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Antithrombotic therapy for secondary stroke prevention in meningitis
October 2014 Volume 165 Number 4
Respiratory viruses in the NICU? — Sarah S. Long, MD
The natural course of HBV infection — William F. Balistreri, MD
Copyright ª 2014 by Elsevier Inc.
T
he clever and enlightening study by Ronchi et al confirms that respiratory viruses can creep into neonatal intensive care units (NICUs) and probably cause symptoms that make healthcare providers want to “rule out sepsis.” In NICUs in Texas and Rhode Island during 2012, infants were entered prospectively into the study if they had been inborn and never discharged, and had evaluation and empiric antibiotic therapy prescribed for possible late-onset septicemia. A nasopharyngeal specimen was obtained using a flocked nylon swab and tested by multiplex reverse transcriptase polymerase chain reaction assays. Six percent of 135 sepsis evaluations had a respiratory virus detected. In bivariate analysis, older age, exposure to an individual with respiratory tract viral symptoms, and testing for respiratory viruses ordered by healthcare provider (HCP) on clinical grounds were each significantly associated with virus detection. In multivariate regression analysis, the best predictor was testing ordered by the provider (although the test performed in real time in clinical laboratories missed most detections made using the study protocol). Sadly, the source of virus in cases identified likely was symptomatic HCPs. Application of molecular biologic techniques in routine clinical laboratory testing already has proved to be a powerful tool for diagnosis of infectious diseases in hospitalized patients. Undoubtedly, this will apply to the NICU. Clinically skilled interpretation and patient management still will be needed, however, to correctly ascribe any/ all symptoms to the virus detected. Dual bacterial-viral infections are not uncommon. Additionally, we do not know how frequently a respiratory virus might be detected from asymptomatic young infants. The need to pursue “rule out sepsis” and provide empiric antibiotic therapy will not (and should not) disappear. However, the clinically critical tenet—that antibiotic therapy should be discontinued when no bacterial infection is identified—still holds, and is further bolstered by evidence, such as in the study by Ronchi et al, that viruses probably are causative in some instances. Article page 690<
P
erinatal transmission of chronic hepatitis B virus (HBV) leads to “immune tolerance,” in which patients manifest high serum levels of HBV DNA and normal liver enzymes. Some patients will spontaneously clear hepatitis B e antigen (HBeAg) and develop antibody (anti-HBe). In contrast to HBeAg loss, clearance of hepatitis B surface antigen (HBsAg) rarely occurs; the annual rate of HBsAg loss is <1%. Thus, HBeAg seroconversion is no longer the ultimate goal for the management of patients with chronic hepatitis B; the desired outcome is clearance of HBsAg because this is associated with the best outcomes. Chiu et al determined the factors that predict spontaneous clearance of HBsAg in a prospective study of 349 children followed into adult life. They used a new quantitative method for the determination of serum HBsAg titers. This study documented the longitudinal natural decay rates in HBsAg titers and the annual spontaneous HBsAg clearance rate. Overall 12% cleared HBsAg spontaneously. The HBsAg titers declined with age, with an average annual clearance rate of 0.6%. Those with an HBsAg titer #1000 IU/mL at enrollment (during childhood) had a higher rate of HBsAg clearance (HR = 5.23; P < .001). The sensitivity of an HBsAg titer #1000 IU/mL to predict HBsAg clearance was 38%, the specificity was 91%, the positive predictive value was 3%, 647
and the negative predictive value was 91%. The authors conclude that during longterm follow-up, spontaneous HBsAg clearance is most likely to occur in a patient who was an HBeAg seroconverter and had an initial HBsAg level #1000IU/mL. This information will be useful in counseling patients/families and in monitoring the response in antiviral therapeutic trials. Article page 767<
Neurologic complications of varicella-zoster virus infection still occur — Sarah S. Long, MD
Fetal response to maternal smoking — Alan H. Jobe, MD, PhD
Physical activity and quality of life — Stephen R. Daniels, MD, PhD
648
I
