets accounted for by TPB affected maternal intention and decision making.

Additionally, the study’s design captured partial-night bed-sharing, where an infant may start the night in a separate bed but be brought to bed for feeding or comforting, then share a bed with the mother for the remainder of the night. “Unintended bed-sharing may explain our finding that there is frequent inconsistency between those whose near-future intention is to room-share without bed-sharing but whose actual practice includes bed-sharing,” the authors wrote.

“Attitudes, social norms, and doctor advice are associated with infant sleep location and may be potential targets for educational interventions,” concluded Dr. Kellams and coinvestigators.

Dr. Kellams and associates reported no relevant financial disclosures. The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health.

[email protected]

SOURCE: Kellams A et al. Pediatrics. 2020 Feb 7;145(3):e20191523.

Most of us did our postgraduate training in tertiary medical centers, ivory towers of medicine often attached to or closely affiliated with medical schools. These are the places where the buck stops. Occasionally, a very complex patient might be sent to another tertiary center that claims to have a supersubspecialist, a one-of-a-kind physician with nationally recognized expertise. But for most patients, the tertiary medical center is the end of the line, and his or her physicians must manage with the resources at hand. They may confer with one another but there is no place for them to pass the buck.

Yuri_Arcurs/DigitalVision/Getty Images

But most of us who chose primary care left the comforting cocoon of the teaching hospital complex when we finished our training. Those first few months and years in the hinterland can be angst producing. Until we have established our own personal networks of consultants and mentors, patients with more than run-of-the-mill complaints may prompt us to reach for the phone or fire off an email call for help to our recently departed mother ship.

It can take awhile to establish the self-confidence – or at least the appearance of self-confidence – that physicians are expected to exude. But even after years of experience, none of us wants to watch a patient die or suffer preventable complications under our care when we know there is another facility that can provide a higher lever of care just an ambulance ride or short helicopter trip away.

Our primary concern is of course assuring that our patient is receiving the best care. How quickly we reach for the phone to refer out the most fragile patients depends on several factors. Do we practice in a community that has a historic reputation of having a low threshold for malpractice suits? How well do we know the patient and her family? Have we had time to establish bidirectional trust?

Is the patient’s diagnosis one that we feel comfortable with or is the diagnosis one that we believe could quickly deteriorate without warning? For example, a recently published study revealed that 20% of pediatric trauma patients were overtriaged and that the mechanism of injury – firearms or motor vehicle accidents – appeared to have an outsized influence in the triage decision (Trauma Surg Acute Care Open. 2019 Dec 29. doi: 10.1136/tsaco-2019-000300).

Courtesy Dr. William G. Wilkoff

Because I have no experience with firearm injuries and minimal experience with motor vehicle injuries I can understand why the emergency medical technicians might be quick to ship these patients to the trauma center. However, I hope that, were I offered better training and more opportunities to gain experience with these types of injuries, I would have a lower overtriage percentage.

Which begs the question of what is an acceptable rate of overtriage or overreferral? It’s the same old question of how many normal appendixes should one remove to avoid a fatal outcome. Each of us arrives at a given clinical crossroads with our own level of experience and comfort level. Our level of confidence in our local peer and specialty support network helps us decide when it is time to transfer a patient to a higher-level facility.

But in the final analysis it boils down to a personal decision and our own basic level of anxiety. Let’s face it, some of us worry more than others. Physicians come in all shades of anxiety. A hot potato in your hands may feel only room temperature to me.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Most of us did our postgraduate training in tertiary medical centers, ivory towers of medicine often attached to or closely affiliated with medical schools. These are the places where the buck stops. Occasionally, a very complex patient might be sent to another tertiary center that claims to have a supersubspecialist, a one-of-a-kind physician with nationally recognized expertise. But for most patients, the tertiary medical center is the end of the line, and his or her physicians must manage with the resources at hand. They may confer with one another but there is no place for them to pass the buck.

Yuri_Arcurs/DigitalVision/Getty Images

But most of us who chose primary care left the comforting cocoon of the teaching hospital complex when we finished our training. Those first few months and years in the hinterland can be angst producing. Until we have established our own personal networks of consultants and mentors, patients with more than run-of-the-mill complaints may prompt us to reach for the phone or fire off an email call for help to our recently departed mother ship.

It can take awhile to establish the self-confidence – or at least the appearance of self-confidence – that physicians are expected to exude. But even after years of experience, none of us wants to watch a patient die or suffer preventable complications under our care when we know there is another facility that can provide a higher lever of care just an ambulance ride or short helicopter trip away.

Our primary concern is of course assuring that our patient is receiving the best care. How quickly we reach for the phone to refer out the most fragile patients depends on several factors. Do we practice in a community that has a historic reputation of having a low threshold for malpractice suits? How well do we know the patient and her family? Have we had time to establish bidirectional trust?

Is the patient’s diagnosis one that we feel comfortable with or is the diagnosis one that we believe could quickly deteriorate without warning? For example, a recently published study revealed that 20% of pediatric trauma patients were overtriaged and that the mechanism of injury – firearms or motor vehicle accidents – appeared to have an outsized influence in the triage decision (Trauma Surg Acute Care Open. 2019 Dec 29. doi: 10.1136/tsaco-2019-000300).

Courtesy Dr. William G. Wilkoff

Because I have no experience with firearm injuries and minimal experience with motor vehicle injuries I can understand why the emergency medical technicians might be quick to ship these patients to the trauma center. However, I hope that, were I offered better training and more opportunities to gain experience with these types of injuries, I would have a lower overtriage percentage.

Which begs the question of what is an acceptable rate of overtriage or overreferral? It’s the same old question of how many normal appendixes should one remove to avoid a fatal outcome. Each of us arrives at a given clinical crossroads with our own level of experience and comfort level. Our level of confidence in our local peer and specialty support network helps us decide when it is time to transfer a patient to a higher-level facility.

But in the final analysis it boils down to a personal decision and our own basic level of anxiety. Let’s face it, some of us worry more than others. Physicians come in all shades of anxiety. A hot potato in your hands may feel only room temperature to me.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Most of us did our postgraduate training in tertiary medical centers, ivory towers of medicine often attached to or closely affiliated with medical schools. These are the places where the buck stops. Occasionally, a very complex patient might be sent to another tertiary center that claims to have a supersubspecialist, a one-of-a-kind physician with nationally recognized expertise. But for most patients, the tertiary medical center is the end of the line, and his or her physicians must manage with the resources at hand. They may confer with one another but there is no place for them to pass the buck.

Yuri_Arcurs/DigitalVision/Getty Images

But most of us who chose primary care left the comforting cocoon of the teaching hospital complex when we finished our training. Those first few months and years in the hinterland can be angst producing. Until we have established our own personal networks of consultants and mentors, patients with more than run-of-the-mill complaints may prompt us to reach for the phone or fire off an email call for help to our recently departed mother ship.

It can take awhile to establish the self-confidence – or at least the appearance of self-confidence – that physicians are expected to exude. But even after years of experience, none of us wants to watch a patient die or suffer preventable complications under our care when we know there is another facility that can provide a higher lever of care just an ambulance ride or short helicopter trip away.

Our primary concern is of course assuring that our patient is receiving the best care. How quickly we reach for the phone to refer out the most fragile patients depends on several factors. Do we practice in a community that has a historic reputation of having a low threshold for malpractice suits? How well do we know the patient and her family? Have we had time to establish bidirectional trust?

Is the patient’s diagnosis one that we feel comfortable with or is the diagnosis one that we believe could quickly deteriorate without warning? For example, a recently published study revealed that 20% of pediatric trauma patients were overtriaged and that the mechanism of injury – firearms or motor vehicle accidents – appeared to have an outsized influence in the triage decision (Trauma Surg Acute Care Open. 2019 Dec 29. doi: 10.1136/tsaco-2019-000300).

Courtesy Dr. William G. Wilkoff

Because I have no experience with firearm injuries and minimal experience with motor vehicle injuries I can understand why the emergency medical technicians might be quick to ship these patients to the trauma center. However, I hope that, were I offered better training and more opportunities to gain experience with these types of injuries, I would have a lower overtriage percentage.

Which begs the question of what is an acceptable rate of overtriage or overreferral? It’s the same old question of how many normal appendixes should one remove to avoid a fatal outcome. Each of us arrives at a given clinical crossroads with our own level of experience and comfort level. Our level of confidence in our local peer and specialty support network helps us decide when it is time to transfer a patient to a higher-level facility.

But in the final analysis it boils down to a personal decision and our own basic level of anxiety. Let’s face it, some of us worry more than others. Physicians come in all shades of anxiety. A hot potato in your hands may feel only room temperature to me.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

I agree wholeheartedly with Dr. William G. Wilkoff’s doubts that an increase in medical schools/students and/or foreign medical graduates is the answer to the physician shortage felt by many areas of the country (Letters From Maine, “Help Wanted,” Nov. 2019, page 19). All you have to do is look at the glut of physicians – and just about any other profession – in metropolitan areas versus rural America, and ask basic questions regarding why those doctors practice where they do. You will quickly discover that most are willing to trade the possibility of a higher salary in areas where their presence is more needed to achieve more school choices, jobs for a spouse, and likely a more favorable call schedule. Something more attractive than salary or the prospect of more “elbow room” is desired.

