Pediatrics

To the Editor:

A 3.5-year-old boy presented with asymptomatic subcutaneous nodules on the left side of the forehead and frontal scalp of approximately 6 months’ duration. There was no history of trauma or preceding rash. His medical history was remarkable only for allergic rhinitis. A review of systems was otherwise negative. Computed tomography ordered by the patient’s pediatrician prior to referral to dermatology showed soft tissue masses on the forehead and frontal scalp with no associated bone or brain parenchymal signal abnormalities.

At presentation to dermatology, physical examination revealed a 6×7-cm, flesh-colored cluster of firm, nontender, fixed, subcutaneous nodules on the left superior forehead and anterior part of the left frontal scalp (Figure 1A), as well as 2×1.5-cm, firm, fixed, flesh-colored nodule inferior to the larger cluster of lesions (Figure 1B). The remainder of the skin examination was unremarkable.

Granuloma annulare is a benign dermatosis that presents in various forms, including localized, generalized, perforating, and subcutaneous subtypes. Subcutaneous GA (SGA) occurs most commonly in young children. The typical presentation of SGA is single or multiple flesh-colored to pink subcutaneous nodules on the arms, legs, or scalp.¹ On the scalp, SGA has a predilection for the parietal and occipital regions. In some cases, there may be a history of preceding trauma to the area. Typically, lesions on the arms and legs are mobile whereas lesions on the scalp may be fixed due to their close proximity to the periosteum. Patients often are asymptomatic, and in the majority of cases, lesions resolve spontaneously over several months to years. Approximately 50% of cases resolve within 2 years of onset.²

Histologically, SGA appears as a nodule of fibrinoid or necrotic degeneration surrounded by palisaded histiocytes and lymphocytes in the deep dermis or subcutaneous tissue. Subcutaneous granuloma annulare is an accurate term for our case due to the subcutaneous location of the granulomatous change; however, some practitioners may prefer to use the term deep GA when the histologic findings are in the deep dermis vs the subcutis. Often, prominent deposition of mucin may be found. Histologically, SGA can closely resemble a rheumatoid nodule or necrobiosis lipoidica.¹

Subcutaneous GA presenting on the scalp and forehead, such as in our case, can present a diagnostic challenge due to the extensive differential diagnoses that must be considered, including trauma, infection, bone or skin disease, and inflammatory or autoimmune disease.^2,3 Additionally, the firm fixed characteristics of some lesions may raise additional concerns for possible malignant diagnoses such as epithelial sarcoma, peripheral nerve sheath tumor, rhabdomyosarcoma, or Langerhans cell histiocytosis, as highlighted by Agrawal et al.⁴ For these reasons, imaging and biopsy often are necessary for histologic diagnosis.

There is no consensus on the etiology of SGA, and no specific disease associations have been proven. Some case reports and case series have proposed a link between SGA and type 1 diabetes mellitus.^1,4 In one retrospective case series, Grogg and Nascimento¹ found that 2 of 34 (5.9%) pediatric patients with SGA had known or subsequently diagnosed diabetes mellitus; however, a definitive association between the 2 entities has not been elucidated. Underlying type 1 diabetes mellitus should be considered in patients with isolated SGA, but laboratory screening for diabetes is not necessary in patients with a negative review of systems.

Treatment of SGA typically is not required, as it is a self-limited condition. Often, once a histologic diagnosis is established, no further evaluation or treatment is warranted. Multiple treatment modalities have been reported, including intralesional and topical corticosteroids, laser therapy, cryotherapy, and systemic agents such as isotretinoin or corticosteroids; however, no treatment has been shown to be consistently efficacious.⁵ Excision of the lesions may be performed, but the risk for recurrence often precludes it as a viable option. In some case series, there have been recurrence rates as high as 40% to 75% in the months to years following surgical excision/biopsy.^1,6

Patients presenting with presumed SGA should undergo a thorough history, review of systems, and full-body skin examination. In some cases, imaging and biopsy may be necessary to make a definitive diagnosis and exclude a more serious condition.

To the Editor:

A 3.5-year-old boy presented with asymptomatic subcutaneous nodules on the left side of the forehead and frontal scalp of approximately 6 months’ duration. There was no history of trauma or preceding rash. His medical history was remarkable only for allergic rhinitis. A review of systems was otherwise negative. Computed tomography ordered by the patient’s pediatrician prior to referral to dermatology showed soft tissue masses on the forehead and frontal scalp with no associated bone or brain parenchymal signal abnormalities.

At presentation to dermatology, physical examination revealed a 6×7-cm, flesh-colored cluster of firm, nontender, fixed, subcutaneous nodules on the left superior forehead and anterior part of the left frontal scalp (Figure 1A), as well as 2×1.5-cm, firm, fixed, flesh-colored nodule inferior to the larger cluster of lesions (Figure 1B). The remainder of the skin examination was unremarkable.

Granuloma annulare is a benign dermatosis that presents in various forms, including localized, generalized, perforating, and subcutaneous subtypes. Subcutaneous GA (SGA) occurs most commonly in young children. The typical presentation of SGA is single or multiple flesh-colored to pink subcutaneous nodules on the arms, legs, or scalp.¹ On the scalp, SGA has a predilection for the parietal and occipital regions. In some cases, there may be a history of preceding trauma to the area. Typically, lesions on the arms and legs are mobile whereas lesions on the scalp may be fixed due to their close proximity to the periosteum. Patients often are asymptomatic, and in the majority of cases, lesions resolve spontaneously over several months to years. Approximately 50% of cases resolve within 2 years of onset.²

Histologically, SGA appears as a nodule of fibrinoid or necrotic degeneration surrounded by palisaded histiocytes and lymphocytes in the deep dermis or subcutaneous tissue. Subcutaneous granuloma annulare is an accurate term for our case due to the subcutaneous location of the granulomatous change; however, some practitioners may prefer to use the term deep GA when the histologic findings are in the deep dermis vs the subcutis. Often, prominent deposition of mucin may be found. Histologically, SGA can closely resemble a rheumatoid nodule or necrobiosis lipoidica.¹

Subcutaneous GA presenting on the scalp and forehead, such as in our case, can present a diagnostic challenge due to the extensive differential diagnoses that must be considered, including trauma, infection, bone or skin disease, and inflammatory or autoimmune disease.^2,3 Additionally, the firm fixed characteristics of some lesions may raise additional concerns for possible malignant diagnoses such as epithelial sarcoma, peripheral nerve sheath tumor, rhabdomyosarcoma, or Langerhans cell histiocytosis, as highlighted by Agrawal et al.⁴ For these reasons, imaging and biopsy often are necessary for histologic diagnosis.

There is no consensus on the etiology of SGA, and no specific disease associations have been proven. Some case reports and case series have proposed a link between SGA and type 1 diabetes mellitus.^1,4 In one retrospective case series, Grogg and Nascimento¹ found that 2 of 34 (5.9%) pediatric patients with SGA had known or subsequently diagnosed diabetes mellitus; however, a definitive association between the 2 entities has not been elucidated. Underlying type 1 diabetes mellitus should be considered in patients with isolated SGA, but laboratory screening for diabetes is not necessary in patients with a negative review of systems.

Treatment of SGA typically is not required, as it is a self-limited condition. Often, once a histologic diagnosis is established, no further evaluation or treatment is warranted. Multiple treatment modalities have been reported, including intralesional and topical corticosteroids, laser therapy, cryotherapy, and systemic agents such as isotretinoin or corticosteroids; however, no treatment has been shown to be consistently efficacious.⁵ Excision of the lesions may be performed, but the risk for recurrence often precludes it as a viable option. In some case series, there have been recurrence rates as high as 40% to 75% in the months to years following surgical excision/biopsy.^1,6

Patients presenting with presumed SGA should undergo a thorough history, review of systems, and full-body skin examination. In some cases, imaging and biopsy may be necessary to make a definitive diagnosis and exclude a more serious condition.

To the Editor:

A 3.5-year-old boy presented with asymptomatic subcutaneous nodules on the left side of the forehead and frontal scalp of approximately 6 months’ duration. There was no history of trauma or preceding rash. His medical history was remarkable only for allergic rhinitis. A review of systems was otherwise negative. Computed tomography ordered by the patient’s pediatrician prior to referral to dermatology showed soft tissue masses on the forehead and frontal scalp with no associated bone or brain parenchymal signal abnormalities.

At presentation to dermatology, physical examination revealed a 6×7-cm, flesh-colored cluster of firm, nontender, fixed, subcutaneous nodules on the left superior forehead and anterior part of the left frontal scalp (Figure 1A), as well as 2×1.5-cm, firm, fixed, flesh-colored nodule inferior to the larger cluster of lesions (Figure 1B). The remainder of the skin examination was unremarkable.

Granuloma annulare is a benign dermatosis that presents in various forms, including localized, generalized, perforating, and subcutaneous subtypes. Subcutaneous GA (SGA) occurs most commonly in young children. The typical presentation of SGA is single or multiple flesh-colored to pink subcutaneous nodules on the arms, legs, or scalp.¹ On the scalp, SGA has a predilection for the parietal and occipital regions. In some cases, there may be a history of preceding trauma to the area. Typically, lesions on the arms and legs are mobile whereas lesions on the scalp may be fixed due to their close proximity to the periosteum. Patients often are asymptomatic, and in the majority of cases, lesions resolve spontaneously over several months to years. Approximately 50% of cases resolve within 2 years of onset.²

Histologically, SGA appears as a nodule of fibrinoid or necrotic degeneration surrounded by palisaded histiocytes and lymphocytes in the deep dermis or subcutaneous tissue. Subcutaneous granuloma annulare is an accurate term for our case due to the subcutaneous location of the granulomatous change; however, some practitioners may prefer to use the term deep GA when the histologic findings are in the deep dermis vs the subcutis. Often, prominent deposition of mucin may be found. Histologically, SGA can closely resemble a rheumatoid nodule or necrobiosis lipoidica.¹

Subcutaneous GA presenting on the scalp and forehead, such as in our case, can present a diagnostic challenge due to the extensive differential diagnoses that must be considered, including trauma, infection, bone or skin disease, and inflammatory or autoimmune disease.^2,3 Additionally, the firm fixed characteristics of some lesions may raise additional concerns for possible malignant diagnoses such as epithelial sarcoma, peripheral nerve sheath tumor, rhabdomyosarcoma, or Langerhans cell histiocytosis, as highlighted by Agrawal et al.⁴ For these reasons, imaging and biopsy often are necessary for histologic diagnosis.

There is no consensus on the etiology of SGA, and no specific disease associations have been proven. Some case reports and case series have proposed a link between SGA and type 1 diabetes mellitus.^1,4 In one retrospective case series, Grogg and Nascimento¹ found that 2 of 34 (5.9%) pediatric patients with SGA had known or subsequently diagnosed diabetes mellitus; however, a definitive association between the 2 entities has not been elucidated. Underlying type 1 diabetes mellitus should be considered in patients with isolated SGA, but laboratory screening for diabetes is not necessary in patients with a negative review of systems.

Treatment of SGA typically is not required, as it is a self-limited condition. Often, once a histologic diagnosis is established, no further evaluation or treatment is warranted. Multiple treatment modalities have been reported, including intralesional and topical corticosteroids, laser therapy, cryotherapy, and systemic agents such as isotretinoin or corticosteroids; however, no treatment has been shown to be consistently efficacious.⁵ Excision of the lesions may be performed, but the risk for recurrence often precludes it as a viable option. In some case series, there have been recurrence rates as high as 40% to 75% in the months to years following surgical excision/biopsy.^1,6

Patients presenting with presumed SGA should undergo a thorough history, review of systems, and full-body skin examination. In some cases, imaging and biopsy may be necessary to make a definitive diagnosis and exclude a more serious condition.

More than 1,625 pediatricians have applied to take the first pediatric hospitalist certification exam in November 2019, and approximately 93% of them have been accepted, according to a statement from the American Board of Pediatrics.

It was the rejection of the 7%, however, that set off a firestorm on the electronic discussion board for American Academy of Pediatrics (AAP) hospital medicine this summer, and led to a petition to the board to revise its eligibility requirements, ensure that the requirements are fair to women, and bring transparency to its decision process. The petition has more than 1,400 signatures.

Seattle Children’s Hospital and Yale New Haven (Conn.) Children’s Hospital have both said they will not consider board certification in hiring decisions until the situation is resolved.

The American Board of Pediatrics (ABP) declined an interview request pending its formal response to the Aug. 6 petition, but in a statement to this news organization, executive vice president Suzanne Woods, MD, said, “The percentage of women and men meeting the eligibility requirements for the exam did not differ. We stress this point because a concern about possible gender bias appears to have been the principal reason for this ... petition, and we wanted to offer immediate reassurance that no unintended bias has occurred.”

“We are carefully considering the requests and will release detailed data to hospitalists on the AAP’s [pediatric hospital medicine (PHM) electronic discussion board] ... and on the ABP’s website. We are conferring with ABP PHM subboard members as well as leaders from our volunteer community. We expect to provide a thoughtful response within the next 3 weeks,” Dr. Woods said in the Aug. 15 statement.
 

“Case-by-case” exceptions

The backstory is that, for better or worse depending on who you talk to, pediatric hospital medicine is becoming a board certified subspecialty. A fellowship will be required to sit for the exam after a few years, which is standard for subspecialties.

What’s generated concern is how the board is grandfathering current pediatric hospitalists into certification via a “practice pathway” until the fellowship requirement takes hold after 2023.

To qualify for the November test, hospitalists had to complete 4 years of full-time practice by June 30, 2019, which has been understood to mean 48 months of continual employment. At least 50% of that time had to be devoted to “professional activities ... related to the care of hospitalized children,” and at least 25% of that “devoted to direct patient care.” Assuming about 2,000 work hours per year, it translated to “450-500 hours” of direct patient care “per year over the most recent four years” to sit for the test, the board said.

“For individuals who have interrupted practice during the most recent four years for family leave or other such circumstances, an exception may be considered if there is substantial prior experience in pediatric hospital medicine. ... Such exceptions are made at the discretion of the ABP and will be considered on a case-by-case basis.” Specific criteria for exceptions were not spelled out.