nvestigators from the Hospital for Sick Children in Toronto collected a series of 84 children 1-18 years of age with central nervous system (CNS) complications associated with varicella-zoster virus (VZV) infection between 1999 and 2012. Cases occurred after recommendation by Canada’s National Advisory Committee on Immunization for use of VZV vaccine in children 1 year of age and older in 1999, and public funding for universal vaccination in 2004. Only four of 84 patients had a history of VZV immunization. The series serves as an excellent modern compendium of the variety of neurologic syndromes occurring around the time of VZV rash onset (median 5 days, range 6 days before onset to 42 days after onset, and occasionally in absence of rash): cerebellar ataxia, encephalitis, isolated seizures, meningitis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, and Ramsay Hunt syndrome. Additionally, an under-appreciated complication, stroke, occurred in 10 patients at a median 16 weeks (range 2-26 weeks) after rash onset; typical neuroimaging findings were focal ischemia or infarction, with angiographic evidence of characteristic vasculopathy (ie, narrowing or beading in cerebral arteries). Three important reminders from this study, which hopefully would be the last series possible in the era of widespread availability of VZV vaccine, are: (1) neurologic complications of VZV often are severe and continue to occur, not because of ineffective vaccine, but because of its suboptimal uptake; (2) vaccination of the majority of children has lessened circulation of VZV but has not eliminated exposure; and (3) the role of VZV should be considered for many neurologic conditions, especially in unimmunized individuals and even in the absence of a history of rash. Article page 779<
A
lthough it is well known that maternal smoking is associated with decreased fetal weight, there is not much granular information about the effects of maternal smoking on the fetus. In this issue of The Journal, Harrod et al evaluated the timing and the amount of maternal smoking during pregnancy on fetal body composition using the PEA POD system (COSMED, Rome, Italy). They found that infants weighed 2.8 grams less for each pack of cigarettes their mothers smoked during pregnancy—a very provocative dose-response observation. Further, most of the weight difference was a decrease in fat-free body mass. Women who stopped smoking during late pregnancy did not have fetuses that weighed less than those in the no smoking control group. This observation may be effectively used to encourage women who smoke to discontinue before late pregnancy. Overall, the clear message is that smoking effects are dose and time in pregnancy dependent, and less smoking late in pregnancy is better if women cannot stop smoking. Article page 707<
I
t is clear that the development of obesity is associated with diminished quality of life. What is less clear is how to improve quality of life in young individuals with obesity. In this issue of The Journal, Rank et al present the results of an inpatient weight loss program. They showed that body mass index (BMI) improved, as did health-related quality of life. What is most interesting, however, is what occurred during two years of follow-up. BMI remained lower, but only by 0.5 kg/m2. On average, physical activity and sedentary behavior were not different between 24 months compared Vol. 165, No. 4
with baseline. However, the positive changes in health-related quality of life persisted, especially improvement in self-esteem. Long-term improvements in physical activity, not BMI, were most closely associated with improved ongoing quality of life. These results emphasize the benefits and importance of physical activity in weight management programs for adolescents. Article page 732<
Antithrombotic therapy for secondary stroke prevention in meningitis — Sarah S. Long, MD
Visual acuity to detect amblyopia in infants with congenital ptosis — Sarah S. Long, MD
October 2014
n this issue of The Journal, Boelman et al present a 15-year retrospective cohort experience of management and follow-up of 22 patients with stroke complicating bacterial meningitis cared for at the Hospital for Sick Children, Toronto, and the British Columbia Children’s Hospital, Vancouver. Cases of bacterial meningitis with complicating stroke were found through likelyto-be comprehensive methods unique to each site. Cases were excluded if they had fewer than two serial neuroimaging studies during the hospital admission of the acute presentation or if cerebral sinus venous thrombosis was detected prior to the stroke. Management regarding antithrombotic therapy following a stroke was the intervention of note (heparin, aspirin, or neither), and a recurrent stroke was the primary outcome measured. First and recurrent strokes complicating bacterial meningitis all were