Here in Mississippi we may have found an answer to the problem. A few years ago our state legislature started the Mississippi Rural Health Scholarship Program that pays for recipients to attend a state-run medical school on scholarship in exchange for agreeing to practice at least 4 years in a rural area of the state (less than 20k population) following their primary care residency (family medicine, pediatrics, ob.gyn., med-peds, internal medicine, and, recently added, psychiatry). Although a recent increase in the number of pediatric residency slots at our state’s sole program will no doubt also have a positive effect to this end, such a scholarship program as the one implemented by Mississippi is the best way to compete with the various intangibles that lead people to choose bigger cities over rural areas of the state to practice their trade. Once there, many – like myself – will find that such a practice is not only a good business decision but often is a wonderful place to raise a family. Meanwhile, our own practice just added a fourth physician as a result of said Rural Health Scholarship Program, and we could not be more satisfied with the result.
 

I agree wholeheartedly with Dr. William G. Wilkoff’s doubts that an increase in medical schools/students and/or foreign medical graduates is the answer to the physician shortage felt by many areas of the country (Letters From Maine, “Help Wanted,” Nov. 2019, page 19). All you have to do is look at the glut of physicians – and just about any other profession – in metropolitan areas versus rural America, and ask basic questions regarding why those doctors practice where they do. You will quickly discover that most are willing to trade the possibility of a higher salary in areas where their presence is more needed to achieve more school choices, jobs for a spouse, and likely a more favorable call schedule. Something more attractive than salary or the prospect of more “elbow room” is desired.

Here in Mississippi we may have found an answer to the problem. A few years ago our state legislature started the Mississippi Rural Health Scholarship Program that pays for recipients to attend a state-run medical school on scholarship in exchange for agreeing to practice at least 4 years in a rural area of the state (less than 20k population) following their primary care residency (family medicine, pediatrics, ob.gyn., med-peds, internal medicine, and, recently added, psychiatry). Although a recent increase in the number of pediatric residency slots at our state’s sole program will no doubt also have a positive effect to this end, such a scholarship program as the one implemented by Mississippi is the best way to compete with the various intangibles that lead people to choose bigger cities over rural areas of the state to practice their trade. Once there, many – like myself – will find that such a practice is not only a good business decision but often is a wonderful place to raise a family. Meanwhile, our own practice just added a fourth physician as a result of said Rural Health Scholarship Program, and we could not be more satisfied with the result.
 

I agree wholeheartedly with Dr. William G. Wilkoff’s doubts that an increase in medical schools/students and/or foreign medical graduates is the answer to the physician shortage felt by many areas of the country (Letters From Maine, “Help Wanted,” Nov. 2019, page 19). All you have to do is look at the glut of physicians – and just about any other profession – in metropolitan areas versus rural America, and ask basic questions regarding why those doctors practice where they do. You will quickly discover that most are willing to trade the possibility of a higher salary in areas where their presence is more needed to achieve more school choices, jobs for a spouse, and likely a more favorable call schedule. Something more attractive than salary or the prospect of more “elbow room” is desired.

Here in Mississippi we may have found an answer to the problem. A few years ago our state legislature started the Mississippi Rural Health Scholarship Program that pays for recipients to attend a state-run medical school on scholarship in exchange for agreeing to practice at least 4 years in a rural area of the state (less than 20k population) following their primary care residency (family medicine, pediatrics, ob.gyn., med-peds, internal medicine, and, recently added, psychiatry). Although a recent increase in the number of pediatric residency slots at our state’s sole program will no doubt also have a positive effect to this end, such a scholarship program as the one implemented by Mississippi is the best way to compete with the various intangibles that lead people to choose bigger cities over rural areas of the state to practice their trade. Once there, many – like myself – will find that such a practice is not only a good business decision but often is a wonderful place to raise a family. Meanwhile, our own practice just added a fourth physician as a result of said Rural Health Scholarship Program, and we could not be more satisfied with the result.
 

Cervical cancer is the second most common cancer among women in lower- and middle-income countries, but universal human papillomavirus vaccination for girls would reduce new cervical cancer cases by about 90% over the next century, according to researchers.

Adding twice-lifetime cervical screening with human papillomavirus (HPV) testing would further reduce the incidence of cervical cancer, including in countries with the highest burden, the researchers reported in The Lancet.

Marc Brisson, PhD, of Laval University, Quebec City, and colleagues conducted this study using three models identified by the World Health Organization. The models were used to project reductions in cervical cancer incidence for women in 78 low- and middle-income countries based on the following HPV vaccination and screening scenarios:

• Universal girls-only vaccination at age 9 years, assuming 90% of girls vaccinated and a vaccine that is perfectly effective
• Girls-only vaccination plus cervical screening with HPV testing at age 35 years
• Girls-only vaccination plus screening at ages 35 and 45.

All three scenarios modeled would result in the elimination of cervical cancer, Dr. Brisson and colleagues found. Elimination was defined as four or fewer new cases per 100,000 women-years.

The simplest scenario, universal girls-only vaccination, was predicted to reduce age-standardized cervical cancer incidence from 19.8 cases per 100,000 women-years to 2.1 cases per 100,000 women-years (89.4% reduction) by 2120. That amounts to about 61 million potential cases avoided, with elimination targets reached in 60% of the countries studied.

HPV vaccination plus one-time screening was predicted to reduce the incidence of cervical cancer to 1.0 case per 100,000 women-years (95.0% reduction), and HPV vaccination plus twice-lifetime screening was predicted to reduce the incidence to 0.7 cases per 100,000 women-years (96.7% reduction).

Dr. Brisson and colleagues reported that, for the countries with the highest burden of cervical cancer (more than 25 cases per 100,000 women-years), adding screening would be necessary to achieve elimination.

To meet the same targets across all 78 countries, “our models predict that scale-up of both girls-only HPV vaccination and twice-lifetime screening is necessary, with 90% HPV vaccination coverage, 90% screening uptake, and long-term protection against HPV types 16, 18, 31, 33, 45, 52, and 58,” the researchers wrote.

Dr. Brisson and colleagues claimed that a strength of this study is the modeling approach, which compared three models “that have been extensively peer reviewed and validated with postvaccination surveillance data.”

The researchers acknowledged, however, that their modeling could not account for variations in sexual behavior from country to country, and the study was not designed to anticipate behavioral or technological changes that could affect cervical cancer incidence in the decades to come.

The study was funded by the WHO, the United Nations, and the Canadian and Australian governments. The WHO contributed to the study design, data analysis and interpretation, and writing of the manuscript. Two study authors reported receiving indirect industry funding for a cervical screening trial in Australia.

SOURCE: Brisson M et al. Lancet. 2020 Jan 30. doi: 10.1016/S0140-6736(20)30068-4.

Cervical cancer is the second most common cancer among women in lower- and middle-income countries, but universal human papillomavirus vaccination for girls would reduce new cervical cancer cases by about 90% over the next century, according to researchers.

Adding twice-lifetime cervical screening with human papillomavirus (HPV) testing would further reduce the incidence of cervical cancer, including in countries with the highest burden, the researchers reported in The Lancet.

Marc Brisson, PhD, of Laval University, Quebec City, and colleagues conducted this study using three models identified by the World Health Organization. The models were used to project reductions in cervical cancer incidence for women in 78 low- and middle-income countries based on the following HPV vaccination and screening scenarios:

• Universal girls-only vaccination at age 9 years, assuming 90% of girls vaccinated and a vaccine that is perfectly effective
• Girls-only vaccination plus cervical screening with HPV testing at age 35 years
• Girls-only vaccination plus screening at ages 35 and 45.

All three scenarios modeled would result in the elimination of cervical cancer, Dr. Brisson and colleagues found. Elimination was defined as four or fewer new cases per 100,000 women-years.

The simplest scenario, universal girls-only vaccination, was predicted to reduce age-standardized cervical cancer incidence from 19.8 cases per 100,000 women-years to 2.1 cases per 100,000 women-years (89.4% reduction) by 2120. That amounts to about 61 million potential cases avoided, with elimination targets reached in 60% of the countries studied.

HPV vaccination plus one-time screening was predicted to reduce the incidence of cervical cancer to 1.0 case per 100,000 women-years (95.0% reduction), and HPV vaccination plus twice-lifetime screening was predicted to reduce the incidence to 0.7 cases per 100,000 women-years (96.7% reduction).

Dr. Brisson and colleagues reported that, for the countries with the highest burden of cervical cancer (more than 25 cases per 100,000 women-years), adding screening would be necessary to achieve elimination.

To meet the same targets across all 78 countries, “our models predict that scale-up of both girls-only HPV vaccination and twice-lifetime screening is necessary, with 90% HPV vaccination coverage, 90% screening uptake, and long-term protection against HPV types 16, 18, 31, 33, 45, 52, and 58,” the researchers wrote.

Dr. Brisson and colleagues claimed that a strength of this study is the modeling approach, which compared three models “that have been extensively peer reviewed and validated with postvaccination surveillance data.”

The researchers acknowledged, however, that their modeling could not account for variations in sexual behavior from country to country, and the study was not designed to anticipate behavioral or technological changes that could affect cervical cancer incidence in the decades to come.

The study was funded by the WHO, the United Nations, and the Canadian and Australian governments. The WHO contributed to the study design, data analysis and interpretation, and writing of the manuscript. Two study authors reported receiving indirect industry funding for a cervical screening trial in Australia.

SOURCE: Brisson M et al. Lancet. 2020 Jan 30. doi: 10.1016/S0140-6736(20)30068-4.

Cervical cancer is the second most common cancer among women in lower- and middle-income countries, but universal human papillomavirus vaccination for girls would reduce new cervical cancer cases by about 90% over the next century, according to researchers.

Adding twice-lifetime cervical screening with human papillomavirus (HPV) testing would further reduce the incidence of cervical cancer, including in countries with the highest burden, the researchers reported in The Lancet.