In the end, there were more than a few surprises when denial letters went out in recent months, and scores of appeals have been filed. There’s “a lot of tension and a lot of confusion” about why some people with practice gaps during the 4 years were approved, but others were denied. There’s been “a lack of transparency on the ABP’s part,” said H. Barrett Fromme, MD, section chief of pediatric hospital medicine and a professor of pediatrics at the University of Chicago.
 

“The standard has to be reasonable”

There are concerns about the availability of fellowship slots and other issues, but the 4-year rule – instead of averaging clinical hours over 4 or 5 years, for instance – is the main sticking point. It’s a gender issue because “women take maternity; women move with their spouse; women take care of elders; women tend to be in these roles that require time off” more than men do, Dr. Fromme said.

Until the board releases its data, the gender breakdown of the denials and the degree to which practice gaps due to such issues led to them is unknown. There’s concern that women have been unfairly penalized.

The storm was set off on the discussion board this summer by stories from physicians such as Chandani DeZure, MD, a pediatric hospitalist currently working in the neonatal ICU at Stanford (Calif.) University. She was denied a seat at the table in November, appealed, and was denied again.

She was a full-time pediatric hospitalist at Children’s National Medical Center in Washington, from 2014, when she graduated residency, until Oct. 2018, when her husband, also a doctor, was offered a promising research position in California, and “we decided to take it,” Dr. DeZure said.

They moved to California with their young son in November. Dr. DeZure got her California medical license in 6 weeks, was hired by Stanford in January, and started her new postion in mid-April.

Because of the move, she worked only 3.5 years in the board’s 4 year practice window, but, as is common with young physicians, that time was spent in direct patient care, for a total of over 6,000 hours.

“How is that not good enough? How is a person that worked 500 hours with patients for 4 years” – for a total of 2,000 hours – “better qualified than someone who worked 100% for 3 and a half years? Nobody is saying there shouldn’t be a standard, but the standard has to be reasonable,” Dr. DeZure said.
 

“Illegal regardless of intent”

It’s situations like Dr. DeZure’s that led to the petition. One of demands is that ABP “revise the practice pathway criteria to be more inclusive of applicants with interrupted practice and varied clinical experience, to include clear-cut parameters rather than considering these applications on a closed-door ‘case-by-case basis...at the discretion of the ABP.’ ” Also, the petition asks the board to “clarify the appeals process and improve responsiveness to appeals and inquiries regarding denials.”

As ABP noted in its statement, however, the major demand is that the board “facilitate a timely analysis to determine if gender bias is present.” The petition noted that signers “do not suspect intentional bias on the part of the ABP; however, if gender bias is present it is unethical and potentially illegal regardless of intent.”

For now, the perception is that the board has “a hard 48-month rule” with not many exceptions; there are people who are “very concerned that, ‘Oh my gosh, I can’t have children for 4 years because I won’t be able to sit for the boards.’ No one should ever have to have that in their head,” Dr. Fromme said. At this point, it seems that 3 months off for maternity is being grandfathered in, but perhaps not 6 months for a second child; no one knows for sure.

Dr. DeZure, meanwhile, continues to study for the board exam, just in case.

Looking back over the past year, she said “I could have somehow picked up one shift a week moonlighting that would have kept me eligible, but the [board] didn’t respond to me” when contacted about her situation during the California move.

“The other option was for me was to live cross country from my husband with a small child,” she said.

[email protected]

More than 1,625 pediatricians have applied to take the first pediatric hospitalist certification exam in November 2019, and approximately 93% of them have been accepted, according to a statement from the American Board of Pediatrics.

It was the rejection of the 7%, however, that set off a firestorm on the electronic discussion board for American Academy of Pediatrics (AAP) hospital medicine this summer, and led to a petition to the board to revise its eligibility requirements, ensure that the requirements are fair to women, and bring transparency to its decision process. The petition has more than 1,400 signatures.

Seattle Children’s Hospital and Yale New Haven (Conn.) Children’s Hospital have both said they will not consider board certification in hiring decisions until the situation is resolved.

The American Board of Pediatrics (ABP) declined an interview request pending its formal response to the Aug. 6 petition, but in a statement to this news organization, executive vice president Suzanne Woods, MD, said, “The percentage of women and men meeting the eligibility requirements for the exam did not differ. We stress this point because a concern about possible gender bias appears to have been the principal reason for this ... petition, and we wanted to offer immediate reassurance that no unintended bias has occurred.”

“We are carefully considering the requests and will release detailed data to hospitalists on the AAP’s [pediatric hospital medicine (PHM) electronic discussion board] ... and on the ABP’s website. We are conferring with ABP PHM subboard members as well as leaders from our volunteer community. We expect to provide a thoughtful response within the next 3 weeks,” Dr. Woods said in the Aug. 15 statement.
 

“Case-by-case” exceptions

The backstory is that, for better or worse depending on who you talk to, pediatric hospital medicine is becoming a board certified subspecialty. A fellowship will be required to sit for the exam after a few years, which is standard for subspecialties.

What’s generated concern is how the board is grandfathering current pediatric hospitalists into certification via a “practice pathway” until the fellowship requirement takes hold after 2023.

To qualify for the November test, hospitalists had to complete 4 years of full-time practice by June 30, 2019, which has been understood to mean 48 months of continual employment. At least 50% of that time had to be devoted to “professional activities ... related to the care of hospitalized children,” and at least 25% of that “devoted to direct patient care.” Assuming about 2,000 work hours per year, it translated to “450-500 hours” of direct patient care “per year over the most recent four years” to sit for the test, the board said.

“For individuals who have interrupted practice during the most recent four years for family leave or other such circumstances, an exception may be considered if there is substantial prior experience in pediatric hospital medicine. ... Such exceptions are made at the discretion of the ABP and will be considered on a case-by-case basis.” Specific criteria for exceptions were not spelled out.

In the end, there were more than a few surprises when denial letters went out in recent months, and scores of appeals have been filed. There’s “a lot of tension and a lot of confusion” about why some people with practice gaps during the 4 years were approved, but others were denied. There’s been “a lack of transparency on the ABP’s part,” said H. Barrett Fromme, MD, section chief of pediatric hospital medicine and a professor of pediatrics at the University of Chicago.
 

“The standard has to be reasonable”

There are concerns about the availability of fellowship slots and other issues, but the 4-year rule – instead of averaging clinical hours over 4 or 5 years, for instance – is the main sticking point. It’s a gender issue because “women take maternity; women move with their spouse; women take care of elders; women tend to be in these roles that require time off” more than men do, Dr. Fromme said.

Until the board releases its data, the gender breakdown of the denials and the degree to which practice gaps due to such issues led to them is unknown. There’s concern that women have been unfairly penalized.

The storm was set off on the discussion board this summer by stories from physicians such as Chandani DeZure, MD, a pediatric hospitalist currently working in the neonatal ICU at Stanford (Calif.) University. She was denied a seat at the table in November, appealed, and was denied again.

She was a full-time pediatric hospitalist at Children’s National Medical Center in Washington, from 2014, when she graduated residency, until Oct. 2018, when her husband, also a doctor, was offered a promising research position in California, and “we decided to take it,” Dr. DeZure said.

They moved to California with their young son in November. Dr. DeZure got her California medical license in 6 weeks, was hired by Stanford in January, and started her new postion in mid-April.

Because of the move, she worked only 3.5 years in the board’s 4 year practice window, but, as is common with young physicians, that time was spent in direct patient care, for a total of over 6,000 hours.

“How is that not good enough? How is a person that worked 500 hours with patients for 4 years” – for a total of 2,000 hours – “better qualified than someone who worked 100% for 3 and a half years? Nobody is saying there shouldn’t be a standard, but the standard has to be reasonable,” Dr. DeZure said.
 

“Illegal regardless of intent”

It’s situations like Dr. DeZure’s that led to the petition. One of demands is that ABP “revise the practice pathway criteria to be more inclusive of applicants with interrupted practice and varied clinical experience, to include clear-cut parameters rather than considering these applications on a closed-door ‘case-by-case basis...at the discretion of the ABP.’ ” Also, the petition asks the board to “clarify the appeals process and improve responsiveness to appeals and inquiries regarding denials.”

As ABP noted in its statement, however, the major demand is that the board “facilitate a timely analysis to determine if gender bias is present.” The petition noted that signers “do not suspect intentional bias on the part of the ABP; however, if gender bias is present it is unethical and potentially illegal regardless of intent.”

For now, the perception is that the board has “a hard 48-month rule” with not many exceptions; there are people who are “very concerned that, ‘Oh my gosh, I can’t have children for 4 years because I won’t be able to sit for the boards.’ No one should ever have to have that in their head,” Dr. Fromme said. At this point, it seems that 3 months off for maternity is being grandfathered in, but perhaps not 6 months for a second child; no one knows for sure.

Dr. DeZure, meanwhile, continues to study for the board exam, just in case.

Looking back over the past year, she said “I could have somehow picked up one shift a week moonlighting that would have kept me eligible, but the [board] didn’t respond to me” when contacted about her situation during the California move.

“The other option was for me was to live cross country from my husband with a small child,” she said.

[email protected]

More than 1,625 pediatricians have applied to take the first pediatric hospitalist certification exam in November 2019, and approximately 93% of them have been accepted, according to a statement from the American Board of Pediatrics.

It was the rejection of the 7%, however, that set off a firestorm on the electronic discussion board for American Academy of Pediatrics (AAP) hospital medicine this summer, and led to a petition to the board to revise its eligibility requirements, ensure that the requirements are fair to women, and bring transparency to its decision process. The petition has more than 1,400 signatures.

Seattle Children’s Hospital and Yale New Haven (Conn.) Children’s Hospital have both said they will not consider board certification in hiring decisions until the situation is resolved.

The American Board of Pediatrics (ABP) declined an interview request pending its formal response to the Aug. 6 petition, but in a statement to this news organization, executive vice president Suzanne Woods, MD, said, “The percentage of women and men meeting the eligibility requirements for the exam did not differ. We stress this point because a concern about possible gender bias appears to have been the principal reason for this ... petition, and we wanted to offer immediate reassurance that no unintended bias has occurred.”

“We are carefully considering the requests and will release detailed data to hospitalists on the AAP’s [pediatric hospital medicine (PHM) electronic discussion board] ... and on the ABP’s website. We are conferring with ABP PHM subboard members as well as leaders from our volunteer community. We expect to provide a thoughtful response within the next 3 weeks,” Dr. Woods said in the Aug. 15 statement.
 

“Case-by-case” exceptions

The backstory is that, for better or worse depending on who you talk to, pediatric hospital medicine is becoming a board certified subspecialty. A fellowship will be required to sit for the exam after a few years, which is standard for subspecialties.

What’s generated concern is how the board is grandfathering current pediatric hospitalists into certification via a “practice pathway” until the fellowship requirement takes hold after 2023.

To qualify for the November test, hospitalists had to complete 4 years of full-time practice by June 30, 2019, which has been understood to mean 48 months of continual employment. At least 50% of that time had to be devoted to “professional activities ... related to the care of hospitalized children,” and at least 25% of that “devoted to direct patient care.” Assuming about 2,000 work hours per year, it translated to “450-500 hours” of direct patient care “per year over the most recent four years” to sit for the test, the board said.

“For individuals who have interrupted practice during the most recent four years for family leave or other such circumstances, an exception may be considered if there is substantial prior experience in pediatric hospital medicine. ... Such exceptions are made at the discretion of the ABP and will be considered on a case-by-case basis.” Specific criteria for exceptions were not spelled out.

In the end, there were more than a few surprises when denial letters went out in recent months, and scores of appeals have been filed. There’s “a lot of tension and a lot of confusion” about why some people with practice gaps during the 4 years were approved, but others were denied. There’s been “a lack of transparency on the ABP’s part,” said H. Barrett Fromme, MD, section chief of pediatric hospital medicine and a professor of pediatrics at the University of Chicago.
 

“The standard has to be reasonable”

There are concerns about the availability of fellowship slots and other issues, but the 4-year rule – instead of averaging clinical hours over 4 or 5 years, for instance – is the main sticking point. It’s a gender issue because “women take maternity; women move with their spouse; women take care of elders; women tend to be in these roles that require time off” more than men do, Dr. Fromme said.

Until the board releases its data, the gender breakdown of the denials and the degree to which practice gaps due to such issues led to them is unknown. There’s concern that women have been unfairly penalized.

The storm was set off on the discussion board this summer by stories from physicians such as Chandani DeZure, MD, a pediatric hospitalist currently working in the neonatal ICU at Stanford (Calif.) University. She was denied a seat at the table in November, appealed, and was denied again.

She was a full-time pediatric hospitalist at Children’s National Medical Center in Washington, from 2014, when she graduated residency, until Oct. 2018, when her husband, also a doctor, was offered a promising research position in California, and “we decided to take it,” Dr. DeZure said.

They moved to California with their young son in November. Dr. DeZure got her California medical license in 6 weeks, was hired by Stanford in January, and started her new postion in mid-April.

Because of the move, she worked only 3.5 years in the board’s 4 year practice window, but, as is common with young physicians, that time was spent in direct patient care, for a total of over 6,000 hours.

“How is that not good enough? How is a person that worked 500 hours with patients for 4 years” – for a total of 2,000 hours – “better qualified than someone who worked 100% for 3 and a half years? Nobody is saying there shouldn’t be a standard, but the standard has to be reasonable,” Dr. DeZure said.
 

“Illegal regardless of intent”

It’s situations like Dr. DeZure’s that led to the petition. One of demands is that ABP “revise the practice pathway criteria to be more inclusive of applicants with interrupted practice and varied clinical experience, to include clear-cut parameters rather than considering these applications on a closed-door ‘case-by-case basis...at the discretion of the ABP.’ ” Also, the petition asks the board to “clarify the appeals process and improve responsiveness to appeals and inquiries regarding denials.”

As ABP noted in its statement, however, the major demand is that the board “facilitate a timely analysis to determine if gender bias is present.” The petition noted that signers “do not suspect intentional bias on the part of the ABP; however, if gender bias is present it is unethical and potentially illegal regardless of intent.”

For now, the perception is that the board has “a hard 48-month rule” with not many exceptions; there are people who are “very concerned that, ‘Oh my gosh, I can’t have children for 4 years because I won’t be able to sit for the boards.’ No one should ever have to have that in their head,” Dr. Fromme said. At this point, it seems that 3 months off for maternity is being grandfathered in, but perhaps not 6 months for a second child; no one knows for sure.

