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ACIP adds hexavalent vaccine to VFC program
The pediatric hexavalent vaccine (DTaP-[inactivated poliovirus] IPV-[hepatitis B] HepB-[Haemophilis influenzae type b] Hib) should be included as an option in the Vaccines for Children (VFC) program for the infant series at ages 2, 4, and 6 months, according to unanimous votes at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
The addition of the vaccine to the VFC program required no motions on the part of the committee, but involved separate votes on each component of the vaccine.
Combination vaccination has been associated with increased coverage and more likely completion of the full infant vaccine series, said Sara Oliver, MD, of the CDC’s National Center for Immunization and Respiratory Diseases.
The new vaccine is being developed jointly by Sanofi and Merck, and has been approved by the Food and Drug Administration for use in children through age 4 years.
Dr. Oliver presented evidence that the safety profile of the combination vaccine is consistent with that of the component vaccines. In addition, “use of combination vaccines can reduce the number of injections patient receive and alleviate concern associated with the number of injections,” she said. However, “considerations should include provider assessment, patient preference, and the potential for adverse events.”
although it will not be available until 2021 in order to ensure sufficient supply, Dr. Oliver noted.
The combination vaccination work group considered whether the new vaccine should be preferentially recommended for American Indian and Alaskan Native populations, but they concluded that post–dose one immunogenicity data are needed before such a preferential recommendation can be made.
The ACIP members had no financial conflicts to disclose.
The pediatric hexavalent vaccine (DTaP-[inactivated poliovirus] IPV-[hepatitis B] HepB-[Haemophilis influenzae type b] Hib) should be included as an option in the Vaccines for Children (VFC) program for the infant series at ages 2, 4, and 6 months, according to unanimous votes at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
The addition of the vaccine to the VFC program required no motions on the part of the committee, but involved separate votes on each component of the vaccine.
Combination vaccination has been associated with increased coverage and more likely completion of the full infant vaccine series, said Sara Oliver, MD, of the CDC’s National Center for Immunization and Respiratory Diseases.
The new vaccine is being developed jointly by Sanofi and Merck, and has been approved by the Food and Drug Administration for use in children through age 4 years.
Dr. Oliver presented evidence that the safety profile of the combination vaccine is consistent with that of the component vaccines. In addition, “use of combination vaccines can reduce the number of injections patient receive and alleviate concern associated with the number of injections,” she said. However, “considerations should include provider assessment, patient preference, and the potential for adverse events.”
although it will not be available until 2021 in order to ensure sufficient supply, Dr. Oliver noted.
The combination vaccination work group considered whether the new vaccine should be preferentially recommended for American Indian and Alaskan Native populations, but they concluded that post–dose one immunogenicity data are needed before such a preferential recommendation can be made.
The ACIP members had no financial conflicts to disclose.
The pediatric hexavalent vaccine (DTaP-[inactivated poliovirus] IPV-[hepatitis B] HepB-[Haemophilis influenzae type b] Hib) should be included as an option in the Vaccines for Children (VFC) program for the infant series at ages 2, 4, and 6 months, according to unanimous votes at a meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.
The addition of the vaccine to the VFC program required no motions on the part of the committee, but involved separate votes on each component of the vaccine.
Combination vaccination has been associated with increased coverage and more likely completion of the full infant vaccine series, said Sara Oliver, MD, of the CDC’s National Center for Immunization and Respiratory Diseases.
The new vaccine is being developed jointly by Sanofi and Merck, and has been approved by the Food and Drug Administration for use in children through age 4 years.
Dr. Oliver presented evidence that the safety profile of the combination vaccine is consistent with that of the component vaccines. In addition, “use of combination vaccines can reduce the number of injections patient receive and alleviate concern associated with the number of injections,” she said. However, “considerations should include provider assessment, patient preference, and the potential for adverse events.”
although it will not be available until 2021 in order to ensure sufficient supply, Dr. Oliver noted.
The combination vaccination work group considered whether the new vaccine should be preferentially recommended for American Indian and Alaskan Native populations, but they concluded that post–dose one immunogenicity data are needed before such a preferential recommendation can be made.
The ACIP members had no financial conflicts to disclose.
REPORTING FROM AN ACIP MEETING
Substantial reductions in HPV infections, CIN2+ after vaccination
The introduction of the human papillomavirus according to a meta-analysis of data from more than 60 million individuals worldwide.
Mélanie Drolet, PhD, from the Centre de recherche du CHU de Québec–Université Laval, and coauthors of the HPV Vaccination Impact Study Group reported the results of a systematic review and meta-analysis of 65 studies showing pre- and postvaccination frequency of at least one HPV-related endpoint published in the Lancet. The studies were conducted in 14 high-income countries, 12 of which were vaccinating only women and girls, with the results at 5-8 years published in the Lancet.
At 5-8 years after a vaccination program was implemented, there was a significant 83% reduction in the prevalence of HPV 16 and 18, both of which are targeted by the vaccine, among girls aged 13-19 years; a 66% reduction among women aged 20-24 years; and a 37% reduction in women aged 25-29 years, even though most of these women were unvaccinated.
There also were significant decreases at 5-8 years in the prevalence of HPV subtypes 31, 33, and 45, which are not included in the vaccine but against which the vaccine appears to offer cross-protection. Among girls aged 13-19 years, there was a significant 54% reduction in the prevalence of these subtypes, among women aged 20-24 years there was a nonsignificant 28% decrease, but among women aged 25-29 years, there was no significant decrease.
The analysis also found significant declines in the prevalence of cervical intraepithelial neoplasias (CINs) of grade 2 or above. At 5-9 years after vaccination was introduced, CIN2+ decreased by 51% among girls aged 15-19 years who also were screened for cervical cancer, and by 31% among women aged 20-24 years.
However, over the same time period, the rates of CIN2+ increased by a significant 19% among mostly unvaccinated women aged 25-29 years and 23% among mostly unvaccinated women aged 30-39 years, despite both groups being screened for cervical abnormalities.
While most of the countries in the study vaccinated only girls and women, two studies did find nonsignificant decreases in the prevalence of HPV 16, 18, 31, 33, and 45 among boys aged 16-19 years, but not among men aged 20-24 years.
HPV vaccination also was associated with significant declines in the incidence of anogenital warts among both males and females. In the first 4 years alone, vaccination was associated with significant reductions in anogenital wart diagnoses among females aged 15-29 years, as well as nonsignificant but “substantial” reductions in unvaccinated boys aged 15-19 years.
After 5-8 years, anogenital wart diagnoses decreased by 67% among girls aged 15-19 years, significantly by 54% among women aged 20-24 years, and 31% among women aged 25-29 years – all significant changes. Among boys aged 15-19 years, anogenital wart diagnoses decreased by a significant 48%, and among men aged 20-24 years they decreased by a significant 32%.
The decreases in anogenital wart diagnoses were even greater in countries that implemented vaccination among multiple cohorts simultaneously and achieved high vaccination coverage, compared with countries that vaccinated only one cohort at a time or had low routine vaccination coverage.
“Our study is the first to show the real-world additional benefit of multicohort HPV vaccination and high routine vaccination coverage, and the fast and substantial herd effects of vaccination in countries which implement these measures,” wrote Dr. Drolet and coauthors. “The greater impact of multicohort vaccination was similar when restricting the analyses to countries with high routine vaccination coverage.”
They pointed to the World Health Organization’s recently revised position on HPV vaccination, which now recommends vaccination of multiple cohorts of girls aged 9-14 years, although they raised the question of what might be the optimal number of age cohorts. “Number needed to vaccinate and cost-effectiveness analyses in high-income countries suggest that vaccinating multiple cohorts of individuals up to 18 years of age is highly efficient and cost effective.”
This analysis by Drolet et al. “provides compelling evidence for HPV vaccine efficacy on all outcomes explored and for almost all age strata,” Dr. Silvia de Sanjose, of PATH in Seattle, and Dr. Sinead Delany-Moretlwe of the Wits Reproductive Health and HIV Institute at the University of Witwatersrand in Johannesburg, said in an accompanying editorial (Lancet. 2019 Jun 26. doi: 10.1016/ S0140-6736[19]30549-5). This study shows just how effective HPV vaccination can be across a range of outcomes and ages, and also demonstrates the herd immunity benefits, particularly when multiple cohorts are vaccinated and there is high vaccination coverage.
One key limitation of this analysis is the lack of data from low- and middle-income countries. The data by Drolet et al. “emphasise the importance of redoubling our efforts to tackle the fiscal, supply, and programmatic barriers that currently limit HPV vaccine programmes; with these efforts, HPV vaccination could become a hallmark investment of cancer prevention in the 21st century,” Dr. de Sanjose and Dr. Delany-Moretlwe concluded.
The study was funded by WHO, Canadian Institutes of Health Research, and Fonds de recherche du Québec–Santé. No conflicts of interest were declared.
Dr. de Sanjose declared previous institutional support from Merck.
SOURCE: Drolet M et al. Lancet 2019 Jun 26. doi: 10.1016/ S0140-6736(19)30298-3.
The introduction of the human papillomavirus according to a meta-analysis of data from more than 60 million individuals worldwide.
Mélanie Drolet, PhD, from the Centre de recherche du CHU de Québec–Université Laval, and coauthors of the HPV Vaccination Impact Study Group reported the results of a systematic review and meta-analysis of 65 studies showing pre- and postvaccination frequency of at least one HPV-related endpoint published in the Lancet. The studies were conducted in 14 high-income countries, 12 of which were vaccinating only women and girls, with the results at 5-8 years published in the Lancet.
At 5-8 years after a vaccination program was implemented, there was a significant 83% reduction in the prevalence of HPV 16 and 18, both of which are targeted by the vaccine, among girls aged 13-19 years; a 66% reduction among women aged 20-24 years; and a 37% reduction in women aged 25-29 years, even though most of these women were unvaccinated.
There also were significant decreases at 5-8 years in the prevalence of HPV subtypes 31, 33, and 45, which are not included in the vaccine but against which the vaccine appears to offer cross-protection. Among girls aged 13-19 years, there was a significant 54% reduction in the prevalence of these subtypes, among women aged 20-24 years there was a nonsignificant 28% decrease, but among women aged 25-29 years, there was no significant decrease.
The analysis also found significant declines in the prevalence of cervical intraepithelial neoplasias (CINs) of grade 2 or above. At 5-9 years after vaccination was introduced, CIN2+ decreased by 51% among girls aged 15-19 years who also were screened for cervical cancer, and by 31% among women aged 20-24 years.
However, over the same time period, the rates of CIN2+ increased by a significant 19% among mostly unvaccinated women aged 25-29 years and 23% among mostly unvaccinated women aged 30-39 years, despite both groups being screened for cervical abnormalities.
While most of the countries in the study vaccinated only girls and women, two studies did find nonsignificant decreases in the prevalence of HPV 16, 18, 31, 33, and 45 among boys aged 16-19 years, but not among men aged 20-24 years.
HPV vaccination also was associated with significant declines in the incidence of anogenital warts among both males and females. In the first 4 years alone, vaccination was associated with significant reductions in anogenital wart diagnoses among females aged 15-29 years, as well as nonsignificant but “substantial” reductions in unvaccinated boys aged 15-19 years.
After 5-8 years, anogenital wart diagnoses decreased by 67% among girls aged 15-19 years, significantly by 54% among women aged 20-24 years, and 31% among women aged 25-29 years – all significant changes. Among boys aged 15-19 years, anogenital wart diagnoses decreased by a significant 48%, and among men aged 20-24 years they decreased by a significant 32%.
The decreases in anogenital wart diagnoses were even greater in countries that implemented vaccination among multiple cohorts simultaneously and achieved high vaccination coverage, compared with countries that vaccinated only one cohort at a time or had low routine vaccination coverage.