Marc Brisson, PhD, of Laval University, Quebec City, and colleagues conducted this study using three models identified by the World Health Organization. The models were used to project reductions in cervical cancer incidence for women in 78 low- and middle-income countries based on the following HPV vaccination and screening scenarios:

• Universal girls-only vaccination at age 9 years, assuming 90% of girls vaccinated and a vaccine that is perfectly effective
• Girls-only vaccination plus cervical screening with HPV testing at age 35 years
• Girls-only vaccination plus screening at ages 35 and 45.

All three scenarios modeled would result in the elimination of cervical cancer, Dr. Brisson and colleagues found. Elimination was defined as four or fewer new cases per 100,000 women-years.

The simplest scenario, universal girls-only vaccination, was predicted to reduce age-standardized cervical cancer incidence from 19.8 cases per 100,000 women-years to 2.1 cases per 100,000 women-years (89.4% reduction) by 2120. That amounts to about 61 million potential cases avoided, with elimination targets reached in 60% of the countries studied.

HPV vaccination plus one-time screening was predicted to reduce the incidence of cervical cancer to 1.0 case per 100,000 women-years (95.0% reduction), and HPV vaccination plus twice-lifetime screening was predicted to reduce the incidence to 0.7 cases per 100,000 women-years (96.7% reduction).

Dr. Brisson and colleagues reported that, for the countries with the highest burden of cervical cancer (more than 25 cases per 100,000 women-years), adding screening would be necessary to achieve elimination.

To meet the same targets across all 78 countries, “our models predict that scale-up of both girls-only HPV vaccination and twice-lifetime screening is necessary, with 90% HPV vaccination coverage, 90% screening uptake, and long-term protection against HPV types 16, 18, 31, 33, 45, 52, and 58,” the researchers wrote.

Dr. Brisson and colleagues claimed that a strength of this study is the modeling approach, which compared three models “that have been extensively peer reviewed and validated with postvaccination surveillance data.”

The researchers acknowledged, however, that their modeling could not account for variations in sexual behavior from country to country, and the study was not designed to anticipate behavioral or technological changes that could affect cervical cancer incidence in the decades to come.

The study was funded by the WHO, the United Nations, and the Canadian and Australian governments. The WHO contributed to the study design, data analysis and interpretation, and writing of the manuscript. Two study authors reported receiving indirect industry funding for a cervical screening trial in Australia.

SOURCE: Brisson M et al. Lancet. 2020 Jan 30. doi: 10.1016/S0140-6736(20)30068-4.

NEW ORLEANS – A variety of reasons can contribute to the failure of stimulants to treat ADHD in children, such as comorbidities, missed diagnoses, inadequate medication dosage, side effects, major life changes, and other factors in the home or school environments, said Alison Schonwald, MD, of Harvard Medical School, Boston.

gpointstudio/Thinkstock

Stimulant medications indicated for ADHD usually work in 70%-75% of school-age children, but that leaves one in four children whose condition can be more challenging to treat, she said.

“Look around you,” Dr. Schonwald told a packed room at the annual meeting of the American Academy of Pediatrics. “You’re not the only one struggling with this topic.” She sprinkled her presentation with case studies of patients with ADHD for whom stimulants weren’t working, examples that the audience clearly found familiar.

The three steps you already know to do with treatment-resistant children sound simple: assess the child for factors linked to their poor response; develop a new treatment plan; and use Food and Drug Administration-approved nonstimulant medications, including off-label options, in a new plan.

But in the office, the process can be anything but simple when you must consider school and family environments, comorbidities, and other factors potentially complicating the child’s ability to function well.
 

Comorbidities

To start, Dr. Schonwald provided a chart of common coexisting problems in children with ADHD that included the recommended assessment and intervention:

• Mood and self-esteem issues call for the depression section of the patient health questionnaire (PHQ9) and Moods and Feelings questionnaire (MFQ), followed by interventions such as individual and peer group therapy and exercise.
• Anxiety can be assessed with the Screen for Child Anxiety Related Disorders (SCARED) and Spence Children’s Anxiety Scale, then treated similarly to mood and self-esteem issues.
• Bullying or trauma require taking a history during an interview, and treatment with individual and peer group therapy.
• Substance abuse should be assessed with the CRAFFT screening tool (Car, Relax, Alone, Forget, Friends, Trouble) and Screening to Brief Intervention (S2BI) Tool, then treated according to best practices.
• Executive function, low cognitive abilities, and poor adaptive skills require a review of the child’s Individualized Education Program (IEP) testing, followed by personalized school and home interventions.
• Poor social skills, assessed in an interview, also require personalized interventions at home and in school.

Doctors also may need to consider other common comorbidities in children with ADHD, such as bipolar disorder, depression, learning disabilities, oppositional defiant disorder, and tic disorders.

Tic disorders typically have an onset around 7 years old and peak in midadolescence, declining in late teen years. An estimated 35%-90% of children with Tourette syndrome have ADHD, Dr. Schonwald said (Dev Med Child Neurol. 2006 Jul;48[7]:616-21).
 

Managing treatment with stimulants

A common dosage amount for stimulants is 2.5-5 mg, but that dose may be too low for children, Dr. Schonwald said. She recommended increasing it until an effect is seen and stopping at the effective dose level the child can tolerate. The maximum recommended by the FDA is 60 mg/day for short-acting stimulants and 72 mg/day for extended-release ones, but some research has shown dosage can go even higher without causing toxic effects (J Child Adolesc Psychopharmacol. 2010 Feb;20[1]:49-54).

Dr. Schonwald also suggested trying both methylphenidate and amphetamine medication, while recognizing the latter tends to have more stimulant-related side effects.

Adherence is another consideration because multiple studies show high rates of noncompliance or discontinuation, such as up to 19% discontinuation for long-acting and 38% for short-acting stimulants (J Clin Psychiatry. 2015 Nov;76(11):e1459-68; Postgrad Med. 2012 May;124(3):139-48). A study of a school cohort in Philadelphia found only about one in five children were adherent (J Am Acad Child Adolesc Psychiatry. 2011 May;50[5]:480-9).

One potential solution to adherence challenges are pill reminder smartphone apps, such as Medisafe Medication Management, Pill Reminder-All in One, MyTherapy: Medication Reminder, and CareZone.

Dr. Schonwald noted several factors that can influence children’s response to stimulants. Among children with comorbid intellectual disability, for example, the response rate is lower than the average 75% of children without the disability, hovering around 40%-50% (Res Dev Disabil. 2018 Dec;83:217-32). Those who get more sleep tend to have improved attention, compared with children with less sleep (Atten Defic Hyperact Disord. 2017 Mar;9[1]:31-38).

She also offered strategies to manage problematic adverse effects from stimulants. Those experiencing weight loss can take their stimulant after breakfast, drink whole milk, and consider taking drug holidays.

To reduce stomachaches, children should take their medication with food, and you should look at whether the child is taking the lowest effective dose they can and whether anxiety may be involved. Similarly, children with headaches should take stimulants with food, and you should look at the dosage and ask whether the patient is getting adequate sleep.

Strategies to address difficulty falling asleep can include taking the stimulant earlier in the day or switching to a shorter-acting form, dexmethylphenidate, or another stimulant. If they’re having trouble staying asleep, inquire about sleep hygiene, and look for associations with other factors that might explain why the child is experiencing new problems with staying asleep. If these strategies are unsuccessful, you can consider prescribing melatonin or clonidine.
 

Alternatives to stimulants

Several medications besides stimulants are available to prescribe to children with ADHD if they aren’t responding adequately to stimulants, Dr. Schonwald said.

Atomoxetine performed better than placebo in treatment studies, with similar weight loss effects, albeit the lowest mean effect size in clinician ratings (Lancet Psychiatry. 2018 Sep;5[9]:727-38). Dr. Schonwald recommended starting atomoxetine in children under 40 kg at 0.5 mg/kg for 4 days, then increasing to 1.2 mg/kg/day. For children over 40 kg, the dose can start at 40 mg. Maximum dose can range from 1.4 to 1.8 mg/kg or 100 mg/day.

About 7% of white children and 2% of African American children are poor metabolizers of atomoxetine, and the drug has interactions with dextromethorphan, fluoxetine, and paroxetine, she noted. Side effects can include abdominal pain, dry mouth, fatigue, mood swings, nausea, and vomiting.

Two alpha-adrenergics that you can consider are clonidine and guanfacine. Clonidine, a hypotensive drug given at a dose of 0.05-0.2 mg up to three times a day, is helpful for hyperactivity and impulsivity rather than attention difficulties. Side effects can include depression, headache, rebound hypertension, and sedation, and it’s only FDA approved for ages 12 years and older.

An extended release version of clonidine (Kapvay) is approved for monotherapy or adjunctive therapy for ADHD; it led to improvements in ADHD–Rating Scale-IV scores as soon as the second week in an 8-week randomized controlled trial. Mild to moderate somnolence was the most common adverse event, and changes on electrocardiograms were minor (J Am Acad Child Adolesc Psychiatry. 2011 Feb;50[2]:171-9).

Guanfacine, also a hypotensive drug, given at a dose of 0.5-2 mg up to three times a day, has fewer data about its use for ADHD but appears to treat attention problems more effectively than hyperactivity. Also approved only for ages 12 years and older, guanfacine is less sedating, and its side effects can include agitation, headache , and insomnia. An extended-release version of guanfacine (brand name Intuniv) showed statistically significant reductions in ADHD Rating Scale-IV scores in a 9-week, double-blind, randomized, controlled trial. Side effects including fatigue, sedation, and somnolence occurred in the first 2 weeks but generally resolved, and participants returned to baseline during dose maintenance and tapering (J Am Acad Child Adolesc Psychiatry. 2009 Feb;48[2]:155-65).

