Friday, March 26, 2010

Technical Report: Treatment of the Child With Simple Febrile Seizures

PEDIATRICS Vol. 103 No. 6 June 1999, p. e86


Robert J. Baumann

Overview. Simple febrile seizures that occur in children ages 6 months to 5 years are common events with few adverse outcomes. Those who advocate therapy for this disorder have been concerned that such seizures lead to additional febrile seizures, to epilepsy, and perhaps even to brain injury. Moreover, they note the potential for such seizures to cause parental anxiety. We examined the literature to determine whether there was demonstrable benefit to the treatment of simple febrile seizures and whether such benefits exceeded the potential side effects and risks of therapy. The therapeutic approaches considered included continuous anticonvulsant therapies, intermittent therapy, or no anticonvulsant therapy.

Methods. This analysis focused on the neurologically healthy child between 6 months and 5 years of age whose seizure is brief (<15 minutes), generalized, and occurs only once during a 24-hour period during a fever.
Children whose seizures are attributable to a central nervous system infection and those who have had a previous afebrile seizure or central nervous system abnormality were excluded. A review of the current literature was conducted using articles obtained through searches in MEDLINE and additional databases. Articles were obtained following defined criteria and data abstracted using a standardized literature review form. Abstracted data were summarized into evidence tables (Tables 1 through 7).

Results. Epidemiologic studies demonstrate a high risk of recurrent febrile seizures but a low, though increased, risk of epilepsy. Other adverse outcomes either don't occur or occur so infrequently that their presence is not convincingly demonstrated by the available studies.
Although daily anticonvulsant therapy with phenobarbital or valproic acid is effective in decreasing recurrent febrile seizures, the risks and potential side effects of these medications outweigh this benefit.
No medication has been shown to prevent the future onset of recurrent afebrile seizures (epilepsy).
The use of intermittent diazepam with fever after an initial febrile seizure is likely to decrease the risk of another febrile seizure, but the rate of side effects is high although most families find the perceived benefits to be low.
Although antipyretic therapy has other benefits, it does not prevent additional simple febrile seizures.

Conclusions. The Febrile Seizures Subcommittee of the American Academy of Pediatrics' Committee on Quality Improvement used the results of this analysis to derive evidence-based recommendations for the treatment of simple febrile seizures. The outcomes anticipated as a result of the analysis and development of the practice guideline include: 1) to optimize practitioner understanding of the scientific basis for using or avoiding various proposed treatments for children with simple febrile seizures; 2) to improve the health of children with simple febrile seizures by avoiding therapies with high potential for side effects and no demonstrated ability to improve children's eventual outcomes; 3) to reduce costs by avoiding therapies that will not demonstrably improve children's long-term outcomes; and 4) to help the practitioner educate caregivers about the low risks associated with simple febrile seizures.

Key words: febrile seizures, epilepsy, valproic acid, carbamazepine, phenytoin, diazepam, phenobarbital, sodium valproate, pyridoxine.

Tuesday, March 23, 2010

Eczema Drugs May Need Wider Caution in Kids: FDA

From Reuters Health Information

(Reuters) Mar 18 - Drugs for eczema made by Novartis AG and Astellas Pharma may need their warning labels expanded after dozens of new reported cases of cancer and infection in children, U.S. Food and Drug Administration staff said in documents released on Thursday.

Agency scientists said 46 cancer cases and 71 infection cases have been reported in patients aged 16 and younger from 2004 to 2008 with Novartis' Elidel and Astellas' Protopic.

Both drugs -- also known as pimecrolimus and tacrolimus respectively -- already carry strong warnings about cancer and infection, but officials should consider expanding them to include the new post-marketing reports, they wrote.

The documents were released ahead of an FDA advisory meeting Monday to weigh potential safety concerns with a variety of drugs used in younger patients.

Additionally, other FDA staffers said the warning label for GlaxoSmithKline Plc's herpes drug Valtrex was "insufficient" for certain central nervous system side effects in children, although no other concerns were seen.

Another scientist noted concerns about the use of Pfizer Inc's antibiotic Zmax in pregnant women and the potential for it to cause stomach blockages in newborns.

The FDA will weigh the recommendations from its panel of outside advisers before taking any action.

FDA Temporarily Suspends Use of Rotarix Vaccine

From Medscape Medical News > Alerts, Approvals and Safety Changes > Medscape Alerts

Allison Gandey

Posted: 03/22/2010

March 22, 2010 — The US Food and Drug Administration (FDA) announced today viral contamination of GlaxoSmithKline's Rotarix vaccine.
The agency is recommending that doctors stop using the vaccine until further investigations are complete.

An independent academic research team testing the product recently identified porcine circovirus 1 in the vaccine and notified regulators.

Follow-up tests by GlaxoSmithKline and FDA scientists reportedly confirmed the academic team's findings and suggested that viral components have been present since the early stages of the vaccine's development, including during clinical studies.

FDA commissioner Margaret Hamburg, MD, emphasized to reporters attending a press conference that the virus is not known to cause illness in humans or animals. She also noted that the viral contamination is not the result of animal or other food safety issues.

"We do not believe there is a clinical risk," Dr. Hamburg told Medscape Medical News. "However, as with all vaccines, we recommend that clinicians watch for any serious adverse events and report them."

Porcine Circovirus 1

The Rotarix vaccine is administered by mouth to young infants to prevent rotavirus, which can cause severe diarrhea and dehydration. Dr. Hamburg noted that the vaccine, which has been on the market in the United States since 2008, has an excellent safety record to date.

An estimated 1 million children have already received Rotarix in the United States alone.

