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Combo therapy outcomes for West syndrome prove no better than monotherapy
BANGKOK – Hiroki Nariai, MD, declared at the International Epilepsy Congress.
West syndrome, or infantile spasms with a hypsarrhythmic EEG, is a severe infantile epileptic encephalopathy. It has high morbidity and mortality, and it’s challenging to treat. So neurologists and pediatricians were thrilled by an earlier preliminary report from an open-label, randomized, controlled trial conducted by the International Collaborative Infantile Spasms Study (ICISS) investigators. They reported that a hormonal therapy and vigabatrin (Sabril) combination provided significantly better seizure control between days 14 and 42 of treatment than hormonal therapy alone, albeit at the cost of more side effects (Lancet Neurol. 2017 Jan;16[1]:33-42).
However, a sobering update from the 377-infant study conducted in Australia, Switzerland, Germany, New Zealand, and the United Kingdom concluded that combination therapy didn’t result in improved developmental or epilepsy outcomes at 18 months, Dr. Nariai said at the congress sponsored by the International League Against Epilepsy.
“We still have inconclusive evidence to support the routine use of combination therapy. Clearly we need a better disease-modifying therapy because our best results with hormonal therapy or vigabatrin are only a 50%-70% response rate. And having a biomarker to guide early therapy and follow treatment response would help in establishing a better therapy,” commented Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.
He wasn’t involved in the international trial. He is, however, active in the search for a biomarker that would aid in speedier diagnosis of West syndrome, which in turn would allow for earlier treatment and, potentially, better outcomes. Indeed, Dr. Nariai has done pioneering work in identifying several EEG abnormalities readily measurable noninvasively using scalp electrodes that show considerable promise in this regard. These candidate biomarkers include ictal or interictal high-frequency oscillations at 80 Hz or more, along with cross-frequency coupling of high-frequency oscillations and delta-wave activity.
The primary endpoint in the ICISS study was developmental outcome at 18 months as evaluated using the Vineland Adaptive Behavior Scales composite score. The mean score was 73.9 in the combination therapy group and closely similar at 72.7 in the children on hormonal therapy alone. At 18 months, 30% of children in the combination therapy group carried a diagnosis of epilepsy, as did 29.2% of controls randomized to either high-dose oral steroids or intramuscular depot tetracosactide. About 15% of children randomized to combination therapy still had spasms at 18 months, as did 15.7% on hormonal therapy alone (Lancet Child Adolesc Health. 2018 Oct;2[10]:715-25).
The chief side effects of hormonal therapy included hypertension, hypoglycemia, and immunosuppression. Vigabatrin’s side effects included dose- and duration-dependent peripheral vision loss, movement disorders, and undesirable MRI signal changes.
Dr. Nariai observed that, even though hormonal therapy is widely used as first-line therapy in West syndrome, it remains surrounded by important unanswered questions.
“We don’t have head-to-head comparative studies of ACTH versus high-dose steroids, the optimal dosing protocol is not established, and we really don’t even know the mechanism of action for hormonal therapy and vigabatrin,” he said.
The study was sponsored by the U.K. National Institute of Health Research and other noncommercial entities. Dr. Nariai reported having no financial conflicts regarding his presentation.
BANGKOK – Hiroki Nariai, MD, declared at the International Epilepsy Congress.
West syndrome, or infantile spasms with a hypsarrhythmic EEG, is a severe infantile epileptic encephalopathy. It has high morbidity and mortality, and it’s challenging to treat. So neurologists and pediatricians were thrilled by an earlier preliminary report from an open-label, randomized, controlled trial conducted by the International Collaborative Infantile Spasms Study (ICISS) investigators. They reported that a hormonal therapy and vigabatrin (Sabril) combination provided significantly better seizure control between days 14 and 42 of treatment than hormonal therapy alone, albeit at the cost of more side effects (Lancet Neurol. 2017 Jan;16[1]:33-42).
However, a sobering update from the 377-infant study conducted in Australia, Switzerland, Germany, New Zealand, and the United Kingdom concluded that combination therapy didn’t result in improved developmental or epilepsy outcomes at 18 months, Dr. Nariai said at the congress sponsored by the International League Against Epilepsy.
“We still have inconclusive evidence to support the routine use of combination therapy. Clearly we need a better disease-modifying therapy because our best results with hormonal therapy or vigabatrin are only a 50%-70% response rate. And having a biomarker to guide early therapy and follow treatment response would help in establishing a better therapy,” commented Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.
He wasn’t involved in the international trial. He is, however, active in the search for a biomarker that would aid in speedier diagnosis of West syndrome, which in turn would allow for earlier treatment and, potentially, better outcomes. Indeed, Dr. Nariai has done pioneering work in identifying several EEG abnormalities readily measurable noninvasively using scalp electrodes that show considerable promise in this regard. These candidate biomarkers include ictal or interictal high-frequency oscillations at 80 Hz or more, along with cross-frequency coupling of high-frequency oscillations and delta-wave activity.
The primary endpoint in the ICISS study was developmental outcome at 18 months as evaluated using the Vineland Adaptive Behavior Scales composite score. The mean score was 73.9 in the combination therapy group and closely similar at 72.7 in the children on hormonal therapy alone. At 18 months, 30% of children in the combination therapy group carried a diagnosis of epilepsy, as did 29.2% of controls randomized to either high-dose oral steroids or intramuscular depot tetracosactide. About 15% of children randomized to combination therapy still had spasms at 18 months, as did 15.7% on hormonal therapy alone (Lancet Child Adolesc Health. 2018 Oct;2[10]:715-25).
The chief side effects of hormonal therapy included hypertension, hypoglycemia, and immunosuppression. Vigabatrin’s side effects included dose- and duration-dependent peripheral vision loss, movement disorders, and undesirable MRI signal changes.
Dr. Nariai observed that, even though hormonal therapy is widely used as first-line therapy in West syndrome, it remains surrounded by important unanswered questions.
“We don’t have head-to-head comparative studies of ACTH versus high-dose steroids, the optimal dosing protocol is not established, and we really don’t even know the mechanism of action for hormonal therapy and vigabatrin,” he said.
The study was sponsored by the U.K. National Institute of Health Research and other noncommercial entities. Dr. Nariai reported having no financial conflicts regarding his presentation.
BANGKOK – Hiroki Nariai, MD, declared at the International Epilepsy Congress.
West syndrome, or infantile spasms with a hypsarrhythmic EEG, is a severe infantile epileptic encephalopathy. It has high morbidity and mortality, and it’s challenging to treat. So neurologists and pediatricians were thrilled by an earlier preliminary report from an open-label, randomized, controlled trial conducted by the International Collaborative Infantile Spasms Study (ICISS) investigators. They reported that a hormonal therapy and vigabatrin (Sabril) combination provided significantly better seizure control between days 14 and 42 of treatment than hormonal therapy alone, albeit at the cost of more side effects (Lancet Neurol. 2017 Jan;16[1]:33-42).
However, a sobering update from the 377-infant study conducted in Australia, Switzerland, Germany, New Zealand, and the United Kingdom concluded that combination therapy didn’t result in improved developmental or epilepsy outcomes at 18 months, Dr. Nariai said at the congress sponsored by the International League Against Epilepsy.
“We still have inconclusive evidence to support the routine use of combination therapy. Clearly we need a better disease-modifying therapy because our best results with hormonal therapy or vigabatrin are only a 50%-70% response rate. And having a biomarker to guide early therapy and follow treatment response would help in establishing a better therapy,” commented Dr. Nariai, a pediatric neurologist at the University of California, Los Angeles.
He wasn’t involved in the international trial. He is, however, active in the search for a biomarker that would aid in speedier diagnosis of West syndrome, which in turn would allow for earlier treatment and, potentially, better outcomes. Indeed, Dr. Nariai has done pioneering work in identifying several EEG abnormalities readily measurable noninvasively using scalp electrodes that show considerable promise in this regard. These candidate biomarkers include ictal or interictal high-frequency oscillations at 80 Hz or more, along with cross-frequency coupling of high-frequency oscillations and delta-wave activity.
The primary endpoint in the ICISS study was developmental outcome at 18 months as evaluated using the Vineland Adaptive Behavior Scales composite score. The mean score was 73.9 in the combination therapy group and closely similar at 72.7 in the children on hormonal therapy alone. At 18 months, 30% of children in the combination therapy group carried a diagnosis of epilepsy, as did 29.2% of controls randomized to either high-dose oral steroids or intramuscular depot tetracosactide. About 15% of children randomized to combination therapy still had spasms at 18 months, as did 15.7% on hormonal therapy alone (Lancet Child Adolesc Health. 2018 Oct;2[10]:715-25).
The chief side effects of hormonal therapy included hypertension, hypoglycemia, and immunosuppression. Vigabatrin’s side effects included dose- and duration-dependent peripheral vision loss, movement disorders, and undesirable MRI signal changes.
Dr. Nariai observed that, even though hormonal therapy is widely used as first-line therapy in West syndrome, it remains surrounded by important unanswered questions.
“We don’t have head-to-head comparative studies of ACTH versus high-dose steroids, the optimal dosing protocol is not established, and we really don’t even know the mechanism of action for hormonal therapy and vigabatrin,” he said.
The study was sponsored by the U.K. National Institute of Health Research and other noncommercial entities. Dr. Nariai reported having no financial conflicts regarding his presentation.
EXPERT ANALYSIS FROM IEC 2019
Decision making regarding vaccines varies among accepters, deniers, partial accepters
Parents who accepted, denied, or partially accepted participation in the Dutch National Immunization Program reached their decisions through different methods, according to Kim A.G.J. Romijnders of the National Institute for Public Health and the Environment in Bilthoven, the Netherlands, and associates.
For the study published in Vaccine, the investigators conducted a series of 12 focus groups: 3 with accepters (n = 19), 3 with deniers (n =12), and 6 with partial accepters (n =24); in the partial accepters groups, there were three groups with parents delaying vaccination and three with parents refusing some vaccinations. Three-quarters of participants were women, the average age was 39 years, and 96% had at least university education. Parents were asked about their knowledge, attitudes, deliberation, and information needs regarding childhood vaccination.
Vaccine accepters regarded the decision to vaccinate their children as self-evident, but deniers and partial accepters reported conducting extensive deliberation on the pros and cons of vaccination. Deniers and partial accepters, in general, perceived fewer risks of vaccine-preventable diseases, more risks of vaccine side effects, less social support from their environment, less trust in child welfare centers, and provided less information than accepters.
The investigators noted that This process alienated them from their child vaccine provider, with trust being lost when the provider either refused or was unable to answer questions. Partial accepters also reported a lack of social support from friends, family, and providers regarding partial vaccine acceptance.
“The findings can facilitate informed decision making among parents by promoting an open dialogue at the [child welfare center], and improving the type and form of information presented. An open dialogue between parents and [child vaccine providers] may increase deliberation among parents, strengthen positive attitudes, prevent misperceptions, and resolve decisional conflict,” the investigators concluded.
The study was supported by the Dutch National Institute for Public Health and the Environment; the authors reported no conflicts of interest.
SOURCE: Romijnders KAGJ et al. Vaccine. 2019 Aug 2. doi: 10.1016/j.vaccine.2019.07.060.
Parents who accepted, denied, or partially accepted participation in the Dutch National Immunization Program reached their decisions through different methods, according to Kim A.G.J. Romijnders of the National Institute for Public Health and the Environment in Bilthoven, the Netherlands, and associates.
For the study published in Vaccine, the investigators conducted a series of 12 focus groups: 3 with accepters (n = 19), 3 with deniers (n =12), and 6 with partial accepters (n =24); in the partial accepters groups, there were three groups with parents delaying vaccination and three with parents refusing some vaccinations. Three-quarters of participants were women, the average age was 39 years, and 96% had at least university education. Parents were asked about their knowledge, attitudes, deliberation, and information needs regarding childhood vaccination.
Vaccine accepters regarded the decision to vaccinate their children as self-evident, but deniers and partial accepters reported conducting extensive deliberation on the pros and cons of vaccination. Deniers and partial accepters, in general, perceived fewer risks of vaccine-preventable diseases, more risks of vaccine side effects, less social support from their environment, less trust in child welfare centers, and provided less information than accepters.
The investigators noted that This process alienated them from their child vaccine provider, with trust being lost when the provider either refused or was unable to answer questions. Partial accepters also reported a lack of social support from friends, family, and providers regarding partial vaccine acceptance.
“The findings can facilitate informed decision making among parents by promoting an open dialogue at the [child welfare center], and improving the type and form of information presented. An open dialogue between parents and [child vaccine providers] may increase deliberation among parents, strengthen positive attitudes, prevent misperceptions, and resolve decisional conflict,” the investigators concluded.
The study was supported by the Dutch National Institute for Public Health and the Environment; the authors reported no conflicts of interest.
SOURCE: Romijnders KAGJ et al. Vaccine. 2019 Aug 2. doi: 10.1016/j.vaccine.2019.07.060.
Parents who accepted, denied, or partially accepted participation in the Dutch National Immunization Program reached their decisions through different methods, according to Kim A.G.J. Romijnders of the National Institute for Public Health and the Environment in Bilthoven, the Netherlands, and associates.
For the study published in Vaccine, the investigators conducted a series of 12 focus groups: 3 with accepters (n = 19), 3 with deniers (n =12), and 6 with partial accepters (n =24); in the partial accepters groups, there were three groups with parents delaying vaccination and three with parents refusing some vaccinations. Three-quarters of participants were women, the average age was 39 years, and 96% had at least university education. Parents were asked about their knowledge, attitudes, deliberation, and information needs regarding childhood vaccination.
Vaccine accepters regarded the decision to vaccinate their children as self-evident, but deniers and partial accepters reported conducting extensive deliberation on the pros and cons of vaccination. Deniers and partial accepters, in general, perceived fewer risks of vaccine-preventable diseases, more risks of vaccine side effects, less social support from their environment, less trust in child welfare centers, and provided less information than accepters.
The investigators noted that This process alienated them from their child vaccine provider, with trust being lost when the provider either refused or was unable to answer questions. Partial accepters also reported a lack of social support from friends, family, and providers regarding partial vaccine acceptance.
“The findings can facilitate informed decision making among parents by promoting an open dialogue at the [child welfare center], and improving the type and form of information presented. An open dialogue between parents and [child vaccine providers] may increase deliberation among parents, strengthen positive attitudes, prevent misperceptions, and resolve decisional conflict,” the investigators concluded.
The study was supported by the Dutch National Institute for Public Health and the Environment; the authors reported no conflicts of interest.
SOURCE: Romijnders KAGJ et al. Vaccine. 2019 Aug 2. doi: 10.1016/j.vaccine.2019.07.060.
FROM VACCINE
Tandem transplants provide EFS edge in pediatric neuroblastoma
For young patients with high-risk neuroblastoma, an intensive consolidation regimen with tandem autologous stem cell transplants was associated with significantly better event-free survival, compared with single-transplant consolidation, results of a randomized trial show.
