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Nonwhite race, lower socioeconomic status predicts persistently active AD
SCOTTSDALE, ARIZ. –Among patients with atopic dermatitis, persistently active disease was significantly more common among females of nonwhite race with a history of atopy than among patients without these characteristics, in an analysis of survey data from the Pediatric Elective Eczema Registry.
Annual household income under $50,000 also was a significant predictor of persistently active eczema, according to Katrina Abuabara, MD, of the department of dermatology, University of California, San Francisco, and her associates, who reported their results in a poster at the annual meeting of the Society for Investigative Dermatology.
Atopic dermatitis often persists into adulthood, but few studies have explored contributors to poor disease control. To help fill that gap, the investigators analyzed 65,237 surveys from the Pediatric Eczema Elective Registry (PEER), which tracks children and young adults aged 2-26 years with physician-diagnosed atopic dermatitis. The average age of the 6,237 patients was 7 years at enrollment (standard deviation, 4 years). They were followed at 6-month intervals for up to 10 years, with an average of about 10 surveys per respondent (standard deviation, 6.3 surveys).
In all, 4,607 patients (74% of the cohort) returned surveys spanning early childhood through their mid-20s. Only 15% of patients had “resolving” disease, meaning that as they aged, they increasingly reported complete disease control for periods of 6 months and longer.
The remaining 85% of patients had persistently active disease. In this group, 54% were female, 77% had a household income under $50,000 per year, 71% were nonwhite, and 75% had a history of atopy. Each of these characteristics significantly increased the odds of persistently active atopic dermatitis in the multivariable model (P less than .05 for each association).
Nonwhite race and history of atopy were the strongest predictors of persistently active disease – each lowered the odds of complete disease control by almost 50% (odds ratio, 0.53). Furthermore, females had 37% lower odds of complete disease control compared with males (OR, 0.63), and individuals with household income under $50,000 had 16% lower odds of complete disease control compared with those with higher annual incomes (OR, 0.84).
The link between lower socioeconomic status and persistently active eczema belies previous findings, the researchers noted. Those studies found that individuals of higher socioeconomic status were at greater risk for developing atopic dermatitis, but “failed to account for the chronic nature of the disease. In contrast, our results suggest that atopic dermatitis persistence may be associated with lower income and nonwhite race, and highlight the importance of longitudinal studies that permit analysis of mechanisms of disease control over time.”
Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.
SCOTTSDALE, ARIZ. –Among patients with atopic dermatitis, persistently active disease was significantly more common among females of nonwhite race with a history of atopy than among patients without these characteristics, in an analysis of survey data from the Pediatric Elective Eczema Registry.
Annual household income under $50,000 also was a significant predictor of persistently active eczema, according to Katrina Abuabara, MD, of the department of dermatology, University of California, San Francisco, and her associates, who reported their results in a poster at the annual meeting of the Society for Investigative Dermatology.
Atopic dermatitis often persists into adulthood, but few studies have explored contributors to poor disease control. To help fill that gap, the investigators analyzed 65,237 surveys from the Pediatric Eczema Elective Registry (PEER), which tracks children and young adults aged 2-26 years with physician-diagnosed atopic dermatitis. The average age of the 6,237 patients was 7 years at enrollment (standard deviation, 4 years). They were followed at 6-month intervals for up to 10 years, with an average of about 10 surveys per respondent (standard deviation, 6.3 surveys).
In all, 4,607 patients (74% of the cohort) returned surveys spanning early childhood through their mid-20s. Only 15% of patients had “resolving” disease, meaning that as they aged, they increasingly reported complete disease control for periods of 6 months and longer.
The remaining 85% of patients had persistently active disease. In this group, 54% were female, 77% had a household income under $50,000 per year, 71% were nonwhite, and 75% had a history of atopy. Each of these characteristics significantly increased the odds of persistently active atopic dermatitis in the multivariable model (P less than .05 for each association).
Nonwhite race and history of atopy were the strongest predictors of persistently active disease – each lowered the odds of complete disease control by almost 50% (odds ratio, 0.53). Furthermore, females had 37% lower odds of complete disease control compared with males (OR, 0.63), and individuals with household income under $50,000 had 16% lower odds of complete disease control compared with those with higher annual incomes (OR, 0.84).
The link between lower socioeconomic status and persistently active eczema belies previous findings, the researchers noted. Those studies found that individuals of higher socioeconomic status were at greater risk for developing atopic dermatitis, but “failed to account for the chronic nature of the disease. In contrast, our results suggest that atopic dermatitis persistence may be associated with lower income and nonwhite race, and highlight the importance of longitudinal studies that permit analysis of mechanisms of disease control over time.”
Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.
SCOTTSDALE, ARIZ. –Among patients with atopic dermatitis, persistently active disease was significantly more common among females of nonwhite race with a history of atopy than among patients without these characteristics, in an analysis of survey data from the Pediatric Elective Eczema Registry.
Annual household income under $50,000 also was a significant predictor of persistently active eczema, according to Katrina Abuabara, MD, of the department of dermatology, University of California, San Francisco, and her associates, who reported their results in a poster at the annual meeting of the Society for Investigative Dermatology.
Atopic dermatitis often persists into adulthood, but few studies have explored contributors to poor disease control. To help fill that gap, the investigators analyzed 65,237 surveys from the Pediatric Eczema Elective Registry (PEER), which tracks children and young adults aged 2-26 years with physician-diagnosed atopic dermatitis. The average age of the 6,237 patients was 7 years at enrollment (standard deviation, 4 years). They were followed at 6-month intervals for up to 10 years, with an average of about 10 surveys per respondent (standard deviation, 6.3 surveys).
In all, 4,607 patients (74% of the cohort) returned surveys spanning early childhood through their mid-20s. Only 15% of patients had “resolving” disease, meaning that as they aged, they increasingly reported complete disease control for periods of 6 months and longer.
The remaining 85% of patients had persistently active disease. In this group, 54% were female, 77% had a household income under $50,000 per year, 71% were nonwhite, and 75% had a history of atopy. Each of these characteristics significantly increased the odds of persistently active atopic dermatitis in the multivariable model (P less than .05 for each association).
Nonwhite race and history of atopy were the strongest predictors of persistently active disease – each lowered the odds of complete disease control by almost 50% (odds ratio, 0.53). Furthermore, females had 37% lower odds of complete disease control compared with males (OR, 0.63), and individuals with household income under $50,000 had 16% lower odds of complete disease control compared with those with higher annual incomes (OR, 0.84).
The link between lower socioeconomic status and persistently active eczema belies previous findings, the researchers noted. Those studies found that individuals of higher socioeconomic status were at greater risk for developing atopic dermatitis, but “failed to account for the chronic nature of the disease. In contrast, our results suggest that atopic dermatitis persistence may be associated with lower income and nonwhite race, and highlight the importance of longitudinal studies that permit analysis of mechanisms of disease control over time.”
Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.
AT THE 2016 SID ANNUAL MEETING
Key clinical point: Persistently active atopic dermatitis is associated with nonwhite race, annual household income under $50,000, female sex, and history of atopy.
Major finding: Nonwhite race and history of atopy each lowered the odds of complete disease control by about 43% (odds ratios, 0.53; P less than .05).
Data source: A longitudinal cohort study of 6,237 patients aged 2-26 years from the Pediatric Eczema Elective Registry (PEER).
Disclosures: Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.
Nonwhite race, lower socioeconomic status predicts persistently active AD
SCOTTSDALE, ARIZ. –Among patients with atopic dermatitis, persistently active disease was significantly more common among females of nonwhite race with a history of atopy than among patients without these characteristics, in an analysis of survey data from the Pediatric Elective Eczema Registry.
Annual household income under $50,000 also was a significant predictor of persistently active eczema, according to Katrina Abuabara, MD, of the department of dermatology, University of California, San Francisco, and her associates, who reported their results in a poster at the annual meeting of the Society for Investigative Dermatology.
Atopic dermatitis often persists into adulthood, but few studies have explored contributors to poor disease control. To help fill that gap, the investigators analyzed 65,237 surveys from the Pediatric Eczema Elective Registry (PEER), which tracks children and young adults aged 2-26 years with physician-diagnosed atopic dermatitis. The average age of the 6,237 patients was 7 years at enrollment (standard deviation, 4 years). They were followed at 6-month intervals for up to 10 years, with an average of about 10 surveys per respondent (standard deviation, 6.3 surveys).
In all, 4,607 patients (74% of the cohort) returned surveys spanning early childhood through their mid-20s. Only 15% of patients had “resolving” disease, meaning that as they aged, they increasingly reported complete disease control for periods of 6 months and longer.
The remaining 85% of patients had persistently active disease. In this group, 54% were female, 77% had a household income under $50,000 per year, 71% were nonwhite, and 75% had a history of atopy. Each of these characteristics significantly increased the odds of persistently active atopic dermatitis in the multivariable model (P less than .05 for each association).
Nonwhite race and history of atopy were the strongest predictors of persistently active disease – each lowered the odds of complete disease control by almost 50% (odds ratio, 0.53). Furthermore, females had 37% lower odds of complete disease control compared with males (OR, 0.63), and individuals with household income under $50,000 had 16% lower odds of complete disease control compared with those with higher annual incomes (OR, 0.84).
The link between lower socioeconomic status and persistently active eczema belies previous findings, the researchers noted. Those studies found that individuals of higher socioeconomic status were at greater risk for developing atopic dermatitis, but “failed to account for the chronic nature of the disease. In contrast, our results suggest that atopic dermatitis persistence may be associated with lower income and nonwhite race, and highlight the importance of longitudinal studies that permit analysis of mechanisms of disease control over time.”
Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.
SCOTTSDALE, ARIZ. –Among patients with atopic dermatitis, persistently active disease was significantly more common among females of nonwhite race with a history of atopy than among patients without these characteristics, in an analysis of survey data from the Pediatric Elective Eczema Registry.
Annual household income under $50,000 also was a significant predictor of persistently active eczema, according to Katrina Abuabara, MD, of the department of dermatology, University of California, San Francisco, and her associates, who reported their results in a poster at the annual meeting of the Society for Investigative Dermatology.
Atopic dermatitis often persists into adulthood, but few studies have explored contributors to poor disease control. To help fill that gap, the investigators analyzed 65,237 surveys from the Pediatric Eczema Elective Registry (PEER), which tracks children and young adults aged 2-26 years with physician-diagnosed atopic dermatitis. The average age of the 6,237 patients was 7 years at enrollment (standard deviation, 4 years). They were followed at 6-month intervals for up to 10 years, with an average of about 10 surveys per respondent (standard deviation, 6.3 surveys).
In all, 4,607 patients (74% of the cohort) returned surveys spanning early childhood through their mid-20s. Only 15% of patients had “resolving” disease, meaning that as they aged, they increasingly reported complete disease control for periods of 6 months and longer.
The remaining 85% of patients had persistently active disease. In this group, 54% were female, 77% had a household income under $50,000 per year, 71% were nonwhite, and 75% had a history of atopy. Each of these characteristics significantly increased the odds of persistently active atopic dermatitis in the multivariable model (P less than .05 for each association).
Nonwhite race and history of atopy were the strongest predictors of persistently active disease – each lowered the odds of complete disease control by almost 50% (odds ratio, 0.53). Furthermore, females had 37% lower odds of complete disease control compared with males (OR, 0.63), and individuals with household income under $50,000 had 16% lower odds of complete disease control compared with those with higher annual incomes (OR, 0.84).
The link between lower socioeconomic status and persistently active eczema belies previous findings, the researchers noted. Those studies found that individuals of higher socioeconomic status were at greater risk for developing atopic dermatitis, but “failed to account for the chronic nature of the disease. In contrast, our results suggest that atopic dermatitis persistence may be associated with lower income and nonwhite race, and highlight the importance of longitudinal studies that permit analysis of mechanisms of disease control over time.”
Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.
SCOTTSDALE, ARIZ. –Among patients with atopic dermatitis, persistently active disease was significantly more common among females of nonwhite race with a history of atopy than among patients without these characteristics, in an analysis of survey data from the Pediatric Elective Eczema Registry.
Annual household income under $50,000 also was a significant predictor of persistently active eczema, according to Katrina Abuabara, MD, of the department of dermatology, University of California, San Francisco, and her associates, who reported their results in a poster at the annual meeting of the Society for Investigative Dermatology.
Atopic dermatitis often persists into adulthood, but few studies have explored contributors to poor disease control. To help fill that gap, the investigators analyzed 65,237 surveys from the Pediatric Eczema Elective Registry (PEER), which tracks children and young adults aged 2-26 years with physician-diagnosed atopic dermatitis. The average age of the 6,237 patients was 7 years at enrollment (standard deviation, 4 years). They were followed at 6-month intervals for up to 10 years, with an average of about 10 surveys per respondent (standard deviation, 6.3 surveys).
In all, 4,607 patients (74% of the cohort) returned surveys spanning early childhood through their mid-20s. Only 15% of patients had “resolving” disease, meaning that as they aged, they increasingly reported complete disease control for periods of 6 months and longer.
The remaining 85% of patients had persistently active disease. In this group, 54% were female, 77% had a household income under $50,000 per year, 71% were nonwhite, and 75% had a history of atopy. Each of these characteristics significantly increased the odds of persistently active atopic dermatitis in the multivariable model (P less than .05 for each association).
Nonwhite race and history of atopy were the strongest predictors of persistently active disease – each lowered the odds of complete disease control by almost 50% (odds ratio, 0.53). Furthermore, females had 37% lower odds of complete disease control compared with males (OR, 0.63), and individuals with household income under $50,000 had 16% lower odds of complete disease control compared with those with higher annual incomes (OR, 0.84).