Preliminary testing of another rotavirus vaccine by both academic researchers and FDA scientists has not detected any viral contamination. Regulators are recommending that clinicians continue using Merck's RotaTeq, which has been available in the United States since 2006. Most children vaccinated in the United States already receive RotaTeq.

Regulators report they will continue to gather more information about the porcine circovirus found in the vaccine. Scientists are studying whether intact virus is present, as opposed to DNA fragments.

In about 5 weeks, the FDA will convene an expert advisory committee and will make additional recommendations on the use of rotavirus vaccines.

Friday, March 19, 2010

The Risks of Not Breastfeeding

From JAIDS: Journal of Acquired Immune Deficiency Syndromes
Jean H. Humphrey, ScD


In developing countries, breast-feeding is both the cornerstone of child survival and the cause of about one-third of all infant HIV infections.
Moreover, the same economic and development inequities that make breast-feeding so critical to infant survival in these settings also make formula feeding inAccessible, unFeasible, unAffordable, unSustainable, and unSafe (ie, not AFASS) for most families.
This poignant dilemma has resulted in emotive and sometimes polarizing debate within the public health community as we have wrestled to quantify these competing risks, test interventions to reduce them, and modify policy as our understanding improves.

Four articles in this issue of the Journal of Acquired Immune Deficiency Syndromes shed new light on this issue. To appreciate their design and findings, it is helpful to contextualize them within the rapidly evolving science and policy of HIV and infant feeding.

2006 HIV and Infant Feeding Policy

In October 2006, when HIV and infant feeding policy was again revised; new evidence included an additional evidence that early exclusive breast-feeding is protective against postnatal transmission compared with mixed feeding, findings from 2 randomized trials in which infection-free survival was comparable between infants randomized to formula or breast-feeding from birth and between infants randomized at 4 months of age to continued breast-feeding or abrupt breast-feeding cessation ; and preliminary findings from the 4 studies published in this issue of the Journal of Acquired Immune Deficiency Syndromes.

Reflecting these new data, the 2000 policy which had stated, "When replacement feeding is AFASS, avoidance of all breastfeeding by HIV-infected mothers is recommended…

Otherwise, exclusive breastfeeding is recommended during the first months of life," was rewritten to read "Exclusive breastfeeding is recommended for HIV-infected women for the first six months of life unless replacement feeding is AFASS for them…. When replacement feeding is AFASS, avoidance of all breastfeeding by HIV-infected women is recommended."

The 2006 guidance also specified that breast-feeding should continue beyond 6 months if a replacement feeding is still not AFASS.

Thus, even though replacement feeding remains the best option for HIV-infected women in situations with plentiful nutritious foods and breastmilk substitutes, good sanitation, clean water, cooking fuel, accessible quality health care delivered by a well-functioning health care system, high levels of female education, low rates of underlying infant mortality, and broad social support; and even though there are examples of successful replacement feeding in Africa,[34–36] this subtle shift (in nuance more than substance) in the recommendations reflected the participants' sentiments that:

For the large majority of HIV-exposed infants, exclusive breast-feeding for the first 6 months of life, and continued breast-feeding after that for some yet undetermined duration, will provide the greatest chance of infection-free survival.

Ironically, the HIV epidemic may be the best thing that ever happened to breast-feeding.
It is difficult to imagine an experiment that could provide more compelling momentum for breast-feeding promotion than the natural one the HIV epidemic has provided: an incurable disease that infects up to 30%-40% of antenatal women in some African countries and is transmitted to infants through breast-feeding leads UN agencies and governments to promote and even freely provide formula for exposed infants. Moreover, scores of these infants are already under surveillance by scientists measuring and documenting numerous indices of infant health. In short, the HIV epidemic and our efforts to ameliorate its effect on children provided an ethical opportunity to observe what happens when large number of infants living in conditions of poverty are not breast-fed.

If these observations lead to stronger breast-feeding policy and programming that in turn reduce the 1.4 million child deaths occurring each year due to suboptimal breast-feeding,[37] we will have created one of the epidemic's very few silver linings.

Candidate TB Booster Vaccine Shows Promise in Phase 1 Study

From Medscape Medical News

Megan Brooks

March 18, 2010 — In a phase 1 study, a booster vaccine against Mycobacterium tuberculosis had an acceptable safety profile and was immunogenic in healthy M tuberculosis–uninfected adults from South Africa who had been previously vaccinated with the only currently available tuberculosis (TB) vaccine, Bacille Calmette Guerin (BCG).

The vaccine, AERAS-402, developed by Aeras Global Tuberculosis Foundation and by Dutch biotechnology firm Crucell NV, induced a robust polyfunctional CD4 T cell response as well as a potent and durable CD8 T cell response, which appears "extremely promising," the study team reports in an article published online March 18 in the American Journal of Respiratory and Critical Care Medicine.

AERAS-402 is made up of a recombinant, replication-deficient adenovirus, serotype 35 (Ad35), expressing a fusion protein created from the mycobacterial antigens Ag85A, Ag85B, and TB10.4.

"This is the first clinical report of an Ad35 vectored vaccine given to humans in a heterologous prime-boost strategy," first author Brian Abel, PhD, from the University of Cape Town, South Africa, and colleagues note in their report. Ad35 is an attractive vector, they point out, because worldwide, the seroprevalence and levels of neutralizing antibody titers to this adenovirus are lower relative to other adenoviruses.

In the phase 1 safety and immunogenicity study conducted in South Africa, escalating doses of AERAS-402 were given intramuscularly to 3 groups of healthy, BCG-vaccinated adults not infected with M tuberculosis. A fourth group received 2 shots of the highest dose of the vaccine. Altogether, 29 participants received the AERAS-402 vaccine, and 11 received placebo. All were between 21 and 39 years old.