Intuniv doses should start at 1 mg/day and increase no more than 1 mg/week, Dr. Schonwald said, until reaching a maintenance dose of 1-4 mg once daily, depending on the patient’s clinical response and tolerability. Children also must be able to swallow the pill whole.
 

Treating preschoolers

Preschool children are particularly difficult to diagnose given their normal range of temperament and development, Dr. Schonwald said. Their symptoms could be resulting from another diagnosis or from circumstances in the environment.

You should consider potential comorbidities and whether the child’s symptoms are situational or pervasive. About 55% of preschoolers have at least one comorbidity, she said (Infants & Young Children. 2006 Apr-Jun;19[2]:109-122.)

That said, stimulants usually are effective in very young children whose primary concern is ADHD. In a randomized controlled trial of 303 preschoolers, significantly more children experienced reduced ADHD symptoms with methylphenidate than with placebo. The trial’s “data suggest that preschoolers with ADHD need to start with low methylphenidate doses. Treatment may best begin using methylphenidate–immediate release at 2.5 mg twice daily, and then be increased to 7.5 mg three times a day during the course of 1 week. The mean optimal total daily [methylphenidate] dose for preschoolers was 14.2 plus or minus 8.1 mg/day” (J Am Acad Child Adolesc Psychiatry. 2006 Nov;45[11]:1284-93).

In treating preschoolers, if the patient’s symptoms appear to get worse after starting a stimulant, you can consider a medication change. If symptoms are much worse, consider a lower dose or a different stimulant class, or whether the diagnosis is appropriate.

Five common components of poor behavior in preschoolers with ADHD include agitation, anxiety, explosively, hyperactivity, and impulsivity. If these issues are occurring throughout the day, consider reducing the dose or switching drug classes.

If it’s only occurring in the morning, Dr. Schonwald said, optimize the morning structure and consider giving the medication earlier in the morning or adding a short-acting booster. If it’s occurring in late afternoon, consider a booster and reducing high-demand activities for the child.

If a preschooler experiences some benefit from the stimulant but still has problems, adjunctive atomoxetine or an alpha adrenergic may help. Those medications also are recommended if the child has no benefit with the stimulant or cannot tolerate the lowest therapeutic dose.

Dr. Schonwald said she had no relevant financial disclosures.

NEW ORLEANS – A variety of reasons can contribute to the failure of stimulants to treat ADHD in children, such as comorbidities, missed diagnoses, inadequate medication dosage, side effects, major life changes, and other factors in the home or school environments, said Alison Schonwald, MD, of Harvard Medical School, Boston.

gpointstudio/Thinkstock

Stimulant medications indicated for ADHD usually work in 70%-75% of school-age children, but that leaves one in four children whose condition can be more challenging to treat, she said.

“Look around you,” Dr. Schonwald told a packed room at the annual meeting of the American Academy of Pediatrics. “You’re not the only one struggling with this topic.” She sprinkled her presentation with case studies of patients with ADHD for whom stimulants weren’t working, examples that the audience clearly found familiar.

The three steps you already know to do with treatment-resistant children sound simple: assess the child for factors linked to their poor response; develop a new treatment plan; and use Food and Drug Administration-approved nonstimulant medications, including off-label options, in a new plan.

But in the office, the process can be anything but simple when you must consider school and family environments, comorbidities, and other factors potentially complicating the child’s ability to function well.
 

Comorbidities

To start, Dr. Schonwald provided a chart of common coexisting problems in children with ADHD that included the recommended assessment and intervention:

• Mood and self-esteem issues call for the depression section of the patient health questionnaire (PHQ9) and Moods and Feelings questionnaire (MFQ), followed by interventions such as individual and peer group therapy and exercise.
• Anxiety can be assessed with the Screen for Child Anxiety Related Disorders (SCARED) and Spence Children’s Anxiety Scale, then treated similarly to mood and self-esteem issues.
• Bullying or trauma require taking a history during an interview, and treatment with individual and peer group therapy.
• Substance abuse should be assessed with the CRAFFT screening tool (Car, Relax, Alone, Forget, Friends, Trouble) and Screening to Brief Intervention (S2BI) Tool, then treated according to best practices.
• Executive function, low cognitive abilities, and poor adaptive skills require a review of the child’s Individualized Education Program (IEP) testing, followed by personalized school and home interventions.
• Poor social skills, assessed in an interview, also require personalized interventions at home and in school.

Doctors also may need to consider other common comorbidities in children with ADHD, such as bipolar disorder, depression, learning disabilities, oppositional defiant disorder, and tic disorders.

Tic disorders typically have an onset around 7 years old and peak in midadolescence, declining in late teen years. An estimated 35%-90% of children with Tourette syndrome have ADHD, Dr. Schonwald said (Dev Med Child Neurol. 2006 Jul;48[7]:616-21).
 

Managing treatment with stimulants

A common dosage amount for stimulants is 2.5-5 mg, but that dose may be too low for children, Dr. Schonwald said. She recommended increasing it until an effect is seen and stopping at the effective dose level the child can tolerate. The maximum recommended by the FDA is 60 mg/day for short-acting stimulants and 72 mg/day for extended-release ones, but some research has shown dosage can go even higher without causing toxic effects (J Child Adolesc Psychopharmacol. 2010 Feb;20[1]:49-54).

Dr. Schonwald also suggested trying both methylphenidate and amphetamine medication, while recognizing the latter tends to have more stimulant-related side effects.

Adherence is another consideration because multiple studies show high rates of noncompliance or discontinuation, such as up to 19% discontinuation for long-acting and 38% for short-acting stimulants (J Clin Psychiatry. 2015 Nov;76(11):e1459-68; Postgrad Med. 2012 May;124(3):139-48). A study of a school cohort in Philadelphia found only about one in five children were adherent (J Am Acad Child Adolesc Psychiatry. 2011 May;50[5]:480-9).

One potential solution to adherence challenges are pill reminder smartphone apps, such as Medisafe Medication Management, Pill Reminder-All in One, MyTherapy: Medication Reminder, and CareZone.

Dr. Schonwald noted several factors that can influence children’s response to stimulants. Among children with comorbid intellectual disability, for example, the response rate is lower than the average 75% of children without the disability, hovering around 40%-50% (Res Dev Disabil. 2018 Dec;83:217-32). Those who get more sleep tend to have improved attention, compared with children with less sleep (Atten Defic Hyperact Disord. 2017 Mar;9[1]:31-38).

She also offered strategies to manage problematic adverse effects from stimulants. Those experiencing weight loss can take their stimulant after breakfast, drink whole milk, and consider taking drug holidays.

To reduce stomachaches, children should take their medication with food, and you should look at whether the child is taking the lowest effective dose they can and whether anxiety may be involved. Similarly, children with headaches should take stimulants with food, and you should look at the dosage and ask whether the patient is getting adequate sleep.

Strategies to address difficulty falling asleep can include taking the stimulant earlier in the day or switching to a shorter-acting form, dexmethylphenidate, or another stimulant. If they’re having trouble staying asleep, inquire about sleep hygiene, and look for associations with other factors that might explain why the child is experiencing new problems with staying asleep. If these strategies are unsuccessful, you can consider prescribing melatonin or clonidine.
 

Alternatives to stimulants

Several medications besides stimulants are available to prescribe to children with ADHD if they aren’t responding adequately to stimulants, Dr. Schonwald said.

Atomoxetine performed better than placebo in treatment studies, with similar weight loss effects, albeit the lowest mean effect size in clinician ratings (Lancet Psychiatry. 2018 Sep;5[9]:727-38). Dr. Schonwald recommended starting atomoxetine in children under 40 kg at 0.5 mg/kg for 4 days, then increasing to 1.2 mg/kg/day. For children over 40 kg, the dose can start at 40 mg. Maximum dose can range from 1.4 to 1.8 mg/kg or 100 mg/day.

About 7% of white children and 2% of African American children are poor metabolizers of atomoxetine, and the drug has interactions with dextromethorphan, fluoxetine, and paroxetine, she noted. Side effects can include abdominal pain, dry mouth, fatigue, mood swings, nausea, and vomiting.

Two alpha-adrenergics that you can consider are clonidine and guanfacine. Clonidine, a hypotensive drug given at a dose of 0.05-0.2 mg up to three times a day, is helpful for hyperactivity and impulsivity rather than attention difficulties. Side effects can include depression, headache, rebound hypertension, and sedation, and it’s only FDA approved for ages 12 years and older.

An extended release version of clonidine (Kapvay) is approved for monotherapy or adjunctive therapy for ADHD; it led to improvements in ADHD–Rating Scale-IV scores as soon as the second week in an 8-week randomized controlled trial. Mild to moderate somnolence was the most common adverse event, and changes on electrocardiograms were minor (J Am Acad Child Adolesc Psychiatry. 2011 Feb;50[2]:171-9).

Guanfacine, also a hypotensive drug, given at a dose of 0.5-2 mg up to three times a day, has fewer data about its use for ADHD but appears to treat attention problems more effectively than hyperactivity. Also approved only for ages 12 years and older, guanfacine is less sedating, and its side effects can include agitation, headache , and insomnia. An extended-release version of guanfacine (brand name Intuniv) showed statistically significant reductions in ADHD Rating Scale-IV scores in a 9-week, double-blind, randomized, controlled trial. Side effects including fatigue, sedation, and somnolence occurred in the first 2 weeks but generally resolved, and participants returned to baseline during dose maintenance and tapering (J Am Acad Child Adolesc Psychiatry. 2009 Feb;48[2]:155-65).