Among 355 patients with high-risk neuroblastoma, the 3-year event-free survival (EFS) rate was 61.6% for patients randomized to tandem (sequential) autologous stem cell transplants, compared with 48.4% for patients randomized to a single transplant (P = .006), reported Julie R. Park, MD from Seattle Children’s Hospital in Washington, and coinvestigators in the Children’s Oncology Group’s ANBL0532 trial.
“Results of the current study are consistent with earlier trials demonstrating that induction chemotherapy followed by consolidation with autologous transplant improved EFS, compared with less intensive consolidation, and that further intensification of consolidation benefits some patients,” they wrote in JAMA.
But of the 652 patients enrolled in the study, only 355 were actually randomized. Although the randomization rate was slightly higher than anticipated, the authors acknowledged that the results may not apply to all patients with high-risk neuroblastoma.
Patients eligible for the trial included those with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma aged older than 18 months; INSS stage 3 neuroblastoma aged older than 18 months with International Neuroblastoma Pathology Classification of unfavorable histology; INSS stage 2, 3, 4, or 4S neuroblastoma with MYCN amplification; and INSS stage 4 neuroblastoma diagnosed from age 12-18 months whose tumors showed any unfavorable features. Patients initially diagnosed with non–high-risk neuroblastoma (including stage 1) who had not received chemotherapy and whose disease had progressed to high-risk neuroblastoma were also eligible.
Following induction with two cycles of topotecan and cyclophosphamide, patients underwent peripheral blood stem cell collection, followed by four alternating cycles of cisplatin and etoposide and doxorubicin and cyclophosphamide, and vincristine.
For those patients who did not have primary tumors resected at diagnosis, resection was performed after the fourth or fifth cycle.
Those patients who after induction had no disease progression, no uncontrolled infection, sufficient stem cell levels, and adequate organ function were then eligible for randomization. One patient did not receive any therapy, 27 were nonrandomly assigned to single transplant, 62 were not eligible for randomization, and 207 were not randomized because of physician or family preference.
Of the remaining patients (median age at diagnosis, 36.1 months) 176 were randomized to receive tandem transplant with thiotepa and cyclophosphamide followed by dose-reduced carboplatin, etoposide, and melphalan conditioning, and 179 were randomized to single transplant with standard-dose carboplatin, etoposide, and melphalan.
A total of 17 patients died on study from toxicity; 7 during induction and 10 during consolidation. Significant transplant-related toxicities included mucositis in 11.7% of tandem-transplant patients and 15.4% of single-transplant patients, and infections in 17.8% versus 18.3%, respectively.
As noted before, 3-year EFS from the time of randomization, the primary endpoint, was higher for patients in the tandem-transplant arm (61.6% vs. 48.4%, P = .006).
The median duration of follow-up after randomization for patients without relapse, disease progression, second malignancy, or death was 5.6 years.
A post hoc analysis of the randomized patients showed a 3-year overall survival rate of 71.6%, which did not differ significantly between the study arms (74.1% for the tandem-transplant group vs. 68.1% for the single-transplant group). The analysis also showed that 3-year EFS and overall survival was higher in the tandem- versus single-transplant groups among 250 patients who also received immunotherapy with isotretinoin plus an anti-GD2 chimeric antibody and cytokines.
The trial was supported by grants from the National Institutes of Health, National Cancer Institute, National Clinical Trials Network Operations Center, and St. Baldrick’s Foundation. Dr. Park reported no relevant disclosures. Multiple coauthors disclosed grants or personal feeds outside the submitted work.
SOURCE: Park JR et al. JAMA. 2019;322(8):746-55.
The ANBL0532 trial also does not address the important question as to whether tandem high-dose chemotherapy with autologous stem cell transplant results in benefit for all-comers with high-risk neuroblastoma, because just over half of the eligible patients underwent randomization. Although characteristics of the entire cohort and the randomized cohort were similar with respect to age, stage, tumor histology, and MYCN status, there may be differences unrelated to widely accepted neuroblastoma risk variables. A separate but important challenge in interpretation of these results, as with any clinical trial results, is to understand the generalizability of findings to patient populations who may not be enrolling in trials. Previous work in pediatric oncology showed that trial enrollment correlated with race, age, and zip code, and it is difficult to know whether the results of the ANBL0532 trial are applicable to patient groups who may not be well represented.
An additional challenge is that even though a difference in event-free survival was detected between groups assigned to receive single versus tandem transplant, and a difference in overall survival was detected in a post hoc analysis of patients who received immunotherapy, no difference in overall survival was detected in the overall randomized cohort. Overall survival was evaluated as a secondary outcome but the trial was not powered to detect a difference in overall survival. Moreover, as noted by the authors, overall survival can be influenced by therapies delivered after relapse. This is particularly relevant in an era in which relapse therapies have been shown to induce responses, including periods of remission.
Remarks from Rochelle Bagatell, MD, from the University of Pennsylvania, Philadelphia, and Meredith S. Irwin, MD, from the Hospital for Sick Children in Toronto, are adapted and condensed from an editorial accompanying the study by Park et al. Dr. Bagatell is the vice chair of the Children’s Oncology Group Neuroblastoma Disease Committee. Dr. Irwin reported receiving personal fees from Bayer Canada outside the submitted work and is the vice chair of the Children’s Oncology Group Neuroblastoma Biology Committee. Neither Dr. Bagatell nor Dr. Irwin was involved in the design of the ANBL0532 trial or in the analysis of the results.
The ANBL0532 trial also does not address the important question as to whether tandem high-dose chemotherapy with autologous stem cell transplant results in benefit for all-comers with high-risk neuroblastoma, because just over half of the eligible patients underwent randomization. Although characteristics of the entire cohort and the randomized cohort were similar with respect to age, stage, tumor histology, and MYCN status, there may be differences unrelated to widely accepted neuroblastoma risk variables. A separate but important challenge in interpretation of these results, as with any clinical trial results, is to understand the generalizability of findings to patient populations who may not be enrolling in trials. Previous work in pediatric oncology showed that trial enrollment correlated with race, age, and zip code, and it is difficult to know whether the results of the ANBL0532 trial are applicable to patient groups who may not be well represented.
An additional challenge is that even though a difference in event-free survival was detected between groups assigned to receive single versus tandem transplant, and a difference in overall survival was detected in a post hoc analysis of patients who received immunotherapy, no difference in overall survival was detected in the overall randomized cohort. Overall survival was evaluated as a secondary outcome but the trial was not powered to detect a difference in overall survival. Moreover, as noted by the authors, overall survival can be influenced by therapies delivered after relapse. This is particularly relevant in an era in which relapse therapies have been shown to induce responses, including periods of remission.
Remarks from Rochelle Bagatell, MD, from the University of Pennsylvania, Philadelphia, and Meredith S. Irwin, MD, from the Hospital for Sick Children in Toronto, are adapted and condensed from an editorial accompanying the study by Park et al. Dr. Bagatell is the vice chair of the Children’s Oncology Group Neuroblastoma Disease Committee. Dr. Irwin reported receiving personal fees from Bayer Canada outside the submitted work and is the vice chair of the Children’s Oncology Group Neuroblastoma Biology Committee. Neither Dr. Bagatell nor Dr. Irwin was involved in the design of the ANBL0532 trial or in the analysis of the results.
The ANBL0532 trial also does not address the important question as to whether tandem high-dose chemotherapy with autologous stem cell transplant results in benefit for all-comers with high-risk neuroblastoma, because just over half of the eligible patients underwent randomization. Although characteristics of the entire cohort and the randomized cohort were similar with respect to age, stage, tumor histology, and MYCN status, there may be differences unrelated to widely accepted neuroblastoma risk variables. A separate but important challenge in interpretation of these results, as with any clinical trial results, is to understand the generalizability of findings to patient populations who may not be enrolling in trials. Previous work in pediatric oncology showed that trial enrollment correlated with race, age, and zip code, and it is difficult to know whether the results of the ANBL0532 trial are applicable to patient groups who may not be well represented.
An additional challenge is that even though a difference in event-free survival was detected between groups assigned to receive single versus tandem transplant, and a difference in overall survival was detected in a post hoc analysis of patients who received immunotherapy, no difference in overall survival was detected in the overall randomized cohort. Overall survival was evaluated as a secondary outcome but the trial was not powered to detect a difference in overall survival. Moreover, as noted by the authors, overall survival can be influenced by therapies delivered after relapse. This is particularly relevant in an era in which relapse therapies have been shown to induce responses, including periods of remission.
Remarks from Rochelle Bagatell, MD, from the University of Pennsylvania, Philadelphia, and Meredith S. Irwin, MD, from the Hospital for Sick Children in Toronto, are adapted and condensed from an editorial accompanying the study by Park et al. Dr. Bagatell is the vice chair of the Children’s Oncology Group Neuroblastoma Disease Committee. Dr. Irwin reported receiving personal fees from Bayer Canada outside the submitted work and is the vice chair of the Children’s Oncology Group Neuroblastoma Biology Committee. Neither Dr. Bagatell nor Dr. Irwin was involved in the design of the ANBL0532 trial or in the analysis of the results.
For young patients with high-risk neuroblastoma, an intensive consolidation regimen with tandem autologous stem cell transplants was associated with significantly better event-free survival, compared with single-transplant consolidation, results of a randomized trial show.
Among 355 patients with high-risk neuroblastoma, the 3-year event-free survival (EFS) rate was 61.6% for patients randomized to tandem (sequential) autologous stem cell transplants, compared with 48.4% for patients randomized to a single transplant (P = .006), reported Julie R. Park, MD from Seattle Children’s Hospital in Washington, and coinvestigators in the Children’s Oncology Group’s ANBL0532 trial.
“Results of the current study are consistent with earlier trials demonstrating that induction chemotherapy followed by consolidation with autologous transplant improved EFS, compared with less intensive consolidation, and that further intensification of consolidation benefits some patients,” they wrote in JAMA.
But of the 652 patients enrolled in the study, only 355 were actually randomized. Although the randomization rate was slightly higher than anticipated, the authors acknowledged that the results may not apply to all patients with high-risk neuroblastoma.
Patients eligible for the trial included those with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma aged older than 18 months; INSS stage 3 neuroblastoma aged older than 18 months with International Neuroblastoma Pathology Classification of unfavorable histology; INSS stage 2, 3, 4, or 4S neuroblastoma with MYCN amplification; and INSS stage 4 neuroblastoma diagnosed from age 12-18 months whose tumors showed any unfavorable features. Patients initially diagnosed with non–high-risk neuroblastoma (including stage 1) who had not received chemotherapy and whose disease had progressed to high-risk neuroblastoma were also eligible.
Following induction with two cycles of topotecan and cyclophosphamide, patients underwent peripheral blood stem cell collection, followed by four alternating cycles of cisplatin and etoposide and doxorubicin and cyclophosphamide, and vincristine.
For those patients who did not have primary tumors resected at diagnosis, resection was performed after the fourth or fifth cycle.
Those patients who after induction had no disease progression, no uncontrolled infection, sufficient stem cell levels, and adequate organ function were then eligible for randomization. One patient did not receive any therapy, 27 were nonrandomly assigned to single transplant, 62 were not eligible for randomization, and 207 were not randomized because of physician or family preference.
Of the remaining patients (median age at diagnosis, 36.1 months) 176 were randomized to receive tandem transplant with thiotepa and cyclophosphamide followed by dose-reduced carboplatin, etoposide, and melphalan conditioning, and 179 were randomized to single transplant with standard-dose carboplatin, etoposide, and melphalan.
A total of 17 patients died on study from toxicity; 7 during induction and 10 during consolidation. Significant transplant-related toxicities included mucositis in 11.7% of tandem-transplant patients and 15.4% of single-transplant patients, and infections in 17.8% versus 18.3%, respectively.
As noted before, 3-year EFS from the time of randomization, the primary endpoint, was higher for patients in the tandem-transplant arm (61.6% vs. 48.4%, P = .006).
The median duration of follow-up after randomization for patients without relapse, disease progression, second malignancy, or death was 5.6 years.
A post hoc analysis of the randomized patients showed a 3-year overall survival rate of 71.6%, which did not differ significantly between the study arms (74.1% for the tandem-transplant group vs. 68.1% for the single-transplant group). The analysis also showed that 3-year EFS and overall survival was higher in the tandem- versus single-transplant groups among 250 patients who also received immunotherapy with isotretinoin plus an anti-GD2 chimeric antibody and cytokines.
The trial was supported by grants from the National Institutes of Health, National Cancer Institute, National Clinical Trials Network Operations Center, and St. Baldrick’s Foundation. Dr. Park reported no relevant disclosures. Multiple coauthors disclosed grants or personal feeds outside the submitted work.
SOURCE: Park JR et al. JAMA. 2019;322(8):746-55.
For young patients with high-risk neuroblastoma, an intensive consolidation regimen with tandem autologous stem cell transplants was associated with significantly better event-free survival, compared with single-transplant consolidation, results of a randomized trial show.
Among 355 patients with high-risk neuroblastoma, the 3-year event-free survival (EFS) rate was 61.6% for patients randomized to tandem (sequential) autologous stem cell transplants, compared with 48.4% for patients randomized to a single transplant (P = .006), reported Julie R. Park, MD from Seattle Children’s Hospital in Washington, and coinvestigators in the Children’s Oncology Group’s ANBL0532 trial.
“Results of the current study are consistent with earlier trials demonstrating that induction chemotherapy followed by consolidation with autologous transplant improved EFS, compared with less intensive consolidation, and that further intensification of consolidation benefits some patients,” they wrote in JAMA.
But of the 652 patients enrolled in the study, only 355 were actually randomized. Although the randomization rate was slightly higher than anticipated, the authors acknowledged that the results may not apply to all patients with high-risk neuroblastoma.
Patients eligible for the trial included those with International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma aged older than 18 months; INSS stage 3 neuroblastoma aged older than 18 months with International Neuroblastoma Pathology Classification of unfavorable histology; INSS stage 2, 3, 4, or 4S neuroblastoma with MYCN amplification; and INSS stage 4 neuroblastoma diagnosed from age 12-18 months whose tumors showed any unfavorable features. Patients initially diagnosed with non–high-risk neuroblastoma (including stage 1) who had not received chemotherapy and whose disease had progressed to high-risk neuroblastoma were also eligible.
Following induction with two cycles of topotecan and cyclophosphamide, patients underwent peripheral blood stem cell collection, followed by four alternating cycles of cisplatin and etoposide and doxorubicin and cyclophosphamide, and vincristine.
For those patients who did not have primary tumors resected at diagnosis, resection was performed after the fourth or fifth cycle.
Those patients who after induction had no disease progression, no uncontrolled infection, sufficient stem cell levels, and adequate organ function were then eligible for randomization. One patient did not receive any therapy, 27 were nonrandomly assigned to single transplant, 62 were not eligible for randomization, and 207 were not randomized because of physician or family preference.
Of the remaining patients (median age at diagnosis, 36.1 months) 176 were randomized to receive tandem transplant with thiotepa and cyclophosphamide followed by dose-reduced carboplatin, etoposide, and melphalan conditioning, and 179 were randomized to single transplant with standard-dose carboplatin, etoposide, and melphalan.