There were no serious vaccine-related adverse events, and increasing the vaccine dose did not result in an increase in adverse events, the investigators report. The majority of adverse events were mild (74%) or moderate (19%) in severity, of short duration, and resolved without sequelae.

AERAS-402 induced strong CD4 T cell responses dominated by polyfunctional cells coexpressing gamma interferon, alpha tumor necrosis factor, and interleukin 2, which are thought to be important for protection against intracellular pathogens such as M tuberculosis.

However, what was "most striking," the investigators say, was that the vaccine induced a potent CD8 T cell response, characterized by cells expressing gamma interferon and/or alpha tumor necrosis factor, which persisted throughout the study period.

"To date, most new TB vaccines have been reported to induce reasonable CD4 T cell responses, but relatively negligible CD8 T cell responses," Dr. Abel and colleagues note. Evidence is mounting, they add, that CD8 T cells mediate key roles in protective immunity against TB, leading them to hypothesize that the induction of robust vaccine-specific CD4 and CD8 T cell responses after AERAS-402 "would correlate with a more efficacious outcome."

The findings from this phase 1 study support further clinical trials assessing the efficacy of AERAS-402 as a TB booster vaccine, the investigators conclude.

The study was supported by the Aeras Global Tuberculosis Vaccine Foundation and by Crucell NV. The authors have disclosed no relevant financial relationships.

Am J Respir Crit Care Med. Published online March 18, 2010

WHO, UNICEF Suspend Use of Shantha Bio's Vaccine: Report

From Reuters Health Information > Alerts, Approvals and Safety Changes > Alerts
Posted: 03/18/2010

(Reuters) Mar 17 - The World Health Organization (WHO) and UNICEF have suspended the use and purchase of the Shan5 vaccine from Sanofi Aventis owned Shantha Biotechnics pending a quality investigation.

The combination vaccine is given to prevent diphtheria, pertussis, tetanus, haemophilus influenza B, and hepatitis B.

"Countries are advised to put any remaining vaccine in quarantine until further notice," the joint WHO-UNICEF statement said.

The investigation was launched after reports "of a white sediment which sticks to the glass of the vaccine vial that is difficult or impossible to re-suspend with vigorous shaking (flocculation)," the statement says.

WHO has received no reports of adverse reactions so far in those who have been given the vaccine.

An Economic Times report said the pending investigation threatens a three-year contract worth $350 million.

An official of Shantha Biotechnics could not be reached immediately for a comment by Reuters.

(Reporting by Kaustubh Kulkarni)

Extreme Obesity is Prevalent in Children and Adolescents

From Medscape Medical News
Nancy Fowler Larson

March 18, 2010 — More than 7% of American boys and 5% of American girls are extremely obese, according to a study published online March 18 in the Journal of Pediatrics.

"The American Medical Association and the Centers for Disease Control and Prevention...recommendations on prevention, assessment, and treatment of childhood obesity are based on relatively limited knowledge about extreme childhood obesity at the population level," write Corinna Koebnick, PhD, research scientist, Kaiser Permanente Southern California's Department of Research and Evaluation, Pasadena, and colleagues. "Newer data on recent trends are not available. The present economic burden and health consequences are largely unknown and ill defined."

Reliable figures do exist for nationwide childhood obesity, which affects 17.1% of boys and 15.5% of girls. To determine the scope of extreme obesity in a multicultural, racially diverse population, the research team conducted a cross-sectional study in of 710,949 children aged 2 through 19 years. Approximately half were Hispanic. All were enrolled between 2007 and 2008 in a managed healthcare system that recorded information about height and weight, using electronic health records.

The researchers employed Centers for Disease Control and Prevention definitions for obesity and overweight, which include:

Extreme obesity: weight more than 1.2 times the 95th percentile, or body mass index BMI) greater than or equal to 35 kg/m2
Obesity: weight higher than the 95th percentile, or BMI of 30 kg/m2 or more
Overweight: weight above the 85th percentile, or BMI of 25 kg/m2 or more

Among other findings, the study authors discovered that more boys are extremely obese than girls, and that the condition varies between sexes and among ethnic groups, as follows:

7.3% of boys and 5.5% of girls were extremely obese
Extreme obesity peaked at 10 years of age in boys and at age 12 years in girls, who also demonstrated a second peak at ages 18 years (P value for sex × age interaction = .036); rates of extreme obesity are similar for boys and girls after age 18 years
Hispanic boys (as many as 11.2%) and black girls (up to 11.9%) were the heaviest of all children

The percentage of extreme obesity was lowest in Asian-Pacific Islanders (2.2%) and non-Hispanic white children (3.3)

Extremely obese children are at risk for conditions including heart disease, type 2 diabetes, fatty liver disease, and joint problems decades before those of normal weight
"Children who are extremely obese may continue to be extremely obese as adults, and all the health problems associated with obesity are in these children's futures," Dr. Koebnick said in a press release.
"Without major lifestyle changes, these kids face a 10 to 20 years shorter life span and will develop health problems in their twenties that we typically see in 40-60 year olds."

Subsequent studies will explore the future implications of extreme obesity and its treatment.

J Pediatr. Published online March 18, 2010.

Wednesday, March 17, 2010

The Risks for Varicella Vaccine Refusal

From Medscape Pediatrics > Viewpoints
William T. Basco, Jr., MD

Arch Pediatr Adolesc Med. 2010;164:66-70

Study Summary
The investigators noted that parental refusal of vaccination is an increasing problem, owing to a combination of concern over vaccine safety combined with a belief that children are at low risk for infection because of fewer vaccine-related illnesses in the United States. Varicella, perceived as a less serious illness by parents compared with other vaccine-preventable diseases, appears to be the most commonly refused vaccine.