The link between lower socioeconomic status and persistently active eczema belies previous findings, the researchers noted. Those studies found that individuals of higher socioeconomic status were at greater risk for developing atopic dermatitis, but “failed to account for the chronic nature of the disease. In contrast, our results suggest that atopic dermatitis persistence may be associated with lower income and nonwhite race, and highlight the importance of longitudinal studies that permit analysis of mechanisms of disease control over time.”
Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.
AT THE 2016 SID ANNUAL MEETING
Key clinical point: Persistently active atopic dermatitis is associated with nonwhite race, annual household income under $50,000, female sex, and history of atopy.
Major finding: Nonwhite race and history of atopy each lowered the odds of complete disease control by about 43% (odds ratios, 0.53; P less than .05).
Data source: A longitudinal cohort study of 6,237 patients aged 2-26 years from the Pediatric Eczema Elective Registry (PEER).
Disclosures: Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.
Sleep apnea in pregnancy linked to preterm birth
DENVER – Pregnant women with sleep apnea are more likely to have planned obstetric interventions, results of an Australian population-based cohort study suggest.
The study included all 636,227 in-hospital births during 2002-2012 in New South Wales, Australia’s most populous state. Maternal sleep apnea was also associated with increased rates of planned preterm birth, even though preterm birth is widely considered the greatest contributor to neonatal morbidity and mortality, Yu Sun Bin, PhD, said at the annual meeting of the Associated Professional Sleep Societies.
“Somewhere along the line, clinicians decided that the risks of preterm birth to the baby were outweighed by the risks to the mother of delivering at term,” said Dr. Bin of the University of Sydney.
She and her coinvestigators undertook this study because even though previous studies have linked maternal sleep apnea to increased risks of gestational diabetes and gestational hypertension, most of the prior studies were small, cross-sectional, and/or relied upon snoring as a proxy for sleep apnea, which many sleep specialists consider invalid.
The investigators compared maternal and infant outcomes for mothers with a documented diagnosis of sleep apnea – either central or obstructive – in the year before or during pregnancy with outcomes for mothers without that diagnosis.
There were 519 mothers with diagnosed sleep apnea, for a prevalence of 0.08%. That figure is low in light of other evidence, making it likely that the 635,708 women in the no-sleep-apnea group actually included a substantial number of mothers with undiagnosed sleep apnea. Thus, the investigators’ estimates of the adverse impacts of sleep apnea in pregnancy are “rather conservative,” according to Dr. Bin.
Australian women with sleep apnea were older and less healthy than mothers without sleep apnea were. They had higher baseline rates of obesity, preexisting diabetes, chronic hypertension, and were more likely to be smokers.
The incidence of pregnancy hypertension was 19.7% in the sleep apnea group and 8.7% in controls. In a multivariate regression analysis adjusted for potential confounders, the maternal sleep apnea group had a 40% greater risk of developing hypertension than did controls. However, contrary to previous smaller studies, they did not have a significantly increased rate of gestational diabetes.
Even after controlling for both pregnancy hypertension and gestational diabetes, the sleep apnea group still had a significant 15% increase in the relative likelihood of a planned delivery.
The rate of preterm birth at 36 weeks or earlier was 14.5% in the maternal sleep apnea group, compared with 6.9% in controls, for an adjusted 1.5-fold increased relative risk.
Perinatal death occurred in 1.9% of the sleep apnea group and 0.9% of controls; however, the resultant adjusted 1.73-fold increased risk didn’t attain statistical significance because of the small number of deaths in the study. Dr. Bin said she and her colleagues plan to further investigate this signal to learn whether it is real or an artifact of small numbers.
The incidence of 5-minute Apgar scores below 7 was 4.6% in the sleep apnea group, compared with 2.4% in controls, for an adjusted 1.6-fold increased risk. The rate of neonatal intensive care unit admission in the sleep apnea group was 27.9%, versus 16% in controls, for a 1.61-fold increased relative risk.
The NICU admission rate for preterm infants didn’t differ between the two groups. The difference occurred in term babies, whose NICU admission rate was 20.3% if they were in the sleep apnea group, but just 12.1% in the control group.
“This suggests that maternal sleep apnea is contributing to some condition in the baby that requires additional support,” Dr. Bin observed.
The nature of that condition, however, remains unclear, since all patient data available to the investigators was deidentified.
The incidence of small-for-gestational-age babies was similar in the sleep apnea and control groups. In contrast, the large-for-gestational-age rate was 15.2% in the sleep apnea group, compared with 9.1% in controls, for an adjusted 1.27-fold increased risk.
The two main limitations of the Australian study were the likely underdiagnosis of sleep apnea and the lack of any information on treatment of affected patients, according to Dr. Bin. A key unresolved question, she added, is whether interventions for maternal sleep apnea reduce the risks identified in the New South Wales study. She noted that one 16-patient randomized study of nasal continuous positive airway pressure suggests the answer is yes (Sleep Med. 2007 Dec;9:15-21).
The Australian National Health and Medical Research Council supported the study. Dr. Bin reported having no financial conflicts.
DENVER – Pregnant women with sleep apnea are more likely to have planned obstetric interventions, results of an Australian population-based cohort study suggest.
The study included all 636,227 in-hospital births during 2002-2012 in New South Wales, Australia’s most populous state. Maternal sleep apnea was also associated with increased rates of planned preterm birth, even though preterm birth is widely considered the greatest contributor to neonatal morbidity and mortality, Yu Sun Bin, PhD, said at the annual meeting of the Associated Professional Sleep Societies.
“Somewhere along the line, clinicians decided that the risks of preterm birth to the baby were outweighed by the risks to the mother of delivering at term,” said Dr. Bin of the University of Sydney.
She and her coinvestigators undertook this study because even though previous studies have linked maternal sleep apnea to increased risks of gestational diabetes and gestational hypertension, most of the prior studies were small, cross-sectional, and/or relied upon snoring as a proxy for sleep apnea, which many sleep specialists consider invalid.
The investigators compared maternal and infant outcomes for mothers with a documented diagnosis of sleep apnea – either central or obstructive – in the year before or during pregnancy with outcomes for mothers without that diagnosis.
There were 519 mothers with diagnosed sleep apnea, for a prevalence of 0.08%. That figure is low in light of other evidence, making it likely that the 635,708 women in the no-sleep-apnea group actually included a substantial number of mothers with undiagnosed sleep apnea. Thus, the investigators’ estimates of the adverse impacts of sleep apnea in pregnancy are “rather conservative,” according to Dr. Bin.
Australian women with sleep apnea were older and less healthy than mothers without sleep apnea were. They had higher baseline rates of obesity, preexisting diabetes, chronic hypertension, and were more likely to be smokers.
The incidence of pregnancy hypertension was 19.7% in the sleep apnea group and 8.7% in controls. In a multivariate regression analysis adjusted for potential confounders, the maternal sleep apnea group had a 40% greater risk of developing hypertension than did controls. However, contrary to previous smaller studies, they did not have a significantly increased rate of gestational diabetes.
Even after controlling for both pregnancy hypertension and gestational diabetes, the sleep apnea group still had a significant 15% increase in the relative likelihood of a planned delivery.
The rate of preterm birth at 36 weeks or earlier was 14.5% in the maternal sleep apnea group, compared with 6.9% in controls, for an adjusted 1.5-fold increased relative risk.
Perinatal death occurred in 1.9% of the sleep apnea group and 0.9% of controls; however, the resultant adjusted 1.73-fold increased risk didn’t attain statistical significance because of the small number of deaths in the study. Dr. Bin said she and her colleagues plan to further investigate this signal to learn whether it is real or an artifact of small numbers.
The incidence of 5-minute Apgar scores below 7 was 4.6% in the sleep apnea group, compared with 2.4% in controls, for an adjusted 1.6-fold increased risk. The rate of neonatal intensive care unit admission in the sleep apnea group was 27.9%, versus 16% in controls, for a 1.61-fold increased relative risk.
The NICU admission rate for preterm infants didn’t differ between the two groups. The difference occurred in term babies, whose NICU admission rate was 20.3% if they were in the sleep apnea group, but just 12.1% in the control group.
“This suggests that maternal sleep apnea is contributing to some condition in the baby that requires additional support,” Dr. Bin observed.
The nature of that condition, however, remains unclear, since all patient data available to the investigators was deidentified.
The incidence of small-for-gestational-age babies was similar in the sleep apnea and control groups. In contrast, the large-for-gestational-age rate was 15.2% in the sleep apnea group, compared with 9.1% in controls, for an adjusted 1.27-fold increased risk.
The two main limitations of the Australian study were the likely underdiagnosis of sleep apnea and the lack of any information on treatment of affected patients, according to Dr. Bin. A key unresolved question, she added, is whether interventions for maternal sleep apnea reduce the risks identified in the New South Wales study. She noted that one 16-patient randomized study of nasal continuous positive airway pressure suggests the answer is yes (Sleep Med. 2007 Dec;9:15-21).
The Australian National Health and Medical Research Council supported the study. Dr. Bin reported having no financial conflicts.
DENVER – Pregnant women with sleep apnea are more likely to have planned obstetric interventions, results of an Australian population-based cohort study suggest.
The study included all 636,227 in-hospital births during 2002-2012 in New South Wales, Australia’s most populous state. Maternal sleep apnea was also associated with increased rates of planned preterm birth, even though preterm birth is widely considered the greatest contributor to neonatal morbidity and mortality, Yu Sun Bin, PhD, said at the annual meeting of the Associated Professional Sleep Societies.
“Somewhere along the line, clinicians decided that the risks of preterm birth to the baby were outweighed by the risks to the mother of delivering at term,” said Dr. Bin of the University of Sydney.
She and her coinvestigators undertook this study because even though previous studies have linked maternal sleep apnea to increased risks of gestational diabetes and gestational hypertension, most of the prior studies were small, cross-sectional, and/or relied upon snoring as a proxy for sleep apnea, which many sleep specialists consider invalid.
The investigators compared maternal and infant outcomes for mothers with a documented diagnosis of sleep apnea – either central or obstructive – in the year before or during pregnancy with outcomes for mothers without that diagnosis.
There were 519 mothers with diagnosed sleep apnea, for a prevalence of 0.08%. That figure is low in light of other evidence, making it likely that the 635,708 women in the no-sleep-apnea group actually included a substantial number of mothers with undiagnosed sleep apnea. Thus, the investigators’ estimates of the adverse impacts of sleep apnea in pregnancy are “rather conservative,” according to Dr. Bin.
Australian women with sleep apnea were older and less healthy than mothers without sleep apnea were. They had higher baseline rates of obesity, preexisting diabetes, chronic hypertension, and were more likely to be smokers.
The incidence of pregnancy hypertension was 19.7% in the sleep apnea group and 8.7% in controls. In a multivariate regression analysis adjusted for potential confounders, the maternal sleep apnea group had a 40% greater risk of developing hypertension than did controls. However, contrary to previous smaller studies, they did not have a significantly increased rate of gestational diabetes.
Even after controlling for both pregnancy hypertension and gestational diabetes, the sleep apnea group still had a significant 15% increase in the relative likelihood of a planned delivery.
The rate of preterm birth at 36 weeks or earlier was 14.5% in the maternal sleep apnea group, compared with 6.9% in controls, for an adjusted 1.5-fold increased relative risk.
Perinatal death occurred in 1.9% of the sleep apnea group and 0.9% of controls; however, the resultant adjusted 1.73-fold increased risk didn’t attain statistical significance because of the small number of deaths in the study. Dr. Bin said she and her colleagues plan to further investigate this signal to learn whether it is real or an artifact of small numbers.
The incidence of 5-minute Apgar scores below 7 was 4.6% in the sleep apnea group, compared with 2.4% in controls, for an adjusted 1.6-fold increased risk. The rate of neonatal intensive care unit admission in the sleep apnea group was 27.9%, versus 16% in controls, for a 1.61-fold increased relative risk.
The NICU admission rate for preterm infants didn’t differ between the two groups. The difference occurred in term babies, whose NICU admission rate was 20.3% if they were in the sleep apnea group, but just 12.1% in the control group.
“This suggests that maternal sleep apnea is contributing to some condition in the baby that requires additional support,” Dr. Bin observed.
The nature of that condition, however, remains unclear, since all patient data available to the investigators was deidentified.
The incidence of small-for-gestational-age babies was similar in the sleep apnea and control groups. In contrast, the large-for-gestational-age rate was 15.2% in the sleep apnea group, compared with 9.1% in controls, for an adjusted 1.27-fold increased risk.
The two main limitations of the Australian study were the likely underdiagnosis of sleep apnea and the lack of any information on treatment of affected patients, according to Dr. Bin. A key unresolved question, she added, is whether interventions for maternal sleep apnea reduce the risks identified in the New South Wales study. She noted that one 16-patient randomized study of nasal continuous positive airway pressure suggests the answer is yes (Sleep Med. 2007 Dec;9:15-21).
The Australian National Health and Medical Research Council supported the study. Dr. Bin reported having no financial conflicts.
AT SLEEP 2016
Key clinical point: Maternal sleep apnea is associated with increased rates of obstetric intervention and preterm birth.
Major finding: The rate of preterm birth at 36 weeks or earlier was 14.5% in the group with maternal sleep apnea, compared with 6.9% in controls.
Data source: A population-based cohort study of 636,227 women who gave birth in a New South Wales, Australia, hospital during 2002-2012.
Disclosures: The Australian National Health and Medical Research Council supported the study. Dr. Bin reported having no financial conflicts.