A total of 17 patients died on study from toxicity; 7 during induction and 10 during consolidation. Significant transplant-related toxicities included mucositis in 11.7% of tandem-transplant patients and 15.4% of single-transplant patients, and infections in 17.8% versus 18.3%, respectively.
As noted before, 3-year EFS from the time of randomization, the primary endpoint, was higher for patients in the tandem-transplant arm (61.6% vs. 48.4%, P = .006).
The median duration of follow-up after randomization for patients without relapse, disease progression, second malignancy, or death was 5.6 years.
A post hoc analysis of the randomized patients showed a 3-year overall survival rate of 71.6%, which did not differ significantly between the study arms (74.1% for the tandem-transplant group vs. 68.1% for the single-transplant group). The analysis also showed that 3-year EFS and overall survival was higher in the tandem- versus single-transplant groups among 250 patients who also received immunotherapy with isotretinoin plus an anti-GD2 chimeric antibody and cytokines.
The trial was supported by grants from the National Institutes of Health, National Cancer Institute, National Clinical Trials Network Operations Center, and St. Baldrick’s Foundation. Dr. Park reported no relevant disclosures. Multiple coauthors disclosed grants or personal feeds outside the submitted work.
SOURCE: Park JR et al. JAMA. 2019;322(8):746-55.
FROM JAMA
Before the die is cast
When asked about my decision to choose pediatrics over the other specialty opportunities I was being offered, I have always answered that my choice was primarily based on my desire to work with children. That affinity certainly didn’t stem from my experience with my sister who is 7 years my junior. By her own admission, she was a bratty little thing and a major annoyance during my journey through adolescence. However, during the summers of high school and college I worked as a lifeguard, and one of my duties was to teach swimming classes. The joy and reward of watching children overcome their fear of the water and become competent swimmers left a positive impression, which was in stark contrast to the few classes of adult nonswimmers my coworkers and I taught. Our success rate with adults was pretty close to zero.
If I was going to spend my time and effort becoming a physician, I decided I wanted to be working with patients with the high potential for positive change and ones who had yet to accumulate a several decades long list of bad health habits. I wanted to be practicing in situations well before the die had been cast.
With this background in mind, you can understand why I was drawn to a recent article in the Harvard Gazette titled “Social spending on kids yields the biggest bang for the buck,” by Clea Simon. The article describes a recent study by Opportunity Insights, a Harvard-based institute of policy analysts and social scientists (“A Unified Welfare Analysis of Government Policies” by Nathaniel Hendren, PhD, and Ben Sprung-Keyser). Using computer algorithms capable of mining large pools of data, the researchers looked at 133 government policy changes over the last 50 years and compared the long-term results of those changes by assessing dollars spent against those returned in the form of tax revenue.
The Harvard article quotes Dr. Hendren as saying, This association was most impressive for children who came from lower-income families. This was especially true for programs that aimed at improving child health and increasing educational attainment.
Of course, these observations don’t come as a surprise to those of us who have accepted the challenge of improving the health of children. But it’s always nice to hear some new data that warms our hearts and reinforces our commitment to building healthy communities by focusing our efforts on its youngest members.
However, the paper did provide a finding that disappointed me. This big data analysis revealed that programs aimed at encouraging young people to attend college produced higher future earnings than did those focused on job training. I guess this shouldn’t be much of a surprise, but I believe we have been overemphasizing college track programs when we should be destigmatizing a career path in one of the trades. It may be that job training has been poorly done or at least not flexible enough to meet the changing demands of industry.
The investigators were surprised that their analysis demonstrated that policy changes targeted at children through their middle and high school years and even into college yielded return on investment at least as great if not greater than some successful preschool programs. Dr. Hendren responded to this finding by observing that “it’s never too late.” However, I think his comment deserves the loud and clear caveat, “as long as we are still talking about children.”
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
When asked about my decision to choose pediatrics over the other specialty opportunities I was being offered, I have always answered that my choice was primarily based on my desire to work with children. That affinity certainly didn’t stem from my experience with my sister who is 7 years my junior. By her own admission, she was a bratty little thing and a major annoyance during my journey through adolescence. However, during the summers of high school and college I worked as a lifeguard, and one of my duties was to teach swimming classes. The joy and reward of watching children overcome their fear of the water and become competent swimmers left a positive impression, which was in stark contrast to the few classes of adult nonswimmers my coworkers and I taught. Our success rate with adults was pretty close to zero.
If I was going to spend my time and effort becoming a physician, I decided I wanted to be working with patients with the high potential for positive change and ones who had yet to accumulate a several decades long list of bad health habits. I wanted to be practicing in situations well before the die had been cast.
With this background in mind, you can understand why I was drawn to a recent article in the Harvard Gazette titled “Social spending on kids yields the biggest bang for the buck,” by Clea Simon. The article describes a recent study by Opportunity Insights, a Harvard-based institute of policy analysts and social scientists (“A Unified Welfare Analysis of Government Policies” by Nathaniel Hendren, PhD, and Ben Sprung-Keyser). Using computer algorithms capable of mining large pools of data, the researchers looked at 133 government policy changes over the last 50 years and compared the long-term results of those changes by assessing dollars spent against those returned in the form of tax revenue.
The Harvard article quotes Dr. Hendren as saying, This association was most impressive for children who came from lower-income families. This was especially true for programs that aimed at improving child health and increasing educational attainment.
Of course, these observations don’t come as a surprise to those of us who have accepted the challenge of improving the health of children. But it’s always nice to hear some new data that warms our hearts and reinforces our commitment to building healthy communities by focusing our efforts on its youngest members.
However, the paper did provide a finding that disappointed me. This big data analysis revealed that programs aimed at encouraging young people to attend college produced higher future earnings than did those focused on job training. I guess this shouldn’t be much of a surprise, but I believe we have been overemphasizing college track programs when we should be destigmatizing a career path in one of the trades. It may be that job training has been poorly done or at least not flexible enough to meet the changing demands of industry.
The investigators were surprised that their analysis demonstrated that policy changes targeted at children through their middle and high school years and even into college yielded return on investment at least as great if not greater than some successful preschool programs. Dr. Hendren responded to this finding by observing that “it’s never too late.” However, I think his comment deserves the loud and clear caveat, “as long as we are still talking about children.”
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
When asked about my decision to choose pediatrics over the other specialty opportunities I was being offered, I have always answered that my choice was primarily based on my desire to work with children. That affinity certainly didn’t stem from my experience with my sister who is 7 years my junior. By her own admission, she was a bratty little thing and a major annoyance during my journey through adolescence. However, during the summers of high school and college I worked as a lifeguard, and one of my duties was to teach swimming classes. The joy and reward of watching children overcome their fear of the water and become competent swimmers left a positive impression, which was in stark contrast to the few classes of adult nonswimmers my coworkers and I taught. Our success rate with adults was pretty close to zero.
If I was going to spend my time and effort becoming a physician, I decided I wanted to be working with patients with the high potential for positive change and ones who had yet to accumulate a several decades long list of bad health habits. I wanted to be practicing in situations well before the die had been cast.
With this background in mind, you can understand why I was drawn to a recent article in the Harvard Gazette titled “Social spending on kids yields the biggest bang for the buck,” by Clea Simon. The article describes a recent study by Opportunity Insights, a Harvard-based institute of policy analysts and social scientists (“A Unified Welfare Analysis of Government Policies” by Nathaniel Hendren, PhD, and Ben Sprung-Keyser). Using computer algorithms capable of mining large pools of data, the researchers looked at 133 government policy changes over the last 50 years and compared the long-term results of those changes by assessing dollars spent against those returned in the form of tax revenue.
The Harvard article quotes Dr. Hendren as saying, This association was most impressive for children who came from lower-income families. This was especially true for programs that aimed at improving child health and increasing educational attainment.
Of course, these observations don’t come as a surprise to those of us who have accepted the challenge of improving the health of children. But it’s always nice to hear some new data that warms our hearts and reinforces our commitment to building healthy communities by focusing our efforts on its youngest members.
However, the paper did provide a finding that disappointed me. This big data analysis revealed that programs aimed at encouraging young people to attend college produced higher future earnings than did those focused on job training. I guess this shouldn’t be much of a surprise, but I believe we have been overemphasizing college track programs when we should be destigmatizing a career path in one of the trades. It may be that job training has been poorly done or at least not flexible enough to meet the changing demands of industry.
The investigators were surprised that their analysis demonstrated that policy changes targeted at children through their middle and high school years and even into college yielded return on investment at least as great if not greater than some successful preschool programs. Dr. Hendren responded to this finding by observing that “it’s never too late.” However, I think his comment deserves the loud and clear caveat, “as long as we are still talking about children.”
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
MenB vaccination coverage higher in those receiving MenB-4C
While meningococcal group B (MenB) vaccination remains suboptimal in the United States, completion was significantly higher for the MenB-4C (Bexsero) vaccine, compared with the other vaccine option, MenB-FHbp (Trumenba), according to Elizabeth Packnett of IBM Watson Health in Bethesda, Md., and associates.
In a study published in Vaccine, the investigators retrospectively analyzed 65,205 (36,118 received MenB-4C; 29,087 received MenB-FHbp) commercially insured individuals from the MarketScan Commercial Claims and Encounters Database during Jan. 1, 2015–Feb. 28, 2018, as well as 13,535 (10,153 received MenB-4C; 3,382 received MenB-FHbp) Medicaid-covered individuals from the Medicaid Multi-State Database during Jan. 1, 2015–Dec. 31, 2017.
The rate of vaccine completion in the MarketScan database within 15 months of initiation was 63% for MenB-4C and 52% for MenB-FHbp, and dosing schedule adherence was 62% for MenB-4C and 18% for MenB-FHbp. The median time to completion among those who finished vaccination was 68 days for MenB-4C versus 258 days for MenB-FHbp.
In the Medicaid database, the rate of vaccine completion within 15 months of initiation was 49% for MenB-4C and 31% for MenB-FHbp; dosing schedule adherence was 48% and 8%, respectively. Median time to vaccine completion was 88 days for MenB-4C versus 309 days for MenB-FHbp.
“The observations of improved completion and schedule adherence rates for MenB-4C, compared with MenB-FHbp, were consistent across both the commercial and Medicaid populations, and persisted after adjusting for individual factors in multivariable analyses, suggesting that the results were not skewed by population differences in demographic or other characteristics,” the investigators noted, adding that the significant difference in completion and schedule adherence between vaccines likely reflects the MenB-4C flexible dosing schedule.
The study was funded by GlaxoSmithKline, the maker of MenB-4C, and four coauthors reported being employed by the company. Five coauthors were employed by IBM Watson Health, which conducted the study.
SOURCE: Packnett E et al. Vaccine. 2019 Aug 20. doi: 10.1016/j.vaccine.2019.06.065.
While meningococcal group B (MenB) vaccination remains suboptimal in the United States, completion was significantly higher for the MenB-4C (Bexsero) vaccine, compared with the other vaccine option, MenB-FHbp (Trumenba), according to Elizabeth Packnett of IBM Watson Health in Bethesda, Md., and associates.
In a study published in Vaccine, the investigators retrospectively analyzed 65,205 (36,118 received MenB-4C; 29,087 received MenB-FHbp) commercially insured individuals from the MarketScan Commercial Claims and Encounters Database during Jan. 1, 2015–Feb. 28, 2018, as well as 13,535 (10,153 received MenB-4C; 3,382 received MenB-FHbp) Medicaid-covered individuals from the Medicaid Multi-State Database during Jan. 1, 2015–Dec. 31, 2017.
The rate of vaccine completion in the MarketScan database within 15 months of initiation was 63% for MenB-4C and 52% for MenB-FHbp, and dosing schedule adherence was 62% for MenB-4C and 18% for MenB-FHbp. The median time to completion among those who finished vaccination was 68 days for MenB-4C versus 258 days for MenB-FHbp.
In the Medicaid database, the rate of vaccine completion within 15 months of initiation was 49% for MenB-4C and 31% for MenB-FHbp; dosing schedule adherence was 48% and 8%, respectively. Median time to vaccine completion was 88 days for MenB-4C versus 309 days for MenB-FHbp.
“The observations of improved completion and schedule adherence rates for MenB-4C, compared with MenB-FHbp, were consistent across both the commercial and Medicaid populations, and persisted after adjusting for individual factors in multivariable analyses, suggesting that the results were not skewed by population differences in demographic or other characteristics,” the investigators noted, adding that the significant difference in completion and schedule adherence between vaccines likely reflects the MenB-4C flexible dosing schedule.
The study was funded by GlaxoSmithKline, the maker of MenB-4C, and four coauthors reported being employed by the company. Five coauthors were employed by IBM Watson Health, which conducted the study.
SOURCE: Packnett E et al. Vaccine. 2019 Aug 20. doi: 10.1016/j.vaccine.2019.06.065.
While meningococcal group B (MenB) vaccination remains suboptimal in the United States, completion was significantly higher for the MenB-4C (Bexsero) vaccine, compared with the other vaccine option, MenB-FHbp (Trumenba), according to Elizabeth Packnett of IBM Watson Health in Bethesda, Md., and associates.
In a study published in Vaccine, the investigators retrospectively analyzed 65,205 (36,118 received MenB-4C; 29,087 received MenB-FHbp) commercially insured individuals from the MarketScan Commercial Claims and Encounters Database during Jan. 1, 2015–Feb. 28, 2018, as well as 13,535 (10,153 received MenB-4C; 3,382 received MenB-FHbp) Medicaid-covered individuals from the Medicaid Multi-State Database during Jan. 1, 2015–Dec. 31, 2017.
The rate of vaccine completion in the MarketScan database within 15 months of initiation was 63% for MenB-4C and 52% for MenB-FHbp, and dosing schedule adherence was 62% for MenB-4C and 18% for MenB-FHbp. The median time to completion among those who finished vaccination was 68 days for MenB-4C versus 258 days for MenB-FHbp.
In the Medicaid database, the rate of vaccine completion within 15 months of initiation was 49% for MenB-4C and 31% for MenB-FHbp; dosing schedule adherence was 48% and 8%, respectively. Median time to vaccine completion was 88 days for MenB-4C versus 309 days for MenB-FHbp.
“The observations of improved completion and schedule adherence rates for MenB-4C, compared with MenB-FHbp, were consistent across both the commercial and Medicaid populations, and persisted after adjusting for individual factors in multivariable analyses, suggesting that the results were not skewed by population differences in demographic or other characteristics,” the investigators noted, adding that the significant difference in completion and schedule adherence between vaccines likely reflects the MenB-4C flexible dosing schedule.
The study was funded by GlaxoSmithKline, the maker of MenB-4C, and four coauthors reported being employed by the company. Five coauthors were employed by IBM Watson Health, which conducted the study.
SOURCE: Packnett E et al. Vaccine. 2019 Aug 20. doi: 10.1016/j.vaccine.2019.06.065.