This study used Kaiser Permanente data from Colorado over a 10-year period to determine the risk for varicella in nonimmunized children who were 1-12 years old. The investigators searched clinical databases for patients with a diagnosis of varicella or any tests ordered to diagnose varicella. After identifying potential cases, the research team reviewed the individual records to determine symptoms; physical findings; laboratory evaluation results; and other clinical outcomes, including complications from varicella, such as impetigo or cellulitis. The chart review included searching for contacts from whom the child may have contracted varicella. Children were considered "cases" if they were diagnosed with varicella by a physician. After identifying cases, the investigators matched them to 4 controls each on the basis of age, sex, and length of enrollment in the health plan.

After matching cases and controls, a different abstractor reviewed vaccination status, noting whether children had received the varicella vaccine at least 14 days before their varicella infection. Only children who were unvaccinated and who had vaccine refusal documented in their charts were considered vaccine refusers. Children who were unvaccinated, but for whom the reason for nonvaccination could not be determined, were excluded. Among 86,000 children screened for inclusion, the investigators identified 133 who had varicella and complete data. These patients were matched to 493 controls.

Among all cases and controls, only 10 children were vaccine refusers, and 7 of them contracted varicella, for a varicella infection frequency of 70% among vaccine refusers. Vaccine refusers were overrepresented in the cases, comprising 5.3% of cases compared with only 0.6% of controls.
Refusal of vaccine greatly increased the odds that a child would contract varicella (odds ratio 8.6, 95% confidence interval 2.2-33.3). By calculating the attributable risk, the investigators determined that all 7 of the varicella infections among vaccine refusers were related to vaccine refusal.
For the total population, the investigators estimated that 4.7% of all varicella cases were a consequence of vaccine refusal. Just under 5% (4.5%) of the cases of varicella experienced bacterial infection, with 1.5% developing cellulitis.

The study authors concluded that children whose parents refuse varicella vaccination are at high risk of contracting varicella.

The study authors pointed out that the greatest advantage of this study is perhaps the data that it provides for discussions between families and providers about vaccine concerns. Given all of the media coverage of vaccine concerns, these discussions likely are happening more frequently now than at any time in the recent past.
The economic argument around universal vaccination for varicella hinged mainly on the savings from less parental missed work, and that may be a more difficult argument to make with some parents.
However, mild morbidities from varicella infection are common; furthermore, refusal of varicella opens up a slippery slope that may encourage parents to consider skipping other vaccines. Reassurance by a trusted healthcare provider, with data to back up these discussions, is perhaps the best way to encourage parents not to let slip our substantial progress in preventing infectious diseases.

Thursday, March 11, 2010

"Solid" Evidence That Nut Allergy Is Becoming More Common in Children

From Reuters Health Information

NEW YORK (Reuters Health) Mar 02 - The prevalence of peanut and tree nut allergy is increasing in US children, according to data reported this week at the annual meeting of the American Academy of Allergy, Asthma and Immunology in New Orleans.

Dr. Hugh A. Sampson of Mount Sinai School of Medicine in New York and colleagues determined the prevalence of peanut, tree nut and sesame allergy in 2008 and compared the results (for peanut and tree nuts) to similar surveys conducted in 1997 and 2002.

The same methodology was used in all three time periods -- a nationwide, cross-sectional random-digit telephone survey. A total of 5,300 households (13,534 individuals) were surveyed.

The investigators report that the prevalence of peanut and/or tree nut allergy in children younger than age 18 years was 2.1% in 2008, up from 1.2% in 2002 and 0.6% in 1997.

The prevalence of peanut allergy in children rose from 0.4% in 1997 to 0.8% in 2002 and 1.4% in 2008. There was a similar increase in the prevalence of tree nut allergy -- from 0.2% in 1997 to 0.5% in 2002, and 1.1% in 2008.

The change in peanut and tree nut allergy prevalence in US children seen from 1997 to 2002 "is the most solid data that we have that nut allergy really did go up in that five-year period," Dr. Robert A. Wood, of Johns Hopkins University School of Medicine in Baltimore, Maryland, who was not involved in the study, said at a gathering of reporters Monday.

He acknowledged that random-digit dialing surveys "may overestimate prevalence because some people may think they have an allergy when they don't, but because the methodology was the same, we can be pretty confident that the increase that was seen in an 11-year period from 0.4 to 1.4 (in children) has to be real. It's hard to imagine that it is not."

In 2008, sesame allergy was reported by 0.1% of those surveyed. Sesame allergy was not asked about in the two earlier surveys.

Dr. Wood said there are "at least a dozen" theories as to why nut allergies are increasing in children.

The hygiene theory -- which postulates that reduced microbial exposure because of improved sanitation and cleaner lifestyles leaves a young child's immune system unchallenged and therefore at greater risk for allergies -- is perhaps the "most intriguing" one, he noted, "and probably makes sense when you look at an underdeveloped country versus a developed country."

Rates of allergy are much higher in developed countries, and if a country becomes more developed its inhabitants seem to develop more allergies, he said. "But when you look at certain populations, there are huge holes in the hygiene theory that can't explain everything. For example, in developed countries, we see lots of allergies in urban, inner city populations where exposures are high," Dr. Wood pointed out.

Two other theories revolve around nutritional issues. One involves vitamin D and charges that a higher rate of vitamin D deficiency has predisposed people to allergy. "The way that might make sense is we do believe that there is much more vitamin D deficiency over the last 10 to 20 years," Dr. Wood said, and in epidemiological studies there is an association between vitamin D deficiency and higher rates of allergy. Whether there is a cause-and-effect link is still being determined.

Another nutritional theory says that having too much folate can predispose to allergy. This, too, has been shown in a couple of epidemiological studies, Dr. Wood explained, and the theory makes some sense from a timing standpoint, given that in the 1980s, there was an influx of folate into the diet of pregnant women via folate supplementation at the time that allergies seemed to be rising.