“Our study is the first to show the real-world additional benefit of multicohort HPV vaccination and high routine vaccination coverage, and the fast and substantial herd effects of vaccination in countries which implement these measures,” wrote Dr. Drolet and coauthors. “The greater impact of multicohort vaccination was similar when restricting the analyses to countries with high routine vaccination coverage.”
They pointed to the World Health Organization’s recently revised position on HPV vaccination, which now recommends vaccination of multiple cohorts of girls aged 9-14 years, although they raised the question of what might be the optimal number of age cohorts. “Number needed to vaccinate and cost-effectiveness analyses in high-income countries suggest that vaccinating multiple cohorts of individuals up to 18 years of age is highly efficient and cost effective.”
This analysis by Drolet et al. “provides compelling evidence for HPV vaccine efficacy on all outcomes explored and for almost all age strata,” Dr. Silvia de Sanjose, of PATH in Seattle, and Dr. Sinead Delany-Moretlwe of the Wits Reproductive Health and HIV Institute at the University of Witwatersrand in Johannesburg, said in an accompanying editorial (Lancet. 2019 Jun 26. doi: 10.1016/ S0140-6736[19]30549-5). This study shows just how effective HPV vaccination can be across a range of outcomes and ages, and also demonstrates the herd immunity benefits, particularly when multiple cohorts are vaccinated and there is high vaccination coverage.
One key limitation of this analysis is the lack of data from low- and middle-income countries. The data by Drolet et al. “emphasise the importance of redoubling our efforts to tackle the fiscal, supply, and programmatic barriers that currently limit HPV vaccine programmes; with these efforts, HPV vaccination could become a hallmark investment of cancer prevention in the 21st century,” Dr. de Sanjose and Dr. Delany-Moretlwe concluded.
The study was funded by WHO, Canadian Institutes of Health Research, and Fonds de recherche du Québec–Santé. No conflicts of interest were declared.
Dr. de Sanjose declared previous institutional support from Merck.
SOURCE: Drolet M et al. Lancet 2019 Jun 26. doi: 10.1016/ S0140-6736(19)30298-3.
The introduction of the human papillomavirus according to a meta-analysis of data from more than 60 million individuals worldwide.
Mélanie Drolet, PhD, from the Centre de recherche du CHU de Québec–Université Laval, and coauthors of the HPV Vaccination Impact Study Group reported the results of a systematic review and meta-analysis of 65 studies showing pre- and postvaccination frequency of at least one HPV-related endpoint published in the Lancet. The studies were conducted in 14 high-income countries, 12 of which were vaccinating only women and girls, with the results at 5-8 years published in the Lancet.
At 5-8 years after a vaccination program was implemented, there was a significant 83% reduction in the prevalence of HPV 16 and 18, both of which are targeted by the vaccine, among girls aged 13-19 years; a 66% reduction among women aged 20-24 years; and a 37% reduction in women aged 25-29 years, even though most of these women were unvaccinated.
There also were significant decreases at 5-8 years in the prevalence of HPV subtypes 31, 33, and 45, which are not included in the vaccine but against which the vaccine appears to offer cross-protection. Among girls aged 13-19 years, there was a significant 54% reduction in the prevalence of these subtypes, among women aged 20-24 years there was a nonsignificant 28% decrease, but among women aged 25-29 years, there was no significant decrease.
The analysis also found significant declines in the prevalence of cervical intraepithelial neoplasias (CINs) of grade 2 or above. At 5-9 years after vaccination was introduced, CIN2+ decreased by 51% among girls aged 15-19 years who also were screened for cervical cancer, and by 31% among women aged 20-24 years.
However, over the same time period, the rates of CIN2+ increased by a significant 19% among mostly unvaccinated women aged 25-29 years and 23% among mostly unvaccinated women aged 30-39 years, despite both groups being screened for cervical abnormalities.
While most of the countries in the study vaccinated only girls and women, two studies did find nonsignificant decreases in the prevalence of HPV 16, 18, 31, 33, and 45 among boys aged 16-19 years, but not among men aged 20-24 years.
HPV vaccination also was associated with significant declines in the incidence of anogenital warts among both males and females. In the first 4 years alone, vaccination was associated with significant reductions in anogenital wart diagnoses among females aged 15-29 years, as well as nonsignificant but “substantial” reductions in unvaccinated boys aged 15-19 years.
After 5-8 years, anogenital wart diagnoses decreased by 67% among girls aged 15-19 years, significantly by 54% among women aged 20-24 years, and 31% among women aged 25-29 years – all significant changes. Among boys aged 15-19 years, anogenital wart diagnoses decreased by a significant 48%, and among men aged 20-24 years they decreased by a significant 32%.
The decreases in anogenital wart diagnoses were even greater in countries that implemented vaccination among multiple cohorts simultaneously and achieved high vaccination coverage, compared with countries that vaccinated only one cohort at a time or had low routine vaccination coverage.
“Our study is the first to show the real-world additional benefit of multicohort HPV vaccination and high routine vaccination coverage, and the fast and substantial herd effects of vaccination in countries which implement these measures,” wrote Dr. Drolet and coauthors. “The greater impact of multicohort vaccination was similar when restricting the analyses to countries with high routine vaccination coverage.”
They pointed to the World Health Organization’s recently revised position on HPV vaccination, which now recommends vaccination of multiple cohorts of girls aged 9-14 years, although they raised the question of what might be the optimal number of age cohorts. “Number needed to vaccinate and cost-effectiveness analyses in high-income countries suggest that vaccinating multiple cohorts of individuals up to 18 years of age is highly efficient and cost effective.”
This analysis by Drolet et al. “provides compelling evidence for HPV vaccine efficacy on all outcomes explored and for almost all age strata,” Dr. Silvia de Sanjose, of PATH in Seattle, and Dr. Sinead Delany-Moretlwe of the Wits Reproductive Health and HIV Institute at the University of Witwatersrand in Johannesburg, said in an accompanying editorial (Lancet. 2019 Jun 26. doi: 10.1016/ S0140-6736[19]30549-5). This study shows just how effective HPV vaccination can be across a range of outcomes and ages, and also demonstrates the herd immunity benefits, particularly when multiple cohorts are vaccinated and there is high vaccination coverage.
One key limitation of this analysis is the lack of data from low- and middle-income countries. The data by Drolet et al. “emphasise the importance of redoubling our efforts to tackle the fiscal, supply, and programmatic barriers that currently limit HPV vaccine programmes; with these efforts, HPV vaccination could become a hallmark investment of cancer prevention in the 21st century,” Dr. de Sanjose and Dr. Delany-Moretlwe concluded.
The study was funded by WHO, Canadian Institutes of Health Research, and Fonds de recherche du Québec–Santé. No conflicts of interest were declared.
Dr. de Sanjose declared previous institutional support from Merck.
SOURCE: Drolet M et al. Lancet 2019 Jun 26. doi: 10.1016/ S0140-6736(19)30298-3.
FROM THE LANCET
Key clinical point: Significant declines in HPV infections, CIN2+, and anogenital warts have occurred after the introduction of HPV vaccine programs, some because of herd effects.
Major finding: The HPV vaccination program is associated with a significant 83% reduction in the prevalence of HPV 16 and 18 among girls aged 13-19 years in 14 high-income countries.
Study details: Systematic review and meta-analysis of 65 studies involving more than 60 million individuals in 14 countries.
Disclosures: The study was funded by World Health Organization, Canadian Institutes of Health Research, and Fonds de recherche du Québec – Santé. No conflicts of interest were declared.
Source: Drolet M et al. Lancet 2019 Jun 26. doi: 10.1016/ S0140-6736(19)30298-3.
‘Robust antitumor immune responses’ observed in pediatric ALL
Pediatric acute lymphoblastic leukemia (ALL) may be more vulnerable to immunotherapies than previously thought, according to researchers.
Prior studies suggested that tumors with a low mutational burden don’t elicit strong antitumor responses and therefore aren’t very susceptible to immunotherapy.
Now, researchers have found evidence to suggest that pediatric ALL induces “robust antitumor immune responses” despite a low mutational burden. The investigators identified tumor-associated CD8+ T cells that responded to 86% of neoantigens tested and recognized 68% of neoepitopes tested.
Anthony E. Zamora, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues recounted these findings in Science Translational Medicine.
The researchers analyzed samples from pediatric patients with ETV-associated ALL (n = 9) or ERG-associated ALL (n = 2) to determine how endogenous CD8+ T cells respond to patient-specific cancer neoantigens.
The investigators first assessed the ability of tumor-specific mutations and gene fusions to generate neoepitopes, or neoantigens predicted to bind patient-specific human leukocyte antigen (HLA) proteins. The team identified 5-28 neoepitopes per patient, including epitopes that spanned the fusion junction in patients with ETV6-RUNX1 fusions.
The researchers then tested whether CD8+ tumor infiltrating lymphocytes (TILs) were directly responsive to mutated neoepitopes. They observed cytokine responses across patient samples, noting that 31 of the 36 putative neoantigens tested (86%) were “immunogenic and capable of inducing robust cytokine responses.”
Next, the investigators mapped TIL responses to specific epitopes using patient-specific tetramers that corresponded to the previously identified neoepitopes. Seventeen of the 25 patient-specific tetramers (68%) bound to TILs above the background set by irrelevant HLA-matched tetramers.
“Within those responses, we observed immunodominance hierarchies among the distinct TIL populations, with a majority of tetramer-bound CD8+ T cells restricted to one or two putative neoepitopes,” the researchers noted.
The team also pointed out that seven of nine patients tested had CD8+ T cells that responded to ETV6-RUNX1.
Finally, the investigators performed transcriptional profiling of ALL-specific CD8+ TILs to assess inter- and intrapatient heterogeneity. The team identified three hierarchical clusters, which were characterized by transcriptional factors and regulators associated with:
- Functional effector CD8+ T cells (TBX21 and EOMES).
- Dysfunctional CD8+ T cells (STAT1/3/4, NR4A2/3, and BCL6).
- Exhausted CD8+ T cells (EOMES, MAF, PRDM1, and BATF).
Considering these findings together, the researchers concluded that “pediatric ALL elicits a potent neoepitope-specific CD8+ T-cell response.” Therefore, adoptive T-cell, monoclonal antibody, and targeted T-cell receptor therapies “should be explored” in pediatric ALL.
This research was supported by the National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, Key for a Cure Foundation, and American Lebanese Syrian Associated Charities. The researchers disclosed patent applications and relationships with Pfizer, Amgen, and other companies.
SOURCE: Zamora AE et al. Sci. Transl. Med. 2019 Jun 26. doi: 10.1126/scitranslmed.aat8549.
Pediatric acute lymphoblastic leukemia (ALL) may be more vulnerable to immunotherapies than previously thought, according to researchers.
Prior studies suggested that tumors with a low mutational burden don’t elicit strong antitumor responses and therefore aren’t very susceptible to immunotherapy.
Now, researchers have found evidence to suggest that pediatric ALL induces “robust antitumor immune responses” despite a low mutational burden. The investigators identified tumor-associated CD8+ T cells that responded to 86% of neoantigens tested and recognized 68% of neoepitopes tested.
Anthony E. Zamora, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues recounted these findings in Science Translational Medicine.
The researchers analyzed samples from pediatric patients with ETV-associated ALL (n = 9) or ERG-associated ALL (n = 2) to determine how endogenous CD8+ T cells respond to patient-specific cancer neoantigens.
The investigators first assessed the ability of tumor-specific mutations and gene fusions to generate neoepitopes, or neoantigens predicted to bind patient-specific human leukocyte antigen (HLA) proteins. The team identified 5-28 neoepitopes per patient, including epitopes that spanned the fusion junction in patients with ETV6-RUNX1 fusions.