FROM VACCINE
Use hospital MRSA rates to guide pediatric osteomyelitis treatment
SEATTLE – If your hospital’s methicillin-resistant Staphylococcus aureus rate is less than 10%, cefazolin is a reasonable empiric choice for pediatric acute hematogenous osteomyelitis (AHO). It covers the usual suspects: methicillin-susceptible Staphylococcus aureus, group A Streptococcus, and Kingella.
Above the 10% mark, coverage should include considerations of MRSA; clindamycin is good option so long as 85% of isolates are susceptible. Above that, it’s time for vancomycin, according to Nivedita Srinivas, MD, a pediatric infectious disease specialist at Stanford (Calif.) University.
There are no practice guidelines in the United States for the diagnosis and management of AHO in children; Dr. Srinivas and colleagues sought to plug the gaps in a talk at Pediatric Hospitalist Medicine.
Pediatric AHO is more common in children under 5 years old and in boys. Lower extremities are the usual targets. Staphylococcus aureus, group B Streptococcus, and gram negatives are the most common causes in newborns; Staphylococcus aureus, group A Streptococcus, and Kingella in older infants and preschoolers; and Staphylococcus aureus and group A Streptococcus in older children.
About half the time, treatment remains empiric because nothing grows out on culture, and there are a few clinical pearls to keep in mind in those cases. A family history of boils or spider bites is suspicious for MRSA, and coverage should include Salmonella in children with abnormal hemoglobins and Streptococcus pneumoniae in children without a spleen or with functional asplenia. Pseudomonas has to be kept in mind with puncture wounds, and Brucella in children who drink unpasteurized milk, Dr. Srinivas said.
A switch from IV to oral therapy is appropriate when C-reactive protein (CRP) drops 50% from its peak or below 3 mg/dL, positive cultures – if any – turn negative, fever has been absent for 24 hours, there’s no sign of metastatic disease, and patients have markedly reduced pain and can bear weight on the infected limb, said copresenter Marie Wang, MD, also a pediatric infectious disease specialist at Stanford.
The oral switch, of course, must have similar coverage as the IV antibiotic: high-dose cephalexin for cefazolin, for instance. Children can be sent home on a PICC line to continue IV treatment, but they won’t do any better than children switched to an oral treatment, and the indwelling catheter can cause problems, she said.
Pleuritic or other sudden pain at a distant site suggests septic emboli. “[Staphylococcus aureus] is notorious for going places you don’t” expect it to go “and forming microabscesses, which become larger abscesses” and need to be drained, said the third presenter, Russell McCulloh, MD, a pediatric infectious disease specialist at the University of Nebraska Medical Center, Omaha.
Four weeks of antibiotics are usually enough, so long as there aren’t complications such as septic thrombophlebitis, endocarditis, sickle cell disease, skull involvement, or immunodeficiencies. Source control and good, postdischarge care – including regular CRP and antibiotic toxicity labs – are critical. Monitoring is recommended for a year.
“X-rays are good at looking for longer-term complications, but bony abnormalities are not going to show up for the first 2 weeks,” Dr. McCulloh said.
The presenters didn’t have any relevant disclosures. The meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
SEATTLE – If your hospital’s methicillin-resistant Staphylococcus aureus rate is less than 10%, cefazolin is a reasonable empiric choice for pediatric acute hematogenous osteomyelitis (AHO). It covers the usual suspects: methicillin-susceptible Staphylococcus aureus, group A Streptococcus, and Kingella.
Above the 10% mark, coverage should include considerations of MRSA; clindamycin is good option so long as 85% of isolates are susceptible. Above that, it’s time for vancomycin, according to Nivedita Srinivas, MD, a pediatric infectious disease specialist at Stanford (Calif.) University.
There are no practice guidelines in the United States for the diagnosis and management of AHO in children; Dr. Srinivas and colleagues sought to plug the gaps in a talk at Pediatric Hospitalist Medicine.
Pediatric AHO is more common in children under 5 years old and in boys. Lower extremities are the usual targets. Staphylococcus aureus, group B Streptococcus, and gram negatives are the most common causes in newborns; Staphylococcus aureus, group A Streptococcus, and Kingella in older infants and preschoolers; and Staphylococcus aureus and group A Streptococcus in older children.
About half the time, treatment remains empiric because nothing grows out on culture, and there are a few clinical pearls to keep in mind in those cases. A family history of boils or spider bites is suspicious for MRSA, and coverage should include Salmonella in children with abnormal hemoglobins and Streptococcus pneumoniae in children without a spleen or with functional asplenia. Pseudomonas has to be kept in mind with puncture wounds, and Brucella in children who drink unpasteurized milk, Dr. Srinivas said.
A switch from IV to oral therapy is appropriate when C-reactive protein (CRP) drops 50% from its peak or below 3 mg/dL, positive cultures – if any – turn negative, fever has been absent for 24 hours, there’s no sign of metastatic disease, and patients have markedly reduced pain and can bear weight on the infected limb, said copresenter Marie Wang, MD, also a pediatric infectious disease specialist at Stanford.
The oral switch, of course, must have similar coverage as the IV antibiotic: high-dose cephalexin for cefazolin, for instance. Children can be sent home on a PICC line to continue IV treatment, but they won’t do any better than children switched to an oral treatment, and the indwelling catheter can cause problems, she said.
Pleuritic or other sudden pain at a distant site suggests septic emboli. “[Staphylococcus aureus] is notorious for going places you don’t” expect it to go “and forming microabscesses, which become larger abscesses” and need to be drained, said the third presenter, Russell McCulloh, MD, a pediatric infectious disease specialist at the University of Nebraska Medical Center, Omaha.
Four weeks of antibiotics are usually enough, so long as there aren’t complications such as septic thrombophlebitis, endocarditis, sickle cell disease, skull involvement, or immunodeficiencies. Source control and good, postdischarge care – including regular CRP and antibiotic toxicity labs – are critical. Monitoring is recommended for a year.
“X-rays are good at looking for longer-term complications, but bony abnormalities are not going to show up for the first 2 weeks,” Dr. McCulloh said.
The presenters didn’t have any relevant disclosures. The meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
SEATTLE – If your hospital’s methicillin-resistant Staphylococcus aureus rate is less than 10%, cefazolin is a reasonable empiric choice for pediatric acute hematogenous osteomyelitis (AHO). It covers the usual suspects: methicillin-susceptible Staphylococcus aureus, group A Streptococcus, and Kingella.
Above the 10% mark, coverage should include considerations of MRSA; clindamycin is good option so long as 85% of isolates are susceptible. Above that, it’s time for vancomycin, according to Nivedita Srinivas, MD, a pediatric infectious disease specialist at Stanford (Calif.) University.
There are no practice guidelines in the United States for the diagnosis and management of AHO in children; Dr. Srinivas and colleagues sought to plug the gaps in a talk at Pediatric Hospitalist Medicine.
Pediatric AHO is more common in children under 5 years old and in boys. Lower extremities are the usual targets. Staphylococcus aureus, group B Streptococcus, and gram negatives are the most common causes in newborns; Staphylococcus aureus, group A Streptococcus, and Kingella in older infants and preschoolers; and Staphylococcus aureus and group A Streptococcus in older children.
About half the time, treatment remains empiric because nothing grows out on culture, and there are a few clinical pearls to keep in mind in those cases. A family history of boils or spider bites is suspicious for MRSA, and coverage should include Salmonella in children with abnormal hemoglobins and Streptococcus pneumoniae in children without a spleen or with functional asplenia. Pseudomonas has to be kept in mind with puncture wounds, and Brucella in children who drink unpasteurized milk, Dr. Srinivas said.
A switch from IV to oral therapy is appropriate when C-reactive protein (CRP) drops 50% from its peak or below 3 mg/dL, positive cultures – if any – turn negative, fever has been absent for 24 hours, there’s no sign of metastatic disease, and patients have markedly reduced pain and can bear weight on the infected limb, said copresenter Marie Wang, MD, also a pediatric infectious disease specialist at Stanford.
The oral switch, of course, must have similar coverage as the IV antibiotic: high-dose cephalexin for cefazolin, for instance. Children can be sent home on a PICC line to continue IV treatment, but they won’t do any better than children switched to an oral treatment, and the indwelling catheter can cause problems, she said.
Pleuritic or other sudden pain at a distant site suggests septic emboli. “[Staphylococcus aureus] is notorious for going places you don’t” expect it to go “and forming microabscesses, which become larger abscesses” and need to be drained, said the third presenter, Russell McCulloh, MD, a pediatric infectious disease specialist at the University of Nebraska Medical Center, Omaha.
Four weeks of antibiotics are usually enough, so long as there aren’t complications such as septic thrombophlebitis, endocarditis, sickle cell disease, skull involvement, or immunodeficiencies. Source control and good, postdischarge care – including regular CRP and antibiotic toxicity labs – are critical. Monitoring is recommended for a year.
“X-rays are good at looking for longer-term complications, but bony abnormalities are not going to show up for the first 2 weeks,” Dr. McCulloh said.
The presenters didn’t have any relevant disclosures. The meeting was sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
EXPERT ANALYSIS FROM PHM 2019
Mysterious vaping lung injuries may have flown under regulatory radar
It was the arrival of the second man in his early 20s gasping for air that alarmed Dixie Harris, MD. Young patients rarely get so sick, so fast, with a severe lung illness, and this was her second case in a matter of days.
Then she saw three more patients at her Utah telehealth clinic with similar symptoms. They did not have infections, but all had been vaping. When Dr. Harris heard several teenagers in Wisconsin had been hospitalized in similar cases, she quickly alerted her state health department.
As patients in hospitals across the country combat a mysterious illness linked to e-cigarettes, federal and state investigators are frantically trying to trace the outbreaks to specific vaping products that, until recently, were virtually unregulated.
As of Aug. 22, 2019, 193 potential vaping-related illnesses in 22 states had been reported to the Centers for Disease Control and Prevention. Wisconsin, which first put out an alert in July, has at least 16 confirmed and 15 suspected cases. Illinois has reported 34 patients, 1 of whom has died. Indiana is investigating 24 cases.
Lung doctors said they had seen warning signs for years that vaping could be hazardous as they treated patients. Medically it seemed problematic since it often involved inhaling chemicals not normally inhaled into the lungs. Despite that, assessing the safety of a new product storming the market fell between regulatory cracks, leaving doctors unsure where to register concerns before the outbreak. The Food and Drug Administration took years to regulate e-cigarettes once a court determined it had the authority to do so.
“You don’t know what you’re putting into your lungs when you vape,” said Dr. Harris, a critical care pulmonologist. “It’s purported to be safe, but how do you know if it’s safe? To me, it’s a very dangerous thing.”
Off the radar
When e-cigarettes came to market about a decade ago, they fell into a regulatory no man’s land. They are not a food, not a drug, and not a medical device, any of which would have put them immediately in the FDA’s purview. And, until a few years ago, they weren’t even lumped in with tobacco products.
As a result, billions of dollars of vaping products have been sold online, at big-box retailers, and in corner stores without going through the FDA’s rigorous review process to assess their safety. Companies like Juul, Blu, and NJoy quickly established their brands of devices and cartridges, or pods. And thousands of related products are sold, sometimes on the black market, over the Internet, or beyond.
“It makes it really tough because we don’t know what we’re looking for,” said Ruth Lynfield, MD, the state epidemiologist for Minnesota, where several patients were admitted to the ICU as a result of the illness. She added that, if it turns out that the products in question were sold by unregistered retailers and manufacturers “on the street,” outbreak sleuths will have a harder time figuring out exactly what is in them.
With e-cigarettes, people can vape – or smoke – nicotine products, selecting flavorings like mint, mango, blueberry crème brûlée, or cookies and milk. They can also inhale cannabis products. Many are hopeful that e-cigarettes might be useful smoking cessation tools, but some research has called that into question.
The mysterious pulmonary disease cases have been linked to vaping, but it’s unclear whether there is a common device or chemical. In some states, including California and Utah, all of the patients had vaped cannabis products. One or more substances could be involved, health officials have said. The products used by several victims are being tested to see what they contained.
And this has apparently been the case for years.
Multiple doctors described seeing earlier cases of severe lung problems linked to vaping that were not officially reported or included in the current CDC count.
Laura Crotty Alexander, MD, a pulmonologist and researcher with the University of California, San Diego, said she saw her first case about 2 years ago. A young man had been vaping for months with the same device but developed acute lung injury when he switched flavors. She strongly suspected a link, but did not report the illness anywhere.
“It wasn’t that I didn’t want to report it, it’s that there’s no pathway” to do so, Dr. Alexander said.
She said she’s concerned that many physicians haven’t been asking patients about e-cigarette use and that there’s no way to document a case like this in the medical coding system.
John E. Parker, MD, of West Virginia University, Morgantown, said he saw his first patient with pneumonia tied to vaping in 2015. Doctors there were intrigued enough to report on the case at the annual meeting of the American College of Chest Physicians. Dr. Parker and his team didn’t contact a federal agency, and Dr. Parker said it was unclear whom to call.
Numerous other cases have been reported in medical journals and at professional conferences in the years since. The FDA’s voluntary system for reporting tobacco-related health problems included 96 seizures and only 1 lung ailment tied to e-cigarettes between April and June 2019. The system appears to be utilized most by concerned citizens, rather than manufacturers or health care professionals.
But several lung specialists said that due to the patchwork nature of regulatory oversight over the years, the true scope of the problem is yet to be identified.
“We do know that e-cigarettes do not emit a harmless aerosol,” said Brian King, PhD, MPH, a deputy director in the Office on Smoking and Health at the CDC in a call with media on Aug. 23 about the outbreak. “It is possible that some of these cases were already occurring but we were not picking them up.”
Regulatory limits
The FDA has had limited authority to regulate e-cigarettes over the years.
In 2009, Congress passed the Family Smoking Prevention and Tobacco Control Act, empowering the FDA to oversee the safety and sale of tobacco products. But e-cigarettes, still new, were not top of mind.
Later that year, the FDA tried to block imports of e-cigarettes, saying the combination drug-device products were unapproved and therefore illegal for sale in the United States. Two vaping companies, Smoking Everywhere and NJoy, sued, and a federal judge ruled in 2010 that the FDA should regulate e-cigarettes as tobacco products.
It took the agency 6 years to finalize what’s become known as the “deeming rule,” in which it formally began regulating e-cigarettes and e-liquids.
By then, it was May 2016, and the e-cigarette market had swelled to an estimated $4.1 billion, Wells Fargo Securities analyst Bonnie Herzog said at the time. Market researchers now project that the global industry could reach $48 billion by 2023.
Critics say the FDA took too long to act.
“I think the fact that FDA has been dillydallying [has made] figuring out what’s going on [with this outbreak] much harder,” said Stanton Glantz, PhD, a University of California, San Francisco, professor in its Center for Tobacco Control Research and Education. “No question.”
The agency began by banning e-cigarette sales to minors and requiring all new vaping products to submit applications for authorization before they could come to market. Companies and retailers with thousands of products already on the market were granted 2 years to submit applications, and the FDA would get an additional year to evaluate the applications. Meanwhile, existing products could still be sold.