Dr. DeZure, meanwhile, continues to study for the board exam, just in case.

Looking back over the past year, she said “I could have somehow picked up one shift a week moonlighting that would have kept me eligible, but the [board] didn’t respond to me” when contacted about her situation during the California move.

“The other option was for me was to live cross country from my husband with a small child,” she said.

[email protected]

BANGKOK – A prediction tool that determines the risk of a pediatric epilepsy diagnosis eventually being made in a child who has had one or more paroxysmal events of possible epileptic origin is now available, and the clarity it provides makes life considerably easier for physicians and worried parents, Kees P. Braun, MD, PhD, said at the International Epilepsy Congress.

Bruce Jancin/MDedge News

This prediction tool is highly practical. It relies upon certain clinical characteristics and a first interictal EEG, all information readily available at the time of the family’s first consultation with a neurologist or pediatrician with access to EEG, noted Dr. Braun, professor of neurology at Utrecht (the Netherlands) University.

The tool is freely available online (http://epilepsypredictiontools.info/first-consultation). The details of how Dr. Braun and coinvestigators developed the prediction tool have been published (Pediatrics. 2018 Dec;142[6]:e20180931. doi: 10.1542/peds.2018-0931), he said at the congress sponsored by the International League Against Epilepsy.

Early and accurate diagnosis or exclusion of epilepsy following a suspicious paroxysmal event deserves to be a high priority. Diagnostic delay is common, with resultant unrecognized recurrent epileptic seizures that can cause cognitive and behavioral impairments. And overdiagnosis of pediatric epilepsy unnecessarily exposes a child to the risks of antiepileptic drug therapy, not to mention the potential social stigma.

The predictive tool was developed through retrospective, multidimensional analysis of detailed data on 451 children who visited the outpatient pediatric neurology clinic at University Medical Center Utrecht for a diagnostic work-up after one or more paroxysmal events that might have been seizures, all of whom were subsequently followed for a year or longer. The resultant predictive model was then independently validated in a separate cohort of 187 children seen for the same reason at another Dutch university.

The model had an area under the receiver operating characteristic curve of 0.86, which statisticians consider to be excellent discriminatory power. The tool’s sensitivity and specificity varied according to the diagnostic probability threshold selected by the parents and physicians. For example, the predictive tool had a sensitivity of 18%, specificity of 99%, positive predictive value of 94%, and negative predictive value of 80% for identification of individuals with a greater than 80% probability of being diagnosed with epilepsy. For identification of all patients with a greater than 20% likelihood of receiving the diagnosis, the sensitivity was 73%, specificity 82%, positive predictive value 76%, and negative predictive value 79%.

The clinical characteristics incorporated in the predictive model include age at first seizure, gender, details of the paroxysmal event, and specifics of the child’s medical history. The relevant features of the standard interictal EEG recorded at the time of consultation include the presence or absence of focal epileptiform abnormalities if focal spikes or spike-wave complexes were detected, generalized epileptiform abnormalities in the presence of generalized spikes or spike-wave complexes, and nonspecific nonepileptiform abnormalities.
 

Future predictive refinements are under study

Dr. Braun and coworkers have reported that examining EEG functional network characteristics – that is, the functional networks of correlated brain activity in an individual patient’s brain – improves the EEG’s predictive value for epilepsy (PLoS One. 2013;8[4]:e59764. doi: 10.1371/journal.pone.0059764), a conclusion further reinforced in their systematic review and meta-analysis incorporating 11 additional studies (PLoS One. 2014 Dec 10;9[12]:e114606. doi: 10.1371/journal.pone.0114606).

In addition, the Dutch investigators have shown that ripples superimposed on rolandic spikes seen in scalp EEG recordings have prognostic significance. An absence of ripples superimposed on rolandic spikes identified children without epilepsy. In contrast, more than five ripples predicted atypical and symptomatic rolandic epilepsy with a substantial seizure risk warranting consideration of antiepileptic drug therapy (Epilepsia. 2016 Jul;57[7]:1179-89).

A Boston group using a fully automated spike ripple detector subsequently confirmed that ripples occurring in conjunction with epileptiform discharges on scalp EEG constitute a noninvasive biomarker for seizure risk that outperforms analysis of spikes alone and could potentially be useful in guiding medication tapering decisions in children (Brain. 2019 May 1;142[5]:1296-1309).

Dr. Braun reported having no financial conflicts regarding his presentation.

[email protected]

BANGKOK – A prediction tool that determines the risk of a pediatric epilepsy diagnosis eventually being made in a child who has had one or more paroxysmal events of possible epileptic origin is now available, and the clarity it provides makes life considerably easier for physicians and worried parents, Kees P. Braun, MD, PhD, said at the International Epilepsy Congress.

Bruce Jancin/MDedge News

This prediction tool is highly practical. It relies upon certain clinical characteristics and a first interictal EEG, all information readily available at the time of the family’s first consultation with a neurologist or pediatrician with access to EEG, noted Dr. Braun, professor of neurology at Utrecht (the Netherlands) University.

The tool is freely available online (http://epilepsypredictiontools.info/first-consultation). The details of how Dr. Braun and coinvestigators developed the prediction tool have been published (Pediatrics. 2018 Dec;142[6]:e20180931. doi: 10.1542/peds.2018-0931), he said at the congress sponsored by the International League Against Epilepsy.

Early and accurate diagnosis or exclusion of epilepsy following a suspicious paroxysmal event deserves to be a high priority. Diagnostic delay is common, with resultant unrecognized recurrent epileptic seizures that can cause cognitive and behavioral impairments. And overdiagnosis of pediatric epilepsy unnecessarily exposes a child to the risks of antiepileptic drug therapy, not to mention the potential social stigma.

The predictive tool was developed through retrospective, multidimensional analysis of detailed data on 451 children who visited the outpatient pediatric neurology clinic at University Medical Center Utrecht for a diagnostic work-up after one or more paroxysmal events that might have been seizures, all of whom were subsequently followed for a year or longer. The resultant predictive model was then independently validated in a separate cohort of 187 children seen for the same reason at another Dutch university.

The model had an area under the receiver operating characteristic curve of 0.86, which statisticians consider to be excellent discriminatory power. The tool’s sensitivity and specificity varied according to the diagnostic probability threshold selected by the parents and physicians. For example, the predictive tool had a sensitivity of 18%, specificity of 99%, positive predictive value of 94%, and negative predictive value of 80% for identification of individuals with a greater than 80% probability of being diagnosed with epilepsy. For identification of all patients with a greater than 20% likelihood of receiving the diagnosis, the sensitivity was 73%, specificity 82%, positive predictive value 76%, and negative predictive value 79%.

The clinical characteristics incorporated in the predictive model include age at first seizure, gender, details of the paroxysmal event, and specifics of the child’s medical history. The relevant features of the standard interictal EEG recorded at the time of consultation include the presence or absence of focal epileptiform abnormalities if focal spikes or spike-wave complexes were detected, generalized epileptiform abnormalities in the presence of generalized spikes or spike-wave complexes, and nonspecific nonepileptiform abnormalities.
 

Future predictive refinements are under study

Dr. Braun and coworkers have reported that examining EEG functional network characteristics – that is, the functional networks of correlated brain activity in an individual patient’s brain – improves the EEG’s predictive value for epilepsy (PLoS One. 2013;8[4]:e59764. doi: 10.1371/journal.pone.0059764), a conclusion further reinforced in their systematic review and meta-analysis incorporating 11 additional studies (PLoS One. 2014 Dec 10;9[12]:e114606. doi: 10.1371/journal.pone.0114606).

In addition, the Dutch investigators have shown that ripples superimposed on rolandic spikes seen in scalp EEG recordings have prognostic significance. An absence of ripples superimposed on rolandic spikes identified children without epilepsy. In contrast, more than five ripples predicted atypical and symptomatic rolandic epilepsy with a substantial seizure risk warranting consideration of antiepileptic drug therapy (Epilepsia. 2016 Jul;57[7]:1179-89).

A Boston group using a fully automated spike ripple detector subsequently confirmed that ripples occurring in conjunction with epileptiform discharges on scalp EEG constitute a noninvasive biomarker for seizure risk that outperforms analysis of spikes alone and could potentially be useful in guiding medication tapering decisions in children (Brain. 2019 May 1;142[5]:1296-1309).

Dr. Braun reported having no financial conflicts regarding his presentation.

[email protected]

BANGKOK – A prediction tool that determines the risk of a pediatric epilepsy diagnosis eventually being made in a child who has had one or more paroxysmal events of possible epileptic origin is now available, and the clarity it provides makes life considerably easier for physicians and worried parents, Kees P. Braun, MD, PhD, said at the International Epilepsy Congress.

Bruce Jancin/MDedge News

This prediction tool is highly practical. It relies upon certain clinical characteristics and a first interictal EEG, all information readily available at the time of the family’s first consultation with a neurologist or pediatrician with access to EEG, noted Dr. Braun, professor of neurology at Utrecht (the Netherlands) University.

The tool is freely available online (http://epilepsypredictiontools.info/first-consultation). The details of how Dr. Braun and coinvestigators developed the prediction tool have been published (Pediatrics. 2018 Dec;142[6]:e20180931. doi: 10.1542/peds.2018-0931), he said at the congress sponsored by the International League Against Epilepsy.

Early and accurate diagnosis or exclusion of epilepsy following a suspicious paroxysmal event deserves to be a high priority. Diagnostic delay is common, with resultant unrecognized recurrent epileptic seizures that can cause cognitive and behavioral impairments. And overdiagnosis of pediatric epilepsy unnecessarily exposes a child to the risks of antiepileptic drug therapy, not to mention the potential social stigma.

The predictive tool was developed through retrospective, multidimensional analysis of detailed data on 451 children who visited the outpatient pediatric neurology clinic at University Medical Center Utrecht for a diagnostic work-up after one or more paroxysmal events that might have been seizures, all of whom were subsequently followed for a year or longer. The resultant predictive model was then independently validated in a separate cohort of 187 children seen for the same reason at another Dutch university.

The model had an area under the receiver operating characteristic curve of 0.86, which statisticians consider to be excellent discriminatory power. The tool’s sensitivity and specificity varied according to the diagnostic probability threshold selected by the parents and physicians. For example, the predictive tool had a sensitivity of 18%, specificity of 99%, positive predictive value of 94%, and negative predictive value of 80% for identification of individuals with a greater than 80% probability of being diagnosed with epilepsy. For identification of all patients with a greater than 20% likelihood of receiving the diagnosis, the sensitivity was 73%, specificity 82%, positive predictive value 76%, and negative predictive value 79%.

The clinical characteristics incorporated in the predictive model include age at first seizure, gender, details of the paroxysmal event, and specifics of the child’s medical history. The relevant features of the standard interictal EEG recorded at the time of consultation include the presence or absence of focal epileptiform abnormalities if focal spikes or spike-wave complexes were detected, generalized epileptiform abnormalities in the presence of generalized spikes or spike-wave complexes, and nonspecific nonepileptiform abnormalities.
 

Future predictive refinements are under study

Dr. Braun and coworkers have reported that examining EEG functional network characteristics – that is, the functional networks of correlated brain activity in an individual patient’s brain – improves the EEG’s predictive value for epilepsy (PLoS One. 2013;8[4]:e59764. doi: 10.1371/journal.pone.0059764), a conclusion further reinforced in their systematic review and meta-analysis incorporating 11 additional studies (PLoS One. 2014 Dec 10;9[12]:e114606. doi: 10.1371/journal.pone.0114606).

In addition, the Dutch investigators have shown that ripples superimposed on rolandic spikes seen in scalp EEG recordings have prognostic significance. An absence of ripples superimposed on rolandic spikes identified children without epilepsy. In contrast, more than five ripples predicted atypical and symptomatic rolandic epilepsy with a substantial seizure risk warranting consideration of antiepileptic drug therapy (Epilepsia. 2016 Jul;57[7]:1179-89).

A Boston group using a fully automated spike ripple detector subsequently confirmed that ripples occurring in conjunction with epileptiform discharges on scalp EEG constitute a noninvasive biomarker for seizure risk that outperforms analysis of spikes alone and could potentially be useful in guiding medication tapering decisions in children (Brain. 2019 May 1;142[5]:1296-1309).

Dr. Braun reported having no financial conflicts regarding his presentation.

[email protected]

BANGKOK – Interim results of long-term, open-label extension trials of add-on prescription cannabidiol in patients with Dravet syndrome or Lennox-Gastaut syndrome show sustained, clinically meaningful seizure reductions with no new safety concerns, Anup D. Patel, MD, reported at the International Epilepsy Congress.

“Overall, this is a very promising and sustainable result that we were happy to see,” said Dr. Patel, chief of child neurology at Nationwide Children’s Hospital in Columbus, Ohio.

Epidiolex is the brand name for the plant-derived, highly purified cannabidiol (CBD) in an oil-based oral solution at 100 mg/mL. Dr. Patel has been involved in the medication’s development program since the earliest open-label compassionate use study, which was followed by rigorous phase 3, double-blind, placebo-controlled randomized trials, eventually leading to Food and Drug Administration marketing approval for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in patients 2 years of age or older.

“On June 25th, 2018, history was made: for the first time in United States history, a plant-based derivative of marijuana was approved for use as a medication, and it was also the first FDA-approved treatment for Dravet syndrome,” Dr. Patel noted at the congress sponsored by the International League Against Epilepsy.

A total of 96% of the 289 children with Dravet syndrome who completed the 14-week, double-blind, controlled randomized trials enrolled in the open-label, long-term extension study, during which they were on a median of three concurrent antiepileptic drugs along with a mean modal dose of CBD at 22 mg/kg/day. Although the target maintenance dose of CBD was 20 mg/kg/day, as advised in the product labeling, physicians could reduce or increase the dose up to 30 mg/kg/day.

“In the initial compassionate-use study, our site could go up to 50 mg/kg/day,” according to Dr. Patel. “We have plenty of data showing efficacy and continued safety beyond the FDA-recommended dose.”