Adalimumab approved to treat noninfectious uveitis
The U.S. Food and Drug Administration has approved adalimumab for treatment of noninfectious intermediate, posterior, and panuveitis in adults, making it the only approved drug for the condition that is not a corticosteroid.
The approval marks the 10th approved indication for adalimumab (Humira) in the United States. It was recently approved for this indication in the European Union as well.
Patients on adalimumab had about half the risk of those on placebo to experience treatment failure (a combination of uveitis flare and decrease in visual acuity) in two pivotal phase III studies, VISUAL-I (hazard ratio, 0.5 for VISUAL-I; P less than .001) and VISUAL-II (HR, 0.57; P = .004). In the trials, patients were treated with an 80-mg loading dose of adalimumab at baseline, followed by a 40-mg subcutaneous injection at week 1 and then 40 mg every other week for up to 80 weeks.
“These approvals provide a valuable option for patients experiencing flare and vision impairment associated with this group of inflammatory diseases of the eye,” Glenn J. Jaffe, MD, of Duke University, Durham, N.C., said in an announcement from the manufacturer of adalimumab, AbbVie. “Data from the robust VISUAL clinical trial program demonstrate the value of Humira as a treatment option for patients with these serious diseases.”
The U.S. Food and Drug Administration has approved adalimumab for treatment of noninfectious intermediate, posterior, and panuveitis in adults, making it the only approved drug for the condition that is not a corticosteroid.
The approval marks the 10th approved indication for adalimumab (Humira) in the United States. It was recently approved for this indication in the European Union as well.
Patients on adalimumab had about half the risk of those on placebo to experience treatment failure (a combination of uveitis flare and decrease in visual acuity) in two pivotal phase III studies, VISUAL-I (hazard ratio, 0.5 for VISUAL-I; P less than .001) and VISUAL-II (HR, 0.57; P = .004). In the trials, patients were treated with an 80-mg loading dose of adalimumab at baseline, followed by a 40-mg subcutaneous injection at week 1 and then 40 mg every other week for up to 80 weeks.
“These approvals provide a valuable option for patients experiencing flare and vision impairment associated with this group of inflammatory diseases of the eye,” Glenn J. Jaffe, MD, of Duke University, Durham, N.C., said in an announcement from the manufacturer of adalimumab, AbbVie. “Data from the robust VISUAL clinical trial program demonstrate the value of Humira as a treatment option for patients with these serious diseases.”
The U.S. Food and Drug Administration has approved adalimumab for treatment of noninfectious intermediate, posterior, and panuveitis in adults, making it the only approved drug for the condition that is not a corticosteroid.
The approval marks the 10th approved indication for adalimumab (Humira) in the United States. It was recently approved for this indication in the European Union as well.
Patients on adalimumab had about half the risk of those on placebo to experience treatment failure (a combination of uveitis flare and decrease in visual acuity) in two pivotal phase III studies, VISUAL-I (hazard ratio, 0.5 for VISUAL-I; P less than .001) and VISUAL-II (HR, 0.57; P = .004). In the trials, patients were treated with an 80-mg loading dose of adalimumab at baseline, followed by a 40-mg subcutaneous injection at week 1 and then 40 mg every other week for up to 80 weeks.
“These approvals provide a valuable option for patients experiencing flare and vision impairment associated with this group of inflammatory diseases of the eye,” Glenn J. Jaffe, MD, of Duke University, Durham, N.C., said in an announcement from the manufacturer of adalimumab, AbbVie. “Data from the robust VISUAL clinical trial program demonstrate the value of Humira as a treatment option for patients with these serious diseases.”
Pediatric Cancer Survivors at Increased Risk for Endocrine Abnormalities
Patients who survived pediatric-onset cancer are at increased risk for developing or experiencing endocrine abnormalities.
Risk was significantly higher in survivors who underwent high-risk therapeutic exposures compared with survivors not so exposed. Moreover, the incidence and prevalence of endocrine abnormalities increased across the lifespan of survivors, reported Sogol Mostoufi-Moab, MD, of University of Pennsylvania, Philadelphia, and his associates (J Clin Oncol. 2016 Jul. doi: 10.1200/JCO.2016.66.6545).
A total of 14,290 patients met the study’s eligibility requirements, which included a diagnosis of cancer before age 21 years and 5-year survival following diagnosis. Cancer diagnoses included leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms tumor, neuroblastoma, sarcoma, bone malignancy, and central nervous system malignancy. Baseline and follow-up questionnaires collected endocrine-related outcomes of interest, demographic information, and medical histories for both cancer survivors and their siblings (n = 4,031). For survivors, median age at diagnosis was 6 years and median age at last follow-up was 32 years. For siblings, median age at last follow-up was 34 years.
Overall 44% of cancer survivors had at least one endocrinopathy, 16.7% had at least two, and 6.6% had three or more. Survivors of Hodgkin lymphoma had the highest frequency of endocrine abnormality (60.1%) followed by survivors of CNS malignancy (54%), leukemia (45.6%), sarcoma (41.3%), non-Hodgkin lymphoma (39.7%), and neuroblastoma (31.9%).
Specifically, thyroid disorders were more frequent among cancer survivors than among their siblings: underactive thyroid (hazard ratio, 2.2; 95% confidence interval, 1.8-2.7), overactive thyroid (HR, 2.4; 95% CI, 1.7-3.3), thyroid nodules (HR, 3.9; 95% CI, 2.9-5.4), and thyroid cancer (HR 2.5; 95% CI, 1.2-5.3).
Compared to their siblings, cancer survivors showed increased risk of developing diabetes (RR, 1.8; 95% CI, 1.4-2.3).
Among survivors, those exposed to high-risk therapies (defined by the Children’s Oncology Group’s Long-Term Follow-Up Guidelinesfor Survivors of Childhood, Adolescent, and Young Adult Cancers) were at a greater risk of developing primary hypothyroidism (HR, 6.6; 95% CI, 5.6-7.8) central hypothyroidism (HR, 3.9; 95% CI, 2.9-5.2), an overactive thyroid (HR, 1.8; 95% CI, 1.2-2.8), thyroid nodules (HR, 6.3; 95% CI, 5.2-7.5), and thyroid cancer (HR, 9.2; 95% CI, 6.2-13.7) compared with survivors not so exposed.
The National Cancer Institute, the Cancer Center Support Grant, and the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital funded the study. Dr. Mostoufi-Moab and nine other investigators had no disclosures to report. Two investigators reported receiving financial compensation or honoraria from Merck or Sandoz.
Patients who survived pediatric-onset cancer are at increased risk for developing or experiencing endocrine abnormalities.
Risk was significantly higher in survivors who underwent high-risk therapeutic exposures compared with survivors not so exposed. Moreover, the incidence and prevalence of endocrine abnormalities increased across the lifespan of survivors, reported Sogol Mostoufi-Moab, MD, of University of Pennsylvania, Philadelphia, and his associates (J Clin Oncol. 2016 Jul. doi: 10.1200/JCO.2016.66.6545).
A total of 14,290 patients met the study’s eligibility requirements, which included a diagnosis of cancer before age 21 years and 5-year survival following diagnosis. Cancer diagnoses included leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms tumor, neuroblastoma, sarcoma, bone malignancy, and central nervous system malignancy. Baseline and follow-up questionnaires collected endocrine-related outcomes of interest, demographic information, and medical histories for both cancer survivors and their siblings (n = 4,031). For survivors, median age at diagnosis was 6 years and median age at last follow-up was 32 years. For siblings, median age at last follow-up was 34 years.
Overall 44% of cancer survivors had at least one endocrinopathy, 16.7% had at least two, and 6.6% had three or more. Survivors of Hodgkin lymphoma had the highest frequency of endocrine abnormality (60.1%) followed by survivors of CNS malignancy (54%), leukemia (45.6%), sarcoma (41.3%), non-Hodgkin lymphoma (39.7%), and neuroblastoma (31.9%).
Specifically, thyroid disorders were more frequent among cancer survivors than among their siblings: underactive thyroid (hazard ratio, 2.2; 95% confidence interval, 1.8-2.7), overactive thyroid (HR, 2.4; 95% CI, 1.7-3.3), thyroid nodules (HR, 3.9; 95% CI, 2.9-5.4), and thyroid cancer (HR 2.5; 95% CI, 1.2-5.3).
Compared to their siblings, cancer survivors showed increased risk of developing diabetes (RR, 1.8; 95% CI, 1.4-2.3).
Among survivors, those exposed to high-risk therapies (defined by the Children’s Oncology Group’s Long-Term Follow-Up Guidelinesfor Survivors of Childhood, Adolescent, and Young Adult Cancers) were at a greater risk of developing primary hypothyroidism (HR, 6.6; 95% CI, 5.6-7.8) central hypothyroidism (HR, 3.9; 95% CI, 2.9-5.2), an overactive thyroid (HR, 1.8; 95% CI, 1.2-2.8), thyroid nodules (HR, 6.3; 95% CI, 5.2-7.5), and thyroid cancer (HR, 9.2; 95% CI, 6.2-13.7) compared with survivors not so exposed.
The National Cancer Institute, the Cancer Center Support Grant, and the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital funded the study. Dr. Mostoufi-Moab and nine other investigators had no disclosures to report. Two investigators reported receiving financial compensation or honoraria from Merck or Sandoz.
Patients who survived pediatric-onset cancer are at increased risk for developing or experiencing endocrine abnormalities.
Risk was significantly higher in survivors who underwent high-risk therapeutic exposures compared with survivors not so exposed. Moreover, the incidence and prevalence of endocrine abnormalities increased across the lifespan of survivors, reported Sogol Mostoufi-Moab, MD, of University of Pennsylvania, Philadelphia, and his associates (J Clin Oncol. 2016 Jul. doi: 10.1200/JCO.2016.66.6545).
A total of 14,290 patients met the study’s eligibility requirements, which included a diagnosis of cancer before age 21 years and 5-year survival following diagnosis. Cancer diagnoses included leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms tumor, neuroblastoma, sarcoma, bone malignancy, and central nervous system malignancy. Baseline and follow-up questionnaires collected endocrine-related outcomes of interest, demographic information, and medical histories for both cancer survivors and their siblings (n = 4,031). For survivors, median age at diagnosis was 6 years and median age at last follow-up was 32 years. For siblings, median age at last follow-up was 34 years.
Overall 44% of cancer survivors had at least one endocrinopathy, 16.7% had at least two, and 6.6% had three or more. Survivors of Hodgkin lymphoma had the highest frequency of endocrine abnormality (60.1%) followed by survivors of CNS malignancy (54%), leukemia (45.6%), sarcoma (41.3%), non-Hodgkin lymphoma (39.7%), and neuroblastoma (31.9%).
Specifically, thyroid disorders were more frequent among cancer survivors than among their siblings: underactive thyroid (hazard ratio, 2.2; 95% confidence interval, 1.8-2.7), overactive thyroid (HR, 2.4; 95% CI, 1.7-3.3), thyroid nodules (HR, 3.9; 95% CI, 2.9-5.4), and thyroid cancer (HR 2.5; 95% CI, 1.2-5.3).
Compared to their siblings, cancer survivors showed increased risk of developing diabetes (RR, 1.8; 95% CI, 1.4-2.3).
Among survivors, those exposed to high-risk therapies (defined by the Children’s Oncology Group’s Long-Term Follow-Up Guidelinesfor Survivors of Childhood, Adolescent, and Young Adult Cancers) were at a greater risk of developing primary hypothyroidism (HR, 6.6; 95% CI, 5.6-7.8) central hypothyroidism (HR, 3.9; 95% CI, 2.9-5.2), an overactive thyroid (HR, 1.8; 95% CI, 1.2-2.8), thyroid nodules (HR, 6.3; 95% CI, 5.2-7.5), and thyroid cancer (HR, 9.2; 95% CI, 6.2-13.7) compared with survivors not so exposed.
The National Cancer Institute, the Cancer Center Support Grant, and the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital funded the study. Dr. Mostoufi-Moab and nine other investigators had no disclosures to report. Two investigators reported receiving financial compensation or honoraria from Merck or Sandoz.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Invasive Salmonellosis in a 45-Day-Old Infant
The management of a febrile infant is complex and requires obtaining a detailed history of all possible exposures. Published guidelines alone are not always completely accurate for diagnosing or excluding serious illness, and are not a substitute for a thorough examination and history.
Case
The parents of a 45-day-old girl were referred to our regional pediatric hospital by a local community hospital for emergent evaluation of their infant. The day prior, they had taken the infant to the referring ED because of persistent fussiness and subjective fever. They were neither sure of the tests that were obtained during that visit nor why they were instructed to take their daughter to our pediatric facility. They did, however, recall that during the visit to the community ED, the patient had a rectal temperature of 102.7°F, was given an antibiotic injection, and was well appearing and acting normally. Also, at discharge, the infant’s parents were instructed to follow up with the patient’s pediatrician within 24 hours.
Since their daughter’s discharge from the community ED, both parents noted that she seemed more irritable, felt warm, and had not been feeding well. They confirmed that she was an otherwise healthy infant who had been born full term via normal vaginal delivery and without complications.
On initial assessment at our ED, the patient was fussy and had mottled extremities and dusky nail beds. Her vital signs at presentation were: heart rate, 223 beats/minute; respiratory rate, 36 breaths/minute; and rectal temperature, 103.6°F. Oxygen saturation was 96% on room air. The infant was resuscitated with 20 mL/kg of intravenous (IV) normal saline and given oral acetaminophen. Laboratory studies were obtained, and a lumbar puncture (LP) was performed.