But when Scott Gottlieb, MD, arrived as the new FDA commissioner in 2017, the rule hadn’t been implemented and there was no formal guidance for companies to file applications, he said. As a result, he pushed the deadline back to 2022, drawing ire from public health advocates, who called foul over his previous ties to an e-cigarette retailer called Kure.
“I thought e-cigarettes at the time – and I still believe – that they represent an opportunity for currently addicted adult smokers to transition off of combustible tobacco,” he said in an interview, adding that other parts of the deeming rule went into effect as planned. “All I did was delay the application deadline.”
Dr. Gottlieb’s thinking changed the following year, when a national survey showed a sharp rise in teen vaping, which he called an “epidemic.” He announced that the agency would rethink the extended deadline and weigh whether to take flavors that appeal to kids off the market.
A judge ruled last month that e-cigarette makers would have only 10 more months to submit applications to the FDA. They’re now due in May 2020.
Asked about the lung injuries appearing now, Dr. Gottlieb, who left the FDA in April 2019, said he suspected counterfeit pods are to blame, given the geographic clustering of cases and the fact that, overall, the FDA is inspecting registered e-cigarette makers and retailers to make sure they’re complying with existing regulations.
“I think the manufacturers are culpable if their products are being used, whether the liquids are counterfeit or real,” he said. “Ultimately, they’re responsible for keeping their products out of the hands of kids.”
Juul, the leading e-cigarette maker, agreed that children shouldn’t be able to vape its products, and said curtailing access should be done “through significant regulation” and “enforcement.”
“When people say ‘Why aren’t these being regulated?’ They actually are all being regulated,” Dr. Gottlieb said.
For example, companies are required to label their products as potentially addictive, sell only to adults and comply with manufacturing standards. The agency has conducted thousands of inspections of e-cigarette manufacturers and retailers and taken enforcement actions against companies selling e-cigarettes that look like juice boxes, and against a company that was putting the ingredients found in erectile dysfunction drugs into its vape liquid.
Health departments investigating the outbreak told Kaiser Health News that e-cigarettes’ niche as a tobacco product instead of a drug has presented challenges. Most weren’t aware that adverse events could be reported to a database that tracks problems with tobacco products. And, because e-cigarettes never went through the FDA’s “gold-standard” approval process for drugs, doctors can’t readily look up a detailed list of known side effects.
But like other arms of the FDA, the tobacco office has tools and a team to investigate a public health threat just as the teams for drugs and devices do, Dr. Gottlieb said. It may even be better equipped because of its funding.
“I don’t think FDA is operating in any way with hands tied behind its back because of the way that the statute is set up,” he said.
Teen vaping has exploded during this regulatory tussle. In 2011, 1.5% of high school students reported vaping. By 2018, it was 20.8%, according to a CDC report.
Unknown components
Still, doctors and researchers are concerned about the ingredients in e-cigarettes and how little the public knows about the risks of vaping.
In Juul’s terms and conditions, posted on its website, it says, “We encourage consumers to do their own research regarding vapor products and what is right for them.” Many ingredients in e-cigarette products, however, are protected as trade secrets.
Since at least 2013, the flavor industry has expressed concern about the use of flavoring chemicals in vaping products.
The vast majority of the chemicals have been tested only by ingesting them in small quantities because they’re encountered in foods. For most of these chemicals, there have been no tests to determine whether it is safe to inhale them, as happens daily by millions when they use e-cigarettes.
“Many of the ingredients of vaping products, including flavoring substances, have not been tested for … the exposure one would get from using a vaping device,” said John Hallagan, a senior adviser to the Flavor and Extract Manufacturers Association. The group has sent cease-and-desist letters to e-cigarette companies in previous years for using the food safety certification of the flavor industry to imply that the chemicals are also safe in e-cigarettes.
Some flavor chemicals are thought to be harmful when inhaled in high doses. Research suggests that cinnamaldehyde, the main component of many cinnamon flavors, may impair lung function when inhaled. Sven-Eric Jordt, PhD, a professor at Duke University, Durham, N.C., says he presented evidence of its dangers at an FDA meeting in 2015 — and its relative abundance in many e-cigarette vaping liquids. In response, one major e-cigarette liquid seller, Tasty Vapor, voluntarily took its cinnamon-flavored liquid off the shelves.
In 2017, when Dr. Gottlieb delayed the FDA application deadline, the product was back. A company email to its customers put it this way: “Two years ago, Tasty Vapor allowed itself to be intimidated by scaremongering tactics. … We lost a lot of sales as well as a good number of long-time customers. We no long see reason to disappoint our customers hostage for these shady tactics.”
At the time of publication, Tasty Vapor’s owner did not reply to a request for comment.
Dr. Jordt said he is frustrated by the delays in the regulatory approval process.
“As a parent, I would say that the government has not acted on this,” he said. “You’re basically left to act alone with your addicted kid. It’s kind of terrifying that this was allowed to happen. The industry needs to be held to account.”
Kaiser Health News correspondents Cara Anthony, Markian Hawryluk, and Lauren Weber, as well as reporter Victoria Knight contributed to this report. This story first published on California Healthline, a service of the California Health Care Foundation.
Kaiser Health News is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.
It was the arrival of the second man in his early 20s gasping for air that alarmed Dixie Harris, MD. Young patients rarely get so sick, so fast, with a severe lung illness, and this was her second case in a matter of days.
Then she saw three more patients at her Utah telehealth clinic with similar symptoms. They did not have infections, but all had been vaping. When Dr. Harris heard several teenagers in Wisconsin had been hospitalized in similar cases, she quickly alerted her state health department.
As patients in hospitals across the country combat a mysterious illness linked to e-cigarettes, federal and state investigators are frantically trying to trace the outbreaks to specific vaping products that, until recently, were virtually unregulated.
As of Aug. 22, 2019, 193 potential vaping-related illnesses in 22 states had been reported to the Centers for Disease Control and Prevention. Wisconsin, which first put out an alert in July, has at least 16 confirmed and 15 suspected cases. Illinois has reported 34 patients, 1 of whom has died. Indiana is investigating 24 cases.
Lung doctors said they had seen warning signs for years that vaping could be hazardous as they treated patients. Medically it seemed problematic since it often involved inhaling chemicals not normally inhaled into the lungs. Despite that, assessing the safety of a new product storming the market fell between regulatory cracks, leaving doctors unsure where to register concerns before the outbreak. The Food and Drug Administration took years to regulate e-cigarettes once a court determined it had the authority to do so.
“You don’t know what you’re putting into your lungs when you vape,” said Dr. Harris, a critical care pulmonologist. “It’s purported to be safe, but how do you know if it’s safe? To me, it’s a very dangerous thing.”
Off the radar
When e-cigarettes came to market about a decade ago, they fell into a regulatory no man’s land. They are not a food, not a drug, and not a medical device, any of which would have put them immediately in the FDA’s purview. And, until a few years ago, they weren’t even lumped in with tobacco products.
As a result, billions of dollars of vaping products have been sold online, at big-box retailers, and in corner stores without going through the FDA’s rigorous review process to assess their safety. Companies like Juul, Blu, and NJoy quickly established their brands of devices and cartridges, or pods. And thousands of related products are sold, sometimes on the black market, over the Internet, or beyond.
“It makes it really tough because we don’t know what we’re looking for,” said Ruth Lynfield, MD, the state epidemiologist for Minnesota, where several patients were admitted to the ICU as a result of the illness. She added that, if it turns out that the products in question were sold by unregistered retailers and manufacturers “on the street,” outbreak sleuths will have a harder time figuring out exactly what is in them.
With e-cigarettes, people can vape – or smoke – nicotine products, selecting flavorings like mint, mango, blueberry crème brûlée, or cookies and milk. They can also inhale cannabis products. Many are hopeful that e-cigarettes might be useful smoking cessation tools, but some research has called that into question.
The mysterious pulmonary disease cases have been linked to vaping, but it’s unclear whether there is a common device or chemical. In some states, including California and Utah, all of the patients had vaped cannabis products. One or more substances could be involved, health officials have said. The products used by several victims are being tested to see what they contained.
And this has apparently been the case for years.
Multiple doctors described seeing earlier cases of severe lung problems linked to vaping that were not officially reported or included in the current CDC count.
Laura Crotty Alexander, MD, a pulmonologist and researcher with the University of California, San Diego, said she saw her first case about 2 years ago. A young man had been vaping for months with the same device but developed acute lung injury when he switched flavors. She strongly suspected a link, but did not report the illness anywhere.
“It wasn’t that I didn’t want to report it, it’s that there’s no pathway” to do so, Dr. Alexander said.
She said she’s concerned that many physicians haven’t been asking patients about e-cigarette use and that there’s no way to document a case like this in the medical coding system.
John E. Parker, MD, of West Virginia University, Morgantown, said he saw his first patient with pneumonia tied to vaping in 2015. Doctors there were intrigued enough to report on the case at the annual meeting of the American College of Chest Physicians. Dr. Parker and his team didn’t contact a federal agency, and Dr. Parker said it was unclear whom to call.
Numerous other cases have been reported in medical journals and at professional conferences in the years since. The FDA’s voluntary system for reporting tobacco-related health problems included 96 seizures and only 1 lung ailment tied to e-cigarettes between April and June 2019. The system appears to be utilized most by concerned citizens, rather than manufacturers or health care professionals.
But several lung specialists said that due to the patchwork nature of regulatory oversight over the years, the true scope of the problem is yet to be identified.
“We do know that e-cigarettes do not emit a harmless aerosol,” said Brian King, PhD, MPH, a deputy director in the Office on Smoking and Health at the CDC in a call with media on Aug. 23 about the outbreak. “It is possible that some of these cases were already occurring but we were not picking them up.”
Regulatory limits
The FDA has had limited authority to regulate e-cigarettes over the years.
In 2009, Congress passed the Family Smoking Prevention and Tobacco Control Act, empowering the FDA to oversee the safety and sale of tobacco products. But e-cigarettes, still new, were not top of mind.
Later that year, the FDA tried to block imports of e-cigarettes, saying the combination drug-device products were unapproved and therefore illegal for sale in the United States. Two vaping companies, Smoking Everywhere and NJoy, sued, and a federal judge ruled in 2010 that the FDA should regulate e-cigarettes as tobacco products.
It took the agency 6 years to finalize what’s become known as the “deeming rule,” in which it formally began regulating e-cigarettes and e-liquids.
By then, it was May 2016, and the e-cigarette market had swelled to an estimated $4.1 billion, Wells Fargo Securities analyst Bonnie Herzog said at the time. Market researchers now project that the global industry could reach $48 billion by 2023.
Critics say the FDA took too long to act.
“I think the fact that FDA has been dillydallying [has made] figuring out what’s going on [with this outbreak] much harder,” said Stanton Glantz, PhD, a University of California, San Francisco, professor in its Center for Tobacco Control Research and Education. “No question.”
The agency began by banning e-cigarette sales to minors and requiring all new vaping products to submit applications for authorization before they could come to market. Companies and retailers with thousands of products already on the market were granted 2 years to submit applications, and the FDA would get an additional year to evaluate the applications. Meanwhile, existing products could still be sold.
But when Scott Gottlieb, MD, arrived as the new FDA commissioner in 2017, the rule hadn’t been implemented and there was no formal guidance for companies to file applications, he said. As a result, he pushed the deadline back to 2022, drawing ire from public health advocates, who called foul over his previous ties to an e-cigarette retailer called Kure.
“I thought e-cigarettes at the time – and I still believe – that they represent an opportunity for currently addicted adult smokers to transition off of combustible tobacco,” he said in an interview, adding that other parts of the deeming rule went into effect as planned. “All I did was delay the application deadline.”
Dr. Gottlieb’s thinking changed the following year, when a national survey showed a sharp rise in teen vaping, which he called an “epidemic.” He announced that the agency would rethink the extended deadline and weigh whether to take flavors that appeal to kids off the market.
A judge ruled last month that e-cigarette makers would have only 10 more months to submit applications to the FDA. They’re now due in May 2020.
Asked about the lung injuries appearing now, Dr. Gottlieb, who left the FDA in April 2019, said he suspected counterfeit pods are to blame, given the geographic clustering of cases and the fact that, overall, the FDA is inspecting registered e-cigarette makers and retailers to make sure they’re complying with existing regulations.
“I think the manufacturers are culpable if their products are being used, whether the liquids are counterfeit or real,” he said. “Ultimately, they’re responsible for keeping their products out of the hands of kids.”
Juul, the leading e-cigarette maker, agreed that children shouldn’t be able to vape its products, and said curtailing access should be done “through significant regulation” and “enforcement.”
“When people say ‘Why aren’t these being regulated?’ They actually are all being regulated,” Dr. Gottlieb said.
For example, companies are required to label their products as potentially addictive, sell only to adults and comply with manufacturing standards. The agency has conducted thousands of inspections of e-cigarette manufacturers and retailers and taken enforcement actions against companies selling e-cigarettes that look like juice boxes, and against a company that was putting the ingredients found in erectile dysfunction drugs into its vape liquid.
Health departments investigating the outbreak told Kaiser Health News that e-cigarettes’ niche as a tobacco product instead of a drug has presented challenges. Most weren’t aware that adverse events could be reported to a database that tracks problems with tobacco products. And, because e-cigarettes never went through the FDA’s “gold-standard” approval process for drugs, doctors can’t readily look up a detailed list of known side effects.
But like other arms of the FDA, the tobacco office has tools and a team to investigate a public health threat just as the teams for drugs and devices do, Dr. Gottlieb said. It may even be better equipped because of its funding.
“I don’t think FDA is operating in any way with hands tied behind its back because of the way that the statute is set up,” he said.
Teen vaping has exploded during this regulatory tussle. In 2011, 1.5% of high school students reported vaping. By 2018, it was 20.8%, according to a CDC report.
Unknown components
Still, doctors and researchers are concerned about the ingredients in e-cigarettes and how little the public knows about the risks of vaping.
In Juul’s terms and conditions, posted on its website, it says, “We encourage consumers to do their own research regarding vapor products and what is right for them.” Many ingredients in e-cigarette products, however, are protected as trade secrets.
Since at least 2013, the flavor industry has expressed concern about the use of flavoring chemicals in vaping products.
The vast majority of the chemicals have been tested only by ingesting them in small quantities because they’re encountered in foods. For most of these chemicals, there have been no tests to determine whether it is safe to inhale them, as happens daily by millions when they use e-cigarettes.
“Many of the ingredients of vaping products, including flavoring substances, have not been tested for … the exposure one would get from using a vaping device,” said John Hallagan, a senior adviser to the Flavor and Extract Manufacturers Association. The group has sent cease-and-desist letters to e-cigarette companies in previous years for using the food safety certification of the flavor industry to imply that the chemicals are also safe in e-cigarettes.
Some flavor chemicals are thought to be harmful when inhaled in high doses. Research suggests that cinnamaldehyde, the main component of many cinnamon flavors, may impair lung function when inhaled. Sven-Eric Jordt, PhD, a professor at Duke University, Durham, N.C., says he presented evidence of its dangers at an FDA meeting in 2015 — and its relative abundance in many e-cigarette vaping liquids. In response, one major e-cigarette liquid seller, Tasty Vapor, voluntarily took its cinnamon-flavored liquid off the shelves.