Intuniv doses should start at 1 mg/day and increase no more than 1 mg/week, Dr. Schonwald said, until reaching a maintenance dose of 1-4 mg once daily, depending on the patient’s clinical response and tolerability. Children also must be able to swallow the pill whole.
 

Treating preschoolers

Preschool children are particularly difficult to diagnose given their normal range of temperament and development, Dr. Schonwald said. Their symptoms could be resulting from another diagnosis or from circumstances in the environment.

You should consider potential comorbidities and whether the child’s symptoms are situational or pervasive. About 55% of preschoolers have at least one comorbidity, she said (Infants & Young Children. 2006 Apr-Jun;19[2]:109-122.)

That said, stimulants usually are effective in very young children whose primary concern is ADHD. In a randomized controlled trial of 303 preschoolers, significantly more children experienced reduced ADHD symptoms with methylphenidate than with placebo. The trial’s “data suggest that preschoolers with ADHD need to start with low methylphenidate doses. Treatment may best begin using methylphenidate–immediate release at 2.5 mg twice daily, and then be increased to 7.5 mg three times a day during the course of 1 week. The mean optimal total daily [methylphenidate] dose for preschoolers was 14.2 plus or minus 8.1 mg/day” (J Am Acad Child Adolesc Psychiatry. 2006 Nov;45[11]:1284-93).

In treating preschoolers, if the patient’s symptoms appear to get worse after starting a stimulant, you can consider a medication change. If symptoms are much worse, consider a lower dose or a different stimulant class, or whether the diagnosis is appropriate.

Five common components of poor behavior in preschoolers with ADHD include agitation, anxiety, explosively, hyperactivity, and impulsivity. If these issues are occurring throughout the day, consider reducing the dose or switching drug classes.

If it’s only occurring in the morning, Dr. Schonwald said, optimize the morning structure and consider giving the medication earlier in the morning or adding a short-acting booster. If it’s occurring in late afternoon, consider a booster and reducing high-demand activities for the child.

If a preschooler experiences some benefit from the stimulant but still has problems, adjunctive atomoxetine or an alpha adrenergic may help. Those medications also are recommended if the child has no benefit with the stimulant or cannot tolerate the lowest therapeutic dose.

Dr. Schonwald said she had no relevant financial disclosures.

NEW ORLEANS – A variety of reasons can contribute to the failure of stimulants to treat ADHD in children, such as comorbidities, missed diagnoses, inadequate medication dosage, side effects, major life changes, and other factors in the home or school environments, said Alison Schonwald, MD, of Harvard Medical School, Boston.

gpointstudio/Thinkstock

Stimulant medications indicated for ADHD usually work in 70%-75% of school-age children, but that leaves one in four children whose condition can be more challenging to treat, she said.

“Look around you,” Dr. Schonwald told a packed room at the annual meeting of the American Academy of Pediatrics. “You’re not the only one struggling with this topic.” She sprinkled her presentation with case studies of patients with ADHD for whom stimulants weren’t working, examples that the audience clearly found familiar.

The three steps you already know to do with treatment-resistant children sound simple: assess the child for factors linked to their poor response; develop a new treatment plan; and use Food and Drug Administration-approved nonstimulant medications, including off-label options, in a new plan.

But in the office, the process can be anything but simple when you must consider school and family environments, comorbidities, and other factors potentially complicating the child’s ability to function well.
 

Comorbidities

To start, Dr. Schonwald provided a chart of common coexisting problems in children with ADHD that included the recommended assessment and intervention:

• Mood and self-esteem issues call for the depression section of the patient health questionnaire (PHQ9) and Moods and Feelings questionnaire (MFQ), followed by interventions such as individual and peer group therapy and exercise.
• Anxiety can be assessed with the Screen for Child Anxiety Related Disorders (SCARED) and Spence Children’s Anxiety Scale, then treated similarly to mood and self-esteem issues.
• Bullying or trauma require taking a history during an interview, and treatment with individual and peer group therapy.
• Substance abuse should be assessed with the CRAFFT screening tool (Car, Relax, Alone, Forget, Friends, Trouble) and Screening to Brief Intervention (S2BI) Tool, then treated according to best practices.
• Executive function, low cognitive abilities, and poor adaptive skills require a review of the child’s Individualized Education Program (IEP) testing, followed by personalized school and home interventions.
• Poor social skills, assessed in an interview, also require personalized interventions at home and in school.

Doctors also may need to consider other common comorbidities in children with ADHD, such as bipolar disorder, depression, learning disabilities, oppositional defiant disorder, and tic disorders.

Tic disorders typically have an onset around 7 years old and peak in midadolescence, declining in late teen years. An estimated 35%-90% of children with Tourette syndrome have ADHD, Dr. Schonwald said (Dev Med Child Neurol. 2006 Jul;48[7]:616-21).
 

Managing treatment with stimulants

A common dosage amount for stimulants is 2.5-5 mg, but that dose may be too low for children, Dr. Schonwald said. She recommended increasing it until an effect is seen and stopping at the effective dose level the child can tolerate. The maximum recommended by the FDA is 60 mg/day for short-acting stimulants and 72 mg/day for extended-release ones, but some research has shown dosage can go even higher without causing toxic effects (J Child Adolesc Psychopharmacol. 2010 Feb;20[1]:49-54).

Dr. Schonwald also suggested trying both methylphenidate and amphetamine medication, while recognizing the latter tends to have more stimulant-related side effects.

Adherence is another consideration because multiple studies show high rates of noncompliance or discontinuation, such as up to 19% discontinuation for long-acting and 38% for short-acting stimulants (J Clin Psychiatry. 2015 Nov;76(11):e1459-68; Postgrad Med. 2012 May;124(3):139-48). A study of a school cohort in Philadelphia found only about one in five children were adherent (J Am Acad Child Adolesc Psychiatry. 2011 May;50[5]:480-9).

One potential solution to adherence challenges are pill reminder smartphone apps, such as Medisafe Medication Management, Pill Reminder-All in One, MyTherapy: Medication Reminder, and CareZone.

Dr. Schonwald noted several factors that can influence children’s response to stimulants. Among children with comorbid intellectual disability, for example, the response rate is lower than the average 75% of children without the disability, hovering around 40%-50% (Res Dev Disabil. 2018 Dec;83:217-32). Those who get more sleep tend to have improved attention, compared with children with less sleep (Atten Defic Hyperact Disord. 2017 Mar;9[1]:31-38).

She also offered strategies to manage problematic adverse effects from stimulants. Those experiencing weight loss can take their stimulant after breakfast, drink whole milk, and consider taking drug holidays.

To reduce stomachaches, children should take their medication with food, and you should look at whether the child is taking the lowest effective dose they can and whether anxiety may be involved. Similarly, children with headaches should take stimulants with food, and you should look at the dosage and ask whether the patient is getting adequate sleep.

Strategies to address difficulty falling asleep can include taking the stimulant earlier in the day or switching to a shorter-acting form, dexmethylphenidate, or another stimulant. If they’re having trouble staying asleep, inquire about sleep hygiene, and look for associations with other factors that might explain why the child is experiencing new problems with staying asleep. If these strategies are unsuccessful, you can consider prescribing melatonin or clonidine.
 

Alternatives to stimulants

Several medications besides stimulants are available to prescribe to children with ADHD if they aren’t responding adequately to stimulants, Dr. Schonwald said.

Atomoxetine performed better than placebo in treatment studies, with similar weight loss effects, albeit the lowest mean effect size in clinician ratings (Lancet Psychiatry. 2018 Sep;5[9]:727-38). Dr. Schonwald recommended starting atomoxetine in children under 40 kg at 0.5 mg/kg for 4 days, then increasing to 1.2 mg/kg/day. For children over 40 kg, the dose can start at 40 mg. Maximum dose can range from 1.4 to 1.8 mg/kg or 100 mg/day.

About 7% of white children and 2% of African American children are poor metabolizers of atomoxetine, and the drug has interactions with dextromethorphan, fluoxetine, and paroxetine, she noted. Side effects can include abdominal pain, dry mouth, fatigue, mood swings, nausea, and vomiting.

Two alpha-adrenergics that you can consider are clonidine and guanfacine. Clonidine, a hypotensive drug given at a dose of 0.05-0.2 mg up to three times a day, is helpful for hyperactivity and impulsivity rather than attention difficulties. Side effects can include depression, headache, rebound hypertension, and sedation, and it’s only FDA approved for ages 12 years and older.

An extended release version of clonidine (Kapvay) is approved for monotherapy or adjunctive therapy for ADHD; it led to improvements in ADHD–Rating Scale-IV scores as soon as the second week in an 8-week randomized controlled trial. Mild to moderate somnolence was the most common adverse event, and changes on electrocardiograms were minor (J Am Acad Child Adolesc Psychiatry. 2011 Feb;50[2]:171-9).

Guanfacine, also a hypotensive drug, given at a dose of 0.5-2 mg up to three times a day, has fewer data about its use for ADHD but appears to treat attention problems more effectively than hyperactivity. Also approved only for ages 12 years and older, guanfacine is less sedating, and its side effects can include agitation, headache , and insomnia. An extended-release version of guanfacine (brand name Intuniv) showed statistically significant reductions in ADHD Rating Scale-IV scores in a 9-week, double-blind, randomized, controlled trial. Side effects including fatigue, sedation, and somnolence occurred in the first 2 weeks but generally resolved, and participants returned to baseline during dose maintenance and tapering (J Am Acad Child Adolesc Psychiatry. 2009 Feb;48[2]:155-65).