In the open-label extension study, the median reduction from baseline in monthly seizure frequency assessed in 12-week intervals up to a maximum of week 72 was 44%-57% for convulsive seizures and 49%-67% for total seizures. More than 80% of patients and/or caregivers reported improvement in the patient’s overall condition as assessed on the Subject/Caregiver Global Impression of Change scale.

The pattern of adverse events associated with CBD has been consistent across all of the studies. The most common side effects are diarrhea in about one-third of patients, sleepiness in one-quarter, and decreased appetite in about one-quarter. Seven percent of patients discontinued the long-term extension trial because of adverse events.

Seventy percent of patients remained in the long-term extension study at 1 year.

Twenty-six patients developed liver transaminase levels greater than three times the upper limit of normal, and of note, 23 of the 26 were on concomitant valproic acid. None met criteria for severe drug-induced liver injury, and all recovered either spontaneously or after a reduction in the dose of CBD or valproic acid. But this association between CBD, valproic acid, and increased risk of mild liver injury has been a consistent finding across the clinical trials program.

“This is a very important clinical pearl to take away,” commented Dr. Patel, who is also a pediatric neurologist at Ohio State University.

The interim results of the long-term, open-label extension study of add-on CBD in patients with Lennox-Gastaut syndrome are similar to the Dravet syndrome study. Overall, 99% of the 368 patients with Lennox-Gastaut syndrome who completed the 14-week, double-blind, randomized trials signed up for the open-label extension. During a median follow-up of 61 weeks, the median percent reduction in seizure frequency as assessed in serial 12-week windows was 48%-70% for drop seizures and 48%-63% for total seizures. Twenty-four percent of patients withdrew from the study. Eighty-eight percent of patients or caregivers reported an improvement in overall condition when assessed at weeks 24 and 48. Forty-seven patients developed elevated transaminase levels – typically within the first 2 months on CBD – and 35 of them were on concomitant valproic acid.
 

More on drug-drug interactions

Elsewhere at IEC 2019, Gilmour Morrison of GW Pharmaceuticals, the Cambridge, England, company that markets Epidiolex, presented the findings of a series of drug-drug interaction studies involving coadministration of their CBD with clobazam (Sympazan and Onfi), valproate, stiripentol (Diacomit), or midazolam (Versed) in adult epilepsy patients and healthy volunteers. The researchers reported a bidirectional drug-drug interaction between Epidiolex and clobazam resulting in increased levels of the active metabolites of both drugs. The mechanism is believed to involve inhibition of cytochrome P450 2C19. However, there were no interactions with midazolam or valproate, and the slight bump in stiripentol levels when given with CBD didn’t reach the level of a clinically meaningful drug-drug interaction, according to the investigators.

On the horizon, Canadian researchers are investigating the possibility that since both the tetrahydrocannabinol (THC) and CBD components of marijuana have been shown to have anticonvulsant effects, adding a bit of THC to CBD will result in even better seizure control than with pure CBD in patients with Dravet syndrome. Investigators at Toronto’s Hospital for Sick Children have conducted a prospective, open-label study of a product containing CBD and THC in a 50:1 ratio as add-on therapy in 20 children with Dravet syndrome. The dose was 2-16 mg/kg/day of CBD and 0.04-0.32 mg/kg/day of THC. The cannabis plant extract used in the study was produced by Tilray, a Canadian pharmaceutical company.

Nineteen of the 20 patients completed the 20-week study. The sole noncompleter died of SUDEP (sudden unexpected death in epilepsy) deemed treatment unrelated. Patients experienced a median 71% reduction in motor seizures, compared with baseline. Sixty-three percent of patients had at least a 50% reduction in seizure frequency. Elevated liver transaminases occurred in patients on concomitant valproic acid, as did platelet abnormalities, which have not been seen in the Epidiolex studies, noted Dr. Patel, who was not involved in the Canadian study (Ann Clin Transl Neurol. 2018 Aug 1;5[9]:1077-88).

Dr. Patel reported serving as a consultant to Greenwich Biosciences, a U.S. offshoot of GW Pharmaceuticals. He receives research grants from that company as well as from the National Institutes of Health and the Pediatric Epilepsy Research Foundation.

[email protected]

BANGKOK – Interim results of long-term, open-label extension trials of add-on prescription cannabidiol in patients with Dravet syndrome or Lennox-Gastaut syndrome show sustained, clinically meaningful seizure reductions with no new safety concerns, Anup D. Patel, MD, reported at the International Epilepsy Congress.

“Overall, this is a very promising and sustainable result that we were happy to see,” said Dr. Patel, chief of child neurology at Nationwide Children’s Hospital in Columbus, Ohio.

Epidiolex is the brand name for the plant-derived, highly purified cannabidiol (CBD) in an oil-based oral solution at 100 mg/mL. Dr. Patel has been involved in the medication’s development program since the earliest open-label compassionate use study, which was followed by rigorous phase 3, double-blind, placebo-controlled randomized trials, eventually leading to Food and Drug Administration marketing approval for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in patients 2 years of age or older.

“On June 25th, 2018, history was made: for the first time in United States history, a plant-based derivative of marijuana was approved for use as a medication, and it was also the first FDA-approved treatment for Dravet syndrome,” Dr. Patel noted at the congress sponsored by the International League Against Epilepsy.

A total of 96% of the 289 children with Dravet syndrome who completed the 14-week, double-blind, controlled randomized trials enrolled in the open-label, long-term extension study, during which they were on a median of three concurrent antiepileptic drugs along with a mean modal dose of CBD at 22 mg/kg/day. Although the target maintenance dose of CBD was 20 mg/kg/day, as advised in the product labeling, physicians could reduce or increase the dose up to 30 mg/kg/day.

“In the initial compassionate-use study, our site could go up to 50 mg/kg/day,” according to Dr. Patel. “We have plenty of data showing efficacy and continued safety beyond the FDA-recommended dose.”

In the open-label extension study, the median reduction from baseline in monthly seizure frequency assessed in 12-week intervals up to a maximum of week 72 was 44%-57% for convulsive seizures and 49%-67% for total seizures. More than 80% of patients and/or caregivers reported improvement in the patient’s overall condition as assessed on the Subject/Caregiver Global Impression of Change scale.

The pattern of adverse events associated with CBD has been consistent across all of the studies. The most common side effects are diarrhea in about one-third of patients, sleepiness in one-quarter, and decreased appetite in about one-quarter. Seven percent of patients discontinued the long-term extension trial because of adverse events.

Seventy percent of patients remained in the long-term extension study at 1 year.

Twenty-six patients developed liver transaminase levels greater than three times the upper limit of normal, and of note, 23 of the 26 were on concomitant valproic acid. None met criteria for severe drug-induced liver injury, and all recovered either spontaneously or after a reduction in the dose of CBD or valproic acid. But this association between CBD, valproic acid, and increased risk of mild liver injury has been a consistent finding across the clinical trials program.

“This is a very important clinical pearl to take away,” commented Dr. Patel, who is also a pediatric neurologist at Ohio State University.

The interim results of the long-term, open-label extension study of add-on CBD in patients with Lennox-Gastaut syndrome are similar to the Dravet syndrome study. Overall, 99% of the 368 patients with Lennox-Gastaut syndrome who completed the 14-week, double-blind, randomized trials signed up for the open-label extension. During a median follow-up of 61 weeks, the median percent reduction in seizure frequency as assessed in serial 12-week windows was 48%-70% for drop seizures and 48%-63% for total seizures. Twenty-four percent of patients withdrew from the study. Eighty-eight percent of patients or caregivers reported an improvement in overall condition when assessed at weeks 24 and 48. Forty-seven patients developed elevated transaminase levels – typically within the first 2 months on CBD – and 35 of them were on concomitant valproic acid.
 

More on drug-drug interactions

Elsewhere at IEC 2019, Gilmour Morrison of GW Pharmaceuticals, the Cambridge, England, company that markets Epidiolex, presented the findings of a series of drug-drug interaction studies involving coadministration of their CBD with clobazam (Sympazan and Onfi), valproate, stiripentol (Diacomit), or midazolam (Versed) in adult epilepsy patients and healthy volunteers. The researchers reported a bidirectional drug-drug interaction between Epidiolex and clobazam resulting in increased levels of the active metabolites of both drugs. The mechanism is believed to involve inhibition of cytochrome P450 2C19. However, there were no interactions with midazolam or valproate, and the slight bump in stiripentol levels when given with CBD didn’t reach the level of a clinically meaningful drug-drug interaction, according to the investigators.

On the horizon, Canadian researchers are investigating the possibility that since both the tetrahydrocannabinol (THC) and CBD components of marijuana have been shown to have anticonvulsant effects, adding a bit of THC to CBD will result in even better seizure control than with pure CBD in patients with Dravet syndrome. Investigators at Toronto’s Hospital for Sick Children have conducted a prospective, open-label study of a product containing CBD and THC in a 50:1 ratio as add-on therapy in 20 children with Dravet syndrome. The dose was 2-16 mg/kg/day of CBD and 0.04-0.32 mg/kg/day of THC. The cannabis plant extract used in the study was produced by Tilray, a Canadian pharmaceutical company.

Nineteen of the 20 patients completed the 20-week study. The sole noncompleter died of SUDEP (sudden unexpected death in epilepsy) deemed treatment unrelated. Patients experienced a median 71% reduction in motor seizures, compared with baseline. Sixty-three percent of patients had at least a 50% reduction in seizure frequency. Elevated liver transaminases occurred in patients on concomitant valproic acid, as did platelet abnormalities, which have not been seen in the Epidiolex studies, noted Dr. Patel, who was not involved in the Canadian study (Ann Clin Transl Neurol. 2018 Aug 1;5[9]:1077-88).

Dr. Patel reported serving as a consultant to Greenwich Biosciences, a U.S. offshoot of GW Pharmaceuticals. He receives research grants from that company as well as from the National Institutes of Health and the Pediatric Epilepsy Research Foundation.

[email protected]

BANGKOK – Interim results of long-term, open-label extension trials of add-on prescription cannabidiol in patients with Dravet syndrome or Lennox-Gastaut syndrome show sustained, clinically meaningful seizure reductions with no new safety concerns, Anup D. Patel, MD, reported at the International Epilepsy Congress.

“Overall, this is a very promising and sustainable result that we were happy to see,” said Dr. Patel, chief of child neurology at Nationwide Children’s Hospital in Columbus, Ohio.

Epidiolex is the brand name for the plant-derived, highly purified cannabidiol (CBD) in an oil-based oral solution at 100 mg/mL. Dr. Patel has been involved in the medication’s development program since the earliest open-label compassionate use study, which was followed by rigorous phase 3, double-blind, placebo-controlled randomized trials, eventually leading to Food and Drug Administration marketing approval for the treatment of Dravet syndrome and Lennox-Gastaut syndrome in patients 2 years of age or older.

“On June 25th, 2018, history was made: for the first time in United States history, a plant-based derivative of marijuana was approved for use as a medication, and it was also the first FDA-approved treatment for Dravet syndrome,” Dr. Patel noted at the congress sponsored by the International League Against Epilepsy.

A total of 96% of the 289 children with Dravet syndrome who completed the 14-week, double-blind, controlled randomized trials enrolled in the open-label, long-term extension study, during which they were on a median of three concurrent antiepileptic drugs along with a mean modal dose of CBD at 22 mg/kg/day. Although the target maintenance dose of CBD was 20 mg/kg/day, as advised in the product labeling, physicians could reduce or increase the dose up to 30 mg/kg/day.

“In the initial compassionate-use study, our site could go up to 50 mg/kg/day,” according to Dr. Patel. “We have plenty of data showing efficacy and continued safety beyond the FDA-recommended dose.”

In the open-label extension study, the median reduction from baseline in monthly seizure frequency assessed in 12-week intervals up to a maximum of week 72 was 44%-57% for convulsive seizures and 49%-67% for total seizures. More than 80% of patients and/or caregivers reported improvement in the patient’s overall condition as assessed on the Subject/Caregiver Global Impression of Change scale.

The pattern of adverse events associated with CBD has been consistent across all of the studies. The most common side effects are diarrhea in about one-third of patients, sleepiness in one-quarter, and decreased appetite in about one-quarter. Seven percent of patients discontinued the long-term extension trial because of adverse events.

Seventy percent of patients remained in the long-term extension study at 1 year.

Twenty-six patients developed liver transaminase levels greater than three times the upper limit of normal, and of note, 23 of the 26 were on concomitant valproic acid. None met criteria for severe drug-induced liver injury, and all recovered either spontaneously or after a reduction in the dose of CBD or valproic acid. But this association between CBD, valproic acid, and increased risk of mild liver injury has been a consistent finding across the clinical trials program.

“This is a very important clinical pearl to take away,” commented Dr. Patel, who is also a pediatric neurologist at Ohio State University.

The interim results of the long-term, open-label extension study of add-on CBD in patients with Lennox-Gastaut syndrome are similar to the Dravet syndrome study. Overall, 99% of the 368 patients with Lennox-Gastaut syndrome who completed the 14-week, double-blind, randomized trials signed up for the open-label extension. During a median follow-up of 61 weeks, the median percent reduction in seizure frequency as assessed in serial 12-week windows was 48%-70% for drop seizures and 48%-63% for total seizures. Twenty-four percent of patients withdrew from the study. Eighty-eight percent of patients or caregivers reported an improvement in overall condition when assessed at weeks 24 and 48. Forty-seven patients developed elevated transaminase levels – typically within the first 2 months on CBD – and 35 of them were on concomitant valproic acid.
 

More on drug-drug interactions

Elsewhere at IEC 2019, Gilmour Morrison of GW Pharmaceuticals, the Cambridge, England, company that markets Epidiolex, presented the findings of a series of drug-drug interaction studies involving coadministration of their CBD with clobazam (Sympazan and Onfi), valproate, stiripentol (Diacomit), or midazolam (Versed) in adult epilepsy patients and healthy volunteers. The researchers reported a bidirectional drug-drug interaction between Epidiolex and clobazam resulting in increased levels of the active metabolites of both drugs. The mechanism is believed to involve inhibition of cytochrome P450 2C19. However, there were no interactions with midazolam or valproate, and the slight bump in stiripentol levels when given with CBD didn’t reach the level of a clinically meaningful drug-drug interaction, according to the investigators.