In 2017, when Dr. Gottlieb delayed the FDA application deadline, the product was back. A company email to its customers put it this way: “Two years ago, Tasty Vapor allowed itself to be intimidated by scaremongering tactics. … We lost a lot of sales as well as a good number of long-time customers. We no long see reason to disappoint our customers hostage for these shady tactics.”
At the time of publication, Tasty Vapor’s owner did not reply to a request for comment.
Dr. Jordt said he is frustrated by the delays in the regulatory approval process.
“As a parent, I would say that the government has not acted on this,” he said. “You’re basically left to act alone with your addicted kid. It’s kind of terrifying that this was allowed to happen. The industry needs to be held to account.”
Kaiser Health News correspondents Cara Anthony, Markian Hawryluk, and Lauren Weber, as well as reporter Victoria Knight contributed to this report. This story first published on California Healthline, a service of the California Health Care Foundation.
Kaiser Health News is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.
It was the arrival of the second man in his early 20s gasping for air that alarmed Dixie Harris, MD. Young patients rarely get so sick, so fast, with a severe lung illness, and this was her second case in a matter of days.
Then she saw three more patients at her Utah telehealth clinic with similar symptoms. They did not have infections, but all had been vaping. When Dr. Harris heard several teenagers in Wisconsin had been hospitalized in similar cases, she quickly alerted her state health department.
As patients in hospitals across the country combat a mysterious illness linked to e-cigarettes, federal and state investigators are frantically trying to trace the outbreaks to specific vaping products that, until recently, were virtually unregulated.
As of Aug. 22, 2019, 193 potential vaping-related illnesses in 22 states had been reported to the Centers for Disease Control and Prevention. Wisconsin, which first put out an alert in July, has at least 16 confirmed and 15 suspected cases. Illinois has reported 34 patients, 1 of whom has died. Indiana is investigating 24 cases.
Lung doctors said they had seen warning signs for years that vaping could be hazardous as they treated patients. Medically it seemed problematic since it often involved inhaling chemicals not normally inhaled into the lungs. Despite that, assessing the safety of a new product storming the market fell between regulatory cracks, leaving doctors unsure where to register concerns before the outbreak. The Food and Drug Administration took years to regulate e-cigarettes once a court determined it had the authority to do so.
“You don’t know what you’re putting into your lungs when you vape,” said Dr. Harris, a critical care pulmonologist. “It’s purported to be safe, but how do you know if it’s safe? To me, it’s a very dangerous thing.”
Off the radar
When e-cigarettes came to market about a decade ago, they fell into a regulatory no man’s land. They are not a food, not a drug, and not a medical device, any of which would have put them immediately in the FDA’s purview. And, until a few years ago, they weren’t even lumped in with tobacco products.
As a result, billions of dollars of vaping products have been sold online, at big-box retailers, and in corner stores without going through the FDA’s rigorous review process to assess their safety. Companies like Juul, Blu, and NJoy quickly established their brands of devices and cartridges, or pods. And thousands of related products are sold, sometimes on the black market, over the Internet, or beyond.
“It makes it really tough because we don’t know what we’re looking for,” said Ruth Lynfield, MD, the state epidemiologist for Minnesota, where several patients were admitted to the ICU as a result of the illness. She added that, if it turns out that the products in question were sold by unregistered retailers and manufacturers “on the street,” outbreak sleuths will have a harder time figuring out exactly what is in them.
With e-cigarettes, people can vape – or smoke – nicotine products, selecting flavorings like mint, mango, blueberry crème brûlée, or cookies and milk. They can also inhale cannabis products. Many are hopeful that e-cigarettes might be useful smoking cessation tools, but some research has called that into question.
The mysterious pulmonary disease cases have been linked to vaping, but it’s unclear whether there is a common device or chemical. In some states, including California and Utah, all of the patients had vaped cannabis products. One or more substances could be involved, health officials have said. The products used by several victims are being tested to see what they contained.
And this has apparently been the case for years.
Multiple doctors described seeing earlier cases of severe lung problems linked to vaping that were not officially reported or included in the current CDC count.
Laura Crotty Alexander, MD, a pulmonologist and researcher with the University of California, San Diego, said she saw her first case about 2 years ago. A young man had been vaping for months with the same device but developed acute lung injury when he switched flavors. She strongly suspected a link, but did not report the illness anywhere.
“It wasn’t that I didn’t want to report it, it’s that there’s no pathway” to do so, Dr. Alexander said.
She said she’s concerned that many physicians haven’t been asking patients about e-cigarette use and that there’s no way to document a case like this in the medical coding system.
John E. Parker, MD, of West Virginia University, Morgantown, said he saw his first patient with pneumonia tied to vaping in 2015. Doctors there were intrigued enough to report on the case at the annual meeting of the American College of Chest Physicians. Dr. Parker and his team didn’t contact a federal agency, and Dr. Parker said it was unclear whom to call.
Numerous other cases have been reported in medical journals and at professional conferences in the years since. The FDA’s voluntary system for reporting tobacco-related health problems included 96 seizures and only 1 lung ailment tied to e-cigarettes between April and June 2019. The system appears to be utilized most by concerned citizens, rather than manufacturers or health care professionals.
But several lung specialists said that due to the patchwork nature of regulatory oversight over the years, the true scope of the problem is yet to be identified.
“We do know that e-cigarettes do not emit a harmless aerosol,” said Brian King, PhD, MPH, a deputy director in the Office on Smoking and Health at the CDC in a call with media on Aug. 23 about the outbreak. “It is possible that some of these cases were already occurring but we were not picking them up.”
Regulatory limits
The FDA has had limited authority to regulate e-cigarettes over the years.
In 2009, Congress passed the Family Smoking Prevention and Tobacco Control Act, empowering the FDA to oversee the safety and sale of tobacco products. But e-cigarettes, still new, were not top of mind.
Later that year, the FDA tried to block imports of e-cigarettes, saying the combination drug-device products were unapproved and therefore illegal for sale in the United States. Two vaping companies, Smoking Everywhere and NJoy, sued, and a federal judge ruled in 2010 that the FDA should regulate e-cigarettes as tobacco products.
It took the agency 6 years to finalize what’s become known as the “deeming rule,” in which it formally began regulating e-cigarettes and e-liquids.
By then, it was May 2016, and the e-cigarette market had swelled to an estimated $4.1 billion, Wells Fargo Securities analyst Bonnie Herzog said at the time. Market researchers now project that the global industry could reach $48 billion by 2023.
Critics say the FDA took too long to act.
“I think the fact that FDA has been dillydallying [has made] figuring out what’s going on [with this outbreak] much harder,” said Stanton Glantz, PhD, a University of California, San Francisco, professor in its Center for Tobacco Control Research and Education. “No question.”
The agency began by banning e-cigarette sales to minors and requiring all new vaping products to submit applications for authorization before they could come to market. Companies and retailers with thousands of products already on the market were granted 2 years to submit applications, and the FDA would get an additional year to evaluate the applications. Meanwhile, existing products could still be sold.
But when Scott Gottlieb, MD, arrived as the new FDA commissioner in 2017, the rule hadn’t been implemented and there was no formal guidance for companies to file applications, he said. As a result, he pushed the deadline back to 2022, drawing ire from public health advocates, who called foul over his previous ties to an e-cigarette retailer called Kure.
“I thought e-cigarettes at the time – and I still believe – that they represent an opportunity for currently addicted adult smokers to transition off of combustible tobacco,” he said in an interview, adding that other parts of the deeming rule went into effect as planned. “All I did was delay the application deadline.”
Dr. Gottlieb’s thinking changed the following year, when a national survey showed a sharp rise in teen vaping, which he called an “epidemic.” He announced that the agency would rethink the extended deadline and weigh whether to take flavors that appeal to kids off the market.
A judge ruled last month that e-cigarette makers would have only 10 more months to submit applications to the FDA. They’re now due in May 2020.
Asked about the lung injuries appearing now, Dr. Gottlieb, who left the FDA in April 2019, said he suspected counterfeit pods are to blame, given the geographic clustering of cases and the fact that, overall, the FDA is inspecting registered e-cigarette makers and retailers to make sure they’re complying with existing regulations.
“I think the manufacturers are culpable if their products are being used, whether the liquids are counterfeit or real,” he said. “Ultimately, they’re responsible for keeping their products out of the hands of kids.”
Juul, the leading e-cigarette maker, agreed that children shouldn’t be able to vape its products, and said curtailing access should be done “through significant regulation” and “enforcement.”
“When people say ‘Why aren’t these being regulated?’ They actually are all being regulated,” Dr. Gottlieb said.
For example, companies are required to label their products as potentially addictive, sell only to adults and comply with manufacturing standards. The agency has conducted thousands of inspections of e-cigarette manufacturers and retailers and taken enforcement actions against companies selling e-cigarettes that look like juice boxes, and against a company that was putting the ingredients found in erectile dysfunction drugs into its vape liquid.
Health departments investigating the outbreak told Kaiser Health News that e-cigarettes’ niche as a tobacco product instead of a drug has presented challenges. Most weren’t aware that adverse events could be reported to a database that tracks problems with tobacco products. And, because e-cigarettes never went through the FDA’s “gold-standard” approval process for drugs, doctors can’t readily look up a detailed list of known side effects.
But like other arms of the FDA, the tobacco office has tools and a team to investigate a public health threat just as the teams for drugs and devices do, Dr. Gottlieb said. It may even be better equipped because of its funding.
“I don’t think FDA is operating in any way with hands tied behind its back because of the way that the statute is set up,” he said.
Teen vaping has exploded during this regulatory tussle. In 2011, 1.5% of high school students reported vaping. By 2018, it was 20.8%, according to a CDC report.
Unknown components
Still, doctors and researchers are concerned about the ingredients in e-cigarettes and how little the public knows about the risks of vaping.
In Juul’s terms and conditions, posted on its website, it says, “We encourage consumers to do their own research regarding vapor products and what is right for them.” Many ingredients in e-cigarette products, however, are protected as trade secrets.
Since at least 2013, the flavor industry has expressed concern about the use of flavoring chemicals in vaping products.
The vast majority of the chemicals have been tested only by ingesting them in small quantities because they’re encountered in foods. For most of these chemicals, there have been no tests to determine whether it is safe to inhale them, as happens daily by millions when they use e-cigarettes.
“Many of the ingredients of vaping products, including flavoring substances, have not been tested for … the exposure one would get from using a vaping device,” said John Hallagan, a senior adviser to the Flavor and Extract Manufacturers Association. The group has sent cease-and-desist letters to e-cigarette companies in previous years for using the food safety certification of the flavor industry to imply that the chemicals are also safe in e-cigarettes.
Some flavor chemicals are thought to be harmful when inhaled in high doses. Research suggests that cinnamaldehyde, the main component of many cinnamon flavors, may impair lung function when inhaled. Sven-Eric Jordt, PhD, a professor at Duke University, Durham, N.C., says he presented evidence of its dangers at an FDA meeting in 2015 — and its relative abundance in many e-cigarette vaping liquids. In response, one major e-cigarette liquid seller, Tasty Vapor, voluntarily took its cinnamon-flavored liquid off the shelves.
In 2017, when Dr. Gottlieb delayed the FDA application deadline, the product was back. A company email to its customers put it this way: “Two years ago, Tasty Vapor allowed itself to be intimidated by scaremongering tactics. … We lost a lot of sales as well as a good number of long-time customers. We no long see reason to disappoint our customers hostage for these shady tactics.”
At the time of publication, Tasty Vapor’s owner did not reply to a request for comment.
Dr. Jordt said he is frustrated by the delays in the regulatory approval process.
“As a parent, I would say that the government has not acted on this,” he said. “You’re basically left to act alone with your addicted kid. It’s kind of terrifying that this was allowed to happen. The industry needs to be held to account.”
Kaiser Health News correspondents Cara Anthony, Markian Hawryluk, and Lauren Weber, as well as reporter Victoria Knight contributed to this report. This story first published on California Healthline, a service of the California Health Care Foundation.
Kaiser Health News is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.
ACOG advises bleeding disorder screening for teens with heavy menstruation
Adolescent girls with heavy menstrual bleeding should be assessed for bleeding disorders, according to a Committee Opinion issued by the American College of Obstetricians and Gynecologists.
A bleeding disorder is secondary only to anovulation as a cause of heavy menstrual bleeding in adolescents.
Bleeding disorders affect 1%-2% of the general population, but are “found in approximately 20% of adolescent girls who present for evaluation of heavy menstrual bleeding and in 33% of adolescent girls hospitalized for heavy menstrual bleeding,” wrote Oluyemisi Adeyemi-Fowode, MD, and Judith Simms-Cendan, MD, and members of the ACOG Committee on Adolescent Health Care in the opinion, published in Obstetrics & Gynecology.
The committee advised that physical examination of teens with acute heavy menstrual bleeding should include assessment of hemodynamic stability with orthostatic blood pressure and pulse measurements. A speculum exam is not usually needed in teen girls with heavy menstrual bleeding. Evaluation should include screening for anemia attributable to blood loss with serum ferritin, endocrine disorders, and bleeding disorders. In suspected cases of bleeding disorders, laboratory evaluation and medical management should be done in consultation with a hematologist.
Those who are actively bleeding or hemodynamically unstable should be hospitalized for medical management, they said.
Ultrasonography is not necessary for an initial work-up of teens with heavy menstrual bleeding, but could be useful in patients who fail to respond to medical management.
Adolescent girls without contraindications to estrogen can be treated with hormone therapy in various forms including intravenous conjugated estrogen every 4-6 hours or oral 30-50 mg ethinyl estradiol every 6-8 hours until cessation of bleeding. Antifibrinolytics also can be used to stop bleeding.
Maintenance therapy after correction of acute heavy bleeding can include a combination of treatments such as hormonal contraceptives, oral and injectable progestins, and levonorgestrel-releasing intrauterine devices, the committee wrote. They also recommended oral iron replacement therapy for all women of reproductive age with anemia caused by menstrual bleeding.
If a patient fails to respond to medical therapy, nonmedical options or surgery may be considered, according to the committee. In addition, all teen girls with bleeding disorders should be advised about safe medication use, including the use of aspirin or NSAIDs only on the recommendation of a hematologist.
Patients and their families need education on menstrual issues including possible options for surgery in the future if heavy menstruation does not resolve. If a patient has a known bleeding disorder and is considering surgery, preoperative evaluation should include a consultation with a hematologist and an anesthesiologist, the committee noted.
Melissa Kottke, MD, MPH, said in an interview, “Every ob.gyn. will see a young patient with ‘heavy menstrual bleeding.’ And it becomes part of the art and challenge to work with the patient and family to collectively explore if this is, indeed, ‘heavy’ and of concern … or is it is a ‘normal’ menstrual period and simply reflects a newer life experience that would benefit from some education? And the stakes are high. Young people who have heavy menstrual cycles are much more likely to have an underlying bleeding disorder than the general population (20% vs. 1%-2%), and 75%-80% of adolescents with bleeding disorders report heavy menses as the most common clinical manifestation of their disorder.