She was treated with IV acyclovir, ceftriaxone, and vancomycin. Her complete blood count (CBC) was notable for a white blood cell count (WBC) of 22.60 x 109/L; cerebrospinal fluid (CSF) analysis revealed a WBC of 4.52 x 109/L with 75% neutrophils, and serum glucose of 63 mg/dL.
Since the patient’s parents did not have any paperwork or information from the prior ED visit, our ED contacted the community ED by phone, and a representative provided the following information: the patient had appeared well but was febrile at presentation; laboratory evaluation was obtained, but no LP was performed; she was treated with intramuscular (IM) ceftriaxone and acetaminophen; and she was discharged home in the care of her parents. Regarding laboratory studies performed at the community ED, the only test result made available by phone was the preliminary blood culture report that revealed growth of gram-negative rods with speciation pending, which prompted the referral to our facility.
Based on the information provided by the community ED and our evaluation and work-up, the patient was admitted to the pediatric intensive care unit. Magnetic resonance imaging (MRI) of the brain was performed, which showed debris in the lateral ventricles consistent with ventriculitis—likely secondary to meningitis. The blood, urine, and cerebrospinal fluid (CSF) cultures collected during our evaluation produced no growth; however, blood cultures from the rural ED eventually grew Salmonella.
A further detailed history revealed that the infant and her parents had been living with a family friend who owned an iguana. According to reports, the iguana had free run of the home and often crawled around and across the infant while she was lying on a blanket on the floor. The patient’s parents were not aware of the diseases associated with reptile contact. Due to concerns over the social situation, the patient was kept in the hospital for the entire recommended 21-day course of antibiotic therapy, during which time the parents received assistance finding alternate living arrangements.
Discussion
Current Practice Guidelines for Managing Febrile Infants
Current guidelines from the American Academy of Pediatrics (AAP) and the American College of Emergency Physicians (ACEP) recommend a full sepsis work-up for all neonates (ie, ages 0 to 28 days) who present with a fever (defined as a rectal temperature ≥100.4°F).1,2 The probability of a serious bacterial infection (SBI) in patients in this age group who present with fever is approximately 12%.3 A full sepsis work-up generally includes a CBC, blood cultures, urinalysis with culture, CSF analysis with culture, and stool cultures if diarrhea is present.
Current guidelines for infants 29 to 90 days of age who present with fever differ between professional associations. The AAP and the American Academy of Family Physicians recommend the following for children in this age range: laboratory evaluation with CBC, blood cultures, CSF analysis, urinalysis, and culture. If laboratory evaluation reveals a WBC of less than 15 x 109/L with an absolute neutrophil count of less than 10 x 109/L, along with a normal CSF and urinalysis, the patient can be given IM ceftriaxone and follow-up arranged in 24 hours. This approach is recommended for patients who are otherwise healthy, nontoxic at presentation, and under the care of a responsible adult.4,5 By comparison, the Philadelphia protocol, though suggesting an identical work-up, recommends against the use of antibiotics in infants deemed at low risk for SBI.6
The ACEP does not specifically endorse a management strategy for febrile infants in the 29- to 90-day age group, but instead acknowledges that no age cut-off within this group can be considered absolute when determining management strategy, and suggests that children up to 60 days old should be managed in a manner similar to neonates.2 The published guidelines do not include consideration of specific history exposure in the management recommendations.
Typhoidal Serotypes
Salmonella can be divided into typhoidal (including S typhi and S paratyphi) and nontyphoidal serotypes (NTS), with the two groups manifesting as very different diseases.7 Typhoidal serotypes lead to the disease process known as typhoid, which typically presents with fever, chills, abdominal pain, nonbloody diarrhea or constipation, nausea, anorexia, headache, hepatosplenomegaly, and rose spots.8 These symptoms typically present after a 14-day incubation period and persist for 21 days.9 Humans are the only known infected source of these species, which are spread via the fecal-oral route.10
In contrast, disease from NTS manifests within 12 hours of exposure with watery diarrhea, nausea, vomiting, and fever, with symptoms lasting up to 10 days.11 Both groups cause disease by invading the intestinal epithelium12; however, typhoidal species induce less intestinal inflammation, facilitating bacterial invasion and making systemic disease more likely.13
Transmission
Many animals are known to carry NTS, including reptiles, where Salmonella occurs naturally in their gastrointestinal tract.14 Twenty-five percent of Salmonella infections in children younger than age 5 years have been attributed to contact with a pet,15 with small turtles (shell diameter <4 inches) accounting for 42% of all pet-related Salmonella infections.
Though gastroenteritis is the most common clinical manifestation of infection with NTS, approximately 5% of patients will develop invasive disease, including bacteremia, meningitis, septic arthritis, or osteomyelitis.16 Children with invasive disease are more likely to have been exposed to an iguana, snake, or bearded dragon than to a turtle. If the pet is kept indoors, the risk of invasive disease is more likely. The average age of patients with invasive disease is 62 days, versus 2 years for noninvasive disease.17
Diagnosis
Growth of Salmonella on cultures of stool, blood, urine, or CSF dishes is the mainstay of diagnosis of typhoid and nontyphoidal disease, but bacterial concentrations are higher in bone marrow aspirate, making it superior to blood cultures.18 Biopsy of the rose spots of typhoid may also provide the diagnosis.
Management
Since Salmonella gastroenteritis is usually a self-limited disease, current recommendations reserve treatment with antibiotics for patients with severe disease or who are immunocompromised. When necessary, treatment consists of 7 to 10 days of a fluoroquinolone or third-generation cephalosporin, which is the same regimen suggested for typhoid. Treatment of central nervous system (CNS) salmonellosis consists of at least 3 weeks of a third-generation cephalosporin; the AAP recommends at least 4 weeks of treatment.19
Case Conclusion
Prior to the patient’s transfer to our facility, she was treated empirically with ceftriaxone without prior CSF analysis—an approach that does not follow any current guidelines for the treatment of a febrile infant. Though an LP was not performed until approximately 24 hours after the initial antibiotic was given, the patient demonstrated CSF pleocytosis with no organisms on gram stain and no growth on culture. Given this pleocytosis and Salmonella bacteremia in the context of prior antibiotic treatment, and MRI consistent with CNS involvement, the patient was treated for 21 days for presumed Salmonella meningitis. A CSF analysis performed on her initial visit could have more accurately directed the type and duration of treatment if the findings on subsequent imaging studies and CSF analysis were ambiguous.
Summary
Emergency physicians may underestimate the likelihood of SBI in otherwise well-appearing febrile infants. While certain aspects of the history and physical examination in a febrile, well-appearing infant have been shown to correlate with an increased risk of SBI, no single finding can definitively rule in or rule out the disease.20 Opinions differ as to optimal management strategies for febrile, well-appearing infants outside the neonatal period. However, an appropriate level of clinical suspicion, within the context of a thorough investigation into the infant’s health history and social situation, can aid the clinician and guide treatment and disposition.
1. Baraff LJ, Bass JW, Fleisher GR, et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Agency for Health Care Policy and Research. Ann Emerg Med. 1993;22(7):1198-1210. Erratum in Ann Emerg Med. 1993;22(9):1490.
2. American College of Emergency Physicians Clinical Policies Committee; American College of Emergency Physicians Clinical Policies Subcommittee on Pediatric Fever. Clinical policy for children younger than three years presenting to the emergency department with fever. Ann Emerg Med. 2003;42(4):530-545.
3. Kadish HA, Loveridge B, Tobey J, Bolte RG, Corneli HM. Applying outpatient protocols in febrile infants 1-28 days of age: can the threshold be lowered? Clin Pediatr (Phila). 2000;39(2):81-88.
4. Sur DK, Bukont EL. Evaluating fever of unidentifiable source in young children. Am Fam Physician. 2007;75(12):1805-1811.
5. Baraff LJ, Lee SI, Schriger DL. Outcomes of bacterial meningitis in children: a meta-analysis. Pediatr Infect Dis J. 1993;12(5):389-394.
6. Baker MD, Bell LM, Avner JR. Outpatient management without antibiotics of fever in selected infants. N Eng J Med. 1993;329(20):1437-1441.
7. Gal-Mor O, Boyle EC, Grassl GA. Same species, different diseases: how and why typhoidal and non-typhoidal Salmonella enterica serovars differ. Front in Microbiol. 2014;5:391.
8. Stuart BM, Pullen RL. Typhoid: clinical analysis of 360 cases. Arch Intern Med (Chic). 1946;78(6):
629-661.
9. Olsen SJ, Bleasdale SC, Magnano AR, et al. Outbreaks of typhoid fever in the United States, 1960-99. Epidemiol Infect. 2003;130(1):13-21.
10. Newton AE, Routh JA, Mahon BE. Typhoid and Paratyphoid Fever. In: Brunette GW, Kozarsky PE, Cohen NJ, et al, eds. CDC Health Information for International Travel. New York, NY: Oxford University Press; 2016. http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/typhoid-paratyphoid-fever. Updated July 10, 2015. Accessed June 13, 2016.
11. McGovern VJ, Slavutin LJ. Pathology of Salmonella colitis. Am J Surg Pathol. 1979;3(6):483-490.
12. Liu SL, Ezaki T, Miura H, Matsui K, Yabuuchi E. Intact motility as a Salmonella typhi invasion-related factor. Infect Immun. 1988;56(8):1967-1973.
13. House D, Wain J, Ho VA, et al. Serology of typhoid fever in an area of endemicity and its relevance to diagnosis. J Clin Microbiol. 2001;39(3):1002-1007.
14. Hoelzer K, Moreno Switt AI, Wiedmann M. Animal contact as a source of human non-typhoidal salmonellosis. Vet Res. 2011;42(1):34.
15. Murphy D, Oshin F. Reptile-associated salmonellosis in children aged under 5 years in South West England. Arch Dis Child. 2015;100(4):364-365.
16. Iwamoto M. Infectious diseases related to travel. In: Brunette GW, Kozarsky PE, Cohen NJ, et al, eds. CDC Health Information for International Travel. New York, NY: Oxford University Press; 2016. http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/salmonellosis-nontyphoidal. Updated July 10, 2015. Accessed June 13, 2016.
17. Meyer Sauteur PM, Relly C, Hug M, Wittenbrink MM, Berger C. Risk factors for invasive reptile-associated salmonellosis in children. Vector-Borne and Zoonotic Dis. 2013;13(6):419-421.
18. Gasem MH, Keuter M, Dolmans WM, Van Der Ven-Jongekrijg J, Djokomoeljanto R, Van Der Meer JW. Persistence of Salmonellae in blood and bone marrow: randomized controlled trial comparing ciprofloxacin and chloramphenicol treatments against enteric fever. Antimicrob Agents Chemother. 2003;47(5):1727-1731.
19. Price EH, de Louvois J, Workman MR. Antibiotics for Salmonella meningitis in children. J Antimicrob Chemother. 2000;46(5) 653-655.
20. Craig JC, Williams GJ, Jones M, et al. The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses. BMJ. 2010;340:c1594.
The management of a febrile infant is complex and requires obtaining a detailed history of all possible exposures. Published guidelines alone are not always completely accurate for diagnosing or excluding serious illness, and are not a substitute for a thorough examination and history.
Case
The parents of a 45-day-old girl were referred to our regional pediatric hospital by a local community hospital for emergent evaluation of their infant. The day prior, they had taken the infant to the referring ED because of persistent fussiness and subjective fever. They were neither sure of the tests that were obtained during that visit nor why they were instructed to take their daughter to our pediatric facility. They did, however, recall that during the visit to the community ED, the patient had a rectal temperature of 102.7°F, was given an antibiotic injection, and was well appearing and acting normally. Also, at discharge, the infant’s parents were instructed to follow up with the patient’s pediatrician within 24 hours.
Since their daughter’s discharge from the community ED, both parents noted that she seemed more irritable, felt warm, and had not been feeding well. They confirmed that she was an otherwise healthy infant who had been born full term via normal vaginal delivery and without complications.
On initial assessment at our ED, the patient was fussy and had mottled extremities and dusky nail beds. Her vital signs at presentation were: heart rate, 223 beats/minute; respiratory rate, 36 breaths/minute; and rectal temperature, 103.6°F. Oxygen saturation was 96% on room air. The infant was resuscitated with 20 mL/kg of intravenous (IV) normal saline and given oral acetaminophen. Laboratory studies were obtained, and a lumbar puncture (LP) was performed.
She was treated with IV acyclovir, ceftriaxone, and vancomycin. Her complete blood count (CBC) was notable for a white blood cell count (WBC) of 22.60 x 109/L; cerebrospinal fluid (CSF) analysis revealed a WBC of 4.52 x 109/L with 75% neutrophils, and serum glucose of 63 mg/dL.
Since the patient’s parents did not have any paperwork or information from the prior ED visit, our ED contacted the community ED by phone, and a representative provided the following information: the patient had appeared well but was febrile at presentation; laboratory evaluation was obtained, but no LP was performed; she was treated with intramuscular (IM) ceftriaxone and acetaminophen; and she was discharged home in the care of her parents. Regarding laboratory studies performed at the community ED, the only test result made available by phone was the preliminary blood culture report that revealed growth of gram-negative rods with speciation pending, which prompted the referral to our facility.
Based on the information provided by the community ED and our evaluation and work-up, the patient was admitted to the pediatric intensive care unit. Magnetic resonance imaging (MRI) of the brain was performed, which showed debris in the lateral ventricles consistent with ventriculitis—likely secondary to meningitis. The blood, urine, and cerebrospinal fluid (CSF) cultures collected during our evaluation produced no growth; however, blood cultures from the rural ED eventually grew Salmonella.