On the horizon, Canadian researchers are investigating the possibility that since both the tetrahydrocannabinol (THC) and CBD components of marijuana have been shown to have anticonvulsant effects, adding a bit of THC to CBD will result in even better seizure control than with pure CBD in patients with Dravet syndrome. Investigators at Toronto’s Hospital for Sick Children have conducted a prospective, open-label study of a product containing CBD and THC in a 50:1 ratio as add-on therapy in 20 children with Dravet syndrome. The dose was 2-16 mg/kg/day of CBD and 0.04-0.32 mg/kg/day of THC. The cannabis plant extract used in the study was produced by Tilray, a Canadian pharmaceutical company.

Nineteen of the 20 patients completed the 20-week study. The sole noncompleter died of SUDEP (sudden unexpected death in epilepsy) deemed treatment unrelated. Patients experienced a median 71% reduction in motor seizures, compared with baseline. Sixty-three percent of patients had at least a 50% reduction in seizure frequency. Elevated liver transaminases occurred in patients on concomitant valproic acid, as did platelet abnormalities, which have not been seen in the Epidiolex studies, noted Dr. Patel, who was not involved in the Canadian study (Ann Clin Transl Neurol. 2018 Aug 1;5[9]:1077-88).

Dr. Patel reported serving as a consultant to Greenwich Biosciences, a U.S. offshoot of GW Pharmaceuticals. He receives research grants from that company as well as from the National Institutes of Health and the Pediatric Epilepsy Research Foundation.

[email protected]

Slightly more than half of adolescents in the United States have been fully vaccinated against the human papillomavirus, according to a report published in Morbidity and Mortality Weekly Report.

Joseph Abbott/Thinkstock

Researchers analyzed data from 18,700 adolescents aged 13-17 years – 48% of whom were female – in the 2018 National Immunization Survey–Teen to discover that 51% of adolescents were up to date with the human papillomavirus (HPV) vaccine, and 68% had received at least one dose of the vaccine.

There was an increase in HPV vaccination coverage from 2017 to 2018, but this was attributable to a 4.4 percentage point increase in males who were up to date, compared with a 0.6 percentage point increase in females.

“Although HPV vaccina­tion coverage improved, increases among all adolescents were modest compared with increases in previous years and were observed only among males,” wrote Tanja Y. Walker of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention, and coauthors.

The number of adolescents who had at least one dose of the quadrivalent meningococ­cal conjugate (4MenB) vaccine increased by 1.5 percentage points to 86.6%, while among individuals aged 17 years, coverage with two or more doses of 4MenB vaccine increased by 6.5 percentage points to 50.8%. Tdap coverage remained the same at 89% (MMWR 2019;68(33):718-23).

Slightly more than half of adolescents in the United States have been fully vaccinated against the human papillomavirus, according to a report published in Morbidity and Mortality Weekly Report.

Joseph Abbott/Thinkstock

Researchers analyzed data from 18,700 adolescents aged 13-17 years – 48% of whom were female – in the 2018 National Immunization Survey–Teen to discover that 51% of adolescents were up to date with the human papillomavirus (HPV) vaccine, and 68% had received at least one dose of the vaccine.

There was an increase in HPV vaccination coverage from 2017 to 2018, but this was attributable to a 4.4 percentage point increase in males who were up to date, compared with a 0.6 percentage point increase in females.

“Although HPV vaccina­tion coverage improved, increases among all adolescents were modest compared with increases in previous years and were observed only among males,” wrote Tanja Y. Walker of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention, and coauthors.

The number of adolescents who had at least one dose of the quadrivalent meningococ­cal conjugate (4MenB) vaccine increased by 1.5 percentage points to 86.6%, while among individuals aged 17 years, coverage with two or more doses of 4MenB vaccine increased by 6.5 percentage points to 50.8%. Tdap coverage remained the same at 89% (MMWR 2019;68(33):718-23).

Slightly more than half of adolescents in the United States have been fully vaccinated against the human papillomavirus, according to a report published in Morbidity and Mortality Weekly Report.

Joseph Abbott/Thinkstock

Researchers analyzed data from 18,700 adolescents aged 13-17 years – 48% of whom were female – in the 2018 National Immunization Survey–Teen to discover that 51% of adolescents were up to date with the human papillomavirus (HPV) vaccine, and 68% had received at least one dose of the vaccine.

There was an increase in HPV vaccination coverage from 2017 to 2018, but this was attributable to a 4.4 percentage point increase in males who were up to date, compared with a 0.6 percentage point increase in females.

“Although HPV vaccina­tion coverage improved, increases among all adolescents were modest compared with increases in previous years and were observed only among males,” wrote Tanja Y. Walker of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention, and coauthors.

The number of adolescents who had at least one dose of the quadrivalent meningococ­cal conjugate (4MenB) vaccine increased by 1.5 percentage points to 86.6%, while among individuals aged 17 years, coverage with two or more doses of 4MenB vaccine increased by 6.5 percentage points to 50.8%. Tdap coverage remained the same at 89% (MMWR 2019;68(33):718-23).

LJUBLJANA, SLOVENIA – Fever of unknown origin and pneumonia are two clinical features useful in distinguishing between influenza and respiratory syncytial virus infection as the cause of hospitalization in infants and young children, Cihan Papan, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

Dr. Papan, a pediatrician at University Children’s Hospital Mannheim (Germany) and Heidelberg (Germany) University, presented a retrospective single-center study of all 573 children aged under 2 years hospitalized over the course of several seasons for respiratory syncytial virus (RSV) or influenza as confirmed by rapid antigen testing. Even though these are two of the leading causes of hospitalization among young children, there is surprisingly sparse data comparing the two in terms of disease severity and hospital resource utilization, including antibiotic consumption. That information gap provided the basis for this study.

There were 476 children with confirmed RSV, 96 with influenza, and 1 RSV/influenza coinfection. Notably, even though the RSV group had lower temperatures and C-reactive protein levels, they were nevertheless more likely to be treated with antibiotics, by a margin of 29% to 23%.

“These findings open new possibilities for antimicrobial stewardship in these groups of virally infected children,” observed Dr. Papan.

Fever of unknown origin was present in 68.8% of the influenza-positive patients, compared with just 0.2% of the RSV-positive children. In contrast, 50.2% of the RSV group had pneumonia and 49.6% had bronchitis or bronchiolitis, versus just 22.9% and 6.3% of the influenza patients, respectively. A larger proportion of the young children with RSV infection presented in a severely ill–looking condition. Children with RSV infection also were significantly younger.

Dr. Papan reported having no financial conflicts regarding his study.

[email protected]

LJUBLJANA, SLOVENIA – Fever of unknown origin and pneumonia are two clinical features useful in distinguishing between influenza and respiratory syncytial virus infection as the cause of hospitalization in infants and young children, Cihan Papan, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

Dr. Papan, a pediatrician at University Children’s Hospital Mannheim (Germany) and Heidelberg (Germany) University, presented a retrospective single-center study of all 573 children aged under 2 years hospitalized over the course of several seasons for respiratory syncytial virus (RSV) or influenza as confirmed by rapid antigen testing. Even though these are two of the leading causes of hospitalization among young children, there is surprisingly sparse data comparing the two in terms of disease severity and hospital resource utilization, including antibiotic consumption. That information gap provided the basis for this study.

There were 476 children with confirmed RSV, 96 with influenza, and 1 RSV/influenza coinfection. Notably, even though the RSV group had lower temperatures and C-reactive protein levels, they were nevertheless more likely to be treated with antibiotics, by a margin of 29% to 23%.

“These findings open new possibilities for antimicrobial stewardship in these groups of virally infected children,” observed Dr. Papan.

Fever of unknown origin was present in 68.8% of the influenza-positive patients, compared with just 0.2% of the RSV-positive children. In contrast, 50.2% of the RSV group had pneumonia and 49.6% had bronchitis or bronchiolitis, versus just 22.9% and 6.3% of the influenza patients, respectively. A larger proportion of the young children with RSV infection presented in a severely ill–looking condition. Children with RSV infection also were significantly younger.

Dr. Papan reported having no financial conflicts regarding his study.

[email protected]

LJUBLJANA, SLOVENIA – Fever of unknown origin and pneumonia are two clinical features useful in distinguishing between influenza and respiratory syncytial virus infection as the cause of hospitalization in infants and young children, Cihan Papan, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

Dr. Papan, a pediatrician at University Children’s Hospital Mannheim (Germany) and Heidelberg (Germany) University, presented a retrospective single-center study of all 573 children aged under 2 years hospitalized over the course of several seasons for respiratory syncytial virus (RSV) or influenza as confirmed by rapid antigen testing. Even though these are two of the leading causes of hospitalization among young children, there is surprisingly sparse data comparing the two in terms of disease severity and hospital resource utilization, including antibiotic consumption. That information gap provided the basis for this study.

There were 476 children with confirmed RSV, 96 with influenza, and 1 RSV/influenza coinfection. Notably, even though the RSV group had lower temperatures and C-reactive protein levels, they were nevertheless more likely to be treated with antibiotics, by a margin of 29% to 23%.

“These findings open new possibilities for antimicrobial stewardship in these groups of virally infected children,” observed Dr. Papan.

Fever of unknown origin was present in 68.8% of the influenza-positive patients, compared with just 0.2% of the RSV-positive children. In contrast, 50.2% of the RSV group had pneumonia and 49.6% had bronchitis or bronchiolitis, versus just 22.9% and 6.3% of the influenza patients, respectively. A larger proportion of the young children with RSV infection presented in a severely ill–looking condition. Children with RSV infection also were significantly younger.

Dr. Papan reported having no financial conflicts regarding his study.

[email protected]

Clinical question

Does use of corticosteroids or infliximab in addition to intravenous immunoglobulin improve cardiac outcomes in children with Kawasaki disease and enlarged coronary arteries?

Background

Kawasaki disease is a medium-vessel vasculitis primarily of young children. While the underlying cause remains unknown, treatment with intravenous immunoglobulin (IVIG) substantially lowers the risk of coronary artery aneurysms (CAA), the most serious sequelae of Kawasaki disease. Recent studies have suggested that – in cases of high-risk or treatment-resistant Kawasaki disease – using an immunomodulator, such as a corticosteroid or a TNF-alpha blocker, may improve outcomes, though these studies involved relatively small and homogeneous patient populations. It is unknown if these medications could prevent progression of CAA.

Study design

Retrospective multicenter study.

Setting

Two freestanding children’s hospitals and one mother-child hospital.

Synopsis

The study identified 121 children diagnosed with Kawasaki disease with CAA (z score 2.5-10) from 2008 through 2017 treated at the three study hospitals. Children with giant CAA at the time of diagnosis (z score greater than 10) or significant preexisting congenital heart disease were excluded.

All study hospitals had protocols for treatment of Kawasaki disease: Center 1 used IVIG and corticosteroids, Center 2 used IVIG and infliximab, and Center 3 used IVIG alone. Patients at all centers also received aspirin. Center 1 used methylprednisolone IV initially, changing to oral prednisolone after clinical improvement. The researchers reviewed the charts of each patient and classified them as having complete or incomplete Kawasaki disease. They assigned z scores for CAA size based on both initial and follow-up echocardiograms. The primary outcome was change in z score of CAA over the first year.

The population of patients treated at each center was significantly different. Center 1 reported older patients (median age 2.6 vs. 2.0 and 1.1), as well as a higher rate of male patients (83% vs. 77% and 58%). However, there was no difference in baseline z scores between centers. Patients who initially received IVIG and corticosteroids were less likely to require additional therapy because of persistent fever versus those receiving IVIG only, or IVIG and infliximab (0% vs. 21% vs. 14%, P = .03).

Patients receiving IVIG and corticosteroids, or IVIG and infliximab, were less likely to have progression of CAA size, with 23% and 24% having an increase in z score of more than 1 versus 58% of those who received IVIG alone. No group had significant differences in maximum z score, the rate of giant aneurysms, or the rate of regression of CAA.

Bottom line

Using IVIG + corticosteroids or IVIG + infliximab versus IVIG alone for children with Kawasaki disease with coronary artery aneurysms decreases the rate of aneurysm enlargement.

Citation

Dionne A et al. Treatment intensification in patients with Kawasaki disease and coronary aneurysm at diagnosis. Pediatrics. May 2019:e20183341. doi: 10.1542/peds.2018-3341.

Dr. Stubblefield is a pediatric hospitalist at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., and clinical assistant professor of pediatrics at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia.

Clinical question

Does use of corticosteroids or infliximab in addition to intravenous immunoglobulin improve cardiac outcomes in children with Kawasaki disease and enlarged coronary arteries?

Background

Kawasaki disease is a medium-vessel vasculitis primarily of young children. While the underlying cause remains unknown, treatment with intravenous immunoglobulin (IVIG) substantially lowers the risk of coronary artery aneurysms (CAA), the most serious sequelae of Kawasaki disease. Recent studies have suggested that – in cases of high-risk or treatment-resistant Kawasaki disease – using an immunomodulator, such as a corticosteroid or a TNF-alpha blocker, may improve outcomes, though these studies involved relatively small and homogeneous patient populations. It is unknown if these medications could prevent progression of CAA.

Study design

Retrospective multicenter study.

Setting

Two freestanding children’s hospitals and one mother-child hospital.

Synopsis

The study identified 121 children diagnosed with Kawasaki disease with CAA (z score 2.5-10) from 2008 through 2017 treated at the three study hospitals. Children with giant CAA at the time of diagnosis (z score greater than 10) or significant preexisting congenital heart disease were excluded.

All study hospitals had protocols for treatment of Kawasaki disease: Center 1 used IVIG and corticosteroids, Center 2 used IVIG and infliximab, and Center 3 used IVIG alone. Patients at all centers also received aspirin. Center 1 used methylprednisolone IV initially, changing to oral prednisolone after clinical improvement. The researchers reviewed the charts of each patient and classified them as having complete or incomplete Kawasaki disease. They assigned z scores for CAA size based on both initial and follow-up echocardiograms. The primary outcome was change in z score of CAA over the first year.

The population of patients treated at each center was significantly different. Center 1 reported older patients (median age 2.6 vs. 2.0 and 1.1), as well as a higher rate of male patients (83% vs. 77% and 58%). However, there was no difference in baseline z scores between centers. Patients who initially received IVIG and corticosteroids were less likely to require additional therapy because of persistent fever versus those receiving IVIG only, or IVIG and infliximab (0% vs. 21% vs. 14%, P = .03).