The researchers then tested whether CD8+ tumor infiltrating lymphocytes (TILs) were directly responsive to mutated neoepitopes. They observed cytokine responses across patient samples, noting that 31 of the 36 putative neoantigens tested (86%) were “immunogenic and capable of inducing robust cytokine responses.”
Next, the investigators mapped TIL responses to specific epitopes using patient-specific tetramers that corresponded to the previously identified neoepitopes. Seventeen of the 25 patient-specific tetramers (68%) bound to TILs above the background set by irrelevant HLA-matched tetramers.
“Within those responses, we observed immunodominance hierarchies among the distinct TIL populations, with a majority of tetramer-bound CD8+ T cells restricted to one or two putative neoepitopes,” the researchers noted.
The team also pointed out that seven of nine patients tested had CD8+ T cells that responded to ETV6-RUNX1.
Finally, the investigators performed transcriptional profiling of ALL-specific CD8+ TILs to assess inter- and intrapatient heterogeneity. The team identified three hierarchical clusters, which were characterized by transcriptional factors and regulators associated with:
- Functional effector CD8+ T cells (TBX21 and EOMES).
- Dysfunctional CD8+ T cells (STAT1/3/4, NR4A2/3, and BCL6).
- Exhausted CD8+ T cells (EOMES, MAF, PRDM1, and BATF).
Considering these findings together, the researchers concluded that “pediatric ALL elicits a potent neoepitope-specific CD8+ T-cell response.” Therefore, adoptive T-cell, monoclonal antibody, and targeted T-cell receptor therapies “should be explored” in pediatric ALL.
This research was supported by the National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, Key for a Cure Foundation, and American Lebanese Syrian Associated Charities. The researchers disclosed patent applications and relationships with Pfizer, Amgen, and other companies.
SOURCE: Zamora AE et al. Sci. Transl. Med. 2019 Jun 26. doi: 10.1126/scitranslmed.aat8549.
Pediatric acute lymphoblastic leukemia (ALL) may be more vulnerable to immunotherapies than previously thought, according to researchers.
Prior studies suggested that tumors with a low mutational burden don’t elicit strong antitumor responses and therefore aren’t very susceptible to immunotherapy.
Now, researchers have found evidence to suggest that pediatric ALL induces “robust antitumor immune responses” despite a low mutational burden. The investigators identified tumor-associated CD8+ T cells that responded to 86% of neoantigens tested and recognized 68% of neoepitopes tested.
Anthony E. Zamora, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues recounted these findings in Science Translational Medicine.
The researchers analyzed samples from pediatric patients with ETV-associated ALL (n = 9) or ERG-associated ALL (n = 2) to determine how endogenous CD8+ T cells respond to patient-specific cancer neoantigens.
The investigators first assessed the ability of tumor-specific mutations and gene fusions to generate neoepitopes, or neoantigens predicted to bind patient-specific human leukocyte antigen (HLA) proteins. The team identified 5-28 neoepitopes per patient, including epitopes that spanned the fusion junction in patients with ETV6-RUNX1 fusions.
The researchers then tested whether CD8+ tumor infiltrating lymphocytes (TILs) were directly responsive to mutated neoepitopes. They observed cytokine responses across patient samples, noting that 31 of the 36 putative neoantigens tested (86%) were “immunogenic and capable of inducing robust cytokine responses.”
Next, the investigators mapped TIL responses to specific epitopes using patient-specific tetramers that corresponded to the previously identified neoepitopes. Seventeen of the 25 patient-specific tetramers (68%) bound to TILs above the background set by irrelevant HLA-matched tetramers.
“Within those responses, we observed immunodominance hierarchies among the distinct TIL populations, with a majority of tetramer-bound CD8+ T cells restricted to one or two putative neoepitopes,” the researchers noted.
The team also pointed out that seven of nine patients tested had CD8+ T cells that responded to ETV6-RUNX1.
Finally, the investigators performed transcriptional profiling of ALL-specific CD8+ TILs to assess inter- and intrapatient heterogeneity. The team identified three hierarchical clusters, which were characterized by transcriptional factors and regulators associated with:
- Functional effector CD8+ T cells (TBX21 and EOMES).
- Dysfunctional CD8+ T cells (STAT1/3/4, NR4A2/3, and BCL6).
- Exhausted CD8+ T cells (EOMES, MAF, PRDM1, and BATF).
Considering these findings together, the researchers concluded that “pediatric ALL elicits a potent neoepitope-specific CD8+ T-cell response.” Therefore, adoptive T-cell, monoclonal antibody, and targeted T-cell receptor therapies “should be explored” in pediatric ALL.
This research was supported by the National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, Key for a Cure Foundation, and American Lebanese Syrian Associated Charities. The researchers disclosed patent applications and relationships with Pfizer, Amgen, and other companies.
SOURCE: Zamora AE et al. Sci. Transl. Med. 2019 Jun 26. doi: 10.1126/scitranslmed.aat8549.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point: Preclinical research suggests pediatric acute lymphoblastic leukemia (ALL) induces “robust antitumor immune responses” despite a low mutational burden.
Major finding: Investigators identified tumor-associated CD8+ T cells that responded to 86% of neoantigens tested and recognized 68% of neoepitopes tested.
Study details: Analysis of samples from pediatric patients with ETV-associated ALL (n = 9) or ERG-associated ALL (n = 2).
Disclosures: The research was supported by the National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, Key for a Cure Foundation, and American Lebanese Syrian Associated Charities. The researchers disclosed patent applications and relationships with Pfizer, Amgen, and other companies.
Source: Zamora AE et al. Sci. Transl. Med. 2019 Jun 26. doi: 10.1126/scitranslmed.aat8549.
Parent education improves quick disposal of children’s unused prescription opioids
SAN ANTONIO – Interventions aimed at educating parents about proper disposal methods for leftover prescription opioids and on explaining the risks of retaining opioids can increase the likelihood that parents will dispose of opioids when their children no longer need them, according to new research.
“Cost-effective disposal methods can nudge parents to dispose of their child’s leftover opioids promptly after use, but risk messaging is needed to best affect both early disposal and planned retention,” concluded Terri Voepel-Lewis, PhD, RN, of the University of Michigan, Ann Arbor, and colleagues.
“Such strategies can effectively reduce the presence of risky leftover medications in the home and decrease the risks posed to children and adolescents,” they wrote in a research poster at the annual meeting of College on Problems of Drug Dependence.
The researchers recruited 517 parents of children prescribed a short course of opioids, excluding children with chronic pain or the inability to report their pain.
The 255 parents randomly assigned to the nudge group received visual instructions on how to properly dispose of drugs while the 262 parents in the control group did not receive information on a disposal method. The groups were otherwise similar in terms of parent education, race/ethnicity, the child’s age and past opioid use, the parents’ past opioid use or misuse, whether opioids were kept in the home and whether the child’s procedure had been orthopedic/sports medicine–related.
Parents also were randomly assigned to routine care or to a Scenario-Tailored Opioid Messaging Program (STOMP). The STOMP group received tailored opioid risk information.
After a baseline survey on the child’s past pain, opioid use, misuse of opioids and risk perceptions, parents completed follow-up surveys at 7 and 14 days on opioid use, child pain, and behaviors related to retaining or disposing of opioids.
Just over a third of parents in the nudge group (34.7%) disposed of leftover opioids immediately after use, compared with 24% in the control group (odds ratio, 1.68; P = .01). Parents with the highest rate of disposal were those in the nudge group who participated in STOMP; they were more than twice as likely to dispose of opioids immediately after they were no longer needed (OR, 2.55; compared with control/non-STOMP).
A higher likelihood of disposal for parents in the nudge group alone, however, barely missed significance (OR, 1.77; P = .06) before adjustment. Parents’ intention to dispose of opioids was significantly different only among those who received STOMP education.
After the researchers controlled for child and parent factors, actual early disposal was significantly more likely in both the nudge and STOMP groups.
“Parental past opioid behaviors (kept an opioid in the home and past misuse) as well as orthopedic/sports medicine procedure were strongly associated with parents’ intention to retain [opioids],” the authors reported.
The study results revealed a divergence in parents’ intentions versus their behavior for one of the intervention groups.
“The nudge intervention improved parents’ prompt disposal of leftover prescription opioids but had no effect on planned retention rates,” the researchers reported. “In contrast, STOMP education had significant effects on early disposal behavior and planned retention. ”
Additional findings regarding parents’ past behaviors suggested that those who have kept leftover opioids or previously misused them may see the risks of doing so as low, the authors noted.
“Importantly, parents’ past prescription opioid retention behavior doubled the risk for planned retention, and their past opioid misuse more than tripled the risk,” the researchers wrote. “Assessing parents’ past behaviors and enhancing their perceptions of the real risks posed to children are important targets for risk reduction.”
The National Institute on Drug Addiction funded the research. The authors reported having no conflicts of interest.
SAN ANTONIO – Interventions aimed at educating parents about proper disposal methods for leftover prescription opioids and on explaining the risks of retaining opioids can increase the likelihood that parents will dispose of opioids when their children no longer need them, according to new research.
“Cost-effective disposal methods can nudge parents to dispose of their child’s leftover opioids promptly after use, but risk messaging is needed to best affect both early disposal and planned retention,” concluded Terri Voepel-Lewis, PhD, RN, of the University of Michigan, Ann Arbor, and colleagues.
“Such strategies can effectively reduce the presence of risky leftover medications in the home and decrease the risks posed to children and adolescents,” they wrote in a research poster at the annual meeting of College on Problems of Drug Dependence.
The researchers recruited 517 parents of children prescribed a short course of opioids, excluding children with chronic pain or the inability to report their pain.
The 255 parents randomly assigned to the nudge group received visual instructions on how to properly dispose of drugs while the 262 parents in the control group did not receive information on a disposal method. The groups were otherwise similar in terms of parent education, race/ethnicity, the child’s age and past opioid use, the parents’ past opioid use or misuse, whether opioids were kept in the home and whether the child’s procedure had been orthopedic/sports medicine–related.
Parents also were randomly assigned to routine care or to a Scenario-Tailored Opioid Messaging Program (STOMP). The STOMP group received tailored opioid risk information.
After a baseline survey on the child’s past pain, opioid use, misuse of opioids and risk perceptions, parents completed follow-up surveys at 7 and 14 days on opioid use, child pain, and behaviors related to retaining or disposing of opioids.
Just over a third of parents in the nudge group (34.7%) disposed of leftover opioids immediately after use, compared with 24% in the control group (odds ratio, 1.68; P = .01). Parents with the highest rate of disposal were those in the nudge group who participated in STOMP; they were more than twice as likely to dispose of opioids immediately after they were no longer needed (OR, 2.55; compared with control/non-STOMP).
A higher likelihood of disposal for parents in the nudge group alone, however, barely missed significance (OR, 1.77; P = .06) before adjustment. Parents’ intention to dispose of opioids was significantly different only among those who received STOMP education.
After the researchers controlled for child and parent factors, actual early disposal was significantly more likely in both the nudge and STOMP groups.
“Parental past opioid behaviors (kept an opioid in the home and past misuse) as well as orthopedic/sports medicine procedure were strongly associated with parents’ intention to retain [opioids],” the authors reported.
The study results revealed a divergence in parents’ intentions versus their behavior for one of the intervention groups.
“The nudge intervention improved parents’ prompt disposal of leftover prescription opioids but had no effect on planned retention rates,” the researchers reported. “In contrast, STOMP education had significant effects on early disposal behavior and planned retention. ”
Additional findings regarding parents’ past behaviors suggested that those who have kept leftover opioids or previously misused them may see the risks of doing so as low, the authors noted.