A further detailed history revealed that the infant and her parents had been living with a family friend who owned an iguana. According to reports, the iguana had free run of the home and often crawled around and across the infant while she was lying on a blanket on the floor. The patient’s parents were not aware of the diseases associated with reptile contact. Due to concerns over the social situation, the patient was kept in the hospital for the entire recommended 21-day course of antibiotic therapy, during which time the parents received assistance finding alternate living arrangements.
Discussion
Current Practice Guidelines for Managing Febrile Infants
Current guidelines from the American Academy of Pediatrics (AAP) and the American College of Emergency Physicians (ACEP) recommend a full sepsis work-up for all neonates (ie, ages 0 to 28 days) who present with a fever (defined as a rectal temperature ≥100.4°F).1,2 The probability of a serious bacterial infection (SBI) in patients in this age group who present with fever is approximately 12%.3 A full sepsis work-up generally includes a CBC, blood cultures, urinalysis with culture, CSF analysis with culture, and stool cultures if diarrhea is present.
Current guidelines for infants 29 to 90 days of age who present with fever differ between professional associations. The AAP and the American Academy of Family Physicians recommend the following for children in this age range: laboratory evaluation with CBC, blood cultures, CSF analysis, urinalysis, and culture. If laboratory evaluation reveals a WBC of less than 15 x 109/L with an absolute neutrophil count of less than 10 x 109/L, along with a normal CSF and urinalysis, the patient can be given IM ceftriaxone and follow-up arranged in 24 hours. This approach is recommended for patients who are otherwise healthy, nontoxic at presentation, and under the care of a responsible adult.4,5 By comparison, the Philadelphia protocol, though suggesting an identical work-up, recommends against the use of antibiotics in infants deemed at low risk for SBI.6
The ACEP does not specifically endorse a management strategy for febrile infants in the 29- to 90-day age group, but instead acknowledges that no age cut-off within this group can be considered absolute when determining management strategy, and suggests that children up to 60 days old should be managed in a manner similar to neonates.2 The published guidelines do not include consideration of specific history exposure in the management recommendations.
Typhoidal Serotypes
Salmonella can be divided into typhoidal (including S typhi and S paratyphi) and nontyphoidal serotypes (NTS), with the two groups manifesting as very different diseases.7 Typhoidal serotypes lead to the disease process known as typhoid, which typically presents with fever, chills, abdominal pain, nonbloody diarrhea or constipation, nausea, anorexia, headache, hepatosplenomegaly, and rose spots.8 These symptoms typically present after a 14-day incubation period and persist for 21 days.9 Humans are the only known infected source of these species, which are spread via the fecal-oral route.10
In contrast, disease from NTS manifests within 12 hours of exposure with watery diarrhea, nausea, vomiting, and fever, with symptoms lasting up to 10 days.11 Both groups cause disease by invading the intestinal epithelium12; however, typhoidal species induce less intestinal inflammation, facilitating bacterial invasion and making systemic disease more likely.13
Transmission
Many animals are known to carry NTS, including reptiles, where Salmonella occurs naturally in their gastrointestinal tract.14 Twenty-five percent of Salmonella infections in children younger than age 5 years have been attributed to contact with a pet,15 with small turtles (shell diameter <4 inches) accounting for 42% of all pet-related Salmonella infections.
Though gastroenteritis is the most common clinical manifestation of infection with NTS, approximately 5% of patients will develop invasive disease, including bacteremia, meningitis, septic arthritis, or osteomyelitis.16 Children with invasive disease are more likely to have been exposed to an iguana, snake, or bearded dragon than to a turtle. If the pet is kept indoors, the risk of invasive disease is more likely. The average age of patients with invasive disease is 62 days, versus 2 years for noninvasive disease.17
Diagnosis
Growth of Salmonella on cultures of stool, blood, urine, or CSF dishes is the mainstay of diagnosis of typhoid and nontyphoidal disease, but bacterial concentrations are higher in bone marrow aspirate, making it superior to blood cultures.18 Biopsy of the rose spots of typhoid may also provide the diagnosis.
Management
Since Salmonella gastroenteritis is usually a self-limited disease, current recommendations reserve treatment with antibiotics for patients with severe disease or who are immunocompromised. When necessary, treatment consists of 7 to 10 days of a fluoroquinolone or third-generation cephalosporin, which is the same regimen suggested for typhoid. Treatment of central nervous system (CNS) salmonellosis consists of at least 3 weeks of a third-generation cephalosporin; the AAP recommends at least 4 weeks of treatment.19
Case Conclusion
Prior to the patient’s transfer to our facility, she was treated empirically with ceftriaxone without prior CSF analysis—an approach that does not follow any current guidelines for the treatment of a febrile infant. Though an LP was not performed until approximately 24 hours after the initial antibiotic was given, the patient demonstrated CSF pleocytosis with no organisms on gram stain and no growth on culture. Given this pleocytosis and Salmonella bacteremia in the context of prior antibiotic treatment, and MRI consistent with CNS involvement, the patient was treated for 21 days for presumed Salmonella meningitis. A CSF analysis performed on her initial visit could have more accurately directed the type and duration of treatment if the findings on subsequent imaging studies and CSF analysis were ambiguous.
Summary
Emergency physicians may underestimate the likelihood of SBI in otherwise well-appearing febrile infants. While certain aspects of the history and physical examination in a febrile, well-appearing infant have been shown to correlate with an increased risk of SBI, no single finding can definitively rule in or rule out the disease.20 Opinions differ as to optimal management strategies for febrile, well-appearing infants outside the neonatal period. However, an appropriate level of clinical suspicion, within the context of a thorough investigation into the infant’s health history and social situation, can aid the clinician and guide treatment and disposition.
The management of a febrile infant is complex and requires obtaining a detailed history of all possible exposures. Published guidelines alone are not always completely accurate for diagnosing or excluding serious illness, and are not a substitute for a thorough examination and history.
Case
The parents of a 45-day-old girl were referred to our regional pediatric hospital by a local community hospital for emergent evaluation of their infant. The day prior, they had taken the infant to the referring ED because of persistent fussiness and subjective fever. They were neither sure of the tests that were obtained during that visit nor why they were instructed to take their daughter to our pediatric facility. They did, however, recall that during the visit to the community ED, the patient had a rectal temperature of 102.7°F, was given an antibiotic injection, and was well appearing and acting normally. Also, at discharge, the infant’s parents were instructed to follow up with the patient’s pediatrician within 24 hours.
Since their daughter’s discharge from the community ED, both parents noted that she seemed more irritable, felt warm, and had not been feeding well. They confirmed that she was an otherwise healthy infant who had been born full term via normal vaginal delivery and without complications.
On initial assessment at our ED, the patient was fussy and had mottled extremities and dusky nail beds. Her vital signs at presentation were: heart rate, 223 beats/minute; respiratory rate, 36 breaths/minute; and rectal temperature, 103.6°F. Oxygen saturation was 96% on room air. The infant was resuscitated with 20 mL/kg of intravenous (IV) normal saline and given oral acetaminophen. Laboratory studies were obtained, and a lumbar puncture (LP) was performed.
She was treated with IV acyclovir, ceftriaxone, and vancomycin. Her complete blood count (CBC) was notable for a white blood cell count (WBC) of 22.60 x 109/L; cerebrospinal fluid (CSF) analysis revealed a WBC of 4.52 x 109/L with 75% neutrophils, and serum glucose of 63 mg/dL.
Since the patient’s parents did not have any paperwork or information from the prior ED visit, our ED contacted the community ED by phone, and a representative provided the following information: the patient had appeared well but was febrile at presentation; laboratory evaluation was obtained, but no LP was performed; she was treated with intramuscular (IM) ceftriaxone and acetaminophen; and she was discharged home in the care of her parents. Regarding laboratory studies performed at the community ED, the only test result made available by phone was the preliminary blood culture report that revealed growth of gram-negative rods with speciation pending, which prompted the referral to our facility.
Based on the information provided by the community ED and our evaluation and work-up, the patient was admitted to the pediatric intensive care unit. Magnetic resonance imaging (MRI) of the brain was performed, which showed debris in the lateral ventricles consistent with ventriculitis—likely secondary to meningitis. The blood, urine, and cerebrospinal fluid (CSF) cultures collected during our evaluation produced no growth; however, blood cultures from the rural ED eventually grew Salmonella.
A further detailed history revealed that the infant and her parents had been living with a family friend who owned an iguana. According to reports, the iguana had free run of the home and often crawled around and across the infant while she was lying on a blanket on the floor. The patient’s parents were not aware of the diseases associated with reptile contact. Due to concerns over the social situation, the patient was kept in the hospital for the entire recommended 21-day course of antibiotic therapy, during which time the parents received assistance finding alternate living arrangements.
Discussion
Current Practice Guidelines for Managing Febrile Infants
Current guidelines from the American Academy of Pediatrics (AAP) and the American College of Emergency Physicians (ACEP) recommend a full sepsis work-up for all neonates (ie, ages 0 to 28 days) who present with a fever (defined as a rectal temperature ≥100.4°F).1,2 The probability of a serious bacterial infection (SBI) in patients in this age group who present with fever is approximately 12%.3 A full sepsis work-up generally includes a CBC, blood cultures, urinalysis with culture, CSF analysis with culture, and stool cultures if diarrhea is present.
Current guidelines for infants 29 to 90 days of age who present with fever differ between professional associations. The AAP and the American Academy of Family Physicians recommend the following for children in this age range: laboratory evaluation with CBC, blood cultures, CSF analysis, urinalysis, and culture. If laboratory evaluation reveals a WBC of less than 15 x 109/L with an absolute neutrophil count of less than 10 x 109/L, along with a normal CSF and urinalysis, the patient can be given IM ceftriaxone and follow-up arranged in 24 hours. This approach is recommended for patients who are otherwise healthy, nontoxic at presentation, and under the care of a responsible adult.4,5 By comparison, the Philadelphia protocol, though suggesting an identical work-up, recommends against the use of antibiotics in infants deemed at low risk for SBI.6
The ACEP does not specifically endorse a management strategy for febrile infants in the 29- to 90-day age group, but instead acknowledges that no age cut-off within this group can be considered absolute when determining management strategy, and suggests that children up to 60 days old should be managed in a manner similar to neonates.2 The published guidelines do not include consideration of specific history exposure in the management recommendations.
Typhoidal Serotypes
Salmonella can be divided into typhoidal (including S typhi and S paratyphi) and nontyphoidal serotypes (NTS), with the two groups manifesting as very different diseases.7 Typhoidal serotypes lead to the disease process known as typhoid, which typically presents with fever, chills, abdominal pain, nonbloody diarrhea or constipation, nausea, anorexia, headache, hepatosplenomegaly, and rose spots.8 These symptoms typically present after a 14-day incubation period and persist for 21 days.9 Humans are the only known infected source of these species, which are spread via the fecal-oral route.10
In contrast, disease from NTS manifests within 12 hours of exposure with watery diarrhea, nausea, vomiting, and fever, with symptoms lasting up to 10 days.11 Both groups cause disease by invading the intestinal epithelium12; however, typhoidal species induce less intestinal inflammation, facilitating bacterial invasion and making systemic disease more likely.13
Transmission
Many animals are known to carry NTS, including reptiles, where Salmonella occurs naturally in their gastrointestinal tract.14 Twenty-five percent of Salmonella infections in children younger than age 5 years have been attributed to contact with a pet,15 with small turtles (shell diameter <4 inches) accounting for 42% of all pet-related Salmonella infections.
Though gastroenteritis is the most common clinical manifestation of infection with NTS, approximately 5% of patients will develop invasive disease, including bacteremia, meningitis, septic arthritis, or osteomyelitis.16 Children with invasive disease are more likely to have been exposed to an iguana, snake, or bearded dragon than to a turtle. If the pet is kept indoors, the risk of invasive disease is more likely. The average age of patients with invasive disease is 62 days, versus 2 years for noninvasive disease.17
Diagnosis
Growth of Salmonella on cultures of stool, blood, urine, or CSF dishes is the mainstay of diagnosis of typhoid and nontyphoidal disease, but bacterial concentrations are higher in bone marrow aspirate, making it superior to blood cultures.18 Biopsy of the rose spots of typhoid may also provide the diagnosis.
Management
Since Salmonella gastroenteritis is usually a self-limited disease, current recommendations reserve treatment with antibiotics for patients with severe disease or who are immunocompromised. When necessary, treatment consists of 7 to 10 days of a fluoroquinolone or third-generation cephalosporin, which is the same regimen suggested for typhoid. Treatment of central nervous system (CNS) salmonellosis consists of at least 3 weeks of a third-generation cephalosporin; the AAP recommends at least 4 weeks of treatment.19
Case Conclusion
Prior to the patient’s transfer to our facility, she was treated empirically with ceftriaxone without prior CSF analysis—an approach that does not follow any current guidelines for the treatment of a febrile infant. Though an LP was not performed until approximately 24 hours after the initial antibiotic was given, the patient demonstrated CSF pleocytosis with no organisms on gram stain and no growth on culture. Given this pleocytosis and Salmonella bacteremia in the context of prior antibiotic treatment, and MRI consistent with CNS involvement, the patient was treated for 21 days for presumed Salmonella meningitis. A CSF analysis performed on her initial visit could have more accurately directed the type and duration of treatment if the findings on subsequent imaging studies and CSF analysis were ambiguous.