Patients receiving IVIG and corticosteroids, or IVIG and infliximab, were less likely to have progression of CAA size, with 23% and 24% having an increase in z score of more than 1 versus 58% of those who received IVIG alone. No group had significant differences in maximum z score, the rate of giant aneurysms, or the rate of regression of CAA.

Bottom line

Using IVIG + corticosteroids or IVIG + infliximab versus IVIG alone for children with Kawasaki disease with coronary artery aneurysms decreases the rate of aneurysm enlargement.

Citation

Dionne A et al. Treatment intensification in patients with Kawasaki disease and coronary aneurysm at diagnosis. Pediatrics. May 2019:e20183341. doi: 10.1542/peds.2018-3341.

Dr. Stubblefield is a pediatric hospitalist at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., and clinical assistant professor of pediatrics at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia.

Clinical question

Does use of corticosteroids or infliximab in addition to intravenous immunoglobulin improve cardiac outcomes in children with Kawasaki disease and enlarged coronary arteries?

Background

Kawasaki disease is a medium-vessel vasculitis primarily of young children. While the underlying cause remains unknown, treatment with intravenous immunoglobulin (IVIG) substantially lowers the risk of coronary artery aneurysms (CAA), the most serious sequelae of Kawasaki disease. Recent studies have suggested that – in cases of high-risk or treatment-resistant Kawasaki disease – using an immunomodulator, such as a corticosteroid or a TNF-alpha blocker, may improve outcomes, though these studies involved relatively small and homogeneous patient populations. It is unknown if these medications could prevent progression of CAA.

Study design

Retrospective multicenter study.

Setting

Two freestanding children’s hospitals and one mother-child hospital.

Synopsis

The study identified 121 children diagnosed with Kawasaki disease with CAA (z score 2.5-10) from 2008 through 2017 treated at the three study hospitals. Children with giant CAA at the time of diagnosis (z score greater than 10) or significant preexisting congenital heart disease were excluded.

All study hospitals had protocols for treatment of Kawasaki disease: Center 1 used IVIG and corticosteroids, Center 2 used IVIG and infliximab, and Center 3 used IVIG alone. Patients at all centers also received aspirin. Center 1 used methylprednisolone IV initially, changing to oral prednisolone after clinical improvement. The researchers reviewed the charts of each patient and classified them as having complete or incomplete Kawasaki disease. They assigned z scores for CAA size based on both initial and follow-up echocardiograms. The primary outcome was change in z score of CAA over the first year.

The population of patients treated at each center was significantly different. Center 1 reported older patients (median age 2.6 vs. 2.0 and 1.1), as well as a higher rate of male patients (83% vs. 77% and 58%). However, there was no difference in baseline z scores between centers. Patients who initially received IVIG and corticosteroids were less likely to require additional therapy because of persistent fever versus those receiving IVIG only, or IVIG and infliximab (0% vs. 21% vs. 14%, P = .03).

Patients receiving IVIG and corticosteroids, or IVIG and infliximab, were less likely to have progression of CAA size, with 23% and 24% having an increase in z score of more than 1 versus 58% of those who received IVIG alone. No group had significant differences in maximum z score, the rate of giant aneurysms, or the rate of regression of CAA.

Bottom line

Using IVIG + corticosteroids or IVIG + infliximab versus IVIG alone for children with Kawasaki disease with coronary artery aneurysms decreases the rate of aneurysm enlargement.

Citation

Dionne A et al. Treatment intensification in patients with Kawasaki disease and coronary aneurysm at diagnosis. Pediatrics. May 2019:e20183341. doi: 10.1542/peds.2018-3341.

Dr. Stubblefield is a pediatric hospitalist at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., and clinical assistant professor of pediatrics at Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia.

LJUBLJANA, SLOVENIA – The 4CMenB vaccine didn’t affect carriage of disease-causing genogroups of Neisseria meningitidis in adolescents in the landmark Australian cluster-randomized trial of herd immunity known as the “B Part of It” study, Helen S. Marshall, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

This was the largest-ever randomized trial of adolescents vaccinated against meningococcal disease, and the message, albeit somewhat disappointing, is clear: “MenB [Meningococcal serogroup B] vaccine programs should be designed to provide direct protection for those at highest risk of disease,” declared Dr. Marshall, professor of vaccinology and deputy director of the Robinson Research Institute at the University of Adelaide.

In other words, a protein antigen–based MenB vaccine doesn’t provide indirect protection to unvaccinated adolescents through herd immunity. Youths in the age groups at highest risk of disease – infants and adolescents – need to routinely receive the vaccine.

The B Part of It study, whose sheer scope and rigor drew the attention of infectious disease clinical trialists the world over, randomized nearly 35,000 students at all high schools in the state of South Australia – whether urban, rural, or remote – to two doses of the 4CMenB vaccine known as Bexsero or to a nonvaccinated control group. This massive trial entailed training more than 250 nurses in the study procedures and involved 3,100 miles of travel to transport oropharyngeal swab samples obtained from students in outlying areas for centralized laboratory analysis using real-time polymerase chain reaction with meningococcal genotyping, culture for N. meningitidis, and whole-genome sequencing. Samples were obtained on day 1 of the study and 12 months later.

The investigators created widespread regional enthusiasm for this project through adept use of social media and other methods. As a result, 99.5% of students randomized to the intervention arm received one dose, while 97% got two doses. A gratifying unintended consequence of the study was that parents who’d never previously vaccinated their children enrolled them in B Part of It, Dr. Marshall noted.

The impetus for B Part of It was that, while the Australian national health insurance program covers a single dose of meningococcal conjugate MenACWY vaccine given at age 12 months and 14-19 years, MenB vaccine isn’t covered because of uncertainties about cost effectiveness and the vaccine’s impact on meningococcal carriage and herd immunity. B Part of It was designed to resolve those uncertainties.

South Australia has the highest rate of invasive meningococcal disease in the country, and more than 80% of cases there are caused by meningococcal serogroup B. Moreover, 75% of group B cases in South Australia involve the nasty hypervirulent New Zealand strain known as CC 41/44.

The primary outcome in B Part of It was the difference in carriage of the major disease-causing serotypes – groups A, B, C, W, X, and Y – between vaccinated and unvaccinated students at the 1-year follow-up mark. The carriage prevalence of all N. meningitidis in the vaccinated students went from 2.8% at baseline to 4.0% at 12 months, and similarly from 2.6% to 4.7% in unvaccinated controls. More importantly, the prevalence of disease-causing genotypes rose from 1.3% at baseline to 2.4% at follow-up in the vaccinated subjects, with a near-identical pattern seen in controls, where the prevalence rose from 1.4% to 2.4%. In an as-treated analysis, the rate of acquisition of carriage of disease-causing genotypes was identical at 2.0% in both study arms.

The 4CMenB vaccine proved reassuringly safe and effective in preventing meningococcal disease in vaccinated teens. With more than 58,000 doses of the vaccine given in the study, no new safety concerns or signals emerged. And the observed number of cases of invasive meningococcal disease in South Australian adolescent vaccine recipients to date has been significantly lower than expected.

Secondary and exploratory outcomes

Independent risk factors associated with N. meningitidis carriage in the study participants at the 1-year mark included smoking cigarettes or hookah, intimate kissing within the last week, and being in grades 11-12, as opposed to grade 10.

The vaccine had no significant impact on the carriage rate of the hypervirulent New Zealand serogroup B strain. Nor was there a vaccine impact on carriage density, as Mark McMillan, MD, reported elsewhere at ESPID 2019. But while the 4CMenB vaccine had minimal impact upon N. meningitidis carriage density, it was associated with a significant 41% increase in the likelihood of cleared carriage of disease-causing strains at 12 months, added Dr. McMillan, Dr. Marshall’s coinvestigator at University of Adelaide.

What’s next

The ongoing B Part of It School Leaver study is assessing carriage prevalence in vaccinated versus unvaccinated high schoolers in their first year after graduating.

In addition, the B Part of It investigators plan to prospectively study the impact of the 4CMen B vaccine on N. gonorrhoeae disease in an effort to confirm the intriguing findings of an earlier large, retrospective New Zealand case-control study. The Kiwis found that recipients of an outer membrane vesicle MenB vaccine had an adjusted 31% reduction in the risk of gonorrhea. This was the first-ever report of any vaccine effectiveness against this major global public health problem, in which antibiotic resistance is a growing concern (Lancet. 2017 Sep 30;390[10102]:1603-10). Dr. Marshall reported receiving research funding from GlaxoSmithKline, which markets Bexsero and was the major financial supporter of the B Part of It study.

But wait a minute...

Following Dr. Marshall’s report on the B Part of It study, outgoing ESPID president Adam Finn, MD, PhD, presented longitudinal data that he believes raise the possibility that protein-antigen vaccines such as Bexsero, which promote naturally acquired mucosal immunity, may impact on transmission population wide without reliably preventing acquisition. This would stand in stark contrast to conjugate meningococcus vaccines, which have a well-established massive impact on carriage and acquisition of N. meningitidis.

Bruce Jancin/MDedge News

It may be that in studying throat carriage rates once in individuals immunized 12 months earlier, as in the B Part of It study, investigators are not asking the right question, proposed Dr. Finn, professor of pediatrics at the University of Bristol (England).

His research team has been obtaining throat swabs at monthly intervals in a population of 917 high schoolers aged 16-17 years. In 416 of the students, they also have collected saliva samples weekly both before and after immunization with 4CMenB vaccine, analyzing the samples for N. meningitidis by polymerase chain reaction. This is a novel method of studying meningococcal carriage they have found to be both reliable and far more acceptable to patients than oropharyngeal swabbing, which adolescents balk at if asked to do with any frequency (PLoS One. 2019 Feb 11;14[2]:e0209905).

Dr. Finn said that their findings, which need confirmation, suggest that N. meningitidis carriage is usually brief and dynamic. They also have found that carriage density varies markedly from month to month.

“We see much higher-density carriage in the adolescent population in the early months of the year in conjunction, we think, with viral infection with influenza and so forth,” he said, adding that this could have clinical implications. “It feels sort of intuitive that someone walking around with 1,000 or 10,000 times as many meningococci in their throat is more likely to be more infectious to people around them with a very small number, although this hasn’t been formally proven.”

He hopes that the Be on the TEAM (Teenagers Against Meningitis) study will help provide answers. The study is randomizing 24,000 U.K. high school students to vaccination with the meningococcal B protein–antigen vaccines Bexsero or Trumenba or to no vaccine in order to learn if there are significant herd immunity effects.

Dr. Finn’s meningococcal carriage research is funded by the Meningitis Research Foundation and the National Institute for Health Research. Dr. Marshall reported receiving research funding from GlaxoSmithKline, the major sponsor of the B Part of It study.

[email protected]

LJUBLJANA, SLOVENIA – The 4CMenB vaccine didn’t affect carriage of disease-causing genogroups of Neisseria meningitidis in adolescents in the landmark Australian cluster-randomized trial of herd immunity known as the “B Part of It” study, Helen S. Marshall, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

This was the largest-ever randomized trial of adolescents vaccinated against meningococcal disease, and the message, albeit somewhat disappointing, is clear: “MenB [Meningococcal serogroup B] vaccine programs should be designed to provide direct protection for those at highest risk of disease,” declared Dr. Marshall, professor of vaccinology and deputy director of the Robinson Research Institute at the University of Adelaide.

In other words, a protein antigen–based MenB vaccine doesn’t provide indirect protection to unvaccinated adolescents through herd immunity. Youths in the age groups at highest risk of disease – infants and adolescents – need to routinely receive the vaccine.

The B Part of It study, whose sheer scope and rigor drew the attention of infectious disease clinical trialists the world over, randomized nearly 35,000 students at all high schools in the state of South Australia – whether urban, rural, or remote – to two doses of the 4CMenB vaccine known as Bexsero or to a nonvaccinated control group. This massive trial entailed training more than 250 nurses in the study procedures and involved 3,100 miles of travel to transport oropharyngeal swab samples obtained from students in outlying areas for centralized laboratory analysis using real-time polymerase chain reaction with meningococcal genotyping, culture for N. meningitidis, and whole-genome sequencing. Samples were obtained on day 1 of the study and 12 months later.

The investigators created widespread regional enthusiasm for this project through adept use of social media and other methods. As a result, 99.5% of students randomized to the intervention arm received one dose, while 97% got two doses. A gratifying unintended consequence of the study was that parents who’d never previously vaccinated their children enrolled them in B Part of It, Dr. Marshall noted.

The impetus for B Part of It was that, while the Australian national health insurance program covers a single dose of meningococcal conjugate MenACWY vaccine given at age 12 months and 14-19 years, MenB vaccine isn’t covered because of uncertainties about cost effectiveness and the vaccine’s impact on meningococcal carriage and herd immunity. B Part of It was designed to resolve those uncertainties.

South Australia has the highest rate of invasive meningococcal disease in the country, and more than 80% of cases there are caused by meningococcal serogroup B. Moreover, 75% of group B cases in South Australia involve the nasty hypervirulent New Zealand strain known as CC 41/44.

The primary outcome in B Part of It was the difference in carriage of the major disease-causing serotypes – groups A, B, C, W, X, and Y – between vaccinated and unvaccinated students at the 1-year follow-up mark. The carriage prevalence of all N. meningitidis in the vaccinated students went from 2.8% at baseline to 4.0% at 12 months, and similarly from 2.6% to 4.7% in unvaccinated controls. More importantly, the prevalence of disease-causing genotypes rose from 1.3% at baseline to 2.4% at follow-up in the vaccinated subjects, with a near-identical pattern seen in controls, where the prevalence rose from 1.4% to 2.4%. In an as-treated analysis, the rate of acquisition of carriage of disease-causing genotypes was identical at 2.0% in both study arms.

The 4CMenB vaccine proved reassuringly safe and effective in preventing meningococcal disease in vaccinated teens. With more than 58,000 doses of the vaccine given in the study, no new safety concerns or signals emerged. And the observed number of cases of invasive meningococcal disease in South Australian adolescent vaccine recipients to date has been significantly lower than expected.