These are just a few of the theories, and there are many others, Dr. Wood noted, adding: "I think it's clear that none of them explain the whole thing, even remotely."

Eczema, Peanut Allergy May Be Linked

From WebMD Health News
Charlene Laino

March 3, 2010 (New Orleans) — Infants with eczema are at high risk of having peanut and other food allergies, British researchers report.

"We were shocked to find out that even in the first year of life, over 20% of infants with eczema already were sensitized [showed susceptibility] to peanut allergy," says Graham Roberts, MD, a pediatric allergist at King's College London.

Roberts tells WebMD that by the time they enter school, children with eczema have a high rate of peanut allergies.

"But we didn't know how early the peanut allergy started; we thought may at 3, 4, or 5 years of age," he says.

The new research suggests peanut allergy develop much earlier, Roberts says.

The study involved 640 infants aged 4-11 months with eczema.

The researchers measured blood levels of immunoglobulin E (IgE), an immune system protein the body makes in response to allergens.
A positive result means a person is sensitive to and likely to be allergic to a certain food.

The results showed:

23% of the infants were sensitive to peanuts.
31% were sensitive to cow's milk.
22% were sensitive to sesame.
16% were sensitive to Brazil nuts.
20% were sensitive to hazel nuts.
21% were sensitive to cashews.
14% were sensitive to almonds.
Sixteen percent of the infants tested positive for more than four foods.

The findings were presented here at the annual meeting of the American Academy of Allergy, Asthma & Immunology.

New Food Allergy Theory Being Tested

Roberts says this is the first step in an ongoing study designed to test the hypothesis that giving infants foods to which they are sensitized will prevent allergies later in life.

"Right now, people are told to avoid the food they're allergic to.
Our hypothesis is that by introducing the food into the diet early on, the body will see it as normal and won't become allergic to it.
We're questioning a fundamental preconception," he says.

In the ongoing study, infants with eczema who test positive for sensitivity to peanuts are being divided into two groups; half get peanuts in their diets and half don't. The researchers will compare the rates of peanut allergies in the two groups when the kids reach school age.

Results are expected in three years, Roberts says.

The hypothesis is supported by the fact that Jewish children in London are about 10 times more likely to have peanut allergies than Israeli children "and one of the biggest differences is that kids in Israel are introduced to [peanuts] early in life," says Hugh Sampson, MD, professor of pediatrics, allergy and immunology at Mt. Sinai School of Medicine in New York.

"This is an important study testing whether high-dose early exposure to foods is protective [against allergies]. It's a good theory, but one of several," he tells WebMD.


American Academy of Allergy, Asthma & Immunology Annual Meeting 2010, New Orleans, Feb. 26-March 2, 2010.

Graham Roberts, MD, pediatric allergist, King's College London.

Hugh Sampson, MD, professor, pediatrics, allergy and immunology, Mt. Sinai School of Medicine, New York.

What Rules Should Guide Imaging Decisions in Injured Children?

From Medscape Emergency Medicine > Ask the Experts
William R. Mower, MD

Posted: 02/23/2010

Clinicians often find it difficult to decide whether computed tomography (CT) is appropriate is the evaluation of a child who has a blunt head injury.
CT is an exquisite means of detecting potentially dangerous intracranial injuries, but it exposes particularly vulnerable populations to ionizing radiation and the potential for lethal malignant transformation
This dilemma has stimulated recent efforts to develop clinical rules that guide imaging decisions.
Most of these efforts are ongoing and have yet to achieve conclusive results. However, based on the methodological approaches used in their development, these rules are likely to provide qualitatively similar benefits once they complete final validation.

To use these tools properly, it is important to understand that in creating decision instruments, developers consistently place high value on correctly identifying all children who harbor significant injuries.
Rules developed through this approach are very sensitive, exhibit high negative predictive value, and ensure that injuries are very unlikely to be found among "low-risk" patients. These characteristics make the tools most useful for identifying children who do not need imaging.

The recently validated PECARN rule illustrates these principle.
Children aged 2 years and older are classified as low risk if they exhibit normal mental status, no loss of consciousness, no vomiting, non-severe injury mechanism, no signs of basilar skull fracture, and no severe headache.
Children younger than 2 years of age are considered low risk if they exhibit normal mental status, no scalp hematoma except frontal, no loss of consciousness or loss of consciousness for less than 5 seconds, non-severe injury mechanism, no palpable skull fracture, and acting normally according to parents.

In clinical application the rule was found to have a negative predictive value greater than 99.95%, and correctly identified clinically important injuries in 86 of 88 children (97.7%). The rule assigned low-risk status, and would have omitted imaging, for about 21% of the children who underwent imaging on the basis of clinical judgment.[4] On the other hand, the overall performance of the rule is inferior to clinical judgment; its strict application would have increased overall imaging rates from 35% to about 42%, without increasing sensitivity.[3,4]

The rule's relatively modest benefit derives from its ability to spare imaging for a small proportion of low-risk patients who would otherwise undergo imaging based on clinical judgment.

To date, there has been little effort to develop tools to identify children who are at high risk of intracranial injury and who should undergo routine imaging. Information from current studies indicates that injury prevalence is particularly high among children who have a severe mechanism of injury, exhibit evidence of significant trauma to the calvarium (including skull fracture and lateral hematomas), and those with persistent neurological impairment (including abnormal behavior and altered level of alertness).[2,4] CT is likely to reveal significant injuries in a sizeable proportion of these patients.

While it may be convenient to have decision tools that dictate imaging requirements for all children, it is unlikely that such tools are feasible. Many children present with findings that exclude them from low-risk classification, but do not exhibit high-risk findings.