ischemic events; no one had central nervous system hemorrhage. Six patients were treated with heparin after initial or recurrent infarction; no one had a further stroke episode. Ten patients were treated with aspirin (1.7-5 mg/kg/day); four (40%) patients had infarction(s) while receiving aspirin. Fourteen patients were given neither heparin nor aspirin; eight (57%) had a recurrence of infarction. First stroke occurred in all patients within a day of commencement of antibiotic therapy. Recurrent ischemic injury/ stroke occurred at a median of 2 days after the initial stroke. Poor outcome at a median of 4 years mirrored stroke episodes. Should results of a single retrospective cohort study change practice? One should argue “No.” However, despite the additional noteworthy limitations of small sample size, variation in etiologies of meningitis, and dissimilarities in management choices, the findings are the findings and a prospective study of similar size could only be accomplished by a 20+ year study or multicenter/continental enrollment. Until then, the absence of hemorrhage in those receiving antithrombotic therapy is reassuring. Those physicians who care for critically ill children with bacterial meningitis should read this cohort report and be ready to describe the findings and limitations with families urgently should infarction occur, in an attempt of truly shared decision making. Article page 799<
I
U
sing retrospective longitudinal data collected on 84 young children with moderate or severe congenital ptosis evaluated at Seattle Children’s Hospital, investigators sought to determine the incidence and age at onset of amblyopia, association with underlying systemic disorders, determinants of visual outcomes, and effectiveness of occlusion therapy for amblyopia. Strengths of the study were the size of cohort, longitudinal evaluations, and objective measurements of degree of ptosis and visual acuity. The incidence of amblyopia was 18% in children with moderate to severe congenital ptosis. Pediatricians take note that visual acuity is a better measure of amblyopia than is measurement or estimation of lid margin-to-pupillary distance (ie, degree of droop). In this study, 73% children with amblyopia were treated successfully with occlusion therapy. Children with underlying conditions were more likely to have bilateral ptosis and poorer visual outcomes. Article page 820<
649
Respiratory viruses in the NICU? — Sarah S. Long, MD
The natural course of HBV infection — William F. Balistreri, MD
Copyright ª 2014 by Elsevier Inc.
T
he clever and enlightening study by Ronchi et al confirms that respiratory viruses can creep into neonatal intensive care units (NICUs) and probably cause symptoms that make healthcare providers want to “rule out sepsis.” In NICUs in Texas and Rhode Island during 2012, infants were entered prospectively into the study if they had been inborn and never discharged, and had evaluation and empiric antibiotic therapy prescribed for possible late-onset septicemia. A nasopharyngeal specimen was obtained using a flocked nylon swab and tested by multiplex reverse transcriptase polymerase chain reaction assays. Six percent of 135 sepsis evaluations had a respiratory virus detected. In bivariate analysis, older age, exposure to an individual with respiratory tract viral symptoms, and testing for respiratory viruses ordered by healthcare provider (HCP) on clinical grounds were each significantly associated with virus detection. In multivariate regression analysis, the best predictor was testing ordered by the provider (although the test performed in real time in clinical laboratories missed most detections made using the study protocol). Sadly, the source of virus in cases identified likely was symptomatic HCPs. Application of molecular biologic techniques in routine clinical laboratory testing already has proved to be a powerful tool for diagnosis of infectious diseases in hospitalized patients. Undoubtedly, this will apply to the NICU. Clinically skilled interpretation and patient management still will be needed, however, to correctly ascribe any/ all symptoms to the virus detected. Dual bacterial-viral infections are not uncommon. Additionally, we do not know how frequently a respiratory virus might be detected from asymptomatic young infants. The need to pursue “rule out sepsis” and provide empiric antibiotic therapy will not (and should not) disappear. However, the clinically critical tenet—that antibiotic therapy should be discontinued when no bacterial infection is identified—still holds, and is further bolstered by evidence, such as in the study by Ronchi et al, that viruses probably are causative in some instances. Article page 690<