Summary
Emergency physicians may underestimate the likelihood of SBI in otherwise well-appearing febrile infants. While certain aspects of the history and physical examination in a febrile, well-appearing infant have been shown to correlate with an increased risk of SBI, no single finding can definitively rule in or rule out the disease.20 Opinions differ as to optimal management strategies for febrile, well-appearing infants outside the neonatal period. However, an appropriate level of clinical suspicion, within the context of a thorough investigation into the infant’s health history and social situation, can aid the clinician and guide treatment and disposition.
1. Baraff LJ, Bass JW, Fleisher GR, et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Agency for Health Care Policy and Research. Ann Emerg Med. 1993;22(7):1198-1210. Erratum in Ann Emerg Med. 1993;22(9):1490.
2. American College of Emergency Physicians Clinical Policies Committee; American College of Emergency Physicians Clinical Policies Subcommittee on Pediatric Fever. Clinical policy for children younger than three years presenting to the emergency department with fever. Ann Emerg Med. 2003;42(4):530-545.
3. Kadish HA, Loveridge B, Tobey J, Bolte RG, Corneli HM. Applying outpatient protocols in febrile infants 1-28 days of age: can the threshold be lowered? Clin Pediatr (Phila). 2000;39(2):81-88.
4. Sur DK, Bukont EL. Evaluating fever of unidentifiable source in young children. Am Fam Physician. 2007;75(12):1805-1811.
5. Baraff LJ, Lee SI, Schriger DL. Outcomes of bacterial meningitis in children: a meta-analysis. Pediatr Infect Dis J. 1993;12(5):389-394.
6. Baker MD, Bell LM, Avner JR. Outpatient management without antibiotics of fever in selected infants. N Eng J Med. 1993;329(20):1437-1441.
7. Gal-Mor O, Boyle EC, Grassl GA. Same species, different diseases: how and why typhoidal and non-typhoidal Salmonella enterica serovars differ. Front in Microbiol. 2014;5:391.
8. Stuart BM, Pullen RL. Typhoid: clinical analysis of 360 cases. Arch Intern Med (Chic). 1946;78(6):
629-661.
9. Olsen SJ, Bleasdale SC, Magnano AR, et al. Outbreaks of typhoid fever in the United States, 1960-99. Epidemiol Infect. 2003;130(1):13-21.
10. Newton AE, Routh JA, Mahon BE. Typhoid and Paratyphoid Fever. In: Brunette GW, Kozarsky PE, Cohen NJ, et al, eds. CDC Health Information for International Travel. New York, NY: Oxford University Press; 2016. http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/typhoid-paratyphoid-fever. Updated July 10, 2015. Accessed June 13, 2016.
11. McGovern VJ, Slavutin LJ. Pathology of Salmonella colitis. Am J Surg Pathol. 1979;3(6):483-490.
12. Liu SL, Ezaki T, Miura H, Matsui K, Yabuuchi E. Intact motility as a Salmonella typhi invasion-related factor. Infect Immun. 1988;56(8):1967-1973.
13. House D, Wain J, Ho VA, et al. Serology of typhoid fever in an area of endemicity and its relevance to diagnosis. J Clin Microbiol. 2001;39(3):1002-1007.
14. Hoelzer K, Moreno Switt AI, Wiedmann M. Animal contact as a source of human non-typhoidal salmonellosis. Vet Res. 2011;42(1):34.
15. Murphy D, Oshin F. Reptile-associated salmonellosis in children aged under 5 years in South West England. Arch Dis Child. 2015;100(4):364-365.
16. Iwamoto M. Infectious diseases related to travel. In: Brunette GW, Kozarsky PE, Cohen NJ, et al, eds. CDC Health Information for International Travel. New York, NY: Oxford University Press; 2016. http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/salmonellosis-nontyphoidal. Updated July 10, 2015. Accessed June 13, 2016.
17. Meyer Sauteur PM, Relly C, Hug M, Wittenbrink MM, Berger C. Risk factors for invasive reptile-associated salmonellosis in children. Vector-Borne and Zoonotic Dis. 2013;13(6):419-421.
18. Gasem MH, Keuter M, Dolmans WM, Van Der Ven-Jongekrijg J, Djokomoeljanto R, Van Der Meer JW. Persistence of Salmonellae in blood and bone marrow: randomized controlled trial comparing ciprofloxacin and chloramphenicol treatments against enteric fever. Antimicrob Agents Chemother. 2003;47(5):1727-1731.
19. Price EH, de Louvois J, Workman MR. Antibiotics for Salmonella meningitis in children. J Antimicrob Chemother. 2000;46(5) 653-655.
20. Craig JC, Williams GJ, Jones M, et al. The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses. BMJ. 2010;340:c1594.
1. Baraff LJ, Bass JW, Fleisher GR, et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Agency for Health Care Policy and Research. Ann Emerg Med. 1993;22(7):1198-1210. Erratum in Ann Emerg Med. 1993;22(9):1490.
2. American College of Emergency Physicians Clinical Policies Committee; American College of Emergency Physicians Clinical Policies Subcommittee on Pediatric Fever. Clinical policy for children younger than three years presenting to the emergency department with fever. Ann Emerg Med. 2003;42(4):530-545.
3. Kadish HA, Loveridge B, Tobey J, Bolte RG, Corneli HM. Applying outpatient protocols in febrile infants 1-28 days of age: can the threshold be lowered? Clin Pediatr (Phila). 2000;39(2):81-88.
4. Sur DK, Bukont EL. Evaluating fever of unidentifiable source in young children. Am Fam Physician. 2007;75(12):1805-1811.
5. Baraff LJ, Lee SI, Schriger DL. Outcomes of bacterial meningitis in children: a meta-analysis. Pediatr Infect Dis J. 1993;12(5):389-394.
6. Baker MD, Bell LM, Avner JR. Outpatient management without antibiotics of fever in selected infants. N Eng J Med. 1993;329(20):1437-1441.
7. Gal-Mor O, Boyle EC, Grassl GA. Same species, different diseases: how and why typhoidal and non-typhoidal Salmonella enterica serovars differ. Front in Microbiol. 2014;5:391.
8. Stuart BM, Pullen RL. Typhoid: clinical analysis of 360 cases. Arch Intern Med (Chic). 1946;78(6):
629-661.
9. Olsen SJ, Bleasdale SC, Magnano AR, et al. Outbreaks of typhoid fever in the United States, 1960-99. Epidemiol Infect. 2003;130(1):13-21.
10. Newton AE, Routh JA, Mahon BE. Typhoid and Paratyphoid Fever. In: Brunette GW, Kozarsky PE, Cohen NJ, et al, eds. CDC Health Information for International Travel. New York, NY: Oxford University Press; 2016. http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/typhoid-paratyphoid-fever. Updated July 10, 2015. Accessed June 13, 2016.
11. McGovern VJ, Slavutin LJ. Pathology of Salmonella colitis. Am J Surg Pathol. 1979;3(6):483-490.
12. Liu SL, Ezaki T, Miura H, Matsui K, Yabuuchi E. Intact motility as a Salmonella typhi invasion-related factor. Infect Immun. 1988;56(8):1967-1973.
13. House D, Wain J, Ho VA, et al. Serology of typhoid fever in an area of endemicity and its relevance to diagnosis. J Clin Microbiol. 2001;39(3):1002-1007.
14. Hoelzer K, Moreno Switt AI, Wiedmann M. Animal contact as a source of human non-typhoidal salmonellosis. Vet Res. 2011;42(1):34.
15. Murphy D, Oshin F. Reptile-associated salmonellosis in children aged under 5 years in South West England. Arch Dis Child. 2015;100(4):364-365.
16. Iwamoto M. Infectious diseases related to travel. In: Brunette GW, Kozarsky PE, Cohen NJ, et al, eds. CDC Health Information for International Travel. New York, NY: Oxford University Press; 2016. http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/salmonellosis-nontyphoidal. Updated July 10, 2015. Accessed June 13, 2016.
17. Meyer Sauteur PM, Relly C, Hug M, Wittenbrink MM, Berger C. Risk factors for invasive reptile-associated salmonellosis in children. Vector-Borne and Zoonotic Dis. 2013;13(6):419-421.
18. Gasem MH, Keuter M, Dolmans WM, Van Der Ven-Jongekrijg J, Djokomoeljanto R, Van Der Meer JW. Persistence of Salmonellae in blood and bone marrow: randomized controlled trial comparing ciprofloxacin and chloramphenicol treatments against enteric fever. Antimicrob Agents Chemother. 2003;47(5):1727-1731.
19. Price EH, de Louvois J, Workman MR. Antibiotics for Salmonella meningitis in children. J Antimicrob Chemother. 2000;46(5) 653-655.
20. Craig JC, Williams GJ, Jones M, et al. The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses. BMJ. 2010;340:c1594.
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Brett Radler is SHM’s communications coordinator.
Register, book your hotel, and see the full course schedule at www.phmmeeting.org.
Brett Radler is SHM’s communications coordinator.
Register, book your hotel, and see the full course schedule at www.phmmeeting.org.
Brett Radler is SHM’s communications coordinator.
Supreme Court will not hear pharmacy religious liberty case
The U.S. Supreme Court has refused to decide whether pharmacists with strongly held religious beliefs can be forced to dispense emergency contraception to patients.
Justices did not explain their June 28 denial of Stormans, Inc. vs. Wiesman, but the decision was made over the objection of Chief Justice John G. Roberts Jr., Associate Justice Samuel Alito Jr., and Associate Justice Clarence Thomas. In his dissent, Associate Justice Alito wrote the court should have heard the case to ensure that novel and concededly “unnecessary burden on religious objectors” does not trample fundamental rights.
“If this is a sign of how religious liberty claims will be treated in the years ahead, those who value religious freedom have cause for great concern,” he wrote in his dissent.
At issue in the case is a 2007 rule by Washington state that a family-owned pharmacy in Olympia must provide Plan B contraception to patients. The “delivery rule” creates “a duty for pharmacists to deliver lawfully prescribed drugs or devices in a timely manner and does not allow for conscience-based decisions not to dispense the drug. The Stormans family, who own Ralph’s Thriftway, sued the state over the regulation, alleging violations of the free exercise, equal protection, and due process clauses of the Constitution. The business owners equate emergency contraception to abortion, and they argue that dispensing the medication violates their religious beliefs.
The 9th U.S. Circuit Court of Appeals sided with the state, calling the regulations “neutral and generally applicable.” The plaintiffs appealed to the Supreme Court. The denial by the high court allows the 9th Circuit decision to stand.
Nearly 20 court briefs were issued to the Supreme Court in the case, including briefs by the American Association of Pro-Life Obstetricians and Gynecologists and 4,609 individual health care professionals in support of the pharmacy.
“By effectively prohibiting exemptions for religious reasons, the state of Washington’s regulations depart radically from widely established norms within the health care industry protecting the individual conscience rights of health care professionals,” the health care professionals wrote in their brief. “Such norms favoring the freedom of conscience are particularly well established where, as here, the practitioner’s right to decline care applies to particular treatments, not to individual patients or classes of persons; and where, as here, declining treatment for reasons of religious conscience has no practical impact on quality or availability of care.”
On Twitter @legal_med
The U.S. Supreme Court has refused to decide whether pharmacists with strongly held religious beliefs can be forced to dispense emergency contraception to patients.
Justices did not explain their June 28 denial of Stormans, Inc. vs. Wiesman, but the decision was made over the objection of Chief Justice John G. Roberts Jr., Associate Justice Samuel Alito Jr., and Associate Justice Clarence Thomas. In his dissent, Associate Justice Alito wrote the court should have heard the case to ensure that novel and concededly “unnecessary burden on religious objectors” does not trample fundamental rights.
“If this is a sign of how religious liberty claims will be treated in the years ahead, those who value religious freedom have cause for great concern,” he wrote in his dissent.
At issue in the case is a 2007 rule by Washington state that a family-owned pharmacy in Olympia must provide Plan B contraception to patients. The “delivery rule” creates “a duty for pharmacists to deliver lawfully prescribed drugs or devices in a timely manner and does not allow for conscience-based decisions not to dispense the drug. The Stormans family, who own Ralph’s Thriftway, sued the state over the regulation, alleging violations of the free exercise, equal protection, and due process clauses of the Constitution. The business owners equate emergency contraception to abortion, and they argue that dispensing the medication violates their religious beliefs.
The 9th U.S. Circuit Court of Appeals sided with the state, calling the regulations “neutral and generally applicable.” The plaintiffs appealed to the Supreme Court. The denial by the high court allows the 9th Circuit decision to stand.
Nearly 20 court briefs were issued to the Supreme Court in the case, including briefs by the American Association of Pro-Life Obstetricians and Gynecologists and 4,609 individual health care professionals in support of the pharmacy.
“By effectively prohibiting exemptions for religious reasons, the state of Washington’s regulations depart radically from widely established norms within the health care industry protecting the individual conscience rights of health care professionals,” the health care professionals wrote in their brief. “Such norms favoring the freedom of conscience are particularly well established where, as here, the practitioner’s right to decline care applies to particular treatments, not to individual patients or classes of persons; and where, as here, declining treatment for reasons of religious conscience has no practical impact on quality or availability of care.”
On Twitter @legal_med
The U.S. Supreme Court has refused to decide whether pharmacists with strongly held religious beliefs can be forced to dispense emergency contraception to patients.
Justices did not explain their June 28 denial of Stormans, Inc. vs. Wiesman, but the decision was made over the objection of Chief Justice John G. Roberts Jr., Associate Justice Samuel Alito Jr., and Associate Justice Clarence Thomas. In his dissent, Associate Justice Alito wrote the court should have heard the case to ensure that novel and concededly “unnecessary burden on religious objectors” does not trample fundamental rights.