Secondary and exploratory outcomes

Independent risk factors associated with N. meningitidis carriage in the study participants at the 1-year mark included smoking cigarettes or hookah, intimate kissing within the last week, and being in grades 11-12, as opposed to grade 10.

The vaccine had no significant impact on the carriage rate of the hypervirulent New Zealand serogroup B strain. Nor was there a vaccine impact on carriage density, as Mark McMillan, MD, reported elsewhere at ESPID 2019. But while the 4CMenB vaccine had minimal impact upon N. meningitidis carriage density, it was associated with a significant 41% increase in the likelihood of cleared carriage of disease-causing strains at 12 months, added Dr. McMillan, Dr. Marshall’s coinvestigator at University of Adelaide.

What’s next

The ongoing B Part of It School Leaver study is assessing carriage prevalence in vaccinated versus unvaccinated high schoolers in their first year after graduating.

In addition, the B Part of It investigators plan to prospectively study the impact of the 4CMen B vaccine on N. gonorrhoeae disease in an effort to confirm the intriguing findings of an earlier large, retrospective New Zealand case-control study. The Kiwis found that recipients of an outer membrane vesicle MenB vaccine had an adjusted 31% reduction in the risk of gonorrhea. This was the first-ever report of any vaccine effectiveness against this major global public health problem, in which antibiotic resistance is a growing concern (Lancet. 2017 Sep 30;390[10102]:1603-10). Dr. Marshall reported receiving research funding from GlaxoSmithKline, which markets Bexsero and was the major financial supporter of the B Part of It study.

But wait a minute...

Following Dr. Marshall’s report on the B Part of It study, outgoing ESPID president Adam Finn, MD, PhD, presented longitudinal data that he believes raise the possibility that protein-antigen vaccines such as Bexsero, which promote naturally acquired mucosal immunity, may impact on transmission population wide without reliably preventing acquisition. This would stand in stark contrast to conjugate meningococcus vaccines, which have a well-established massive impact on carriage and acquisition of N. meningitidis.

Bruce Jancin/MDedge News

It may be that in studying throat carriage rates once in individuals immunized 12 months earlier, as in the B Part of It study, investigators are not asking the right question, proposed Dr. Finn, professor of pediatrics at the University of Bristol (England).

His research team has been obtaining throat swabs at monthly intervals in a population of 917 high schoolers aged 16-17 years. In 416 of the students, they also have collected saliva samples weekly both before and after immunization with 4CMenB vaccine, analyzing the samples for N. meningitidis by polymerase chain reaction. This is a novel method of studying meningococcal carriage they have found to be both reliable and far more acceptable to patients than oropharyngeal swabbing, which adolescents balk at if asked to do with any frequency (PLoS One. 2019 Feb 11;14[2]:e0209905).

Dr. Finn said that their findings, which need confirmation, suggest that N. meningitidis carriage is usually brief and dynamic. They also have found that carriage density varies markedly from month to month.

“We see much higher-density carriage in the adolescent population in the early months of the year in conjunction, we think, with viral infection with influenza and so forth,” he said, adding that this could have clinical implications. “It feels sort of intuitive that someone walking around with 1,000 or 10,000 times as many meningococci in their throat is more likely to be more infectious to people around them with a very small number, although this hasn’t been formally proven.”

He hopes that the Be on the TEAM (Teenagers Against Meningitis) study will help provide answers. The study is randomizing 24,000 U.K. high school students to vaccination with the meningococcal B protein–antigen vaccines Bexsero or Trumenba or to no vaccine in order to learn if there are significant herd immunity effects.

Dr. Finn’s meningococcal carriage research is funded by the Meningitis Research Foundation and the National Institute for Health Research. Dr. Marshall reported receiving research funding from GlaxoSmithKline, the major sponsor of the B Part of It study.

[email protected]

LJUBLJANA, SLOVENIA – The 4CMenB vaccine didn’t affect carriage of disease-causing genogroups of Neisseria meningitidis in adolescents in the landmark Australian cluster-randomized trial of herd immunity known as the “B Part of It” study, Helen S. Marshall, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

This was the largest-ever randomized trial of adolescents vaccinated against meningococcal disease, and the message, albeit somewhat disappointing, is clear: “MenB [Meningococcal serogroup B] vaccine programs should be designed to provide direct protection for those at highest risk of disease,” declared Dr. Marshall, professor of vaccinology and deputy director of the Robinson Research Institute at the University of Adelaide.

In other words, a protein antigen–based MenB vaccine doesn’t provide indirect protection to unvaccinated adolescents through herd immunity. Youths in the age groups at highest risk of disease – infants and adolescents – need to routinely receive the vaccine.

The B Part of It study, whose sheer scope and rigor drew the attention of infectious disease clinical trialists the world over, randomized nearly 35,000 students at all high schools in the state of South Australia – whether urban, rural, or remote – to two doses of the 4CMenB vaccine known as Bexsero or to a nonvaccinated control group. This massive trial entailed training more than 250 nurses in the study procedures and involved 3,100 miles of travel to transport oropharyngeal swab samples obtained from students in outlying areas for centralized laboratory analysis using real-time polymerase chain reaction with meningococcal genotyping, culture for N. meningitidis, and whole-genome sequencing. Samples were obtained on day 1 of the study and 12 months later.

The investigators created widespread regional enthusiasm for this project through adept use of social media and other methods. As a result, 99.5% of students randomized to the intervention arm received one dose, while 97% got two doses. A gratifying unintended consequence of the study was that parents who’d never previously vaccinated their children enrolled them in B Part of It, Dr. Marshall noted.

The impetus for B Part of It was that, while the Australian national health insurance program covers a single dose of meningococcal conjugate MenACWY vaccine given at age 12 months and 14-19 years, MenB vaccine isn’t covered because of uncertainties about cost effectiveness and the vaccine’s impact on meningococcal carriage and herd immunity. B Part of It was designed to resolve those uncertainties.

South Australia has the highest rate of invasive meningococcal disease in the country, and more than 80% of cases there are caused by meningococcal serogroup B. Moreover, 75% of group B cases in South Australia involve the nasty hypervirulent New Zealand strain known as CC 41/44.

The primary outcome in B Part of It was the difference in carriage of the major disease-causing serotypes – groups A, B, C, W, X, and Y – between vaccinated and unvaccinated students at the 1-year follow-up mark. The carriage prevalence of all N. meningitidis in the vaccinated students went from 2.8% at baseline to 4.0% at 12 months, and similarly from 2.6% to 4.7% in unvaccinated controls. More importantly, the prevalence of disease-causing genotypes rose from 1.3% at baseline to 2.4% at follow-up in the vaccinated subjects, with a near-identical pattern seen in controls, where the prevalence rose from 1.4% to 2.4%. In an as-treated analysis, the rate of acquisition of carriage of disease-causing genotypes was identical at 2.0% in both study arms.

The 4CMenB vaccine proved reassuringly safe and effective in preventing meningococcal disease in vaccinated teens. With more than 58,000 doses of the vaccine given in the study, no new safety concerns or signals emerged. And the observed number of cases of invasive meningococcal disease in South Australian adolescent vaccine recipients to date has been significantly lower than expected.

Secondary and exploratory outcomes

Independent risk factors associated with N. meningitidis carriage in the study participants at the 1-year mark included smoking cigarettes or hookah, intimate kissing within the last week, and being in grades 11-12, as opposed to grade 10.

The vaccine had no significant impact on the carriage rate of the hypervirulent New Zealand serogroup B strain. Nor was there a vaccine impact on carriage density, as Mark McMillan, MD, reported elsewhere at ESPID 2019. But while the 4CMenB vaccine had minimal impact upon N. meningitidis carriage density, it was associated with a significant 41% increase in the likelihood of cleared carriage of disease-causing strains at 12 months, added Dr. McMillan, Dr. Marshall’s coinvestigator at University of Adelaide.

What’s next

The ongoing B Part of It School Leaver study is assessing carriage prevalence in vaccinated versus unvaccinated high schoolers in their first year after graduating.

In addition, the B Part of It investigators plan to prospectively study the impact of the 4CMen B vaccine on N. gonorrhoeae disease in an effort to confirm the intriguing findings of an earlier large, retrospective New Zealand case-control study. The Kiwis found that recipients of an outer membrane vesicle MenB vaccine had an adjusted 31% reduction in the risk of gonorrhea. This was the first-ever report of any vaccine effectiveness against this major global public health problem, in which antibiotic resistance is a growing concern (Lancet. 2017 Sep 30;390[10102]:1603-10). Dr. Marshall reported receiving research funding from GlaxoSmithKline, which markets Bexsero and was the major financial supporter of the B Part of It study.

But wait a minute...

Following Dr. Marshall’s report on the B Part of It study, outgoing ESPID president Adam Finn, MD, PhD, presented longitudinal data that he believes raise the possibility that protein-antigen vaccines such as Bexsero, which promote naturally acquired mucosal immunity, may impact on transmission population wide without reliably preventing acquisition. This would stand in stark contrast to conjugate meningococcus vaccines, which have a well-established massive impact on carriage and acquisition of N. meningitidis.

Bruce Jancin/MDedge News

It may be that in studying throat carriage rates once in individuals immunized 12 months earlier, as in the B Part of It study, investigators are not asking the right question, proposed Dr. Finn, professor of pediatrics at the University of Bristol (England).

His research team has been obtaining throat swabs at monthly intervals in a population of 917 high schoolers aged 16-17 years. In 416 of the students, they also have collected saliva samples weekly both before and after immunization with 4CMenB vaccine, analyzing the samples for N. meningitidis by polymerase chain reaction. This is a novel method of studying meningococcal carriage they have found to be both reliable and far more acceptable to patients than oropharyngeal swabbing, which adolescents balk at if asked to do with any frequency (PLoS One. 2019 Feb 11;14[2]:e0209905).

Dr. Finn said that their findings, which need confirmation, suggest that N. meningitidis carriage is usually brief and dynamic. They also have found that carriage density varies markedly from month to month.

“We see much higher-density carriage in the adolescent population in the early months of the year in conjunction, we think, with viral infection with influenza and so forth,” he said, adding that this could have clinical implications. “It feels sort of intuitive that someone walking around with 1,000 or 10,000 times as many meningococci in their throat is more likely to be more infectious to people around them with a very small number, although this hasn’t been formally proven.”

He hopes that the Be on the TEAM (Teenagers Against Meningitis) study will help provide answers. The study is randomizing 24,000 U.K. high school students to vaccination with the meningococcal B protein–antigen vaccines Bexsero or Trumenba or to no vaccine in order to learn if there are significant herd immunity effects.

Dr. Finn’s meningococcal carriage research is funded by the Meningitis Research Foundation and the National Institute for Health Research. Dr. Marshall reported receiving research funding from GlaxoSmithKline, the major sponsor of the B Part of It study.

[email protected]

The Diagnosis: Granulosis Rubra Nasi 

A history of prominent nasal sweating was later elicited and the patient was subsequently diagnosed with granulosis rubra nasi. She was instructed to continue daily use of topical pimecrolimus with the addition of topical atropine, resulting in complete resolution of the eruption at 6-week follow-up (Figure, A). She was then maintained on topical atropine monotherapy, only noting recurrence with cessation of the atropine (Figure, B).  

Other successful treatment regimens of granulosis rubra nasi include injection of botulinum toxin into the nose,¹ monotherapy with topical tacrolimus,² topical indomethacin, steroids, and cryotherapy, among other modalities.¹ Topical atropine and pimecrolimus were selected as first-line agents for treating our pediatric patient due to tolerability and their anti-inflammatory and anticholinergic properties.  

Granulosis rubra nasi is a form of focal hyperhidrosis that presents as erythematous papules, pustules, and vesicles of the midface, especially the nose.3 It is a fairly rare condition that can mimic many other common clinical entities, including comedonal acne, nevus comedonicus, periorificial dermatitis, and tinea faciei, but is resistant to treatments aimed at these disorders. It was first described as a "peculiar disease of the skin of the nose in children" in a case report by Jadassohn⁴ in 1901. It is most common in children aged 7 to 12 years and typically resolves at puberty; adults rarely are affected. Although the etiology has not yet been elucidated, autosomal-dominant transmission has been described, and the cutaneous changes are hypothesized to be secondary to hyperhidrosis.⁵ This postulation is further corroborated by a case report of a pheochromocytoma-associated granulosis rubra nasi that resolved with surgical excision of the pheochromocytoma.⁶ It is not uncommon for patients to have concomitant palmoplantar hyperhidrosis and acrocyanosis.⁵ Histopathologic examination is not necessary for diagnosis, but when performed, it discloses a mononuclear cellular infiltrate surrounding eccrine sweat ducts, blood vessels, and lymphatics without other abnormalities of the epidermis or pilosebaceous unit.^1-3,7 
 

The Diagnosis: Granulosis Rubra Nasi 

A history of prominent nasal sweating was later elicited and the patient was subsequently diagnosed with granulosis rubra nasi. She was instructed to continue daily use of topical pimecrolimus with the addition of topical atropine, resulting in complete resolution of the eruption at 6-week follow-up (Figure, A). She was then maintained on topical atropine monotherapy, only noting recurrence with cessation of the atropine (Figure, B).  

Other successful treatment regimens of granulosis rubra nasi include injection of botulinum toxin into the nose,¹ monotherapy with topical tacrolimus,² topical indomethacin, steroids, and cryotherapy, among other modalities.¹ Topical atropine and pimecrolimus were selected as first-line agents for treating our pediatric patient due to tolerability and their anti-inflammatory and anticholinergic properties.  