Intuniv doses should start at 1 mg/day and increase no more than 1 mg/week, Dr. Schonwald said, until reaching a maintenance dose of 1-4 mg once daily, depending on the patient’s clinical response and tolerability. Children also must be able to swallow the pill whole.
 

Treating preschoolers

Preschool children are particularly difficult to diagnose given their normal range of temperament and development, Dr. Schonwald said. Their symptoms could be resulting from another diagnosis or from circumstances in the environment.

You should consider potential comorbidities and whether the child’s symptoms are situational or pervasive. About 55% of preschoolers have at least one comorbidity, she said (Infants & Young Children. 2006 Apr-Jun;19[2]:109-122.)

That said, stimulants usually are effective in very young children whose primary concern is ADHD. In a randomized controlled trial of 303 preschoolers, significantly more children experienced reduced ADHD symptoms with methylphenidate than with placebo. The trial’s “data suggest that preschoolers with ADHD need to start with low methylphenidate doses. Treatment may best begin using methylphenidate–immediate release at 2.5 mg twice daily, and then be increased to 7.5 mg three times a day during the course of 1 week. The mean optimal total daily [methylphenidate] dose for preschoolers was 14.2 plus or minus 8.1 mg/day” (J Am Acad Child Adolesc Psychiatry. 2006 Nov;45[11]:1284-93).

In treating preschoolers, if the patient’s symptoms appear to get worse after starting a stimulant, you can consider a medication change. If symptoms are much worse, consider a lower dose or a different stimulant class, or whether the diagnosis is appropriate.

Five common components of poor behavior in preschoolers with ADHD include agitation, anxiety, explosively, hyperactivity, and impulsivity. If these issues are occurring throughout the day, consider reducing the dose or switching drug classes.

If it’s only occurring in the morning, Dr. Schonwald said, optimize the morning structure and consider giving the medication earlier in the morning or adding a short-acting booster. If it’s occurring in late afternoon, consider a booster and reducing high-demand activities for the child.

If a preschooler experiences some benefit from the stimulant but still has problems, adjunctive atomoxetine or an alpha adrenergic may help. Those medications also are recommended if the child has no benefit with the stimulant or cannot tolerate the lowest therapeutic dose.

Dr. Schonwald said she had no relevant financial disclosures.

Fevers were no less common or less severe when influenza vaccine was delayed 2 weeks for children receiving DTaP and pneumococcal vaccinations, according to a randomized trial.

MarianVejcik/Getty Images

An increased risk for febrile seizures had been seen when the three vaccines were administered together, wrote Emmanuel B. Walter, MD, MPH, and coauthors, so they constructed a trial that compared a simultaneous administration strategy that delayed inactivated influenza vaccine (IIV) administration by about 2 weeks.

In all, 221 children aged 12-16 months were enrolled in the randomized study. A total of 110 children received quadrivalent IIV (IIV4), DTaP, and 13-valent pneumococcal conjugate vaccine (PCV13) simultaneously and returned for a dental health education visit 2 weeks later. For 111 children, DTaP and PCV13 were administered at study visit 1, and IIV4 was given along with dental health education 2 weeks later. Most children in both groups also received at least one nonstudy vaccine at the first study visit. Eleven children in the simultaneous group and four in the sequential group didn’t complete the study.

There was no difference between study groups in the combined rates of fever on the first 2 days after study visits 1 and 2 taken together: 8% of children in the simultaneous group and 9% of those in the sequential group had fever of 38° C or higher (adjusted relative risk, 0.87; 95% confidence interval, 0.36-2.10).

However, children in the simultaneous group were more likely to receive antipyretic medication in the first 2 days after visit 1 (37% versus 22%; P = .020), reported Dr. Walter, professor of pediatrics at Duke University, Durham, N.C., and coauthors. Because it’s rare for febrile seizures to occur after immunization, the authors didn’t make the occurrence of febrile seizure a primary or secondary endpoint of the study; no seizures occurred in study participants. They did hypothesize that the total proportion of children having fever would be higher in the simultaneous than in the sequential group – a hypothesis not supported by the study findings.

Children were excluded, or their study vaccinations were delayed, if they had received antipyretic medication within the 72 hours preceding the visit or at the study visit, or if they had a temperature of 38° C or more.

Parents monitored participants’ temperatures for 8 days after visits by using a study-provided temporal thermometer once daily at about the same time, and also by checking the temperature if their child felt feverish. Parents also recorded any antipyretic use, medical care, other symptoms, and febrile seizures.

The study was stopped earlier than anticipated because unexpectedly high levels of influenza activity made it unethical to delay influenza immunization, explained Dr. Walter and coauthors.

Participants were a median 15 months old; most were non-Hispanic white and had private insurance. Most participants didn’t attend day care.

“Nearly all fever episodes and days of fever on days 1-2 after the study visits occurred after visit 1,” reported Dr. Walter and coinvestigators. They saw no difference between groups in the proportion of children who had a fever of 38.6° C on days 1-2 after either study visit.

The mean peak temperature – about 38.5° C – on combined study visits 1 and 2 didn’t differ between groups. Similarly, for those participants who had a fever, the mean postvisit fever duration of 1.3 days was identical between groups.

Parents also were asked about their perceptions of the vaccination schedule their children received. Over half of parents overall (56%) reported that they disliked having to bring their child in for two separate clinic visits, with more parents in the sequential group than the simultaneous group reporting this (65% versus 48%).

Generalizability of the findings and comparison with previous studies are limited, noted Dr. Walter and coinvestigators, because the composition of influenza vaccine varies from year to year. No signal for seizures was seen in the Vaccine Safety Datalink after IIV during the 2017-2018 influenza season, wrote the investigators. The 2010-2011 influenza season’s IIV formulation was associated with increased febrile seizure risk, indicating that the IIV formulation for that year may have been more pyrogenic than the 2017-2018 formulation.

Also, children deemed at higher risk of febrile seizure were excluded from the study, so findings may have limited applicability to these children. The lack of parental blinding also may have influenced antipyretic administration or other symptom reporting, although objective temperature measurement should not have been affected by the lack of blinding, wrote Dr. Walker and collaborators.

The study was funded by the Centers for Disease Control and Prevention. One coauthor reported potential conflicts of interest from financial support received from GlaxoSmithKline, Sanofi Pasteur, Pfizer, Merck, Protein Science, Dynavax, and Medimmune. The remaining authors have no relevant financial disclosures.

[email protected]

SOURCE: Walter EB et al. Pediatrics. 2020;145(3):e20191909.

Fevers were no less common or less severe when influenza vaccine was delayed 2 weeks for children receiving DTaP and pneumococcal vaccinations, according to a randomized trial.

MarianVejcik/Getty Images

An increased risk for febrile seizures had been seen when the three vaccines were administered together, wrote Emmanuel B. Walter, MD, MPH, and coauthors, so they constructed a trial that compared a simultaneous administration strategy that delayed inactivated influenza vaccine (IIV) administration by about 2 weeks.

In all, 221 children aged 12-16 months were enrolled in the randomized study. A total of 110 children received quadrivalent IIV (IIV4), DTaP, and 13-valent pneumococcal conjugate vaccine (PCV13) simultaneously and returned for a dental health education visit 2 weeks later. For 111 children, DTaP and PCV13 were administered at study visit 1, and IIV4 was given along with dental health education 2 weeks later. Most children in both groups also received at least one nonstudy vaccine at the first study visit. Eleven children in the simultaneous group and four in the sequential group didn’t complete the study.

There was no difference between study groups in the combined rates of fever on the first 2 days after study visits 1 and 2 taken together: 8% of children in the simultaneous group and 9% of those in the sequential group had fever of 38° C or higher (adjusted relative risk, 0.87; 95% confidence interval, 0.36-2.10).

However, children in the simultaneous group were more likely to receive antipyretic medication in the first 2 days after visit 1 (37% versus 22%; P = .020), reported Dr. Walter, professor of pediatrics at Duke University, Durham, N.C., and coauthors. Because it’s rare for febrile seizures to occur after immunization, the authors didn’t make the occurrence of febrile seizure a primary or secondary endpoint of the study; no seizures occurred in study participants. They did hypothesize that the total proportion of children having fever would be higher in the simultaneous than in the sequential group – a hypothesis not supported by the study findings.

Children were excluded, or their study vaccinations were delayed, if they had received antipyretic medication within the 72 hours preceding the visit or at the study visit, or if they had a temperature of 38° C or more.

Parents monitored participants’ temperatures for 8 days after visits by using a study-provided temporal thermometer once daily at about the same time, and also by checking the temperature if their child felt feverish. Parents also recorded any antipyretic use, medical care, other symptoms, and febrile seizures.

The study was stopped earlier than anticipated because unexpectedly high levels of influenza activity made it unethical to delay influenza immunization, explained Dr. Walter and coauthors.

Participants were a median 15 months old; most were non-Hispanic white and had private insurance. Most participants didn’t attend day care.

“Nearly all fever episodes and days of fever on days 1-2 after the study visits occurred after visit 1,” reported Dr. Walter and coinvestigators. They saw no difference between groups in the proportion of children who had a fever of 38.6° C on days 1-2 after either study visit.