“If this is a sign of how religious liberty claims will be treated in the years ahead, those who value religious freedom have cause for great concern,” he wrote in his dissent.
At issue in the case is a 2007 rule by Washington state that a family-owned pharmacy in Olympia must provide Plan B contraception to patients. The “delivery rule” creates “a duty for pharmacists to deliver lawfully prescribed drugs or devices in a timely manner and does not allow for conscience-based decisions not to dispense the drug. The Stormans family, who own Ralph’s Thriftway, sued the state over the regulation, alleging violations of the free exercise, equal protection, and due process clauses of the Constitution. The business owners equate emergency contraception to abortion, and they argue that dispensing the medication violates their religious beliefs.
The 9th U.S. Circuit Court of Appeals sided with the state, calling the regulations “neutral and generally applicable.” The plaintiffs appealed to the Supreme Court. The denial by the high court allows the 9th Circuit decision to stand.
Nearly 20 court briefs were issued to the Supreme Court in the case, including briefs by the American Association of Pro-Life Obstetricians and Gynecologists and 4,609 individual health care professionals in support of the pharmacy.
“By effectively prohibiting exemptions for religious reasons, the state of Washington’s regulations depart radically from widely established norms within the health care industry protecting the individual conscience rights of health care professionals,” the health care professionals wrote in their brief. “Such norms favoring the freedom of conscience are particularly well established where, as here, the practitioner’s right to decline care applies to particular treatments, not to individual patients or classes of persons; and where, as here, declining treatment for reasons of religious conscience has no practical impact on quality or availability of care.”
On Twitter @legal_med
Sticks and stones and words
“Sticks and stones may break my bones, but words will never hurt me.” This mantra was the retort of choice for thousands of apparently resilient premillennial children. But you and I, and just about everyone else, know that words can be very hurtful. A recent article in the journal Eating and Weight Disorders entitled, “ ‘Don’t eat so much’: How parent comments relate to female weight satisfaction” (Eat Weight Disord. 2016 Jun 6. [Epub ahead of print]) reminds us that the pain can last forever.
In a retrospective study of 501 young women aged 20-35 years, the investigators asked whether the women could recall their parents making any comments about their weight when they were young children. What the authors discovered was that even among young women who were of normal weight, those who could recall their parents making a comment about their weight were more dissatisfied with their body weight than the young women who could not recall such a comment. However, if the comment had been about eating habits and not weight, then there was no significant association with weight dissatisfaction.
Before we rush out to send all of the parents of weight-dissatisfied young women on a guilt trip, let’s remember that this was a retrospective study. Let’s consider the not unlikely explanation that there may be something built into the psyche of weight-dissatisfied young women that sharpens their memory for negative comments from friends and family.
Regardless of how we interpret the findings from this study, it is probably safe to say that telling a young girl that she is overweight doesn’t help and should be avoided. This is just another example of how poorly chosen words can be hurtful. But it is also an example of how words alone are seldom shapers of positive behaviors. You can’t talk a picky eater into eating spinach anymore than you can talk the child in the middle of a tantrum into settling down. Good manners are best learned by modeling the behavior of respected adults and not by being subjected to a series of parental lectures. Telling a child she is overweight won’t solve the problem.
So what is the parent of an obese child to do? Unfortunately, many parents of obese children don’t perceive their child as being significantly overweight. But let’s assume we have cleared that hurdle of denial. If telling the child she is overweight is the wrong thing to do, then her parents are forced into using strategies that are subliminal, applied slowly and patiently – silently.
These strategies could include gradually decreasing the child’s screen time, hoping that it will be replaced by calorie-burning activities; changing the food available for all the inhabitants of the home to increase the likelihood that healthier choices will dominate; and decreasing serving sizes. It is critical that these changes are done so slowly that they go unnoticed by the child. If the child questions the changes, then the response should be that they are being done to help the entire family to be healthier, and that they are not being targeted at any one individual. Of course, the big problem is getting the rest of the family to buy into the changes so that the overweight child doesn’t become a scapegoat.
Shielding the overweight child from the blame game is much easier if the parents have been careful to avoid labeling from the moment they realized or accepted that the child had a weight problem. Here is where we pediatricians can play a critical role in our choice of words, and the setting in which we discuss the child’s weight with the parents. We must point out to the parents that their words can create a hurt that may not ever go away.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”
“Sticks and stones may break my bones, but words will never hurt me.” This mantra was the retort of choice for thousands of apparently resilient premillennial children. But you and I, and just about everyone else, know that words can be very hurtful. A recent article in the journal Eating and Weight Disorders entitled, “ ‘Don’t eat so much’: How parent comments relate to female weight satisfaction” (Eat Weight Disord. 2016 Jun 6. [Epub ahead of print]) reminds us that the pain can last forever.
In a retrospective study of 501 young women aged 20-35 years, the investigators asked whether the women could recall their parents making any comments about their weight when they were young children. What the authors discovered was that even among young women who were of normal weight, those who could recall their parents making a comment about their weight were more dissatisfied with their body weight than the young women who could not recall such a comment. However, if the comment had been about eating habits and not weight, then there was no significant association with weight dissatisfaction.
Before we rush out to send all of the parents of weight-dissatisfied young women on a guilt trip, let’s remember that this was a retrospective study. Let’s consider the not unlikely explanation that there may be something built into the psyche of weight-dissatisfied young women that sharpens their memory for negative comments from friends and family.
Regardless of how we interpret the findings from this study, it is probably safe to say that telling a young girl that she is overweight doesn’t help and should be avoided. This is just another example of how poorly chosen words can be hurtful. But it is also an example of how words alone are seldom shapers of positive behaviors. You can’t talk a picky eater into eating spinach anymore than you can talk the child in the middle of a tantrum into settling down. Good manners are best learned by modeling the behavior of respected adults and not by being subjected to a series of parental lectures. Telling a child she is overweight won’t solve the problem.
So what is the parent of an obese child to do? Unfortunately, many parents of obese children don’t perceive their child as being significantly overweight. But let’s assume we have cleared that hurdle of denial. If telling the child she is overweight is the wrong thing to do, then her parents are forced into using strategies that are subliminal, applied slowly and patiently – silently.
These strategies could include gradually decreasing the child’s screen time, hoping that it will be replaced by calorie-burning activities; changing the food available for all the inhabitants of the home to increase the likelihood that healthier choices will dominate; and decreasing serving sizes. It is critical that these changes are done so slowly that they go unnoticed by the child. If the child questions the changes, then the response should be that they are being done to help the entire family to be healthier, and that they are not being targeted at any one individual. Of course, the big problem is getting the rest of the family to buy into the changes so that the overweight child doesn’t become a scapegoat.
Shielding the overweight child from the blame game is much easier if the parents have been careful to avoid labeling from the moment they realized or accepted that the child had a weight problem. Here is where we pediatricians can play a critical role in our choice of words, and the setting in which we discuss the child’s weight with the parents. We must point out to the parents that their words can create a hurt that may not ever go away.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”
“Sticks and stones may break my bones, but words will never hurt me.” This mantra was the retort of choice for thousands of apparently resilient premillennial children. But you and I, and just about everyone else, know that words can be very hurtful. A recent article in the journal Eating and Weight Disorders entitled, “ ‘Don’t eat so much’: How parent comments relate to female weight satisfaction” (Eat Weight Disord. 2016 Jun 6. [Epub ahead of print]) reminds us that the pain can last forever.
In a retrospective study of 501 young women aged 20-35 years, the investigators asked whether the women could recall their parents making any comments about their weight when they were young children. What the authors discovered was that even among young women who were of normal weight, those who could recall their parents making a comment about their weight were more dissatisfied with their body weight than the young women who could not recall such a comment. However, if the comment had been about eating habits and not weight, then there was no significant association with weight dissatisfaction.
Before we rush out to send all of the parents of weight-dissatisfied young women on a guilt trip, let’s remember that this was a retrospective study. Let’s consider the not unlikely explanation that there may be something built into the psyche of weight-dissatisfied young women that sharpens their memory for negative comments from friends and family.
Regardless of how we interpret the findings from this study, it is probably safe to say that telling a young girl that she is overweight doesn’t help and should be avoided. This is just another example of how poorly chosen words can be hurtful. But it is also an example of how words alone are seldom shapers of positive behaviors. You can’t talk a picky eater into eating spinach anymore than you can talk the child in the middle of a tantrum into settling down. Good manners are best learned by modeling the behavior of respected adults and not by being subjected to a series of parental lectures. Telling a child she is overweight won’t solve the problem.
So what is the parent of an obese child to do? Unfortunately, many parents of obese children don’t perceive their child as being significantly overweight. But let’s assume we have cleared that hurdle of denial. If telling the child she is overweight is the wrong thing to do, then her parents are forced into using strategies that are subliminal, applied slowly and patiently – silently.
These strategies could include gradually decreasing the child’s screen time, hoping that it will be replaced by calorie-burning activities; changing the food available for all the inhabitants of the home to increase the likelihood that healthier choices will dominate; and decreasing serving sizes. It is critical that these changes are done so slowly that they go unnoticed by the child. If the child questions the changes, then the response should be that they are being done to help the entire family to be healthier, and that they are not being targeted at any one individual. Of course, the big problem is getting the rest of the family to buy into the changes so that the overweight child doesn’t become a scapegoat.
Shielding the overweight child from the blame game is much easier if the parents have been careful to avoid labeling from the moment they realized or accepted that the child had a weight problem. Here is where we pediatricians can play a critical role in our choice of words, and the setting in which we discuss the child’s weight with the parents. We must point out to the parents that their words can create a hurt that may not ever go away.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”
Malaria vaccine disappoints in phase II trial
The efficacy of an investigational malaria vaccine waned from 36% to 2.5% over a period of 7 years in Kenya, at which time it was even associated with an excess of cases in areas of high malaria transmission.
The overall vaccine efficacy during the entire follow-up period was 4.4%, Ally Olotu, PhD, and colleagues wrote in the June 29 issue of the New England Journal of Medicine (2016;374:2519-29. doi: 10.1056/NEJMoa1515257). But after 7 years, in areas of high malaria risk, the vaccine was associated with 141 excess cases per 1,000 vaccinated children.
“We found that RTS,S/AS01 provided protective efficacy in the first year after vaccination but that the efficacy subsequently waned,” wrote Dr. Olotu of the Kenya Medical Research Institute in Africa and associates. “Efficacy was close to zero in the fourth year and may have been negative in the fifth year. This result eroded the benefits that were seen in early years.”
The rebound in cases probably occurred because the vaccine targets only a particular early-stage form of Plasmodium falciparum, they noted. “[It] protects against malaria sporozoites but does not induce clinical immunity against blood-stage parasites. We and others have previously found lower levels of antibodies against blood-stage parasites in children who have been immunized with the RTS,S/AS01 vaccine than in those given the control vaccine. The reduced exposure to blood-stage parasites among persons who have received the vaccine may lead to a slower acquisition of immunity to blood-stage parasites, leading to an increase in episodes of clinical malaria in later life.”
The phase II study comprised 447 children aged 5-17 months who were randomized to three doses of RTS,S/AS01 or a control rabies vaccine, administered at baseline and at 1 and 2 months. Children were followed for 7 years. The study had a large attrition rate, with 312 children completing all the follow-up visits.
In an intent-to-treat analysis, 150 incident cases of malaria developed among 223 children in the active group, and 157 cases among 224 in the control group. This equated to a vaccine efficacy of 27% against a first episode of malaria.
Overall, there were 1,002 episodes of malaria in the vaccine group and 992 in the control group. When the investigators grouped the children according to the endemic potential of their environment (high- vs. low-risk exposure), they observed that efficacy was consistently better in the low-risk group than the high-risk group (16.6% vs. –2.4%)
They then examined this finding year by year. Vaccine efficacy declined from 36% in year 1 to 3.6% in year 7. At year 5, there was significant negative efficacy in the high-risk exposure cohort (–56.8%, P = .008).
Overall, the vaccine averted 317 cases of clinical malaria per 1,000 children vaccinated, but the investigators noted that this finding was nonsignificant. In the low-exposure cohort, the vaccine did better, averting 718 cases per 1,000 vaccinated children. “However, in the high-exposure cohort … there were more cumulative cases among participants in the RTS,S/AS01 group than among those in the control group … which more than offset the cases that were averted in earlier years,” leading to an excess of 141 cases per 1,000 vaccinated children over baseline levels.
The rate of serious adverse events was similar between the vaccine and control groups (17.9% vs. 25.4%). No cases of meningitis occurred.
The investigators said a larger, phase III trial is being conducted in several areas with varying levels of transmission, and with different dosing schedules. “It will be essential to monitor efficacy in longer-term follow-up for year 5 and beyond to accurately measure the benefit and potential risk of vaccination with the RTS,S/AS01 vaccine,” they wrote.
The study was funded by grants from the PATH Malaria Vaccine Initiative, GlaxoSmithKline Biologicals, the Bill and Melinda Gates Foundation, and the Wellcome Trust. Two of the investigators, Amanda Leach and Marc Lievens, reported receiving personal fees and other support from GlaxoSmithKline Vaccines.
On Twitter @Alz_Gal
The findings of this extended follow-up of a 2008 phase II trial suggest that the RTS,S/AS01 malaria vaccine should be further investigated, but shouldn’t impede studies to prepare for large-scale vaccine deployment by the World Health Organization, according to John Clemens, MD, and Vasee Moorthy, PhD, in an editorial accompanying the study (N Engl J Med. 2016;374:2596-7. doi:10.1056/NEJMe1606007).