Imaging decisions in these children should be based on clinical impressions, and it is likely that clinical judgment will continue to play an important role in the foreseeable future in the treatment of many children who have sustained blunt head injury.

Ready-to-eat Cereal Breakfasts are Associated with Improved Nutrient Intake and Dietary Adequacy but Not Body Mass Index in Black Adolescents

From American Journal of Lifestyle Medicine

Improved Nutrient Intake and Dietary Adequacy but Not Body Mass Index
Brandy M. Williams; Carol E. O'Neil, PhD, MPH, LDN, RD; Debra R. Keast, PhD; Susan Cho, PhD; Theresa A. Nicklas, DrPH

Posted: 02/23/2010; Am J Lifestyle Med. 2009;3(6):500-8.

The goal of this study was to determine whether nutrient intake, dietary adequacy, and weight status were associated with type of breakfast consumption: skipping breakfast, consuming ready-to-eat cereal (RTEC) at breakfast, or consuming other types of foods at breakfast.

Data from black adolescents 13 to 18 years of age (n = 988) participating in the 1999–2002 National Health and Nutrition Examination Survey were used in a secondary data analysis. Thirty-seven percent of black adolescents skipped breakfast, 19% consumed RTEC at breakfast, and 44% consumed other breakfasts. RTEC breakfast and other breakfast consumers had higher mean energy intakes than breakfast skippers (P ≤ .05).

After adjusting for gender and energy intake, RTEC breakfast consumers had higher intakes of thiamin, riboflavin, niacin, folate, calcium, phosphorus, magnesium, iron, zinc, potassium, and vitamins A, B6, and B12 than breakfast skippers and other breakfast consumers (P ≤ .05). RTEC breakfast consumers had the highest mean adequacy ratio, followed by other breakfast consumers, then breakfast skippers (P ≤ .05). Those consuming RTEC at breakfast had lower mean body mass index (P ≤ .05) and waist circumference (P ≤ .05) than breakfast skippers; however, there was no difference between those consuming RTEC and other breakfasts.

If confirmed in prospective studies, consuming a breakfast meal with RTEC may be a useful strategy to encourage in black adolescents as a way to improve nutrient intake and dietary adequacy without increasing weight.


Adolescence is a time of rapid growth and development, making this a period of nutritional vulnerability. At the same time, adolescents demonstrate increasing control over their own food choices[1,2] and may make poor dietary choices.[3,4] Discretionary fat and added sugars make up more than 40% of total energy intake in the diet of adolescents.[3] Black adolescents may be especially vulnerable to poor diets because they are less likely than white adolescents to meet dietary recommendations for several essential nutrients.[5–7]

Skipping breakfast is an example of a poor dietary practice commonly seen in adolescents.[8] Although breakfast has been called the most important meal of the day, it is the meal that is skipped most frequently.[9,10]

Black adolescents tend to skip breakfast more often than their white counterparts.[11–13] The importance of breakfast is underscored because regular consumption of breakfast is associated with improved cognition[14] and nutrient intake in adolescents.
Skipping breakfast may result in inadequate nutrient intake that is not compensated for at other times during the day.[15] Skipping breakfast is also associated with lower energy intake but higher body mass index (BMI).[8,9,16,17]

The prevalence of overweight in adolescents increased markedly from 1999 to 2002[18] and from 2003 to 2006,[19] with the prevalence of overweight and obesity higher and increasing more rapidly in black adolescents compared to their white counterparts.[18] Overweight is a leading indicator of health status[20] and is associated with elevated blood pressure, dyslipidemia, metabolic syndrome, type 2 diabetes mellitus, and reduced insulin sensitivity.[21]

Childhood overweight tracks into young adulthood,[22] and tracking may show racial differences.
Eighty-four percent of overweight black girls and 82% of overweight black boys will be obese adults; these rates are higher than their white counterparts,[23] suggesting it is important to assess factors associated with overweight in black children and adolescents. Increases in overweight adolescents will increase the burden of adult diseases associated with unhealthy weight status.[24]

Consumption of ready-to-eat cereals (RTECs) at breakfast may help adolescents maintain a healthy weight and improve nutrient intake. RTECs are those cereals that can be consumed without further preparation, so they are convenient; furthermore, most are low fat, and more than 90% of RTECs are fortified with essential micronutrients.[25,26] In the United States, RTECs are often fortified with vitamins B6 and B12, thiamin, niacin, folate, and iron. Consumption of RTECs has been associated with higher intakes of iron, folic acid, vitamin C, and zinc and with lower intakes of total fat and cholesterol.[7,27] Adolescents who consume RTECs for breakfast also have increased intakes of milk and calcium.[28] Breakfasts that include RTECs have been associated with lower BMI in individuals 9 to 19 years of age.[8,17,18] Thus, RTECs may be an excellent food choice for adolescents.

Recently, the importance of consuming RTECs for nutrient intake and dietary adequacy at breakfast in the diets of black children was demonstrated;[29] however, the association of breakfast consumption patterns of black adolescents with diet and weight status has been understudied. The objectives of this study were to examine nutrient intake, dietary adequacy, and weight status in a nationally representative sample of black adolescents who skipped breakfast, consumed a breakfast that included RTECs, or consumed other foods at breakfast.

Respiratory Viral RNA on Toys in Pediatric Office Waiting Rooms

From The Pediatric Infectious Disease Journal®
Diane E. Pappas, MD, JD; J. Owen Hendley, MD; Richard H. Schwartz, MD

Posted: 02/26/2010; Pediatr Infect Dis J. 2010;29(2):102-104.

Background: Toys in pediatric office waiting rooms may be fomites for transmission of viruses.