The mean peak temperature – about 38.5° C – on combined study visits 1 and 2 didn’t differ between groups. Similarly, for those participants who had a fever, the mean postvisit fever duration of 1.3 days was identical between groups.

Parents also were asked about their perceptions of the vaccination schedule their children received. Over half of parents overall (56%) reported that they disliked having to bring their child in for two separate clinic visits, with more parents in the sequential group than the simultaneous group reporting this (65% versus 48%).

Generalizability of the findings and comparison with previous studies are limited, noted Dr. Walter and coinvestigators, because the composition of influenza vaccine varies from year to year. No signal for seizures was seen in the Vaccine Safety Datalink after IIV during the 2017-2018 influenza season, wrote the investigators. The 2010-2011 influenza season’s IIV formulation was associated with increased febrile seizure risk, indicating that the IIV formulation for that year may have been more pyrogenic than the 2017-2018 formulation.

Also, children deemed at higher risk of febrile seizure were excluded from the study, so findings may have limited applicability to these children. The lack of parental blinding also may have influenced antipyretic administration or other symptom reporting, although objective temperature measurement should not have been affected by the lack of blinding, wrote Dr. Walker and collaborators.

The study was funded by the Centers for Disease Control and Prevention. One coauthor reported potential conflicts of interest from financial support received from GlaxoSmithKline, Sanofi Pasteur, Pfizer, Merck, Protein Science, Dynavax, and Medimmune. The remaining authors have no relevant financial disclosures.

[email protected]

SOURCE: Walter EB et al. Pediatrics. 2020;145(3):e20191909.

Fevers were no less common or less severe when influenza vaccine was delayed 2 weeks for children receiving DTaP and pneumococcal vaccinations, according to a randomized trial.

MarianVejcik/Getty Images

An increased risk for febrile seizures had been seen when the three vaccines were administered together, wrote Emmanuel B. Walter, MD, MPH, and coauthors, so they constructed a trial that compared a simultaneous administration strategy that delayed inactivated influenza vaccine (IIV) administration by about 2 weeks.

In all, 221 children aged 12-16 months were enrolled in the randomized study. A total of 110 children received quadrivalent IIV (IIV4), DTaP, and 13-valent pneumococcal conjugate vaccine (PCV13) simultaneously and returned for a dental health education visit 2 weeks later. For 111 children, DTaP and PCV13 were administered at study visit 1, and IIV4 was given along with dental health education 2 weeks later. Most children in both groups also received at least one nonstudy vaccine at the first study visit. Eleven children in the simultaneous group and four in the sequential group didn’t complete the study.

There was no difference between study groups in the combined rates of fever on the first 2 days after study visits 1 and 2 taken together: 8% of children in the simultaneous group and 9% of those in the sequential group had fever of 38° C or higher (adjusted relative risk, 0.87; 95% confidence interval, 0.36-2.10).

However, children in the simultaneous group were more likely to receive antipyretic medication in the first 2 days after visit 1 (37% versus 22%; P = .020), reported Dr. Walter, professor of pediatrics at Duke University, Durham, N.C., and coauthors. Because it’s rare for febrile seizures to occur after immunization, the authors didn’t make the occurrence of febrile seizure a primary or secondary endpoint of the study; no seizures occurred in study participants. They did hypothesize that the total proportion of children having fever would be higher in the simultaneous than in the sequential group – a hypothesis not supported by the study findings.

Children were excluded, or their study vaccinations were delayed, if they had received antipyretic medication within the 72 hours preceding the visit or at the study visit, or if they had a temperature of 38° C or more.

Parents monitored participants’ temperatures for 8 days after visits by using a study-provided temporal thermometer once daily at about the same time, and also by checking the temperature if their child felt feverish. Parents also recorded any antipyretic use, medical care, other symptoms, and febrile seizures.

The study was stopped earlier than anticipated because unexpectedly high levels of influenza activity made it unethical to delay influenza immunization, explained Dr. Walter and coauthors.

Participants were a median 15 months old; most were non-Hispanic white and had private insurance. Most participants didn’t attend day care.

“Nearly all fever episodes and days of fever on days 1-2 after the study visits occurred after visit 1,” reported Dr. Walter and coinvestigators. They saw no difference between groups in the proportion of children who had a fever of 38.6° C on days 1-2 after either study visit.

The mean peak temperature – about 38.5° C – on combined study visits 1 and 2 didn’t differ between groups. Similarly, for those participants who had a fever, the mean postvisit fever duration of 1.3 days was identical between groups.

Parents also were asked about their perceptions of the vaccination schedule their children received. Over half of parents overall (56%) reported that they disliked having to bring their child in for two separate clinic visits, with more parents in the sequential group than the simultaneous group reporting this (65% versus 48%).

Generalizability of the findings and comparison with previous studies are limited, noted Dr. Walter and coinvestigators, because the composition of influenza vaccine varies from year to year. No signal for seizures was seen in the Vaccine Safety Datalink after IIV during the 2017-2018 influenza season, wrote the investigators. The 2010-2011 influenza season’s IIV formulation was associated with increased febrile seizure risk, indicating that the IIV formulation for that year may have been more pyrogenic than the 2017-2018 formulation.

Also, children deemed at higher risk of febrile seizure were excluded from the study, so findings may have limited applicability to these children. The lack of parental blinding also may have influenced antipyretic administration or other symptom reporting, although objective temperature measurement should not have been affected by the lack of blinding, wrote Dr. Walker and collaborators.

The study was funded by the Centers for Disease Control and Prevention. One coauthor reported potential conflicts of interest from financial support received from GlaxoSmithKline, Sanofi Pasteur, Pfizer, Merck, Protein Science, Dynavax, and Medimmune. The remaining authors have no relevant financial disclosures.

[email protected]

SOURCE: Walter EB et al. Pediatrics. 2020;145(3):e20191909.

LONDON – Treatment with the antihypertensive drug losartan raised no safety concerns in the treatment of children with epidermolysis bullosa (EB) and reduced signs of fibrosis in an early clinical study.

In the ongoing phase 1/2 REFLECT (Recessive dystrophic EB: Mechanisms of fibrosis and its prevention with Losartan in vivo) trial, involving 29 children, no severe complications have been noted so far, according to one of the study investigators, Dimitra Kiritsi, MD, of the University of Freiburg, Germany. At the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA), she presented interim data on 18 patients in the trial, emphasizing that the primary aim of the trial was to evaluate the safety of this treatment approach.

Over the 2 years the trial has been underway, 65 adverse events have been reported, of which 4 have been severe. Two of these were bacterial infections that required hospital treatment and the other two were a reduction in the general health condition of the child.

Losartan is an angiotensin-II receptor blocker (ARB) that has been in clinical use for more than 25 years in adults and 15 years in children over the age of 6 years.

The drug may be used for treating recessive dystrophic EB (RDEB) in the future, Dr. Kiritsi said, because it attenuates tumor necrosis factor–beta (TGF-beta) signaling, which is thought to be involved in the fibrotic process. So while it may not target the genetic defect, it could help ameliorate the effects of the disease.

The precursor to REFLECT was a study performed in a mouse disease model of EB (EMBO Mol Med. 2015;7:1211-28) where a reduction in fibrotic scarring was seen with losartan with “remarkable effects” on “mitten” deformity, Dr. Kiritsi said. The results of that study suggested that the earlier treatment with losartan was started in the course of the disease, the better the effect, she added. (Mitten deformity is the result of fused skin between the fingers or toes, and the subsequent buildup of fibrotic tissue causes the hand or foot to contract.)

REFLECT is an investigator-initiated trial that started in 2017 and is being funded by DEBRA International. It is a dual-center, nonrandomized, single-arm study in which children aged 3-16 years with RDEB are treated with losartan for 10 months, with follow-up at 3 months.

Various secondary endpoints were included to look for the first signs of any efficacy: the Physician’s Global Assessment (PGA), the Birmingham Epidermolysis Bullosa Severity Score (BEBS), the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI), the Itch Assessment Scale for the Pediatric Burn Patients, and two quality of life indices: the Quality of Life in EB (QOLEB) questionnaire and the Children’s Dermatology Life Quality Index (CDLQI).

Dr. Kiritsi highlighted a few of the secondary endpoint findings, saying that reduced BEBS scores showed there was “amelioration of the patients’ phenotype” and that EBDASI scores also decreased, with “nearly 60% of the patients having significant improvement of their skin disease.” Importantly, itch improved in most of the patients, she said. Reductions in CDLQI were observed, “meaning that quality of life was significantly better at the end of the trial.” There were also decreases in inflammatory markers, such as C-reactive protein, interleukin-6, and TNF-alpha.

Although there is no validated tool available to assess hand function, Dr. Kiritsi and her team used their own morphometric scoring instrument to measure how far the hand could stretch; their evaluations suggested that this measure improved – or at least did not worsen – with losartan treatment, she noted.

A larger, randomized trial is needed to confirm if there is any benefit of losartan, but first, a new, easy-to-swallow losartan formulation needs to be developed specifically for EB in the pediatric population, Dr. Kiritsi said. Although a pediatric suspension of losartan was previously available, it is no longer on the market, so the next step is to develop a formulation that could be used in a pivotal clinical trial, she noted.

“Losartan faces fewer technical hurdles compared to other novel treatments as it is an established medicine,” Dr. Kiritsi and associates observed in a poster presentation. There are still economic hurdles, however, since “with losartan patents expired, companies cannot expect to recoup an investment into clinical studies” and alternative funding sources are needed.