The three-dose regimen examined in the study is not the one that WHO agreed upon based on the vaccine’s most recent phase III trial, conducted in 15,500 children. That study looked at a three- and four-dose regimen in two different age groups. While efficacy waned in both groups over the 32-month study period, the four-dose regimen declined more slowly. WHO has thus given its support only to the four-dose regimen in the 5- to 17-month age group, and recommended pilot implementation studies in several sub-Saharan countries with moderate to high levels of malaria transmission.
The new data from the phase II trial cast even more negative light on the complex interplay of this vaccine and the malaria risk in areas in which it is to be deployed. But, the authors said, it should not be cause for abandoning the vaccine protocol.
“The interpretation of these findings requires caution, in view of the high attrition of the original cohort over time and the emergence of these findings in the context of many analyses, with the attendant risk of increased type I error,” the authors of the editorial wrote. “Fortunately, three other sites participating in the phase III trial are extending surveillance beyond the 4th year and include cohorts receiving either a three-dose or four-dose regimen; these sites will provide an important resource to test and better understand the findings of this trial. To maximize the usefulness and ensure the validity of these additional trials, it will be critical that the analyses be done conjointly, with the use of common a priori analytic plans and definitions. In the meantime, it would be unwise to postpone the planning of the WHO-recommended pilot implementation studies, which will be designed to yield data of importance to decisions regarding the deployment of this vaccine.”
Dr. Clemens is professor and vice chairman in the department of epidemiology, as well as the founding director of the center for global infectious diseases at the University of California, Los Angeles. He has received grant support from GlaxoSmithKline. Dr. Moorthy is an infectious disease specialist with the World Health Organization. He had no financial conflicts to disclose.
The findings of this extended follow-up of a 2008 phase II trial suggest that the RTS,S/AS01 malaria vaccine should be further investigated, but shouldn’t impede studies to prepare for large-scale vaccine deployment by the World Health Organization, according to John Clemens, MD, and Vasee Moorthy, PhD, in an editorial accompanying the study (N Engl J Med. 2016;374:2596-7. doi:10.1056/NEJMe1606007).
The three-dose regimen examined in the study is not the one that WHO agreed upon based on the vaccine’s most recent phase III trial, conducted in 15,500 children. That study looked at a three- and four-dose regimen in two different age groups. While efficacy waned in both groups over the 32-month study period, the four-dose regimen declined more slowly. WHO has thus given its support only to the four-dose regimen in the 5- to 17-month age group, and recommended pilot implementation studies in several sub-Saharan countries with moderate to high levels of malaria transmission.
The new data from the phase II trial cast even more negative light on the complex interplay of this vaccine and the malaria risk in areas in which it is to be deployed. But, the authors said, it should not be cause for abandoning the vaccine protocol.
“The interpretation of these findings requires caution, in view of the high attrition of the original cohort over time and the emergence of these findings in the context of many analyses, with the attendant risk of increased type I error,” the authors of the editorial wrote. “Fortunately, three other sites participating in the phase III trial are extending surveillance beyond the 4th year and include cohorts receiving either a three-dose or four-dose regimen; these sites will provide an important resource to test and better understand the findings of this trial. To maximize the usefulness and ensure the validity of these additional trials, it will be critical that the analyses be done conjointly, with the use of common a priori analytic plans and definitions. In the meantime, it would be unwise to postpone the planning of the WHO-recommended pilot implementation studies, which will be designed to yield data of importance to decisions regarding the deployment of this vaccine.”
Dr. Clemens is professor and vice chairman in the department of epidemiology, as well as the founding director of the center for global infectious diseases at the University of California, Los Angeles. He has received grant support from GlaxoSmithKline. Dr. Moorthy is an infectious disease specialist with the World Health Organization. He had no financial conflicts to disclose.
The findings of this extended follow-up of a 2008 phase II trial suggest that the RTS,S/AS01 malaria vaccine should be further investigated, but shouldn’t impede studies to prepare for large-scale vaccine deployment by the World Health Organization, according to John Clemens, MD, and Vasee Moorthy, PhD, in an editorial accompanying the study (N Engl J Med. 2016;374:2596-7. doi:10.1056/NEJMe1606007).
The three-dose regimen examined in the study is not the one that WHO agreed upon based on the vaccine’s most recent phase III trial, conducted in 15,500 children. That study looked at a three- and four-dose regimen in two different age groups. While efficacy waned in both groups over the 32-month study period, the four-dose regimen declined more slowly. WHO has thus given its support only to the four-dose regimen in the 5- to 17-month age group, and recommended pilot implementation studies in several sub-Saharan countries with moderate to high levels of malaria transmission.
The new data from the phase II trial cast even more negative light on the complex interplay of this vaccine and the malaria risk in areas in which it is to be deployed. But, the authors said, it should not be cause for abandoning the vaccine protocol.
“The interpretation of these findings requires caution, in view of the high attrition of the original cohort over time and the emergence of these findings in the context of many analyses, with the attendant risk of increased type I error,” the authors of the editorial wrote. “Fortunately, three other sites participating in the phase III trial are extending surveillance beyond the 4th year and include cohorts receiving either a three-dose or four-dose regimen; these sites will provide an important resource to test and better understand the findings of this trial. To maximize the usefulness and ensure the validity of these additional trials, it will be critical that the analyses be done conjointly, with the use of common a priori analytic plans and definitions. In the meantime, it would be unwise to postpone the planning of the WHO-recommended pilot implementation studies, which will be designed to yield data of importance to decisions regarding the deployment of this vaccine.”
Dr. Clemens is professor and vice chairman in the department of epidemiology, as well as the founding director of the center for global infectious diseases at the University of California, Los Angeles. He has received grant support from GlaxoSmithKline. Dr. Moorthy is an infectious disease specialist with the World Health Organization. He had no financial conflicts to disclose.
The efficacy of an investigational malaria vaccine waned from 36% to 2.5% over a period of 7 years in Kenya, at which time it was even associated with an excess of cases in areas of high malaria transmission.
The overall vaccine efficacy during the entire follow-up period was 4.4%, Ally Olotu, PhD, and colleagues wrote in the June 29 issue of the New England Journal of Medicine (2016;374:2519-29. doi: 10.1056/NEJMoa1515257). But after 7 years, in areas of high malaria risk, the vaccine was associated with 141 excess cases per 1,000 vaccinated children.
“We found that RTS,S/AS01 provided protective efficacy in the first year after vaccination but that the efficacy subsequently waned,” wrote Dr. Olotu of the Kenya Medical Research Institute in Africa and associates. “Efficacy was close to zero in the fourth year and may have been negative in the fifth year. This result eroded the benefits that were seen in early years.”
The rebound in cases probably occurred because the vaccine targets only a particular early-stage form of Plasmodium falciparum, they noted. “[It] protects against malaria sporozoites but does not induce clinical immunity against blood-stage parasites. We and others have previously found lower levels of antibodies against blood-stage parasites in children who have been immunized with the RTS,S/AS01 vaccine than in those given the control vaccine. The reduced exposure to blood-stage parasites among persons who have received the vaccine may lead to a slower acquisition of immunity to blood-stage parasites, leading to an increase in episodes of clinical malaria in later life.”
The phase II study comprised 447 children aged 5-17 months who were randomized to three doses of RTS,S/AS01 or a control rabies vaccine, administered at baseline and at 1 and 2 months. Children were followed for 7 years. The study had a large attrition rate, with 312 children completing all the follow-up visits.
In an intent-to-treat analysis, 150 incident cases of malaria developed among 223 children in the active group, and 157 cases among 224 in the control group. This equated to a vaccine efficacy of 27% against a first episode of malaria.
Overall, there were 1,002 episodes of malaria in the vaccine group and 992 in the control group. When the investigators grouped the children according to the endemic potential of their environment (high- vs. low-risk exposure), they observed that efficacy was consistently better in the low-risk group than the high-risk group (16.6% vs. –2.4%)
They then examined this finding year by year. Vaccine efficacy declined from 36% in year 1 to 3.6% in year 7. At year 5, there was significant negative efficacy in the high-risk exposure cohort (–56.8%, P = .008).
Overall, the vaccine averted 317 cases of clinical malaria per 1,000 children vaccinated, but the investigators noted that this finding was nonsignificant. In the low-exposure cohort, the vaccine did better, averting 718 cases per 1,000 vaccinated children. “However, in the high-exposure cohort … there were more cumulative cases among participants in the RTS,S/AS01 group than among those in the control group … which more than offset the cases that were averted in earlier years,” leading to an excess of 141 cases per 1,000 vaccinated children over baseline levels.
The rate of serious adverse events was similar between the vaccine and control groups (17.9% vs. 25.4%). No cases of meningitis occurred.
The investigators said a larger, phase III trial is being conducted in several areas with varying levels of transmission, and with different dosing schedules. “It will be essential to monitor efficacy in longer-term follow-up for year 5 and beyond to accurately measure the benefit and potential risk of vaccination with the RTS,S/AS01 vaccine,” they wrote.
The study was funded by grants from the PATH Malaria Vaccine Initiative, GlaxoSmithKline Biologicals, the Bill and Melinda Gates Foundation, and the Wellcome Trust. Two of the investigators, Amanda Leach and Marc Lievens, reported receiving personal fees and other support from GlaxoSmithKline Vaccines.
On Twitter @Alz_Gal
The efficacy of an investigational malaria vaccine waned from 36% to 2.5% over a period of 7 years in Kenya, at which time it was even associated with an excess of cases in areas of high malaria transmission.
The overall vaccine efficacy during the entire follow-up period was 4.4%, Ally Olotu, PhD, and colleagues wrote in the June 29 issue of the New England Journal of Medicine (2016;374:2519-29. doi: 10.1056/NEJMoa1515257). But after 7 years, in areas of high malaria risk, the vaccine was associated with 141 excess cases per 1,000 vaccinated children.
“We found that RTS,S/AS01 provided protective efficacy in the first year after vaccination but that the efficacy subsequently waned,” wrote Dr. Olotu of the Kenya Medical Research Institute in Africa and associates. “Efficacy was close to zero in the fourth year and may have been negative in the fifth year. This result eroded the benefits that were seen in early years.”
The rebound in cases probably occurred because the vaccine targets only a particular early-stage form of Plasmodium falciparum, they noted. “[It] protects against malaria sporozoites but does not induce clinical immunity against blood-stage parasites. We and others have previously found lower levels of antibodies against blood-stage parasites in children who have been immunized with the RTS,S/AS01 vaccine than in those given the control vaccine. The reduced exposure to blood-stage parasites among persons who have received the vaccine may lead to a slower acquisition of immunity to blood-stage parasites, leading to an increase in episodes of clinical malaria in later life.”
The phase II study comprised 447 children aged 5-17 months who were randomized to three doses of RTS,S/AS01 or a control rabies vaccine, administered at baseline and at 1 and 2 months. Children were followed for 7 years. The study had a large attrition rate, with 312 children completing all the follow-up visits.
In an intent-to-treat analysis, 150 incident cases of malaria developed among 223 children in the active group, and 157 cases among 224 in the control group. This equated to a vaccine efficacy of 27% against a first episode of malaria.
Overall, there were 1,002 episodes of malaria in the vaccine group and 992 in the control group. When the investigators grouped the children according to the endemic potential of their environment (high- vs. low-risk exposure), they observed that efficacy was consistently better in the low-risk group than the high-risk group (16.6% vs. –2.4%)
They then examined this finding year by year. Vaccine efficacy declined from 36% in year 1 to 3.6% in year 7. At year 5, there was significant negative efficacy in the high-risk exposure cohort (–56.8%, P = .008).
Overall, the vaccine averted 317 cases of clinical malaria per 1,000 children vaccinated, but the investigators noted that this finding was nonsignificant. In the low-exposure cohort, the vaccine did better, averting 718 cases per 1,000 vaccinated children. “However, in the high-exposure cohort … there were more cumulative cases among participants in the RTS,S/AS01 group than among those in the control group … which more than offset the cases that were averted in earlier years,” leading to an excess of 141 cases per 1,000 vaccinated children over baseline levels.
The rate of serious adverse events was similar between the vaccine and control groups (17.9% vs. 25.4%). No cases of meningitis occurred.
The investigators said a larger, phase III trial is being conducted in several areas with varying levels of transmission, and with different dosing schedules. “It will be essential to monitor efficacy in longer-term follow-up for year 5 and beyond to accurately measure the benefit and potential risk of vaccination with the RTS,S/AS01 vaccine,” they wrote.
The study was funded by grants from the PATH Malaria Vaccine Initiative, GlaxoSmithKline Biologicals, the Bill and Melinda Gates Foundation, and the Wellcome Trust. Two of the investigators, Amanda Leach and Marc Lievens, reported receiving personal fees and other support from GlaxoSmithKline Vaccines.
On Twitter @Alz_Gal
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: An investigational malaria vaccine lost efficacy over a 7-year period, and was associated with increased cases in late follow-up.
Major finding: Vaccine efficacy waned from 36% to 2.5% over 7 years, when 141 excess cases per 1,000 children were observed.
Data source: The phase II study randomized 447 children to three doses of the malaria vaccine or a control rabies vaccine.
Disclosures: The study was funded by grants from the PATH Malaria Vaccine Initiative, GlaxoSmithKline Biologicals, the Bill and Melinda Gates Foundation, and the Wellcome Trust. Two of the investigators, Amanda Leach and Marc Lievens, reported receiving personal fees and other support from GlaxoSmithKline Vaccines.