“Importantly, parents’ past prescription opioid retention behavior doubled the risk for planned retention, and their past opioid misuse more than tripled the risk,” the researchers wrote. “Assessing parents’ past behaviors and enhancing their perceptions of the real risks posed to children are important targets for risk reduction.”
The National Institute on Drug Addiction funded the research. The authors reported having no conflicts of interest.
SAN ANTONIO – Interventions aimed at educating parents about proper disposal methods for leftover prescription opioids and on explaining the risks of retaining opioids can increase the likelihood that parents will dispose of opioids when their children no longer need them, according to new research.
“Cost-effective disposal methods can nudge parents to dispose of their child’s leftover opioids promptly after use, but risk messaging is needed to best affect both early disposal and planned retention,” concluded Terri Voepel-Lewis, PhD, RN, of the University of Michigan, Ann Arbor, and colleagues.
“Such strategies can effectively reduce the presence of risky leftover medications in the home and decrease the risks posed to children and adolescents,” they wrote in a research poster at the annual meeting of College on Problems of Drug Dependence.
The researchers recruited 517 parents of children prescribed a short course of opioids, excluding children with chronic pain or the inability to report their pain.
The 255 parents randomly assigned to the nudge group received visual instructions on how to properly dispose of drugs while the 262 parents in the control group did not receive information on a disposal method. The groups were otherwise similar in terms of parent education, race/ethnicity, the child’s age and past opioid use, the parents’ past opioid use or misuse, whether opioids were kept in the home and whether the child’s procedure had been orthopedic/sports medicine–related.
Parents also were randomly assigned to routine care or to a Scenario-Tailored Opioid Messaging Program (STOMP). The STOMP group received tailored opioid risk information.
After a baseline survey on the child’s past pain, opioid use, misuse of opioids and risk perceptions, parents completed follow-up surveys at 7 and 14 days on opioid use, child pain, and behaviors related to retaining or disposing of opioids.
Just over a third of parents in the nudge group (34.7%) disposed of leftover opioids immediately after use, compared with 24% in the control group (odds ratio, 1.68; P = .01). Parents with the highest rate of disposal were those in the nudge group who participated in STOMP; they were more than twice as likely to dispose of opioids immediately after they were no longer needed (OR, 2.55; compared with control/non-STOMP).
A higher likelihood of disposal for parents in the nudge group alone, however, barely missed significance (OR, 1.77; P = .06) before adjustment. Parents’ intention to dispose of opioids was significantly different only among those who received STOMP education.
After the researchers controlled for child and parent factors, actual early disposal was significantly more likely in both the nudge and STOMP groups.
“Parental past opioid behaviors (kept an opioid in the home and past misuse) as well as orthopedic/sports medicine procedure were strongly associated with parents’ intention to retain [opioids],” the authors reported.
The study results revealed a divergence in parents’ intentions versus their behavior for one of the intervention groups.
“The nudge intervention improved parents’ prompt disposal of leftover prescription opioids but had no effect on planned retention rates,” the researchers reported. “In contrast, STOMP education had significant effects on early disposal behavior and planned retention. ”
Additional findings regarding parents’ past behaviors suggested that those who have kept leftover opioids or previously misused them may see the risks of doing so as low, the authors noted.
“Importantly, parents’ past prescription opioid retention behavior doubled the risk for planned retention, and their past opioid misuse more than tripled the risk,” the researchers wrote. “Assessing parents’ past behaviors and enhancing their perceptions of the real risks posed to children are important targets for risk reduction.”
The National Institute on Drug Addiction funded the research. The authors reported having no conflicts of interest.
REPORTING FROM CPDD 2019
What’s new in pediatric sepsis
LJUBLJANA, SLOVENIA – The dogma of the “Golden Hour” for the immediate management of pediatric sepsis has been oversold and actually is based upon weak evidence, Luregn J. Schlapbach, MD, asserted at the annual meeting of the European Society for Paediatric Infectious Diseases.
The true Golden Hour – that is, the time frame within which it’s imperative to administer the sepsis bundle comprised of appropriate antibiotics, fluids, and inotropes – is probably more like 3 hours.
“The evidence suggests that up to 3 hours you don’t really have a big difference in outcomes for sepsis. If you recognize shock there’s no question: You should not even wait 1 hour. But if you’re not certain, it may be better to give up to 3 hours to work up the child and get the senior clinician involved before you make decisions about treatment. So I’m not advocating to delay anything, said Dr. Schlapbach, a pediatric intensivist at the Child Health Research Center at the University of Queensland in South Brisbane, Australia.
The problem with a 1-hour mandate for delivery of the sepsis bundle, as recommended in guidelines by the Surviving Sepsis Campaign and the American College of Critical Care Medicine, and endorsed in quality improvement initiatives, is that the time pressure pushes physicians to overprescribe antibiotics to children who don’t actually have a serious bacterial infection. And that, he noted, contributes to the growing problem of antimicrobial resistance.
“You may have a child where you’re not too sure. Usually you would have done a urine culture because UTI [urinary tract infection] is quite a common cause of these infections, and many of these kids aren’t necessarily septic. But if people tell you that within 1 hour you need to treat, are you going to take the time to do the urine culture, or are you just going to decide to treat?” he asked rhetorically.
Dr. Schlapbach is a world-renowned pediatric sepsis researcher. He is far from alone in his reservations about the Golden Hour mandate.
“This is one of the reasons why IDSA [the Infectious Diseases Society of America] has not endorsed the Surviving Sepsis Campaign,” according to the physician, who noted that, in a position statement, IDSA officials have declared that discrimination of sepsis from noninfectious conditions remains a challenge, and that a 60-minute time to antibiotics may jeopardize patient reassessment (Clin Infect Dis. 2018 May 15;66[10]:1631-5).
Dr. Schlapbach highlighted other recent developments in pediatric sepsis.
The definition of adult sepsis has changed, and the pediatric version needs to as well
The revised definition of sepsis, known as Sepsis-3, issued by the International Sepsis Definition Task Force in 2016 notably dropped systemic inflammatory response syndrome (SIRS), as a requirement for sepsis (JAMA. 2016;315[8]:801-10). The revised definition characterizes sepsis as a dysregulated host response to infection resulting in life-threatening organ dysfunction. But Sepsis-3 is based entirely on adult data and is not considered applicable to children.
The current Pediatric Sepsis Consensus Conference definition dates back to 2005. A comprehensive revision is getting underway. It, too, is likely to drop SIRS into the wastebasket, Dr. Schlapbach said.
“It is probably time to abandon the old view of sepsis disease progression, which proposes a progression from infection to SIRS to severe sepsis with organ dysfunction to septic shock, because most children with infection do manifest signs of SIRS, such as tachycardia, tachypnea, and fever, and these probably should be considered as more of an adaptive rather than a maladaptive response,” he explained.
The goal of the pediatric sepsis redefinition project is to come up with something more useful for clinicians than the Sepsis-3 definition. While the Sepsis-3 concept of a dysregulated host response to infection sounds nice, he explained, “we don’t actually know what it is.
“One of the challenges that you all know as pediatricians is that children who develop sepsis get sick very, very quickly. We all have memories of children who we saw and may have discharged, and they were dead 12 hours later,” he noted.
Indeed, he and others have shown in multiple studies that up to 50% of pediatric deaths caused by sepsis happen within 24 hours of presentation.
“So whatever happens, it happens very quickly. The true question for us is actually how and why do children progress from no organ dysfunction, where the mortality is close to zero, to organ dysfunction, where all of a sudden mortality jumps up dramatically. It’s this progression that we don’t understand at all,” according to Dr. Schlapbach.
The genetic contribution to fulminant sepsis in children may be substantial
One-third of pediatric sepsis deaths in high-income countries happen in previously healthy children. In a proof-of-concept study, Dr. Schlapbach and coinvestigators in the Swiss Pediatric Sepsis Study Group conducted exome-sequencing genetic studies in eight previously healthy children with no family history of immunodeficiency who died of severe sepsis because of community-acquired Pseudomonas aeruginosa infection. Two of the eight had rare loss-of-function mutations in genes known to cause primary immunodeficiencies. The investigators proposed that unusually severe sepsis in previously healthy children warrants exome sequencing to look for underlying previously undetected primary immunodeficiencies. That’s important information for survivors and/or affected families to have, they argued (Front Immunol. 2016 Sep 20;7:357. eCollection 2016).
“There are some indications that the genetic contribution in children with sepsis may be larger than previously assumed,” he said.
The longstanding practice of fluid bolus therapy for resuscitation in pediatric sepsis is being reexamined
The FEAST (Fluid Expansion As Supportive Therapy) study, a randomized trial of more than 3,000 children with severe febrile illness and impaired perfusion in sub-Saharan Africa, turned heads with its finding that fluid boluses significantly increased 48-hour mortality (BMC Med. 2013 Mar 14;11:67).
Indeed, the FEAST findings, supported by mechanistic animal studies, were sufficiently compelling that the use of fluid boluses in both pediatric and adult septic shock is now under scrutiny in two major randomized trials: RIFTS (the Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock), and CLOVERS (Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis). Stay tuned.
Dr. Schlapbach reported having no financial conflicts regarding his presentation.
LJUBLJANA, SLOVENIA – The dogma of the “Golden Hour” for the immediate management of pediatric sepsis has been oversold and actually is based upon weak evidence, Luregn J. Schlapbach, MD, asserted at the annual meeting of the European Society for Paediatric Infectious Diseases.
The true Golden Hour – that is, the time frame within which it’s imperative to administer the sepsis bundle comprised of appropriate antibiotics, fluids, and inotropes – is probably more like 3 hours.
“The evidence suggests that up to 3 hours you don’t really have a big difference in outcomes for sepsis. If you recognize shock there’s no question: You should not even wait 1 hour. But if you’re not certain, it may be better to give up to 3 hours to work up the child and get the senior clinician involved before you make decisions about treatment. So I’m not advocating to delay anything, said Dr. Schlapbach, a pediatric intensivist at the Child Health Research Center at the University of Queensland in South Brisbane, Australia.
The problem with a 1-hour mandate for delivery of the sepsis bundle, as recommended in guidelines by the Surviving Sepsis Campaign and the American College of Critical Care Medicine, and endorsed in quality improvement initiatives, is that the time pressure pushes physicians to overprescribe antibiotics to children who don’t actually have a serious bacterial infection. And that, he noted, contributes to the growing problem of antimicrobial resistance.
“You may have a child where you’re not too sure. Usually you would have done a urine culture because UTI [urinary tract infection] is quite a common cause of these infections, and many of these kids aren’t necessarily septic. But if people tell you that within 1 hour you need to treat, are you going to take the time to do the urine culture, or are you just going to decide to treat?” he asked rhetorically.
Dr. Schlapbach is a world-renowned pediatric sepsis researcher. He is far from alone in his reservations about the Golden Hour mandate.
“This is one of the reasons why IDSA [the Infectious Diseases Society of America] has not endorsed the Surviving Sepsis Campaign,” according to the physician, who noted that, in a position statement, IDSA officials have declared that discrimination of sepsis from noninfectious conditions remains a challenge, and that a 60-minute time to antibiotics may jeopardize patient reassessment (Clin Infect Dis. 2018 May 15;66[10]:1631-5).
Dr. Schlapbach highlighted other recent developments in pediatric sepsis.
The definition of adult sepsis has changed, and the pediatric version needs to as well
The revised definition of sepsis, known as Sepsis-3, issued by the International Sepsis Definition Task Force in 2016 notably dropped systemic inflammatory response syndrome (SIRS), as a requirement for sepsis (JAMA. 2016;315[8]:801-10). The revised definition characterizes sepsis as a dysregulated host response to infection resulting in life-threatening organ dysfunction. But Sepsis-3 is based entirely on adult data and is not considered applicable to children.