In 2019, losartan was granted an orphan drug designation for the treatment of EB from both the Food and Drug Administration and the European Medicines Agency, but its use remains off label in children. “We decided to treat children,” Dr. Kiritsi said, “because we wanted to start as early as possible. If you already have mitten deformities, these cannot be reversed.”

DEBRA International funded the study. Dr. Kiritsi received research support from Rheacell GmbH and honoraria or consultation fees from Amryt Pharma and Rheacell GmbH. She has received other support from DEBRA International, EB Research Partnership, Fritz Thyssen Stiftung, German Research Foundation (funding of research projects), and 3R Pharma Consulting and Midas Pharma GmbH (consultation for losartan new drug formulation).

SOURCE: Kiritsi D et al. EB 2020. Poster 47.
 

LONDON – Treatment with the antihypertensive drug losartan raised no safety concerns in the treatment of children with epidermolysis bullosa (EB) and reduced signs of fibrosis in an early clinical study.

In the ongoing phase 1/2 REFLECT (Recessive dystrophic EB: Mechanisms of fibrosis and its prevention with Losartan in vivo) trial, involving 29 children, no severe complications have been noted so far, according to one of the study investigators, Dimitra Kiritsi, MD, of the University of Freiburg, Germany. At the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA), she presented interim data on 18 patients in the trial, emphasizing that the primary aim of the trial was to evaluate the safety of this treatment approach.

Over the 2 years the trial has been underway, 65 adverse events have been reported, of which 4 have been severe. Two of these were bacterial infections that required hospital treatment and the other two were a reduction in the general health condition of the child.

Losartan is an angiotensin-II receptor blocker (ARB) that has been in clinical use for more than 25 years in adults and 15 years in children over the age of 6 years.

The drug may be used for treating recessive dystrophic EB (RDEB) in the future, Dr. Kiritsi said, because it attenuates tumor necrosis factor–beta (TGF-beta) signaling, which is thought to be involved in the fibrotic process. So while it may not target the genetic defect, it could help ameliorate the effects of the disease.

The precursor to REFLECT was a study performed in a mouse disease model of EB (EMBO Mol Med. 2015;7:1211-28) where a reduction in fibrotic scarring was seen with losartan with “remarkable effects” on “mitten” deformity, Dr. Kiritsi said. The results of that study suggested that the earlier treatment with losartan was started in the course of the disease, the better the effect, she added. (Mitten deformity is the result of fused skin between the fingers or toes, and the subsequent buildup of fibrotic tissue causes the hand or foot to contract.)

REFLECT is an investigator-initiated trial that started in 2017 and is being funded by DEBRA International. It is a dual-center, nonrandomized, single-arm study in which children aged 3-16 years with RDEB are treated with losartan for 10 months, with follow-up at 3 months.

Various secondary endpoints were included to look for the first signs of any efficacy: the Physician’s Global Assessment (PGA), the Birmingham Epidermolysis Bullosa Severity Score (BEBS), the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI), the Itch Assessment Scale for the Pediatric Burn Patients, and two quality of life indices: the Quality of Life in EB (QOLEB) questionnaire and the Children’s Dermatology Life Quality Index (CDLQI).

Dr. Kiritsi highlighted a few of the secondary endpoint findings, saying that reduced BEBS scores showed there was “amelioration of the patients’ phenotype” and that EBDASI scores also decreased, with “nearly 60% of the patients having significant improvement of their skin disease.” Importantly, itch improved in most of the patients, she said. Reductions in CDLQI were observed, “meaning that quality of life was significantly better at the end of the trial.” There were also decreases in inflammatory markers, such as C-reactive protein, interleukin-6, and TNF-alpha.

Although there is no validated tool available to assess hand function, Dr. Kiritsi and her team used their own morphometric scoring instrument to measure how far the hand could stretch; their evaluations suggested that this measure improved – or at least did not worsen – with losartan treatment, she noted.

A larger, randomized trial is needed to confirm if there is any benefit of losartan, but first, a new, easy-to-swallow losartan formulation needs to be developed specifically for EB in the pediatric population, Dr. Kiritsi said. Although a pediatric suspension of losartan was previously available, it is no longer on the market, so the next step is to develop a formulation that could be used in a pivotal clinical trial, she noted.

“Losartan faces fewer technical hurdles compared to other novel treatments as it is an established medicine,” Dr. Kiritsi and associates observed in a poster presentation. There are still economic hurdles, however, since “with losartan patents expired, companies cannot expect to recoup an investment into clinical studies” and alternative funding sources are needed.

In 2019, losartan was granted an orphan drug designation for the treatment of EB from both the Food and Drug Administration and the European Medicines Agency, but its use remains off label in children. “We decided to treat children,” Dr. Kiritsi said, “because we wanted to start as early as possible. If you already have mitten deformities, these cannot be reversed.”

DEBRA International funded the study. Dr. Kiritsi received research support from Rheacell GmbH and honoraria or consultation fees from Amryt Pharma and Rheacell GmbH. She has received other support from DEBRA International, EB Research Partnership, Fritz Thyssen Stiftung, German Research Foundation (funding of research projects), and 3R Pharma Consulting and Midas Pharma GmbH (consultation for losartan new drug formulation).

SOURCE: Kiritsi D et al. EB 2020. Poster 47.
 

LONDON – Treatment with the antihypertensive drug losartan raised no safety concerns in the treatment of children with epidermolysis bullosa (EB) and reduced signs of fibrosis in an early clinical study.

In the ongoing phase 1/2 REFLECT (Recessive dystrophic EB: Mechanisms of fibrosis and its prevention with Losartan in vivo) trial, involving 29 children, no severe complications have been noted so far, according to one of the study investigators, Dimitra Kiritsi, MD, of the University of Freiburg, Germany. At the EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA), she presented interim data on 18 patients in the trial, emphasizing that the primary aim of the trial was to evaluate the safety of this treatment approach.

Over the 2 years the trial has been underway, 65 adverse events have been reported, of which 4 have been severe. Two of these were bacterial infections that required hospital treatment and the other two were a reduction in the general health condition of the child.

Losartan is an angiotensin-II receptor blocker (ARB) that has been in clinical use for more than 25 years in adults and 15 years in children over the age of 6 years.

The drug may be used for treating recessive dystrophic EB (RDEB) in the future, Dr. Kiritsi said, because it attenuates tumor necrosis factor–beta (TGF-beta) signaling, which is thought to be involved in the fibrotic process. So while it may not target the genetic defect, it could help ameliorate the effects of the disease.

The precursor to REFLECT was a study performed in a mouse disease model of EB (EMBO Mol Med. 2015;7:1211-28) where a reduction in fibrotic scarring was seen with losartan with “remarkable effects” on “mitten” deformity, Dr. Kiritsi said. The results of that study suggested that the earlier treatment with losartan was started in the course of the disease, the better the effect, she added. (Mitten deformity is the result of fused skin between the fingers or toes, and the subsequent buildup of fibrotic tissue causes the hand or foot to contract.)

REFLECT is an investigator-initiated trial that started in 2017 and is being funded by DEBRA International. It is a dual-center, nonrandomized, single-arm study in which children aged 3-16 years with RDEB are treated with losartan for 10 months, with follow-up at 3 months.

Various secondary endpoints were included to look for the first signs of any efficacy: the Physician’s Global Assessment (PGA), the Birmingham Epidermolysis Bullosa Severity Score (BEBS), the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI), the Itch Assessment Scale for the Pediatric Burn Patients, and two quality of life indices: the Quality of Life in EB (QOLEB) questionnaire and the Children’s Dermatology Life Quality Index (CDLQI).

Dr. Kiritsi highlighted a few of the secondary endpoint findings, saying that reduced BEBS scores showed there was “amelioration of the patients’ phenotype” and that EBDASI scores also decreased, with “nearly 60% of the patients having significant improvement of their skin disease.” Importantly, itch improved in most of the patients, she said. Reductions in CDLQI were observed, “meaning that quality of life was significantly better at the end of the trial.” There were also decreases in inflammatory markers, such as C-reactive protein, interleukin-6, and TNF-alpha.

Although there is no validated tool available to assess hand function, Dr. Kiritsi and her team used their own morphometric scoring instrument to measure how far the hand could stretch; their evaluations suggested that this measure improved – or at least did not worsen – with losartan treatment, she noted.

A larger, randomized trial is needed to confirm if there is any benefit of losartan, but first, a new, easy-to-swallow losartan formulation needs to be developed specifically for EB in the pediatric population, Dr. Kiritsi said. Although a pediatric suspension of losartan was previously available, it is no longer on the market, so the next step is to develop a formulation that could be used in a pivotal clinical trial, she noted.

“Losartan faces fewer technical hurdles compared to other novel treatments as it is an established medicine,” Dr. Kiritsi and associates observed in a poster presentation. There are still economic hurdles, however, since “with losartan patents expired, companies cannot expect to recoup an investment into clinical studies” and alternative funding sources are needed.

In 2019, losartan was granted an orphan drug designation for the treatment of EB from both the Food and Drug Administration and the European Medicines Agency, but its use remains off label in children. “We decided to treat children,” Dr. Kiritsi said, “because we wanted to start as early as possible. If you already have mitten deformities, these cannot be reversed.”

DEBRA International funded the study. Dr. Kiritsi received research support from Rheacell GmbH and honoraria or consultation fees from Amryt Pharma and Rheacell GmbH. She has received other support from DEBRA International, EB Research Partnership, Fritz Thyssen Stiftung, German Research Foundation (funding of research projects), and 3R Pharma Consulting and Midas Pharma GmbH (consultation for losartan new drug formulation).

SOURCE: Kiritsi D et al. EB 2020. Poster 47.