“Fortunately, Committee Opinion 785, ‘Screening and Management of Bleeding Disorders in Adolescents with Heavy Menstrual Bleeding’ from the ACOG Committee on Adolescent Health Care is detailed and pragmatic. It outlines how to translate everyday conversations with young people about their menses into a quantifiable estimate of bleeding, including a very teen-friendly Pictorial Blood Loss Assessment Chart. It also gives ob.gyns. ever-important guidance about what to do next for evaluation and diagnosis. This committee opinion nicely outlines how to help manage heavy bleeding in an adolescent with a detailed algorithm. And very importantly, it gives clear management guidance and encourages ob.gyns. to avoid frequently unnecessary (speculum exams and ultrasounds) and excessive (early transfusion or surgical interventions) approaches to management for the young patient. I think it will be a great resource for any provider who is taking care of heavy menstrual bleeding for a young person,” said Dr. Kottke, who is director of the Jane Fonda Center for Adolescent Reproductive Health and associate professor of gynecology and obstetrics, both at Emory University, Atlanta. Dr. Kottke is not a member of the ACOG Committee on Adolescent Health and was asked to comment on the opinion.*
The complete opinion, ACOG Committee Opinion number 785, includes recommended laboratory tests, an eight-question screening tool, and a management algorithm.
The committee members had no financial conflicts to disclose. Dr. Kottke said she had no relevant financial disclosures.
SOURCE: Adeyemi-Fowode O and Simms-Cendan J. Obstet Gynecol. 2019 Sep. 134:e71-83.
*This article was updated on 9/9/2019.
Adolescent girls with heavy menstrual bleeding should be assessed for bleeding disorders, according to a Committee Opinion issued by the American College of Obstetricians and Gynecologists.
A bleeding disorder is secondary only to anovulation as a cause of heavy menstrual bleeding in adolescents.
Bleeding disorders affect 1%-2% of the general population, but are “found in approximately 20% of adolescent girls who present for evaluation of heavy menstrual bleeding and in 33% of adolescent girls hospitalized for heavy menstrual bleeding,” wrote Oluyemisi Adeyemi-Fowode, MD, and Judith Simms-Cendan, MD, and members of the ACOG Committee on Adolescent Health Care in the opinion, published in Obstetrics & Gynecology.
The committee advised that physical examination of teens with acute heavy menstrual bleeding should include assessment of hemodynamic stability with orthostatic blood pressure and pulse measurements. A speculum exam is not usually needed in teen girls with heavy menstrual bleeding. Evaluation should include screening for anemia attributable to blood loss with serum ferritin, endocrine disorders, and bleeding disorders. In suspected cases of bleeding disorders, laboratory evaluation and medical management should be done in consultation with a hematologist.
Those who are actively bleeding or hemodynamically unstable should be hospitalized for medical management, they said.
Ultrasonography is not necessary for an initial work-up of teens with heavy menstrual bleeding, but could be useful in patients who fail to respond to medical management.
Adolescent girls without contraindications to estrogen can be treated with hormone therapy in various forms including intravenous conjugated estrogen every 4-6 hours or oral 30-50 mg ethinyl estradiol every 6-8 hours until cessation of bleeding. Antifibrinolytics also can be used to stop bleeding.
Maintenance therapy after correction of acute heavy bleeding can include a combination of treatments such as hormonal contraceptives, oral and injectable progestins, and levonorgestrel-releasing intrauterine devices, the committee wrote. They also recommended oral iron replacement therapy for all women of reproductive age with anemia caused by menstrual bleeding.
If a patient fails to respond to medical therapy, nonmedical options or surgery may be considered, according to the committee. In addition, all teen girls with bleeding disorders should be advised about safe medication use, including the use of aspirin or NSAIDs only on the recommendation of a hematologist.
Patients and their families need education on menstrual issues including possible options for surgery in the future if heavy menstruation does not resolve. If a patient has a known bleeding disorder and is considering surgery, preoperative evaluation should include a consultation with a hematologist and an anesthesiologist, the committee noted.
Melissa Kottke, MD, MPH, said in an interview, “Every ob.gyn. will see a young patient with ‘heavy menstrual bleeding.’ And it becomes part of the art and challenge to work with the patient and family to collectively explore if this is, indeed, ‘heavy’ and of concern … or is it is a ‘normal’ menstrual period and simply reflects a newer life experience that would benefit from some education? And the stakes are high. Young people who have heavy menstrual cycles are much more likely to have an underlying bleeding disorder than the general population (20% vs. 1%-2%), and 75%-80% of adolescents with bleeding disorders report heavy menses as the most common clinical manifestation of their disorder.
“Fortunately, Committee Opinion 785, ‘Screening and Management of Bleeding Disorders in Adolescents with Heavy Menstrual Bleeding’ from the ACOG Committee on Adolescent Health Care is detailed and pragmatic. It outlines how to translate everyday conversations with young people about their menses into a quantifiable estimate of bleeding, including a very teen-friendly Pictorial Blood Loss Assessment Chart. It also gives ob.gyns. ever-important guidance about what to do next for evaluation and diagnosis. This committee opinion nicely outlines how to help manage heavy bleeding in an adolescent with a detailed algorithm. And very importantly, it gives clear management guidance and encourages ob.gyns. to avoid frequently unnecessary (speculum exams and ultrasounds) and excessive (early transfusion or surgical interventions) approaches to management for the young patient. I think it will be a great resource for any provider who is taking care of heavy menstrual bleeding for a young person,” said Dr. Kottke, who is director of the Jane Fonda Center for Adolescent Reproductive Health and associate professor of gynecology and obstetrics, both at Emory University, Atlanta. Dr. Kottke is not a member of the ACOG Committee on Adolescent Health and was asked to comment on the opinion.*
The complete opinion, ACOG Committee Opinion number 785, includes recommended laboratory tests, an eight-question screening tool, and a management algorithm.
The committee members had no financial conflicts to disclose. Dr. Kottke said she had no relevant financial disclosures.
SOURCE: Adeyemi-Fowode O and Simms-Cendan J. Obstet Gynecol. 2019 Sep. 134:e71-83.
*This article was updated on 9/9/2019.
Adolescent girls with heavy menstrual bleeding should be assessed for bleeding disorders, according to a Committee Opinion issued by the American College of Obstetricians and Gynecologists.
A bleeding disorder is secondary only to anovulation as a cause of heavy menstrual bleeding in adolescents.
Bleeding disorders affect 1%-2% of the general population, but are “found in approximately 20% of adolescent girls who present for evaluation of heavy menstrual bleeding and in 33% of adolescent girls hospitalized for heavy menstrual bleeding,” wrote Oluyemisi Adeyemi-Fowode, MD, and Judith Simms-Cendan, MD, and members of the ACOG Committee on Adolescent Health Care in the opinion, published in Obstetrics & Gynecology.
The committee advised that physical examination of teens with acute heavy menstrual bleeding should include assessment of hemodynamic stability with orthostatic blood pressure and pulse measurements. A speculum exam is not usually needed in teen girls with heavy menstrual bleeding. Evaluation should include screening for anemia attributable to blood loss with serum ferritin, endocrine disorders, and bleeding disorders. In suspected cases of bleeding disorders, laboratory evaluation and medical management should be done in consultation with a hematologist.
Those who are actively bleeding or hemodynamically unstable should be hospitalized for medical management, they said.
Ultrasonography is not necessary for an initial work-up of teens with heavy menstrual bleeding, but could be useful in patients who fail to respond to medical management.
Adolescent girls without contraindications to estrogen can be treated with hormone therapy in various forms including intravenous conjugated estrogen every 4-6 hours or oral 30-50 mg ethinyl estradiol every 6-8 hours until cessation of bleeding. Antifibrinolytics also can be used to stop bleeding.
Maintenance therapy after correction of acute heavy bleeding can include a combination of treatments such as hormonal contraceptives, oral and injectable progestins, and levonorgestrel-releasing intrauterine devices, the committee wrote. They also recommended oral iron replacement therapy for all women of reproductive age with anemia caused by menstrual bleeding.
If a patient fails to respond to medical therapy, nonmedical options or surgery may be considered, according to the committee. In addition, all teen girls with bleeding disorders should be advised about safe medication use, including the use of aspirin or NSAIDs only on the recommendation of a hematologist.
Patients and their families need education on menstrual issues including possible options for surgery in the future if heavy menstruation does not resolve. If a patient has a known bleeding disorder and is considering surgery, preoperative evaluation should include a consultation with a hematologist and an anesthesiologist, the committee noted.
Melissa Kottke, MD, MPH, said in an interview, “Every ob.gyn. will see a young patient with ‘heavy menstrual bleeding.’ And it becomes part of the art and challenge to work with the patient and family to collectively explore if this is, indeed, ‘heavy’ and of concern … or is it is a ‘normal’ menstrual period and simply reflects a newer life experience that would benefit from some education? And the stakes are high. Young people who have heavy menstrual cycles are much more likely to have an underlying bleeding disorder than the general population (20% vs. 1%-2%), and 75%-80% of adolescents with bleeding disorders report heavy menses as the most common clinical manifestation of their disorder.
“Fortunately, Committee Opinion 785, ‘Screening and Management of Bleeding Disorders in Adolescents with Heavy Menstrual Bleeding’ from the ACOG Committee on Adolescent Health Care is detailed and pragmatic. It outlines how to translate everyday conversations with young people about their menses into a quantifiable estimate of bleeding, including a very teen-friendly Pictorial Blood Loss Assessment Chart. It also gives ob.gyns. ever-important guidance about what to do next for evaluation and diagnosis. This committee opinion nicely outlines how to help manage heavy bleeding in an adolescent with a detailed algorithm. And very importantly, it gives clear management guidance and encourages ob.gyns. to avoid frequently unnecessary (speculum exams and ultrasounds) and excessive (early transfusion or surgical interventions) approaches to management for the young patient. I think it will be a great resource for any provider who is taking care of heavy menstrual bleeding for a young person,” said Dr. Kottke, who is director of the Jane Fonda Center for Adolescent Reproductive Health and associate professor of gynecology and obstetrics, both at Emory University, Atlanta. Dr. Kottke is not a member of the ACOG Committee on Adolescent Health and was asked to comment on the opinion.*
The complete opinion, ACOG Committee Opinion number 785, includes recommended laboratory tests, an eight-question screening tool, and a management algorithm.
The committee members had no financial conflicts to disclose. Dr. Kottke said she had no relevant financial disclosures.
SOURCE: Adeyemi-Fowode O and Simms-Cendan J. Obstet Gynecol. 2019 Sep. 134:e71-83.
*This article was updated on 9/9/2019.
FROM OBSTETRICS AND GYNECOLOGY
Blood test may reveal brain injury
researchers reported Aug. 26 in BMJ Paediatrics Open.
“GFAP outperformed UCH-L1 in detecting concussion in both children and adults within 4 hours of injury,” reported lead author Linda Papa, MD, and collaborators. Dr. Papa is an emergency medicine doctor at Orlando Health. “UCH-L1 was expressed at much higher levels than GFAP in those with nonconcussive trauma, particularly in children. Elevations of these biomarkers in nonconcussive head trauma suggest possible subconcussive brain injury. GFAP could be potentially useful to detect concussion for up to a week post injury.”
In 2018 the Food and Drug Administration approved the use of these biomarkers to guide CT scan ordering in adults with mild to moderate traumatic brain injury, but investigators have not established their ability to detect concussion in children or adults. Clinicians lack an objective measure to diagnose concussion acutely.
To assess the ability of GFAP and UCH-L1 to detect concussion, Dr. Papa and colleagues conducted a prospective cohort study. The researchers enrolled trauma patients of all ages at three level I trauma centers in the United States. They included patients with and without head trauma who had a Glasgow Coma Scale score of 15 and who presented within 4 hours of injury. Investigators screened for concussion symptoms, obtained biomarker data from 712 trauma patients, and conducted repeated blood sampling in adults.
They grouped patients by those with concussion (n = 371), those with head trauma without overt signs of concussion (n = 149), and those with peripheral trauma without head trauma or concussion (n = 192). The study included 175 children. Injury mechanisms included car crashes, falls, bicycle accidents, and sports injuries.
Patients with concussion had significantly higher GFAP concentrations, compared with patients with body trauma and patients with nonconcussive head trauma. UCH-L1 levels did not significantly differ between patients with concussion and head trauma controls, however.
“Based on these results, the potential utility of GFAP to distinguish concussion from body trauma controls over 7 days postinjury was fair to excellent,” with area under the receiver operating characteristics curves (AUCs) of 0.75-0.89, the researchers said. “UCH-L1’s ability was guarded and variable with AUCs from poor to good depending on timing of samples.” UCH-L1 demonstrated AUCs that ranged from 0.54 to 0.78; earlier samples performed better.
GFAP elevations in head trauma controls “may represent milder forms of concussion that do not elicit typical signs or symptoms associated with concussion,” the authors wrote. “These injuries may be irrelevant, or they may represent important trauma that is just below the level of clinical detection and referred to as subconcussive trauma. ... Biomarkers (such as GFAP and UCH-L1) could provide a more objective measure of injury and potentially identify those at risk for neurocognitive problems.”
The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Papa is an unpaid scientific consultant for Banyan Biomarkers, which developed kits to measure the biomarkers, and coauthors receive contract research funding from Banyan Biomarkers.
SOURCE: Papa L et al. BMJ Paediatr Open. 2019 Aug 26. doi: 10.1136/bmjpo-2019-000473.
researchers reported Aug. 26 in BMJ Paediatrics Open.
“GFAP outperformed UCH-L1 in detecting concussion in both children and adults within 4 hours of injury,” reported lead author Linda Papa, MD, and collaborators. Dr. Papa is an emergency medicine doctor at Orlando Health. “UCH-L1 was expressed at much higher levels than GFAP in those with nonconcussive trauma, particularly in children. Elevations of these biomarkers in nonconcussive head trauma suggest possible subconcussive brain injury. GFAP could be potentially useful to detect concussion for up to a week post injury.”
In 2018 the Food and Drug Administration approved the use of these biomarkers to guide CT scan ordering in adults with mild to moderate traumatic brain injury, but investigators have not established their ability to detect concussion in children or adults. Clinicians lack an objective measure to diagnose concussion acutely.
To assess the ability of GFAP and UCH-L1 to detect concussion, Dr. Papa and colleagues conducted a prospective cohort study. The researchers enrolled trauma patients of all ages at three level I trauma centers in the United States. They included patients with and without head trauma who had a Glasgow Coma Scale score of 15 and who presented within 4 hours of injury. Investigators screened for concussion symptoms, obtained biomarker data from 712 trauma patients, and conducted repeated blood sampling in adults.
They grouped patients by those with concussion (n = 371), those with head trauma without overt signs of concussion (n = 149), and those with peripheral trauma without head trauma or concussion (n = 192). The study included 175 children. Injury mechanisms included car crashes, falls, bicycle accidents, and sports injuries.
Patients with concussion had significantly higher GFAP concentrations, compared with patients with body trauma and patients with nonconcussive head trauma. UCH-L1 levels did not significantly differ between patients with concussion and head trauma controls, however.