Methods: Eighteen samples were taken from office objects on 3 occasions. Samples were tested for presence of picornavirus (either rhinovirus or enterovirus) on all 3 sample days; in addition, January samples were tested for respiratory syncytial virus and March samples were tested for influenza A and B. In addition, 15 samples were obtained from the sick waiting room before and after cleaning. Polymerase chain reaction was used to detect picornavirus, respiratory syncytial virus, and influenza A or B virus. Finally, 20 samples were obtained from the fingers of a researcher after handling different toys in the sick waiting room, and samples were then obtained from all the same toys; all samples were tested for picornavirus by polymerase chain reaction.

Results: Viral RNA was detected on 11 of 52 (21%) of toys sampled. Ten of the positives were picornavirus; 1 was influenza B virus. Three (30%) of 10 toys from the new toy bag, 6 of 30 (20%) in the sick child waiting room, and 2 of 12 (17%) in the well child waiting room were positive. Six (40%) of 15 toys in the sick waiting room were positive for picornaviral RNA before cleaning; after cleaning, 4 (27%) of 15 were positive in spite of the fact that RNA was removed from 4 of 6 of the original positives. Three (15%) of 20 toys in the sick waiting room were positive for picornaviral RNA, but RNA was not transferred to the fingers of the investigator who handled these toys.

Comment: About 20% of the objects in a pediatric office may be contaminated with respiratory viral RNA, most commonly picornavirus RNA.
Cleaning with a disinfectant cloth was only modestly effective in removing the viral RNA from the surfaces of toys, but transfer of picornaviral RNA from toys to fingers was inefficient.

Many parents are concerned that pediatric office toys are contaminated with germs that may cause well children who play with such toys to become sick after the office visit.
There are few scientific data available to confirm or deny this belief.
Influenza A viral RNA has been detected on objects and surfaces in homes and day care centers during influenza season, with over 50% of surfaces positive for presence of influenza RNA.[1] Bacterial contamination of toys in a pediatric office with coliforms has been demonstrated using eluates of toys placed in broth.

In a study of spread of DNA markers, cauliflower mosaic virus was smeared onto balls in infant and toddler child care settings; the DNA markers spread through the classroom within 1 to 2 hours after introduction and could even be found on environmental surfaces in the childrens' homes the next day.

The presence and transferability of respiratory viral RNA on toys in the pediatric office has not been studied.

In this study we looked for the presence of specific RNA from 3 common respiratory viruses (picornavirus, respiratory syncytial virus, and influenza A and B), on the toys in a pediatric office sick and well waiting rooms during respiratory virus season.

Wednesday, March 10, 2010

Role of Infection in the Development and Exacerbation of Asthma

Interactions between Viral Infections & Allergy
Theresa W Guilbert, MD†

The effect of allergic sensitization on the asthmatic airway response to viral infection has been a topic of much research. The relationship between these two factors appear to be bidirectional, as the atopic state can alter the lower airway response to viral infections,[13,153] viral infections can affect the development of allergen sensitization,[154,155] and synergistic interactions can emerge when individuals are exposed concurrently to both allergens and viruses.[11,156,157] As previously suggested, atopic individuals may have both altered host defenses that increase susceptibility to bacterial and viral infections, and an increased risk of developing asthma.[3,78–82]

Atopy is a risk factor for the development of childhood asthma after virus-induced wheezing illnesses and many investigative groups have explored the mechanisms of this relationship.[158] It has also been proposed that atopy may be an important predisposing factor for the development of acute bronchiolitis during RSV epidemics.[159] Some investigators have reported that atopic parents increase the likelihood of children developing persistent wheezing,[159–161] whereas others have not observed this.[162,163] Similarly, there is controversy over whether personal atopy is more prevalent after bronchiolitis.[12,154,163,164] Albeit, it is clear that children who wheeze in early life and have atopic features such as allergic sensitization, atopic dermatitis and either blood eosinophilia or allergen-specific IgE are at the highest risk for later asthma. These findings have led to the development of predictive indices to estimate the risk of asthma after wheezing in infancy.[165,166]

There are data to support that allergic sensitization is a risk factor for wheezing with common cold infections in later childhood.[17,167] In an emergency department setting, risk factors associated with acute wheezing episodes were reported.[14] These included the detection of a respiratory virus, most commonly HRV, positive allergen-specific IgE, and the presence of eosinophilia.

Notably, viral infections and allergic inflammation synergistically augmented the risk of wheezing. Moreover, experimental inoculation with HRV is more likely to increase airway responsiveness in allergic individuals compared with nonallergic individuals.[168]
Finally, the risk of hospitalization among virus-infected individuals is amplified in patients who are both sensitized and exposed to respiratory allergens.[17] These results imply that individuals with respiratory allergies or eosinophilic airway inflammation are at increased risk for viral-induced wheezing. However, this theory has not been confirmed with experimentally induced colds, as allergen administration before viral inoculation did not increase cold symptoms.[136,169]

Viral infections are proposed to interact with allergic inflammation, leading to airway dysfunction through several mechanisms. Viral infections could potentially damage the barrier function of the airway epithelium, leading to an enhanced absorption of aeroallergens across the airway wall and subsequent inflammation.[170] Moreover, the production of various cytokines (TNF-α, IL-1β and IL-6), chemokines (CCL3/MIP-1α, CCL5/RANTES, CCL2/MCP-1 and CXCL8/IL-8), leukotrienes and adhesion molecules (ICAM-1) may further upregulate cellular recruitment, cell activation and the ongoing inflammatory response.[171]