The current Pediatric Sepsis Consensus Conference definition dates back to 2005. A comprehensive revision is getting underway. It, too, is likely to drop SIRS into the wastebasket, Dr. Schlapbach said.
“It is probably time to abandon the old view of sepsis disease progression, which proposes a progression from infection to SIRS to severe sepsis with organ dysfunction to septic shock, because most children with infection do manifest signs of SIRS, such as tachycardia, tachypnea, and fever, and these probably should be considered as more of an adaptive rather than a maladaptive response,” he explained.
The goal of the pediatric sepsis redefinition project is to come up with something more useful for clinicians than the Sepsis-3 definition. While the Sepsis-3 concept of a dysregulated host response to infection sounds nice, he explained, “we don’t actually know what it is.
“One of the challenges that you all know as pediatricians is that children who develop sepsis get sick very, very quickly. We all have memories of children who we saw and may have discharged, and they were dead 12 hours later,” he noted.
Indeed, he and others have shown in multiple studies that up to 50% of pediatric deaths caused by sepsis happen within 24 hours of presentation.
“So whatever happens, it happens very quickly. The true question for us is actually how and why do children progress from no organ dysfunction, where the mortality is close to zero, to organ dysfunction, where all of a sudden mortality jumps up dramatically. It’s this progression that we don’t understand at all,” according to Dr. Schlapbach.
The genetic contribution to fulminant sepsis in children may be substantial
One-third of pediatric sepsis deaths in high-income countries happen in previously healthy children. In a proof-of-concept study, Dr. Schlapbach and coinvestigators in the Swiss Pediatric Sepsis Study Group conducted exome-sequencing genetic studies in eight previously healthy children with no family history of immunodeficiency who died of severe sepsis because of community-acquired Pseudomonas aeruginosa infection. Two of the eight had rare loss-of-function mutations in genes known to cause primary immunodeficiencies. The investigators proposed that unusually severe sepsis in previously healthy children warrants exome sequencing to look for underlying previously undetected primary immunodeficiencies. That’s important information for survivors and/or affected families to have, they argued (Front Immunol. 2016 Sep 20;7:357. eCollection 2016).
“There are some indications that the genetic contribution in children with sepsis may be larger than previously assumed,” he said.
The longstanding practice of fluid bolus therapy for resuscitation in pediatric sepsis is being reexamined
The FEAST (Fluid Expansion As Supportive Therapy) study, a randomized trial of more than 3,000 children with severe febrile illness and impaired perfusion in sub-Saharan Africa, turned heads with its finding that fluid boluses significantly increased 48-hour mortality (BMC Med. 2013 Mar 14;11:67).
Indeed, the FEAST findings, supported by mechanistic animal studies, were sufficiently compelling that the use of fluid boluses in both pediatric and adult septic shock is now under scrutiny in two major randomized trials: RIFTS (the Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock), and CLOVERS (Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis). Stay tuned.
Dr. Schlapbach reported having no financial conflicts regarding his presentation.
LJUBLJANA, SLOVENIA – The dogma of the “Golden Hour” for the immediate management of pediatric sepsis has been oversold and actually is based upon weak evidence, Luregn J. Schlapbach, MD, asserted at the annual meeting of the European Society for Paediatric Infectious Diseases.
The true Golden Hour – that is, the time frame within which it’s imperative to administer the sepsis bundle comprised of appropriate antibiotics, fluids, and inotropes – is probably more like 3 hours.
“The evidence suggests that up to 3 hours you don’t really have a big difference in outcomes for sepsis. If you recognize shock there’s no question: You should not even wait 1 hour. But if you’re not certain, it may be better to give up to 3 hours to work up the child and get the senior clinician involved before you make decisions about treatment. So I’m not advocating to delay anything, said Dr. Schlapbach, a pediatric intensivist at the Child Health Research Center at the University of Queensland in South Brisbane, Australia.
The problem with a 1-hour mandate for delivery of the sepsis bundle, as recommended in guidelines by the Surviving Sepsis Campaign and the American College of Critical Care Medicine, and endorsed in quality improvement initiatives, is that the time pressure pushes physicians to overprescribe antibiotics to children who don’t actually have a serious bacterial infection. And that, he noted, contributes to the growing problem of antimicrobial resistance.
“You may have a child where you’re not too sure. Usually you would have done a urine culture because UTI [urinary tract infection] is quite a common cause of these infections, and many of these kids aren’t necessarily septic. But if people tell you that within 1 hour you need to treat, are you going to take the time to do the urine culture, or are you just going to decide to treat?” he asked rhetorically.
Dr. Schlapbach is a world-renowned pediatric sepsis researcher. He is far from alone in his reservations about the Golden Hour mandate.
“This is one of the reasons why IDSA [the Infectious Diseases Society of America] has not endorsed the Surviving Sepsis Campaign,” according to the physician, who noted that, in a position statement, IDSA officials have declared that discrimination of sepsis from noninfectious conditions remains a challenge, and that a 60-minute time to antibiotics may jeopardize patient reassessment (Clin Infect Dis. 2018 May 15;66[10]:1631-5).
Dr. Schlapbach highlighted other recent developments in pediatric sepsis.
The definition of adult sepsis has changed, and the pediatric version needs to as well
The revised definition of sepsis, known as Sepsis-3, issued by the International Sepsis Definition Task Force in 2016 notably dropped systemic inflammatory response syndrome (SIRS), as a requirement for sepsis (JAMA. 2016;315[8]:801-10). The revised definition characterizes sepsis as a dysregulated host response to infection resulting in life-threatening organ dysfunction. But Sepsis-3 is based entirely on adult data and is not considered applicable to children.
The current Pediatric Sepsis Consensus Conference definition dates back to 2005. A comprehensive revision is getting underway. It, too, is likely to drop SIRS into the wastebasket, Dr. Schlapbach said.
“It is probably time to abandon the old view of sepsis disease progression, which proposes a progression from infection to SIRS to severe sepsis with organ dysfunction to septic shock, because most children with infection do manifest signs of SIRS, such as tachycardia, tachypnea, and fever, and these probably should be considered as more of an adaptive rather than a maladaptive response,” he explained.
The goal of the pediatric sepsis redefinition project is to come up with something more useful for clinicians than the Sepsis-3 definition. While the Sepsis-3 concept of a dysregulated host response to infection sounds nice, he explained, “we don’t actually know what it is.
“One of the challenges that you all know as pediatricians is that children who develop sepsis get sick very, very quickly. We all have memories of children who we saw and may have discharged, and they were dead 12 hours later,” he noted.
Indeed, he and others have shown in multiple studies that up to 50% of pediatric deaths caused by sepsis happen within 24 hours of presentation.
“So whatever happens, it happens very quickly. The true question for us is actually how and why do children progress from no organ dysfunction, where the mortality is close to zero, to organ dysfunction, where all of a sudden mortality jumps up dramatically. It’s this progression that we don’t understand at all,” according to Dr. Schlapbach.
The genetic contribution to fulminant sepsis in children may be substantial
One-third of pediatric sepsis deaths in high-income countries happen in previously healthy children. In a proof-of-concept study, Dr. Schlapbach and coinvestigators in the Swiss Pediatric Sepsis Study Group conducted exome-sequencing genetic studies in eight previously healthy children with no family history of immunodeficiency who died of severe sepsis because of community-acquired Pseudomonas aeruginosa infection. Two of the eight had rare loss-of-function mutations in genes known to cause primary immunodeficiencies. The investigators proposed that unusually severe sepsis in previously healthy children warrants exome sequencing to look for underlying previously undetected primary immunodeficiencies. That’s important information for survivors and/or affected families to have, they argued (Front Immunol. 2016 Sep 20;7:357. eCollection 2016).
“There are some indications that the genetic contribution in children with sepsis may be larger than previously assumed,” he said.
The longstanding practice of fluid bolus therapy for resuscitation in pediatric sepsis is being reexamined
The FEAST (Fluid Expansion As Supportive Therapy) study, a randomized trial of more than 3,000 children with severe febrile illness and impaired perfusion in sub-Saharan Africa, turned heads with its finding that fluid boluses significantly increased 48-hour mortality (BMC Med. 2013 Mar 14;11:67).
Indeed, the FEAST findings, supported by mechanistic animal studies, were sufficiently compelling that the use of fluid boluses in both pediatric and adult septic shock is now under scrutiny in two major randomized trials: RIFTS (the Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock), and CLOVERS (Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis). Stay tuned.
Dr. Schlapbach reported having no financial conflicts regarding his presentation.
EXPERT ANALYSIS FROM ESPID 2019
About one in four youths prescribed stimulants also use the drugs nonmedically
SAN ANTONIO – Of 196 U.S. youth who reported use of at least one prescribed stimulant in their lifetimes, 25% also said they used the drugs nonmedically, based on a survey of children and adolescents aged 10-17 years.
Another 5% of the youth surveyed reported exclusively nonmedical use of stimulants. The survey participants lived in six U.S. cities and their outlying areas.
“Parents of both users and nonusers should warn their children of the dangers of using others’ stimulants and giving their own stimulants to others,” concluded Linda B. Cottler, PhD, MPH of the University of Florida, and colleagues.
“Physicians and pharmacists should make users and their families aware of the need to take medications as prescribed and not to share medications with others,” they wrote in their research poster at the annual meeting of the College on Problems of Drug Dependence. “Continuous monitoring of these medications in the community should be a priority.”
Though prevalence research has shown increasing stimulant misuse among youth, little data exist for younger children, the researchers noted. They therefore conducted a survey of 1,777 youth aged 10-17 years from September to October 2018 in six cities in California, Texas, and Florida, the most populous U.S. states.
The participants included youth from urban, rural, and suburban areas of Los Angeles, Dallas, Houston, Tampa, Orlando, and Miami. Trained graduate students and professional raters approached the respondents in entertainment venues and obtained assent but did not require parental consent. The respondents received $30 for completing the survey.
A total of 11.1% of respondents reporting having used prescription stimulants in their lifetime, and 7.6% had done so in the past 30 days. Just under a third of those who used stimulants (30.1%) did so for nonmedical purposes, defined as taking the stimulant nonorally (except for the patch Daytrana), getting the stimulant from someone else, or taking more of the drug than prescribed.
A quarter of the respondents who used stimulants reported both medical use and nonmedical use. And 5.1% of these youths reported only using stimulants nonmedically.
Among those with any lifetime stimulant use, 13.8% reported nonoral administration, including 9.7% who snorted or sniffed the drugs, 4.1% who smoked them, and 1.0% who injected them. Just over half (51.8%) of those reporting nonoral use had also used prescription stimulants orally.
The likelihood of using stimulants nonmedically increased with age (P less than .0001). The researchers found no significant associations between nonmedical use and geography or race/ethnicity. Among 10- to 12-year-olds, 3.1% reported only medical use of stimulants, and 0.7% (2 of 286 respondents in this age group) reported any nonmedical use of stimulants.
Of those aged 13-15 years, 2.1% reported any nonmedical stimulant use.
Nonmedical stimulant use was reported by twice as many boys (67.8%) as girls (32.2%), though this finding may not be surprising as the majority of nonmedical users were also medical users and stimulants are prescribed more frequently to boys than to girls (P less than .0006).
The research was funded by Arbor Pharmaceuticals. The authors noted no conflicts of interest.
SAN ANTONIO – Of 196 U.S. youth who reported use of at least one prescribed stimulant in their lifetimes, 25% also said they used the drugs nonmedically, based on a survey of children and adolescents aged 10-17 years.
Another 5% of the youth surveyed reported exclusively nonmedical use of stimulants. The survey participants lived in six U.S. cities and their outlying areas.
“Parents of both users and nonusers should warn their children of the dangers of using others’ stimulants and giving their own stimulants to others,” concluded Linda B. Cottler, PhD, MPH of the University of Florida, and colleagues.