P
erinatal transmission of chronic hepatitis B virus (HBV) leads to “immune tolerance,” in which patients manifest high serum levels of HBV DNA and normal liver enzymes. Some patients will spontaneously clear hepatitis B e antigen (HBeAg) and develop antibody (anti-HBe). In contrast to HBeAg loss, clearance of hepatitis B surface antigen (HBsAg) rarely occurs; the annual rate of HBsAg loss is <1%. Thus, HBeAg seroconversion is no longer the ultimate goal for the management of patients with chronic hepatitis B; the desired outcome is clearance of HBsAg because this is associated with the best outcomes. Chiu et al determined the factors that predict spontaneous clearance of HBsAg in a prospective study of 349 children followed into adult life. They used a new quantitative method for the determination of serum HBsAg titers. This study documented the longitudinal natural decay rates in HBsAg titers and the annual spontaneous HBsAg clearance rate. Overall 12% cleared HBsAg spontaneously. The HBsAg titers declined with age, with an average annual clearance rate of 0.6%. Those with an HBsAg titer #1000 IU/mL at enrollment (during childhood) had a higher rate of HBsAg clearance (HR = 5.23; P < .001). The sensitivity of an HBsAg titer #1000 IU/mL to predict HBsAg clearance was 38%, the specificity was 91%, the positive predictive value was 3%, 647
and the negative predictive value was 91%. The authors conclude that during longterm follow-up, spontaneous HBsAg clearance is most likely to occur in a patient who was an HBeAg seroconverter and had an initial HBsAg level #1000IU/mL. This information will be useful in counseling patients/families and in monitoring the response in antiviral therapeutic trials. Article page 767<
Neurologic complications of varicella-zoster virus infection still occur — Sarah S. Long, MD
Fetal response to maternal smoking — Alan H. Jobe, MD, PhD
Physical activity and quality of life — Stephen R. Daniels, MD, PhD
648
I
nvestigators from the Hospital for Sick Children in Toronto collected a series of 84 children 1-18 years of age with central nervous system (CNS) complications associated with varicella-zoster virus (VZV) infection between 1999 and 2012. Cases occurred after recommendation by Canada’s National Advisory Committee on Immunization for use of VZV vaccine in children 1 year of age and older in 1999, and public funding for universal vaccination in 2004. Only four of 84 patients had a history of VZV immunization. The series serves as an excellent modern compendium of the variety of neurologic syndromes occurring around the time of VZV rash onset (median 5 days, range 6 days before onset to 42 days after onset, and occasionally in absence of rash): cerebellar ataxia, encephalitis, isolated seizures, meningitis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, and Ramsay Hunt syndrome. Additionally, an under-appreciated complication, stroke, occurred in 10 patients at a median 16 weeks (range 2-26 weeks) after rash onset; typical neuroimaging findings were focal ischemia or infarction, with angiographic evidence of characteristic vasculopathy (ie, narrowing or beading in cerebral arteries). Three important reminders from this study, which hopefully would be the last series possible in the era of widespread availability of VZV vaccine, are: (1) neurologic complications of VZV often are severe and continue to occur, not because of ineffective vaccine, but because of its suboptimal uptake; (2) vaccination of the majority of children has lessened circulation of VZV but has not eliminated exposure; and (3) the role of VZV should be considered for many neurologic conditions, especially in unimmunized individuals and even in the absence of a history of rash. Article page 779<
A
lthough it is well known that maternal smoking is associated with decreased fetal weight, there is not much granular information about the effects of maternal smoking on the fetus. In this issue of The Journal, Harrod et al evaluated the timing and the amount of maternal smoking during pregnancy on fetal body composition using the PEA POD system (COSMED, Rome, Italy). They found that infants weighed 2.8 grams less for each pack of cigarettes their mothers smoked during pregnancy—a very provocative dose-response observation. Further, most of the weight difference was a decrease in fat-free body mass. Women who stopped smoking during late pregnancy did not have fetuses that weighed less than those in the no smoking control group. This observation may be effectively used to encourage women who smoke to discontinue before late pregnancy. Overall, the clear message is that smoking effects are dose and time in pregnancy dependent, and less smoking late in pregnancy is better if women cannot stop smoking. Article page 707<