Granulosis rubra nasi is a form of focal hyperhidrosis that presents as erythematous papules, pustules, and vesicles of the midface, especially the nose.3 It is a fairly rare condition that can mimic many other common clinical entities, including comedonal acne, nevus comedonicus, periorificial dermatitis, and tinea faciei, but is resistant to treatments aimed at these disorders. It was first described as a "peculiar disease of the skin of the nose in children" in a case report by Jadassohn⁴ in 1901. It is most common in children aged 7 to 12 years and typically resolves at puberty; adults rarely are affected. Although the etiology has not yet been elucidated, autosomal-dominant transmission has been described, and the cutaneous changes are hypothesized to be secondary to hyperhidrosis.⁵ This postulation is further corroborated by a case report of a pheochromocytoma-associated granulosis rubra nasi that resolved with surgical excision of the pheochromocytoma.⁶ It is not uncommon for patients to have concomitant palmoplantar hyperhidrosis and acrocyanosis.⁵ Histopathologic examination is not necessary for diagnosis, but when performed, it discloses a mononuclear cellular infiltrate surrounding eccrine sweat ducts, blood vessels, and lymphatics without other abnormalities of the epidermis or pilosebaceous unit.^1-3,7 
 

The Diagnosis: Granulosis Rubra Nasi 

A history of prominent nasal sweating was later elicited and the patient was subsequently diagnosed with granulosis rubra nasi. She was instructed to continue daily use of topical pimecrolimus with the addition of topical atropine, resulting in complete resolution of the eruption at 6-week follow-up (Figure, A). She was then maintained on topical atropine monotherapy, only noting recurrence with cessation of the atropine (Figure, B).  

Other successful treatment regimens of granulosis rubra nasi include injection of botulinum toxin into the nose,¹ monotherapy with topical tacrolimus,² topical indomethacin, steroids, and cryotherapy, among other modalities.¹ Topical atropine and pimecrolimus were selected as first-line agents for treating our pediatric patient due to tolerability and their anti-inflammatory and anticholinergic properties.  

Granulosis rubra nasi is a form of focal hyperhidrosis that presents as erythematous papules, pustules, and vesicles of the midface, especially the nose.3 It is a fairly rare condition that can mimic many other common clinical entities, including comedonal acne, nevus comedonicus, periorificial dermatitis, and tinea faciei, but is resistant to treatments aimed at these disorders. It was first described as a "peculiar disease of the skin of the nose in children" in a case report by Jadassohn⁴ in 1901. It is most common in children aged 7 to 12 years and typically resolves at puberty; adults rarely are affected. Although the etiology has not yet been elucidated, autosomal-dominant transmission has been described, and the cutaneous changes are hypothesized to be secondary to hyperhidrosis.⁵ This postulation is further corroborated by a case report of a pheochromocytoma-associated granulosis rubra nasi that resolved with surgical excision of the pheochromocytoma.⁶ It is not uncommon for patients to have concomitant palmoplantar hyperhidrosis and acrocyanosis.⁵ Histopathologic examination is not necessary for diagnosis, but when performed, it discloses a mononuclear cellular infiltrate surrounding eccrine sweat ducts, blood vessels, and lymphatics without other abnormalities of the epidermis or pilosebaceous unit.^1-3,7 
 

Infants with bacteremic urinary tract infections on short-term versus long-term parenteral antibiotics before oral antibiotics had similar outcomes, according to a study.

AndyL/iStock/Getty Images Plus

While previous studies have shown short-term parenteral antibiotic therapy to be safe and equally effective in uncomplicated urinary tract infections (UTIs), short-term therapy safety in bacteremic UTI had not been established, Sanyukta Desai, MD, of the University of Cincinnati and Cincinnati Children’s Hospital and associates wrote in Pediatrics.

“As a result, infants with bacteremic UTI often receive prolonged courses of parenteral antibiotics, which can lead to long hospitalizations and increased costs,” they said.

In a multicenter, retrospective cohort study, Dr. Desai and associates analyzed a group of 115 infants aged 60 days or younger who were admitted to a group of 11 participating EDs between July 1, 2011, and June 30, 2016, if they had a UTI caused by a bacterial pathogen. Half of the infants were administered parenteral antibiotics for 7 days or less before being switched to oral antibiotics, and the rest were given parenteral antibiotics for more than 7 days before switching to oral. Infants were more likely to receive long-term parenteral treatment if they were ill appearing and had growth of a non–Escherichia coli organism.

Six infants (two in the short-term group, four in the long-term group) had a recurrent UTI, each one diagnosed between 15 and 30 days after discharge; the adjusted risk difference between the two groups was 3% (95% confidence interval, –5.8 to 12.7). Two of the infants in the long-term group with a recurrent UTI had a different organism than during the index infection. When comparing only the infants with growth of the same pathogen that caused the index UTI, the adjusted risk difference between the two groups was 0.2% (95% CI, –7.8 to 8.3).

A total of 15 infants (6 in the short-term group, 9 in the long-term group) had 30-day all-cause reutilization, with no significant difference between groups (adjusted risk difference, 3%; 95% CI, –14.6 to 20.4).

Mean length of stay was significantly longer in the long-term treatment group, compared with the short-term group (11 days vs. 5 days; adjusted mean difference, 6 days; 95% CI, 4.0-8.8).

No infants experienced a serious adverse event such as ICU readmission, need for mechanical ventilation or vasopressor use, or signs of neurologic sequelae within 30 days of discharge from the index hospitalization, the investigators noted. Peripherally inserted central catheters were required in 13 infants; of these, 1 infant had to revisit an ED because of a related mechanical complication.

“Researchers in future prospective studies should seek to establish the bioavailability and optimal dosing of oral antibiotics in young infants and assess if there are particular subpopulations of infants with bacteremic UTI who may benefit from longer courses of parenteral antibiotic therapy,” Dr. Desai and associates concluded.

In a related editorial, Natalia V. Leva, MD, and Hillary L. Copp, MD, of the University of California, San Francisco, noted that the study represents a “critical piece of a complicated puzzle that not only includes minimum duration of parenteral antibiotic treatment but also involves bioavailability of antimicrobial agents in infants and total treatment duration, which includes parenteral and oral antibiotic therapy.”

The question that remains is how long a duration of parenteral antibiotic is necessary, Dr. Leva and Dr. Copp wrote. “Desai et al. used a relatively arbitrary cutoff of 7 days on the basis of the distribution of antibiotic course among their patient population; however, this is likely more a reflection of clinical practice than it is evidence based.” They concluded that this study provided evidence that a “short course of parenteral antibiotics in infants [aged 60 days or younger] with bacteremic UTI is safe and effective. Although the current study does not address total duration of antibiotics [parenteral and oral], it does shine a light on where we should focus future research endeavors.”

The study authors reported that they had no conflicts of interest. The study was supported in part by a National Center for Advancing Translational Sciences grant and an Agency for Healthcare Research and Quality grant. The editorialists had no relevant conflicts of interest and received no external funding.

[email protected]

SOURCEs: Desai S et al. Pediatrics. 2019 Aug 20. doi: 10.1542/peds.2018-3844; Leva et al. 2019 Aug 20. doi: 10.1542/peds.2019-1611.

Infants with bacteremic urinary tract infections on short-term versus long-term parenteral antibiotics before oral antibiotics had similar outcomes, according to a study.

AndyL/iStock/Getty Images Plus

While previous studies have shown short-term parenteral antibiotic therapy to be safe and equally effective in uncomplicated urinary tract infections (UTIs), short-term therapy safety in bacteremic UTI had not been established, Sanyukta Desai, MD, of the University of Cincinnati and Cincinnati Children’s Hospital and associates wrote in Pediatrics.

“As a result, infants with bacteremic UTI often receive prolonged courses of parenteral antibiotics, which can lead to long hospitalizations and increased costs,” they said.

In a multicenter, retrospective cohort study, Dr. Desai and associates analyzed a group of 115 infants aged 60 days or younger who were admitted to a group of 11 participating EDs between July 1, 2011, and June 30, 2016, if they had a UTI caused by a bacterial pathogen. Half of the infants were administered parenteral antibiotics for 7 days or less before being switched to oral antibiotics, and the rest were given parenteral antibiotics for more than 7 days before switching to oral. Infants were more likely to receive long-term parenteral treatment if they were ill appearing and had growth of a non–Escherichia coli organism.

Six infants (two in the short-term group, four in the long-term group) had a recurrent UTI, each one diagnosed between 15 and 30 days after discharge; the adjusted risk difference between the two groups was 3% (95% confidence interval, –5.8 to 12.7). Two of the infants in the long-term group with a recurrent UTI had a different organism than during the index infection. When comparing only the infants with growth of the same pathogen that caused the index UTI, the adjusted risk difference between the two groups was 0.2% (95% CI, –7.8 to 8.3).

A total of 15 infants (6 in the short-term group, 9 in the long-term group) had 30-day all-cause reutilization, with no significant difference between groups (adjusted risk difference, 3%; 95% CI, –14.6 to 20.4).

Mean length of stay was significantly longer in the long-term treatment group, compared with the short-term group (11 days vs. 5 days; adjusted mean difference, 6 days; 95% CI, 4.0-8.8).

No infants experienced a serious adverse event such as ICU readmission, need for mechanical ventilation or vasopressor use, or signs of neurologic sequelae within 30 days of discharge from the index hospitalization, the investigators noted. Peripherally inserted central catheters were required in 13 infants; of these, 1 infant had to revisit an ED because of a related mechanical complication.

“Researchers in future prospective studies should seek to establish the bioavailability and optimal dosing of oral antibiotics in young infants and assess if there are particular subpopulations of infants with bacteremic UTI who may benefit from longer courses of parenteral antibiotic therapy,” Dr. Desai and associates concluded.

In a related editorial, Natalia V. Leva, MD, and Hillary L. Copp, MD, of the University of California, San Francisco, noted that the study represents a “critical piece of a complicated puzzle that not only includes minimum duration of parenteral antibiotic treatment but also involves bioavailability of antimicrobial agents in infants and total treatment duration, which includes parenteral and oral antibiotic therapy.”

The question that remains is how long a duration of parenteral antibiotic is necessary, Dr. Leva and Dr. Copp wrote. “Desai et al. used a relatively arbitrary cutoff of 7 days on the basis of the distribution of antibiotic course among their patient population; however, this is likely more a reflection of clinical practice than it is evidence based.” They concluded that this study provided evidence that a “short course of parenteral antibiotics in infants [aged 60 days or younger] with bacteremic UTI is safe and effective. Although the current study does not address total duration of antibiotics [parenteral and oral], it does shine a light on where we should focus future research endeavors.”

The study authors reported that they had no conflicts of interest. The study was supported in part by a National Center for Advancing Translational Sciences grant and an Agency for Healthcare Research and Quality grant. The editorialists had no relevant conflicts of interest and received no external funding.

[email protected]

SOURCEs: Desai S et al. Pediatrics. 2019 Aug 20. doi: 10.1542/peds.2018-3844; Leva et al. 2019 Aug 20. doi: 10.1542/peds.2019-1611.

Infants with bacteremic urinary tract infections on short-term versus long-term parenteral antibiotics before oral antibiotics had similar outcomes, according to a study.

AndyL/iStock/Getty Images Plus

While previous studies have shown short-term parenteral antibiotic therapy to be safe and equally effective in uncomplicated urinary tract infections (UTIs), short-term therapy safety in bacteremic UTI had not been established, Sanyukta Desai, MD, of the University of Cincinnati and Cincinnati Children’s Hospital and associates wrote in Pediatrics.

“As a result, infants with bacteremic UTI often receive prolonged courses of parenteral antibiotics, which can lead to long hospitalizations and increased costs,” they said.

In a multicenter, retrospective cohort study, Dr. Desai and associates analyzed a group of 115 infants aged 60 days or younger who were admitted to a group of 11 participating EDs between July 1, 2011, and June 30, 2016, if they had a UTI caused by a bacterial pathogen. Half of the infants were administered parenteral antibiotics for 7 days or less before being switched to oral antibiotics, and the rest were given parenteral antibiotics for more than 7 days before switching to oral. Infants were more likely to receive long-term parenteral treatment if they were ill appearing and had growth of a non–Escherichia coli organism.

Six infants (two in the short-term group, four in the long-term group) had a recurrent UTI, each one diagnosed between 15 and 30 days after discharge; the adjusted risk difference between the two groups was 3% (95% confidence interval, –5.8 to 12.7). Two of the infants in the long-term group with a recurrent UTI had a different organism than during the index infection. When comparing only the infants with growth of the same pathogen that caused the index UTI, the adjusted risk difference between the two groups was 0.2% (95% CI, –7.8 to 8.3).

A total of 15 infants (6 in the short-term group, 9 in the long-term group) had 30-day all-cause reutilization, with no significant difference between groups (adjusted risk difference, 3%; 95% CI, –14.6 to 20.4).

Mean length of stay was significantly longer in the long-term treatment group, compared with the short-term group (11 days vs. 5 days; adjusted mean difference, 6 days; 95% CI, 4.0-8.8).

No infants experienced a serious adverse event such as ICU readmission, need for mechanical ventilation or vasopressor use, or signs of neurologic sequelae within 30 days of discharge from the index hospitalization, the investigators noted. Peripherally inserted central catheters were required in 13 infants; of these, 1 infant had to revisit an ED because of a related mechanical complication.

“Researchers in future prospective studies should seek to establish the bioavailability and optimal dosing of oral antibiotics in young infants and assess if there are particular subpopulations of infants with bacteremic UTI who may benefit from longer courses of parenteral antibiotic therapy,” Dr. Desai and associates concluded.

In a related editorial, Natalia V. Leva, MD, and Hillary L. Copp, MD, of the University of California, San Francisco, noted that the study represents a “critical piece of a complicated puzzle that not only includes minimum duration of parenteral antibiotic treatment but also involves bioavailability of antimicrobial agents in infants and total treatment duration, which includes parenteral and oral antibiotic therapy.”

The question that remains is how long a duration of parenteral antibiotic is necessary, Dr. Leva and Dr. Copp wrote. “Desai et al. used a relatively arbitrary cutoff of 7 days on the basis of the distribution of antibiotic course among their patient population; however, this is likely more a reflection of clinical practice than it is evidence based.” They concluded that this study provided evidence that a “short course of parenteral antibiotics in infants [aged 60 days or younger] with bacteremic UTI is safe and effective. Although the current study does not address total duration of antibiotics [parenteral and oral], it does shine a light on where we should focus future research endeavors.”

The study authors reported that they had no conflicts of interest. The study was supported in part by a National Center for Advancing Translational Sciences grant and an Agency for Healthcare Research and Quality grant. The editorialists had no relevant conflicts of interest and received no external funding.

[email protected]

SOURCEs: Desai S et al. Pediatrics. 2019 Aug 20. doi: 10.1542/peds.2018-3844; Leva et al. 2019 Aug 20. doi: 10.1542/peds.2019-1611.