“Physicians and pharmacists should make users and their families aware of the need to take medications as prescribed and not to share medications with others,” they wrote in their research poster at the annual meeting of the College on Problems of Drug Dependence. “Continuous monitoring of these medications in the community should be a priority.”
Though prevalence research has shown increasing stimulant misuse among youth, little data exist for younger children, the researchers noted. They therefore conducted a survey of 1,777 youth aged 10-17 years from September to October 2018 in six cities in California, Texas, and Florida, the most populous U.S. states.
The participants included youth from urban, rural, and suburban areas of Los Angeles, Dallas, Houston, Tampa, Orlando, and Miami. Trained graduate students and professional raters approached the respondents in entertainment venues and obtained assent but did not require parental consent. The respondents received $30 for completing the survey.
A total of 11.1% of respondents reporting having used prescription stimulants in their lifetime, and 7.6% had done so in the past 30 days. Just under a third of those who used stimulants (30.1%) did so for nonmedical purposes, defined as taking the stimulant nonorally (except for the patch Daytrana), getting the stimulant from someone else, or taking more of the drug than prescribed.
A quarter of the respondents who used stimulants reported both medical use and nonmedical use. And 5.1% of these youths reported only using stimulants nonmedically.
Among those with any lifetime stimulant use, 13.8% reported nonoral administration, including 9.7% who snorted or sniffed the drugs, 4.1% who smoked them, and 1.0% who injected them. Just over half (51.8%) of those reporting nonoral use had also used prescription stimulants orally.
The likelihood of using stimulants nonmedically increased with age (P less than .0001). The researchers found no significant associations between nonmedical use and geography or race/ethnicity. Among 10- to 12-year-olds, 3.1% reported only medical use of stimulants, and 0.7% (2 of 286 respondents in this age group) reported any nonmedical use of stimulants.
Of those aged 13-15 years, 2.1% reported any nonmedical stimulant use.
Nonmedical stimulant use was reported by twice as many boys (67.8%) as girls (32.2%), though this finding may not be surprising as the majority of nonmedical users were also medical users and stimulants are prescribed more frequently to boys than to girls (P less than .0006).
The research was funded by Arbor Pharmaceuticals. The authors noted no conflicts of interest.
SAN ANTONIO – Of 196 U.S. youth who reported use of at least one prescribed stimulant in their lifetimes, 25% also said they used the drugs nonmedically, based on a survey of children and adolescents aged 10-17 years.
Another 5% of the youth surveyed reported exclusively nonmedical use of stimulants. The survey participants lived in six U.S. cities and their outlying areas.
“Parents of both users and nonusers should warn their children of the dangers of using others’ stimulants and giving their own stimulants to others,” concluded Linda B. Cottler, PhD, MPH of the University of Florida, and colleagues.
“Physicians and pharmacists should make users and their families aware of the need to take medications as prescribed and not to share medications with others,” they wrote in their research poster at the annual meeting of the College on Problems of Drug Dependence. “Continuous monitoring of these medications in the community should be a priority.”
Though prevalence research has shown increasing stimulant misuse among youth, little data exist for younger children, the researchers noted. They therefore conducted a survey of 1,777 youth aged 10-17 years from September to October 2018 in six cities in California, Texas, and Florida, the most populous U.S. states.
The participants included youth from urban, rural, and suburban areas of Los Angeles, Dallas, Houston, Tampa, Orlando, and Miami. Trained graduate students and professional raters approached the respondents in entertainment venues and obtained assent but did not require parental consent. The respondents received $30 for completing the survey.
A total of 11.1% of respondents reporting having used prescription stimulants in their lifetime, and 7.6% had done so in the past 30 days. Just under a third of those who used stimulants (30.1%) did so for nonmedical purposes, defined as taking the stimulant nonorally (except for the patch Daytrana), getting the stimulant from someone else, or taking more of the drug than prescribed.
A quarter of the respondents who used stimulants reported both medical use and nonmedical use. And 5.1% of these youths reported only using stimulants nonmedically.
Among those with any lifetime stimulant use, 13.8% reported nonoral administration, including 9.7% who snorted or sniffed the drugs, 4.1% who smoked them, and 1.0% who injected them. Just over half (51.8%) of those reporting nonoral use had also used prescription stimulants orally.
The likelihood of using stimulants nonmedically increased with age (P less than .0001). The researchers found no significant associations between nonmedical use and geography or race/ethnicity. Among 10- to 12-year-olds, 3.1% reported only medical use of stimulants, and 0.7% (2 of 286 respondents in this age group) reported any nonmedical use of stimulants.
Of those aged 13-15 years, 2.1% reported any nonmedical stimulant use.
Nonmedical stimulant use was reported by twice as many boys (67.8%) as girls (32.2%), though this finding may not be surprising as the majority of nonmedical users were also medical users and stimulants are prescribed more frequently to boys than to girls (P less than .0006).
The research was funded by Arbor Pharmaceuticals. The authors noted no conflicts of interest.
REPORTING FROM CPDD 2019
Penicillin-susceptible Streptococcus pneumoniae most common cause of bacteremic CAP
A study found that only 2% of children hospitalized with community-acquired pneumonia (CAP) actually had any causative pathogen in their blood culture results, despite national guidelines that recommend blood cultures for all children hospitalized with moderate to severe CAP.
The guidelines are the 2011 guidelines for managing CAP published by the Pediatric Infectious Diseases Society (PIDS) and the Infectious Diseases Society of America (IDSA) (Clin Infect Dis. 2011 Oct;53[7]:617-30).
Cristin O. Fritz, MD, of the Children’s Hospital of Colorado, Aurora, and associates conducted a data analysis of the EPIC (Etiology of Pneumonia in the Community) study to estimate prevalence, risk factors, and clinical outcomes in children hospitalized with bacteremic CAP and to evaluate the relationship between positive blood culture results, empirical antibiotics, and changes in antibiotic treatment regimens.
Data were collected at two Tennessee hospitals and one Utah hospital during Jan. 1, 2010–June 30, 2012. Of the 2,358 children with CAP enrolled in the study, 2,143 (91%) with blood cultures were included in Dr. Fritz’s analysis. Of the 53 patients presenting with positive blood culture results, 46 (2%; 95% confidence interval: 1.6%-2.9%) were identified as having bacteremia. Half of all cases observed were caused by Streptococcus pneumoniae, with Staphylococcus aureus and Streptococcus pyogenes noted less frequently, according to the study published in Pediatrics.
A previous meta-analysis of smaller studies also found that children with CAP rarely had positive blood culture results, a pooled prevalence of 5% (Pediatr Infect Dis J. 2013;32[7]:736-40). Although it is believed that positive blood culture results are key to narrowing the choice of antibiotic and predicting treatment outcomes, the literature – to date – reveals a paucity of data supporting this assumption.
Overall, children in the study presenting with bacteremia experienced more severe clinical outcomes, including longer length of stay, greater likelihood of ICU admission, and invasive mechanical ventilation and/or shock. The authors also observed that bacteremia was less likely to be detected in children given antibiotics after admission but before cultures were obtained (0.8% vs 3%; P = .021). Pleural effusion detected with chest radiograph also consistently indicated bacteremic pneumonia, an observation made within this and other similar studies.
Also of note in detection is the biomarker procalcitonin, which is typically present with bacterial disease. Dr. Fritz and colleagues stressed that because the procalcitonin rate was higher in patients presenting with bacteremia, “this information could influence decisions around culturing if results are rapidly available.” Risk-stratification tools also might serve a valuable purpose in ferreting out those patients presenting with moderate to severe pneumonia most at increased risk for bacterial CAP.
Compared with other studies reporting prevalence ranges of 1%-7%, the prevalence of bacteremia in this study is lower at 2%. The authors attributed the difference to a possible potential limitation with the other studies, for which culture data was only available for a median 47% of enrollees. Dr. Fritz and her colleagues caution that “because cultures were obtained at the discretion of the treating clinician in a majority of studies, blood cultures were likely obtained more often in those with more severe illness or who had not already received antibiotics.” In this scenario, the likelihood that prevalence of bacteremia was overestimated is noteworthy.
The authors observed that penicillin-susceptible S. pneumonia was the most common cause of bacteremic CAP. They further acknowledged that their study and findings by Neuman et al. in 2017 give credence to the joint 2011 PIDS/IDSA guideline recommending narrow-spectrum aminopenicillins specifically to treat children hospitalized due to suspected bacterial CAP.
Despite its small sample size, the results of this study clearly demonstrate that children with bacteremia because of S. pyogenes or S. aureus experience increased morbidity, compared with children with S. pneumoniae, they said
While this is acknowledged to be one of the largest studies of its kind to date, a key limitation was the small number of observable patients with bacteremia, which prevented the researchers from conducting a more in-depth analysis of risk factors and pathogen-specific differences. That one-fourth of patients received in-patient antibiotics before cultures could be collected also likely led to an underestimation of risk factors and misclassification bias. Lastly, the use of blood culture instead of whole-blood polymerase chain reaction, which is known to be more sensitive, also may have led to underestimation of overall bacteremia prevalence.
“In an era with widespread pneumococcal vaccination and low prevalence of bacteremia in the United States, noted Dr. Fritz and associates.
Dr. Fritz had no conflicts of interest to report. Some coauthors cited multiple sources of potential conflict of interest related to consulting fees, grant support, and research support from various pharmaceutical companies and agencies. The study was funded by the National Institutes of Health and in part by a grant from the National Institute of Allergy and Infectious Diseases.
SOURCE: Fritz C et al. Pediatrics. 2019;144(1):e20183090.
A study found that only 2% of children hospitalized with community-acquired pneumonia (CAP) actually had any causative pathogen in their blood culture results, despite national guidelines that recommend blood cultures for all children hospitalized with moderate to severe CAP.
The guidelines are the 2011 guidelines for managing CAP published by the Pediatric Infectious Diseases Society (PIDS) and the Infectious Diseases Society of America (IDSA) (Clin Infect Dis. 2011 Oct;53[7]:617-30).
Cristin O. Fritz, MD, of the Children’s Hospital of Colorado, Aurora, and associates conducted a data analysis of the EPIC (Etiology of Pneumonia in the Community) study to estimate prevalence, risk factors, and clinical outcomes in children hospitalized with bacteremic CAP and to evaluate the relationship between positive blood culture results, empirical antibiotics, and changes in antibiotic treatment regimens.
Data were collected at two Tennessee hospitals and one Utah hospital during Jan. 1, 2010–June 30, 2012. Of the 2,358 children with CAP enrolled in the study, 2,143 (91%) with blood cultures were included in Dr. Fritz’s analysis. Of the 53 patients presenting with positive blood culture results, 46 (2%; 95% confidence interval: 1.6%-2.9%) were identified as having bacteremia. Half of all cases observed were caused by Streptococcus pneumoniae, with Staphylococcus aureus and Streptococcus pyogenes noted less frequently, according to the study published in Pediatrics.
A previous meta-analysis of smaller studies also found that children with CAP rarely had positive blood culture results, a pooled prevalence of 5% (Pediatr Infect Dis J. 2013;32[7]:736-40). Although it is believed that positive blood culture results are key to narrowing the choice of antibiotic and predicting treatment outcomes, the literature – to date – reveals a paucity of data supporting this assumption.
Overall, children in the study presenting with bacteremia experienced more severe clinical outcomes, including longer length of stay, greater likelihood of ICU admission, and invasive mechanical ventilation and/or shock. The authors also observed that bacteremia was less likely to be detected in children given antibiotics after admission but before cultures were obtained (0.8% vs 3%; P = .021). Pleural effusion detected with chest radiograph also consistently indicated bacteremic pneumonia, an observation made within this and other similar studies.