I
t is clear that the development of obesity is associated with diminished quality of life. What is less clear is how to improve quality of life in young individuals with obesity. In this issue of The Journal, Rank et al present the results of an inpatient weight loss program. They showed that body mass index (BMI) improved, as did health-related quality of life. What is most interesting, however, is what occurred during two years of follow-up. BMI remained lower, but only by 0.5 kg/m2. On average, physical activity and sedentary behavior were not different between 24 months compared Vol. 165, No. 4
with baseline. However, the positive changes in health-related quality of life persisted, especially improvement in self-esteem. Long-term improvements in physical activity, not BMI, were most closely associated with improved ongoing quality of life. These results emphasize the benefits and importance of physical activity in weight management programs for adolescents. Article page 732<
Antithrombotic therapy for secondary stroke prevention in meningitis — Sarah S. Long, MD
Visual acuity to detect amblyopia in infants with congenital ptosis — Sarah S. Long, MD
October 2014
n this issue of The Journal, Boelman et al present a 15-year retrospective cohort experience of management and follow-up of 22 patients with stroke complicating bacterial meningitis cared for at the Hospital for Sick Children, Toronto, and the British Columbia Children’s Hospital, Vancouver. Cases of bacterial meningitis with complicating stroke were found through likelyto-be comprehensive methods unique to each site. Cases were excluded if they had fewer than two serial neuroimaging studies during the hospital admission of the acute presentation or if cerebral sinus venous thrombosis was detected prior to the stroke. Management regarding antithrombotic therapy following a stroke was the intervention of note (heparin, aspirin, or neither), and a recurrent stroke was the primary outcome measured. First and recurrent strokes complicating bacterial meningitis all were ischemic events; no one had central nervous system hemorrhage. Six patients were treated with heparin after initial or recurrent infarction; no one had a further stroke episode. Ten patients were treated with aspirin (1.7-5 mg/kg/day); four (40%) patients had infarction(s) while receiving aspirin. Fourteen patients were given neither heparin nor aspirin; eight (57%) had a recurrence of infarction. First stroke occurred in all patients within a day of commencement of antibiotic therapy. Recurrent ischemic injury/ stroke occurred at a median of 2 days after the initial stroke. Poor outcome at a median of 4 years mirrored stroke episodes. Should results of a single retrospective cohort study change practice? One should argue “No.” However, despite the additional noteworthy limitations of small sample size, variation in etiologies of meningitis, and dissimilarities in management choices, the findings are the findings and a prospective study of similar size could only be accomplished by a 20+ year study or multicenter/continental enrollment. Until then, the absence of hemorrhage in those receiving antithrombotic therapy is reassuring. Those physicians who care for critically ill children with bacterial meningitis should read this cohort report and be ready to describe the findings and limitations with families urgently should infarction occur, in an attempt of truly shared decision making. Article page 799<
I
U
sing retrospective longitudinal data collected on 84 young children with moderate or severe congenital ptosis evaluated at Seattle Children’s Hospital, investigators sought to determine the incidence and age at onset of amblyopia, association with underlying systemic disorders, determinants of visual outcomes, and effectiveness of occlusion therapy for amblyopia. Strengths of the study were the size of cohort, longitudinal evaluations, and objective measurements of degree of ptosis and visual acuity. The incidence of amblyopia was 18% in children with moderate to severe congenital ptosis. Pediatricians take note that visual acuity is a better measure of amblyopia than is measurement or estimation of lid margin-to-pupillary distance (ie, degree of droop). In this study, 73% children with amblyopia were treated successfully with occlusion therapy. Children with underlying conditions were more likely to have bilateral ptosis and poorer visual outcomes. Article page 820<
649