“Based on these results, the potential utility of GFAP to distinguish concussion from body trauma controls over 7 days postinjury was fair to excellent,” with area under the receiver operating characteristics curves (AUCs) of 0.75-0.89, the researchers said. “UCH-L1’s ability was guarded and variable with AUCs from poor to good depending on timing of samples.” UCH-L1 demonstrated AUCs that ranged from 0.54 to 0.78; earlier samples performed better.
GFAP elevations in head trauma controls “may represent milder forms of concussion that do not elicit typical signs or symptoms associated with concussion,” the authors wrote. “These injuries may be irrelevant, or they may represent important trauma that is just below the level of clinical detection and referred to as subconcussive trauma. ... Biomarkers (such as GFAP and UCH-L1) could provide a more objective measure of injury and potentially identify those at risk for neurocognitive problems.”
The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Papa is an unpaid scientific consultant for Banyan Biomarkers, which developed kits to measure the biomarkers, and coauthors receive contract research funding from Banyan Biomarkers.
SOURCE: Papa L et al. BMJ Paediatr Open. 2019 Aug 26. doi: 10.1136/bmjpo-2019-000473.
researchers reported Aug. 26 in BMJ Paediatrics Open.
“GFAP outperformed UCH-L1 in detecting concussion in both children and adults within 4 hours of injury,” reported lead author Linda Papa, MD, and collaborators. Dr. Papa is an emergency medicine doctor at Orlando Health. “UCH-L1 was expressed at much higher levels than GFAP in those with nonconcussive trauma, particularly in children. Elevations of these biomarkers in nonconcussive head trauma suggest possible subconcussive brain injury. GFAP could be potentially useful to detect concussion for up to a week post injury.”
In 2018 the Food and Drug Administration approved the use of these biomarkers to guide CT scan ordering in adults with mild to moderate traumatic brain injury, but investigators have not established their ability to detect concussion in children or adults. Clinicians lack an objective measure to diagnose concussion acutely.
To assess the ability of GFAP and UCH-L1 to detect concussion, Dr. Papa and colleagues conducted a prospective cohort study. The researchers enrolled trauma patients of all ages at three level I trauma centers in the United States. They included patients with and without head trauma who had a Glasgow Coma Scale score of 15 and who presented within 4 hours of injury. Investigators screened for concussion symptoms, obtained biomarker data from 712 trauma patients, and conducted repeated blood sampling in adults.
They grouped patients by those with concussion (n = 371), those with head trauma without overt signs of concussion (n = 149), and those with peripheral trauma without head trauma or concussion (n = 192). The study included 175 children. Injury mechanisms included car crashes, falls, bicycle accidents, and sports injuries.
Patients with concussion had significantly higher GFAP concentrations, compared with patients with body trauma and patients with nonconcussive head trauma. UCH-L1 levels did not significantly differ between patients with concussion and head trauma controls, however.
“Based on these results, the potential utility of GFAP to distinguish concussion from body trauma controls over 7 days postinjury was fair to excellent,” with area under the receiver operating characteristics curves (AUCs) of 0.75-0.89, the researchers said. “UCH-L1’s ability was guarded and variable with AUCs from poor to good depending on timing of samples.” UCH-L1 demonstrated AUCs that ranged from 0.54 to 0.78; earlier samples performed better.
GFAP elevations in head trauma controls “may represent milder forms of concussion that do not elicit typical signs or symptoms associated with concussion,” the authors wrote. “These injuries may be irrelevant, or they may represent important trauma that is just below the level of clinical detection and referred to as subconcussive trauma. ... Biomarkers (such as GFAP and UCH-L1) could provide a more objective measure of injury and potentially identify those at risk for neurocognitive problems.”
The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Papa is an unpaid scientific consultant for Banyan Biomarkers, which developed kits to measure the biomarkers, and coauthors receive contract research funding from Banyan Biomarkers.
SOURCE: Papa L et al. BMJ Paediatr Open. 2019 Aug 26. doi: 10.1136/bmjpo-2019-000473.
FROM BMJ PAEDIATRICS OPEN
Key clinical point: Levels of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) are lowest in patients with nonconcussive body trauma, higher in patients with nonconcussive head trauma, and highest in patients with concussion.
Major finding: GFAP was fair to excellent at distinguishing concussion from body trauma, with area under the receiver operating characteristics curves of 0.75-0.89.
Study details: A prospective cohort study of 712 trauma patients of all ages at three level I trauma centers in the United States. The study included patients with and without head trauma who had a Glasgow Coma Scale score of 15 and presented within 4 hours of injury.
Disclosures: The study was supported by the National Institute of Neurological Disorders and Stroke. Dr. Papa is an unpaid scientific consultant for Banyan Biomarkers, which developed kits to measure the biomarkers. Coauthors receive contract research funding from Banyan Biomarkers.
Source: Papa L et al. BMJ Paediatr Open. 2019 Aug 26. doi: 10.1136/bmjpo-2019-000473.
CPAP safety for infants with bronchiolitis on the general pediatrics floor
SEATTLE – Rady Children’s Hospital in San Diego has been doing continuous positive airway pressure for infants with bronchiolitis on the general pediatrics floors safely and with no problems for nearly 20 years, according to a presentation at Pediatric Hospital Medicine.
It’s newsworthy because “very, very few” hospitals do bronchiolitis continuous positive airway pressure (CPAP) outside of the ICU. “The perception is that there are complications, and you might miss kids that are really sick if you keep them on the floor.” However, “we have been doing it safely for so long that no one thinks twice about it,” said Christiane Lenzen, MD, a pediatric hospitalist at Rady and an assistant clinical professor of pediatrics at the University of California, San Diego.
It doesn’t matter if children have congenital heart disease, chronic lung disease, or other problems, she said, “if they are stable enough for the floor, we will see if it’s okay.”
Rady’s hand was forced on the issue because it has a large catchment area but limited ICU beds, so for practical reasons and within certain limits, CPAP moved to the floors. One of Dr. Lenzen’s colleagues noted that, as long as there’s nurse and respiratory leadership buy in, “it’s actually quite easy to pull off in a very safe manner.”
Rady has a significant advantage over community hospitals and other places considering the approach, because it has onsite pediatric ICU services for when things head south. Over the past 3 or so years, 52% of the children the pediatric hospital medicine service started on CPAP (168/324) had to be transferred to the ICU; 17% were ultimately intubated.
Many of those transfers were caused by comorbidities, not CPAP failure, but other times children needed greater respiratory support; in general, the floor CPAP limit is 6 cm H2O and a fraction of inspired oxygen of 50%. Also, sometimes children needed to be sedated for CPAP, which isn’t done on the floor.
With the 52% transfer rate, “I would worry about patients who are sick enough to need CPAP staying” in a hospital without quick access to ICU services, Dr. Lenzen said at the meeting sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Even so, among 324 children who at least initially were treated with CPAP on the floor – out of 2,424 admitted to the pediatric hospital medicine service with bronchiolitis – there hasn’t been a single pneumothorax, aspiration event, or CPAP equipment–related injury, she said.
CPAP on the floor has several benefits. ICU resources are conserved, patient handoffs and the work of transfers into and out of the ICU are avoided, families don’t have to get used to a new treatment team, and infants aren’t subjected to the jarring ICU environment.
For it to work, though, staff “really need to be on top of this,” and “it needs to be very tightly controlled” with order sets and other measures, the presenters said. There’s regular training at Rady for nurses, respiratory therapists, and hospitalists on CPAP equipment, airway management, monitoring, troubleshooting, and other essentials.
Almost all children on the pediatric floors have a trial of high-flow nasal cannula with an upper limit of 8 L/min. If the Respiratory Assessment Score hasn’t improved in an hour, CPAP is considered. If a child is admitted with a score above 10 and they seem to be worsening, they go straight to CPAP.
Children alternate between nasal prongs and nasal masks to prevent pressure necrosis, and are kept nil per os while on CPAP. They are on continual pulse oximetry and cardiorespiratory monitoring. Vital signs and respiratory scores are checked frequently, more so for children who are struggling.
The patient-to-nurse ratio drops from the usual 4:1 to 3:1 when a child goes on CPAP, and to 2:1 if necessary. Traveling nurses aren’t allowed to take CPAP cases.
The presenters didn’t report any disclosures.
This article was updated 8/27/19.
SEATTLE – Rady Children’s Hospital in San Diego has been doing continuous positive airway pressure for infants with bronchiolitis on the general pediatrics floors safely and with no problems for nearly 20 years, according to a presentation at Pediatric Hospital Medicine.
It’s newsworthy because “very, very few” hospitals do bronchiolitis continuous positive airway pressure (CPAP) outside of the ICU. “The perception is that there are complications, and you might miss kids that are really sick if you keep them on the floor.” However, “we have been doing it safely for so long that no one thinks twice about it,” said Christiane Lenzen, MD, a pediatric hospitalist at Rady and an assistant clinical professor of pediatrics at the University of California, San Diego.
It doesn’t matter if children have congenital heart disease, chronic lung disease, or other problems, she said, “if they are stable enough for the floor, we will see if it’s okay.”
Rady’s hand was forced on the issue because it has a large catchment area but limited ICU beds, so for practical reasons and within certain limits, CPAP moved to the floors. One of Dr. Lenzen’s colleagues noted that, as long as there’s nurse and respiratory leadership buy in, “it’s actually quite easy to pull off in a very safe manner.”
Rady has a significant advantage over community hospitals and other places considering the approach, because it has onsite pediatric ICU services for when things head south. Over the past 3 or so years, 52% of the children the pediatric hospital medicine service started on CPAP (168/324) had to be transferred to the ICU; 17% were ultimately intubated.
Many of those transfers were caused by comorbidities, not CPAP failure, but other times children needed greater respiratory support; in general, the floor CPAP limit is 6 cm H2O and a fraction of inspired oxygen of 50%. Also, sometimes children needed to be sedated for CPAP, which isn’t done on the floor.
With the 52% transfer rate, “I would worry about patients who are sick enough to need CPAP staying” in a hospital without quick access to ICU services, Dr. Lenzen said at the meeting sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Even so, among 324 children who at least initially were treated with CPAP on the floor – out of 2,424 admitted to the pediatric hospital medicine service with bronchiolitis – there hasn’t been a single pneumothorax, aspiration event, or CPAP equipment–related injury, she said.
CPAP on the floor has several benefits. ICU resources are conserved, patient handoffs and the work of transfers into and out of the ICU are avoided, families don’t have to get used to a new treatment team, and infants aren’t subjected to the jarring ICU environment.
For it to work, though, staff “really need to be on top of this,” and “it needs to be very tightly controlled” with order sets and other measures, the presenters said. There’s regular training at Rady for nurses, respiratory therapists, and hospitalists on CPAP equipment, airway management, monitoring, troubleshooting, and other essentials.
Almost all children on the pediatric floors have a trial of high-flow nasal cannula with an upper limit of 8 L/min. If the Respiratory Assessment Score hasn’t improved in an hour, CPAP is considered. If a child is admitted with a score above 10 and they seem to be worsening, they go straight to CPAP.
Children alternate between nasal prongs and nasal masks to prevent pressure necrosis, and are kept nil per os while on CPAP. They are on continual pulse oximetry and cardiorespiratory monitoring. Vital signs and respiratory scores are checked frequently, more so for children who are struggling.
The patient-to-nurse ratio drops from the usual 4:1 to 3:1 when a child goes on CPAP, and to 2:1 if necessary. Traveling nurses aren’t allowed to take CPAP cases.
The presenters didn’t report any disclosures.
This article was updated 8/27/19.
SEATTLE – Rady Children’s Hospital in San Diego has been doing continuous positive airway pressure for infants with bronchiolitis on the general pediatrics floors safely and with no problems for nearly 20 years, according to a presentation at Pediatric Hospital Medicine.
It’s newsworthy because “very, very few” hospitals do bronchiolitis continuous positive airway pressure (CPAP) outside of the ICU. “The perception is that there are complications, and you might miss kids that are really sick if you keep them on the floor.” However, “we have been doing it safely for so long that no one thinks twice about it,” said Christiane Lenzen, MD, a pediatric hospitalist at Rady and an assistant clinical professor of pediatrics at the University of California, San Diego.
It doesn’t matter if children have congenital heart disease, chronic lung disease, or other problems, she said, “if they are stable enough for the floor, we will see if it’s okay.”
Rady’s hand was forced on the issue because it has a large catchment area but limited ICU beds, so for practical reasons and within certain limits, CPAP moved to the floors. One of Dr. Lenzen’s colleagues noted that, as long as there’s nurse and respiratory leadership buy in, “it’s actually quite easy to pull off in a very safe manner.”
Rady has a significant advantage over community hospitals and other places considering the approach, because it has onsite pediatric ICU services for when things head south. Over the past 3 or so years, 52% of the children the pediatric hospital medicine service started on CPAP (168/324) had to be transferred to the ICU; 17% were ultimately intubated.
Many of those transfers were caused by comorbidities, not CPAP failure, but other times children needed greater respiratory support; in general, the floor CPAP limit is 6 cm H2O and a fraction of inspired oxygen of 50%. Also, sometimes children needed to be sedated for CPAP, which isn’t done on the floor.
With the 52% transfer rate, “I would worry about patients who are sick enough to need CPAP staying” in a hospital without quick access to ICU services, Dr. Lenzen said at the meeting sponsored by the Society of Hospital Medicine, the American Academy of Pediatrics, and the Academic Pediatric Association.
Even so, among 324 children who at least initially were treated with CPAP on the floor – out of 2,424 admitted to the pediatric hospital medicine service with bronchiolitis – there hasn’t been a single pneumothorax, aspiration event, or CPAP equipment–related injury, she said.
CPAP on the floor has several benefits. ICU resources are conserved, patient handoffs and the work of transfers into and out of the ICU are avoided, families don’t have to get used to a new treatment team, and infants aren’t subjected to the jarring ICU environment.
For it to work, though, staff “really need to be on top of this,” and “it needs to be very tightly controlled” with order sets and other measures, the presenters said. There’s regular training at Rady for nurses, respiratory therapists, and hospitalists on CPAP equipment, airway management, monitoring, troubleshooting, and other essentials.
Almost all children on the pediatric floors have a trial of high-flow nasal cannula with an upper limit of 8 L/min. If the Respiratory Assessment Score hasn’t improved in an hour, CPAP is considered. If a child is admitted with a score above 10 and they seem to be worsening, they go straight to CPAP.
Children alternate between nasal prongs and nasal masks to prevent pressure necrosis, and are kept nil per os while on CPAP. They are on continual pulse oximetry and cardiorespiratory monitoring. Vital signs and respiratory scores are checked frequently, more so for children who are struggling.
The patient-to-nurse ratio drops from the usual 4:1 to 3:1 when a child goes on CPAP, and to 2:1 if necessary. Traveling nurses aren’t allowed to take CPAP cases.
The presenters didn’t report any disclosures.
This article was updated 8/27/19.
EXPERT ANALYSIS FROM PHM 2019