Also of note in detection is the biomarker procalcitonin, which is typically present with bacterial disease. Dr. Fritz and colleagues stressed that because the procalcitonin rate was higher in patients presenting with bacteremia, “this information could influence decisions around culturing if results are rapidly available.” Risk-stratification tools also might serve a valuable purpose in ferreting out those patients presenting with moderate to severe pneumonia most at increased risk for bacterial CAP.
Compared with other studies reporting prevalence ranges of 1%-7%, the prevalence of bacteremia in this study is lower at 2%. The authors attributed the difference to a possible potential limitation with the other studies, for which culture data was only available for a median 47% of enrollees. Dr. Fritz and her colleagues caution that “because cultures were obtained at the discretion of the treating clinician in a majority of studies, blood cultures were likely obtained more often in those with more severe illness or who had not already received antibiotics.” In this scenario, the likelihood that prevalence of bacteremia was overestimated is noteworthy.
The authors observed that penicillin-susceptible S. pneumonia was the most common cause of bacteremic CAP. They further acknowledged that their study and findings by Neuman et al. in 2017 give credence to the joint 2011 PIDS/IDSA guideline recommending narrow-spectrum aminopenicillins specifically to treat children hospitalized due to suspected bacterial CAP.
Despite its small sample size, the results of this study clearly demonstrate that children with bacteremia because of S. pyogenes or S. aureus experience increased morbidity, compared with children with S. pneumoniae, they said
While this is acknowledged to be one of the largest studies of its kind to date, a key limitation was the small number of observable patients with bacteremia, which prevented the researchers from conducting a more in-depth analysis of risk factors and pathogen-specific differences. That one-fourth of patients received in-patient antibiotics before cultures could be collected also likely led to an underestimation of risk factors and misclassification bias. Lastly, the use of blood culture instead of whole-blood polymerase chain reaction, which is known to be more sensitive, also may have led to underestimation of overall bacteremia prevalence.
“In an era with widespread pneumococcal vaccination and low prevalence of bacteremia in the United States, noted Dr. Fritz and associates.
Dr. Fritz had no conflicts of interest to report. Some coauthors cited multiple sources of potential conflict of interest related to consulting fees, grant support, and research support from various pharmaceutical companies and agencies. The study was funded by the National Institutes of Health and in part by a grant from the National Institute of Allergy and Infectious Diseases.
SOURCE: Fritz C et al. Pediatrics. 2019;144(1):e20183090.
A study found that only 2% of children hospitalized with community-acquired pneumonia (CAP) actually had any causative pathogen in their blood culture results, despite national guidelines that recommend blood cultures for all children hospitalized with moderate to severe CAP.
The guidelines are the 2011 guidelines for managing CAP published by the Pediatric Infectious Diseases Society (PIDS) and the Infectious Diseases Society of America (IDSA) (Clin Infect Dis. 2011 Oct;53[7]:617-30).
Cristin O. Fritz, MD, of the Children’s Hospital of Colorado, Aurora, and associates conducted a data analysis of the EPIC (Etiology of Pneumonia in the Community) study to estimate prevalence, risk factors, and clinical outcomes in children hospitalized with bacteremic CAP and to evaluate the relationship between positive blood culture results, empirical antibiotics, and changes in antibiotic treatment regimens.
Data were collected at two Tennessee hospitals and one Utah hospital during Jan. 1, 2010–June 30, 2012. Of the 2,358 children with CAP enrolled in the study, 2,143 (91%) with blood cultures were included in Dr. Fritz’s analysis. Of the 53 patients presenting with positive blood culture results, 46 (2%; 95% confidence interval: 1.6%-2.9%) were identified as having bacteremia. Half of all cases observed were caused by Streptococcus pneumoniae, with Staphylococcus aureus and Streptococcus pyogenes noted less frequently, according to the study published in Pediatrics.
A previous meta-analysis of smaller studies also found that children with CAP rarely had positive blood culture results, a pooled prevalence of 5% (Pediatr Infect Dis J. 2013;32[7]:736-40). Although it is believed that positive blood culture results are key to narrowing the choice of antibiotic and predicting treatment outcomes, the literature – to date – reveals a paucity of data supporting this assumption.
Overall, children in the study presenting with bacteremia experienced more severe clinical outcomes, including longer length of stay, greater likelihood of ICU admission, and invasive mechanical ventilation and/or shock. The authors also observed that bacteremia was less likely to be detected in children given antibiotics after admission but before cultures were obtained (0.8% vs 3%; P = .021). Pleural effusion detected with chest radiograph also consistently indicated bacteremic pneumonia, an observation made within this and other similar studies.
Also of note in detection is the biomarker procalcitonin, which is typically present with bacterial disease. Dr. Fritz and colleagues stressed that because the procalcitonin rate was higher in patients presenting with bacteremia, “this information could influence decisions around culturing if results are rapidly available.” Risk-stratification tools also might serve a valuable purpose in ferreting out those patients presenting with moderate to severe pneumonia most at increased risk for bacterial CAP.
Compared with other studies reporting prevalence ranges of 1%-7%, the prevalence of bacteremia in this study is lower at 2%. The authors attributed the difference to a possible potential limitation with the other studies, for which culture data was only available for a median 47% of enrollees. Dr. Fritz and her colleagues caution that “because cultures were obtained at the discretion of the treating clinician in a majority of studies, blood cultures were likely obtained more often in those with more severe illness or who had not already received antibiotics.” In this scenario, the likelihood that prevalence of bacteremia was overestimated is noteworthy.
The authors observed that penicillin-susceptible S. pneumonia was the most common cause of bacteremic CAP. They further acknowledged that their study and findings by Neuman et al. in 2017 give credence to the joint 2011 PIDS/IDSA guideline recommending narrow-spectrum aminopenicillins specifically to treat children hospitalized due to suspected bacterial CAP.
Despite its small sample size, the results of this study clearly demonstrate that children with bacteremia because of S. pyogenes or S. aureus experience increased morbidity, compared with children with S. pneumoniae, they said
While this is acknowledged to be one of the largest studies of its kind to date, a key limitation was the small number of observable patients with bacteremia, which prevented the researchers from conducting a more in-depth analysis of risk factors and pathogen-specific differences. That one-fourth of patients received in-patient antibiotics before cultures could be collected also likely led to an underestimation of risk factors and misclassification bias. Lastly, the use of blood culture instead of whole-blood polymerase chain reaction, which is known to be more sensitive, also may have led to underestimation of overall bacteremia prevalence.
“In an era with widespread pneumococcal vaccination and low prevalence of bacteremia in the United States, noted Dr. Fritz and associates.
Dr. Fritz had no conflicts of interest to report. Some coauthors cited multiple sources of potential conflict of interest related to consulting fees, grant support, and research support from various pharmaceutical companies and agencies. The study was funded by the National Institutes of Health and in part by a grant from the National Institute of Allergy and Infectious Diseases.
SOURCE: Fritz C et al. Pediatrics. 2019;144(1):e20183090.
FROM PEDIATRICS
Measles incidence has slowed as summer begins
There were 33 new measles cases reported last week, bringing the U.S. total to 1,077 for the year through June 20, according to the Centers for Disease Control and Prevention.
The number of new cases is an increase from the 22 reported the week before, but weekly incidence has been trending downward since hitting a high of 90 in mid-April, CDC data show.
The two continuing outbreaks in New York State made up more than half of the new cases, as Rockland County reported nine cases and New York City reported eight (seven in Brooklyn and one in Queens). Only one new case was reported in California as of the CDC’s June 20 cutoff, but the Los Angeles County Department of Public Health said on June 22 that it was assessing two possible cases, with potential public exposures occurring in a theater and a restaurant.
In a survey conducted in April, a majority of physicians with experience treating measles said that summer travel would lead to increased measles outbreaks and deaths.
There were 33 new measles cases reported last week, bringing the U.S. total to 1,077 for the year through June 20, according to the Centers for Disease Control and Prevention.
The number of new cases is an increase from the 22 reported the week before, but weekly incidence has been trending downward since hitting a high of 90 in mid-April, CDC data show.
The two continuing outbreaks in New York State made up more than half of the new cases, as Rockland County reported nine cases and New York City reported eight (seven in Brooklyn and one in Queens). Only one new case was reported in California as of the CDC’s June 20 cutoff, but the Los Angeles County Department of Public Health said on June 22 that it was assessing two possible cases, with potential public exposures occurring in a theater and a restaurant.
In a survey conducted in April, a majority of physicians with experience treating measles said that summer travel would lead to increased measles outbreaks and deaths.
There were 33 new measles cases reported last week, bringing the U.S. total to 1,077 for the year through June 20, according to the Centers for Disease Control and Prevention.
The number of new cases is an increase from the 22 reported the week before, but weekly incidence has been trending downward since hitting a high of 90 in mid-April, CDC data show.
The two continuing outbreaks in New York State made up more than half of the new cases, as Rockland County reported nine cases and New York City reported eight (seven in Brooklyn and one in Queens). Only one new case was reported in California as of the CDC’s June 20 cutoff, but the Los Angeles County Department of Public Health said on June 22 that it was assessing two possible cases, with potential public exposures occurring in a theater and a restaurant.
In a survey conducted in April, a majority of physicians with experience treating measles said that summer travel would lead to increased measles outbreaks and deaths.
CF drug picks up indication for children as young as 6
to include children as young as 6 years old who have cystic fibrosis.
The drug was approved in 2018 for patients aged 12 years and older who have the most common cause of the disease, two alleles for the F508del mutation in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, or at least one other CFTR mutation responsive to the combination, as listed in labeling.
The original approval was based on three phase 3, double blind, placebo-controlled trials, which demonstrated improvements in lung function and other key measures of the disease. One trial that found a 6.8% mean improvement in lung function testing over placebo at 8 weeks, and another that found a 4% improvement at 24 weeks, with fewer respiratory exacerbations and improved respiratory-related quality of life. A third trial in patients without the indicated genetic mutations was ended early for futility.
The efficacy in children under 12 years was extrapolated from those trials, plus an open-label study that found similar effects.
Labeling warns of elevated liver enzymes and cataracts in children, and notes that the drug should be taken with food that contains fat. Labeling also recommends against use with strong cytochrome P450 3A4 (CYP3A) inducers – rifampin, phenobarbital, St. John’s wort, among others – because they might reduce efficacy, and against use with CYP3A inhibitors – ketoconazole, clarithromycin, Seville oranges, grapefruit juice, etc. – because of the risk of increased exposure.
The most common side effects are headache, nausea, sinus congestion, and dizziness. The FDA has cleared a CF gene test to check for the required mutations. Symdeko is marketed by Vertex Pharmaceuticals.
to include children as young as 6 years old who have cystic fibrosis.
The drug was approved in 2018 for patients aged 12 years and older who have the most common cause of the disease, two alleles for the F508del mutation in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, or at least one other CFTR mutation responsive to the combination, as listed in labeling.
The original approval was based on three phase 3, double blind, placebo-controlled trials, which demonstrated improvements in lung function and other key measures of the disease. One trial that found a 6.8% mean improvement in lung function testing over placebo at 8 weeks, and another that found a 4% improvement at 24 weeks, with fewer respiratory exacerbations and improved respiratory-related quality of life. A third trial in patients without the indicated genetic mutations was ended early for futility.
The efficacy in children under 12 years was extrapolated from those trials, plus an open-label study that found similar effects.
Labeling warns of elevated liver enzymes and cataracts in children, and notes that the drug should be taken with food that contains fat. Labeling also recommends against use with strong cytochrome P450 3A4 (CYP3A) inducers – rifampin, phenobarbital, St. John’s wort, among others – because they might reduce efficacy, and against use with CYP3A inhibitors – ketoconazole, clarithromycin, Seville oranges, grapefruit juice, etc. – because of the risk of increased exposure.
The most common side effects are headache, nausea, sinus congestion, and dizziness. The FDA has cleared a CF gene test to check for the required mutations. Symdeko is marketed by Vertex Pharmaceuticals.
to include children as young as 6 years old who have cystic fibrosis.
The drug was approved in 2018 for patients aged 12 years and older who have the most common cause of the disease, two alleles for the F508del mutation in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, or at least one other CFTR mutation responsive to the combination, as listed in labeling.
The original approval was based on three phase 3, double blind, placebo-controlled trials, which demonstrated improvements in lung function and other key measures of the disease. One trial that found a 6.8% mean improvement in lung function testing over placebo at 8 weeks, and another that found a 4% improvement at 24 weeks, with fewer respiratory exacerbations and improved respiratory-related quality of life. A third trial in patients without the indicated genetic mutations was ended early for futility.
The efficacy in children under 12 years was extrapolated from those trials, plus an open-label study that found similar effects.
Labeling warns of elevated liver enzymes and cataracts in children, and notes that the drug should be taken with food that contains fat. Labeling also recommends against use with strong cytochrome P450 3A4 (CYP3A) inducers – rifampin, phenobarbital, St. John’s wort, among others – because they might reduce efficacy, and against use with CYP3A inhibitors – ketoconazole, clarithromycin, Seville oranges, grapefruit juice, etc. – because of the risk of increased exposure.
The most common side effects are headache, nausea, sinus congestion, and dizziness. The FDA has cleared a CF gene test to check for the required mutations. Symdeko is marketed by Vertex Pharmaceuticals.
Cannabis vaping among teens tied to tobacco use
and that practice is associated with cigars, waterpipe and e-cigarette use, findings from a survey of nearly 3,000 adolescents have shown.
“Although the prevalence of e-cigarette use among youth has increased dramatically in the past decade, little epidemiologic data exist on the prevalence of using e-cigarette devices or other specialised devices to vaporise (‘vape’) cannabis in the form of hash oil, tetrahydrocannabinol (THC) wax or oil, or dried cannabis buds or leaves,” wrote Sarah D. Kowitt, PhD, of the University of North Carolina, Chapel Hill, and colleagues. “This is surprising given that (1) cannabis (also referred to as marijuana) and e-cigarettes are the most commonly used substances by adolescents in the USA, (2) evidence exists that adolescents dual use both tobacco e-cigarettes and cannabis, and (3) longitudinal research suggests that use of e-cigarettes is associated with progression to use of cannabis.”
In a study published in BMJ Open, the researchers used data from the 2017 North Carolina Youth Tobacco Survey, a school-based survey of students in grades 6-12. The study population included 2,835 adolescents in grades 9-12.
Overall, 9.6% of students reported ever vaping cannabis. In multivariate analysis, cannabis vaping was significantly more likely among adolescents who reported using e-cigarettes (adjusted odds ratio 3.18), cigars (aOR 3.76), or water pipes (aOR 2.32) in the past 30 days, compared with peers who didn’t use tobacco.
The researchers found no significant association between smokeless tobacco use or traditional cigarette use in the past 30 days and vaping cannabis.
In a bivariate analysis, vaping cannabis was significantly more common among males vs. females (11% vs. 8.2%) and among non-Hispanic white students (11.3%), Hispanic students (10.5%), and other non-Hispanic students (11.8%) compared with non-Hispanic black students (5.0%).
In addition, prevalence of cannabis vaping increased with grade level, from 4.7% of 9th graders to 15.5% of 12th graders.
The health impacts of vaping cannabis are not well researched, but the researchers note that among the potential safety issues are earlier initiation of tobacco or cannabis use, concomitant tobacco and cannabis use, increased frequency of use or misuse of tobacco or cannabis, or increased potency of cannabis.
The results of the study were limited by several factors including the use of data only from the state of North Carolina, the lack of data on frequency or current vaping cannabis behavior, lack of data on specific products, and lack of data on whether teens used specialized devices or e-cigarettes for cannabis vaping. However, the findings are consistent with studies on prevalence of cannabis vaping in other states such as Connecticut and California. “No studies to our knowledge have examined how adolescents who vape cannabis use other specific tobacco products (i.e., cigarettes, cigars, waterpipe, smokeless tobacco),” the researchers wrote.
The findings confirm that a large number of adolescents who use tobacco products have vaped cannabis as well, and this growing public health issue “is likely to affect and be affected by tobacco control and cannabis policies in states and at the federal level in the USA,” the researchers concluded.
“Increased research investigating how youth use e-cigarette devices for other purposes beyond vaping nicotine, like the current study, is needed,” they added.
The study was supported in part by the National Cancer Institute and the Food and Drug Administration’s Center for Tobacco Products. The researchers had no financial conflicts to disclose.
SOURCE: Kowitt SD et al. BMJ Open. 2019 Jun 13. doi: 10.1136/bmjopen-2018-028535.
and that practice is associated with cigars, waterpipe and e-cigarette use, findings from a survey of nearly 3,000 adolescents have shown.
“Although the prevalence of e-cigarette use among youth has increased dramatically in the past decade, little epidemiologic data exist on the prevalence of using e-cigarette devices or other specialised devices to vaporise (‘vape’) cannabis in the form of hash oil, tetrahydrocannabinol (THC) wax or oil, or dried cannabis buds or leaves,” wrote Sarah D. Kowitt, PhD, of the University of North Carolina, Chapel Hill, and colleagues. “This is surprising given that (1) cannabis (also referred to as marijuana) and e-cigarettes are the most commonly used substances by adolescents in the USA, (2) evidence exists that adolescents dual use both tobacco e-cigarettes and cannabis, and (3) longitudinal research suggests that use of e-cigarettes is associated with progression to use of cannabis.”
In a study published in BMJ Open, the researchers used data from the 2017 North Carolina Youth Tobacco Survey, a school-based survey of students in grades 6-12. The study population included 2,835 adolescents in grades 9-12.
Overall, 9.6% of students reported ever vaping cannabis. In multivariate analysis, cannabis vaping was significantly more likely among adolescents who reported using e-cigarettes (adjusted odds ratio 3.18), cigars (aOR 3.76), or water pipes (aOR 2.32) in the past 30 days, compared with peers who didn’t use tobacco.
The researchers found no significant association between smokeless tobacco use or traditional cigarette use in the past 30 days and vaping cannabis.
In a bivariate analysis, vaping cannabis was significantly more common among males vs. females (11% vs. 8.2%) and among non-Hispanic white students (11.3%), Hispanic students (10.5%), and other non-Hispanic students (11.8%) compared with non-Hispanic black students (5.0%).
In addition, prevalence of cannabis vaping increased with grade level, from 4.7% of 9th graders to 15.5% of 12th graders.
The health impacts of vaping cannabis are not well researched, but the researchers note that among the potential safety issues are earlier initiation of tobacco or cannabis use, concomitant tobacco and cannabis use, increased frequency of use or misuse of tobacco or cannabis, or increased potency of cannabis.
The results of the study were limited by several factors including the use of data only from the state of North Carolina, the lack of data on frequency or current vaping cannabis behavior, lack of data on specific products, and lack of data on whether teens used specialized devices or e-cigarettes for cannabis vaping. However, the findings are consistent with studies on prevalence of cannabis vaping in other states such as Connecticut and California. “No studies to our knowledge have examined how adolescents who vape cannabis use other specific tobacco products (i.e., cigarettes, cigars, waterpipe, smokeless tobacco),” the researchers wrote.
The findings confirm that a large number of adolescents who use tobacco products have vaped cannabis as well, and this growing public health issue “is likely to affect and be affected by tobacco control and cannabis policies in states and at the federal level in the USA,” the researchers concluded.
“Increased research investigating how youth use e-cigarette devices for other purposes beyond vaping nicotine, like the current study, is needed,” they added.
The study was supported in part by the National Cancer Institute and the Food and Drug Administration’s Center for Tobacco Products. The researchers had no financial conflicts to disclose.
SOURCE: Kowitt SD et al. BMJ Open. 2019 Jun 13. doi: 10.1136/bmjopen-2018-028535.
and that practice is associated with cigars, waterpipe and e-cigarette use, findings from a survey of nearly 3,000 adolescents have shown.
“Although the prevalence of e-cigarette use among youth has increased dramatically in the past decade, little epidemiologic data exist on the prevalence of using e-cigarette devices or other specialised devices to vaporise (‘vape’) cannabis in the form of hash oil, tetrahydrocannabinol (THC) wax or oil, or dried cannabis buds or leaves,” wrote Sarah D. Kowitt, PhD, of the University of North Carolina, Chapel Hill, and colleagues. “This is surprising given that (1) cannabis (also referred to as marijuana) and e-cigarettes are the most commonly used substances by adolescents in the USA, (2) evidence exists that adolescents dual use both tobacco e-cigarettes and cannabis, and (3) longitudinal research suggests that use of e-cigarettes is associated with progression to use of cannabis.”
In a study published in BMJ Open, the researchers used data from the 2017 North Carolina Youth Tobacco Survey, a school-based survey of students in grades 6-12. The study population included 2,835 adolescents in grades 9-12.
Overall, 9.6% of students reported ever vaping cannabis. In multivariate analysis, cannabis vaping was significantly more likely among adolescents who reported using e-cigarettes (adjusted odds ratio 3.18), cigars (aOR 3.76), or water pipes (aOR 2.32) in the past 30 days, compared with peers who didn’t use tobacco.
The researchers found no significant association between smokeless tobacco use or traditional cigarette use in the past 30 days and vaping cannabis.
In a bivariate analysis, vaping cannabis was significantly more common among males vs. females (11% vs. 8.2%) and among non-Hispanic white students (11.3%), Hispanic students (10.5%), and other non-Hispanic students (11.8%) compared with non-Hispanic black students (5.0%).
In addition, prevalence of cannabis vaping increased with grade level, from 4.7% of 9th graders to 15.5% of 12th graders.
The health impacts of vaping cannabis are not well researched, but the researchers note that among the potential safety issues are earlier initiation of tobacco or cannabis use, concomitant tobacco and cannabis use, increased frequency of use or misuse of tobacco or cannabis, or increased potency of cannabis.
The results of the study were limited by several factors including the use of data only from the state of North Carolina, the lack of data on frequency or current vaping cannabis behavior, lack of data on specific products, and lack of data on whether teens used specialized devices or e-cigarettes for cannabis vaping. However, the findings are consistent with studies on prevalence of cannabis vaping in other states such as Connecticut and California. “No studies to our knowledge have examined how adolescents who vape cannabis use other specific tobacco products (i.e., cigarettes, cigars, waterpipe, smokeless tobacco),” the researchers wrote.
The findings confirm that a large number of adolescents who use tobacco products have vaped cannabis as well, and this growing public health issue “is likely to affect and be affected by tobacco control and cannabis policies in states and at the federal level in the USA,” the researchers concluded.
“Increased research investigating how youth use e-cigarette devices for other purposes beyond vaping nicotine, like the current study, is needed,” they added.
The study was supported in part by the National Cancer Institute and the Food and Drug Administration’s Center for Tobacco Products. The researchers had no financial conflicts to disclose.
SOURCE: Kowitt SD et al. BMJ Open. 2019 Jun 13. doi: 10.1136/bmjopen-2018-028535.
FROM BMJ OPEN
Key clinical point: Use of tobacco products was significantly associated with cannabis vaping in teens.
Major finding: Approximately 10% of adolescents reported vaping cannabis.
Study details: The data come from a survey of 2,835 adolescents in North Carolina.
Disclosures: The study was supported in part by the National Cancer Institute and the FDA Center for Tobacco Products. The researchers had no financial conflicts to disclose.
Source: Kowitt SD et al. BMJ Open. 2019 Jun 13. doi: 10.1136/bmjopen-2018-028535.