Several studies have also demonstrated that HRV infection increases airway hyperresponsiveness in patients with atopy and asthma.[156,167,168,172] Finally, a recent study has demonstrated that the use of prednisolone was associated with less recurrent wheezing in young children with HRV infection but not those with RSV or non-HRV/RSV infections. Thus, HRV infection may be a marker for wheezing children that will respond favorably to corticosteroid treatment.[50]

Probiotics have Clinical, Microbiologic, and Immunologic Efficacy in Acute Infectious Diarrhea

From The Pediatric Infectious Disease Journal®

Chien-Chang Chen, MD; Man-Shan Kong, MD; Ming-Wei Lai, MD; Hsun-Chin Chao, MD; Kuei-Wen Chang, MD; Shih-Yen Chen, MD; Yhu-Chering Huang, MD, PhD; Cheng-Hsun Chiu, MD, PhD; Wen-Chen Li, MD; Pen-Yi Lin, MD; Chih-Jung Chen, MD; Tzou-Yien Lin, MD

Posted: 03/04/2010; Pediatr Infect Dis J. 2010;29(2):135-138. © 2010 Lippincott Williams & Wilkins

Background: Acute infectious diarrhea is a major cause of childhood morbidity and economic burden for families. We evaluate the clinical, microbiologic, and immunologic effects of probiotics in acute infectious diarrhea.

Methods: Children (n = 304) aged 3 months to 6 years hospitalized for acute diarrhea were randomized to receive Bio-three (a mixture of Bacillus mesentericus, Enterococcus faecalis, and Clostridium butyricum) or placebo orally 3 times daily for 7 days. Fecal samples were homogenized for bacterial culture and blood cells were isolated for cell culture and cytokine analysis.

Results: The mean duration of diarrhea after start of therapy was 60.1 hours in the probiotics group versus 86.3 hours in the placebo group (P = 0.003).
Hospital stay was shorter in the probiotics group than in the placebo group (P = 0.009).
Counts of Bifidobacteria and Lactobacillus species were elevated in stool culture of the probiotics (Bio-three) group. IL-10 was increased in the serum and supernatants of cell culture in the probiotics group, and tumor necrosis factor-α values were down-regulated. Interferon-γ and IL-12 were mildly elevated in the probiotics group, compared with the placebo group.

Conclusions: This probiotics mixture reduced the severity of diarrhea and length of hospital stay in children with acute diarrhea.
In addition to restoring beneficial intestinal flora, probiotics may enhance host protective immunity such as down-regulation of pro-inflammatory cytokines and up-regulation of anti-inflammatory cytokines.

Probiotics may be beneficial in the management of acute diarrhea. Some studies reported that probiotics can reduce the severity of viral diarrhea and rotavirus shedding.
Few trials have investigated the effect of probiotics in bacterial diarrhea. Guandalini et al[3] and Shornikova et al[4] reported that diarrhea was not reduced in the probiotic group compared with the control group.

A probiotics preparation (Bio-three, TOA Pharmaceutical Ltd, Japan; containing Bacillus mesentericus TO-A, Enterococcus faecalis T-110, Clostridium butyricum TO-A) had an effect on normalization of enterobacterial flora, inhibition of pathogenic bacteria, and promotion of the growth of beneficial bacteria.

This probiotics preparation may prevent growth of enterohemorrhagic E. coli in the intestine and associated diarrhea in a rabbit model.

The mechanism by which probiotics bacteria inhabit the gastrointestinal tracts of host and exert their beneficial effects is unclear. Our study sought to determine whether probiotics (Bio-three) inhibited infectious diarrhea and reduced the associated inflammatory response. Bacterial counts (microbiology) and subsequent immune reaction were investigated. No previous human studies have explored clinical, microbiologic, and immunologic effects of probiotics in acute diarrhea simultaneously.

"Choking Game" Awareness and Participation among 8th Graders — Oregon, 2008

From Morbidity & Mortality Weekly Report
SK Ramowski, MSW; RJ Nystrom, MA; NR Chaumeton, PhD; KD Rosenberg, MD; J Gilchrist, MD

02/26/2010; Morbidity & Mortality Weekly Report. 2010;59(1):1-5. © 2010 Centers for Disease Control and Prevention (CDC)

The "choking game" is an activity in which persons strangulate themselves to achieve euphoria through brief hypoxia.

It is differentiated from autoerotic asphyxiation. The activity can cause long-term disability and death among youths.
In 2008, CDC reported 82 deaths attributed to the choking game and other strangulation activities during the period 1995–2007; most victims were adolescent males aged 11–16 years.

To assess the awareness and prevalence of this behavior among 8th graders in Oregon, the Oregon Public Health Division added a question to the 2008 Oregon Healthy Teens survey concerning familiarity with and participation in this activity.
This report describes the results of that survey, which indicated that 36.2% of 8th-grade respondents had heard of the choking game, 30.4% had heard of someone participating, and 5.7% had participated themselves. Youths in rural areas were significantly more likely (6.7%) to have participated than youths in urban areas (4.9%). Choking game participation was higher among 8th graders who reported mental health risk factors (4.0%), substance use (7.9%), or both (15.8%), compared with those who reported neither (1.7%).
Public health surveillance of these strangulation activities among youths should be expanded to better quantify the risks and understand the motives and circumstances surrounding participation. Parents, educators, counselors, and others who work with youths should be aware of strangulation activities and their serious health effects; they should watch for signs of participation in strangulation activities, especially among youths with suspected substance use or mental health risk factors.

Parents, educators, counselors, health-care providers, and others who work with youths should become aware of strangulation activities and the signs of participation (e.g., mention of the choking game [or the game by its other names]; bloodshot eyes; marks on the neck; frequent, severe headaches; disorientation after spending time alone; and ropes, scarves, and belts tied to bedroom furniture or doorknobs or found knotted on the floor).

Nearly one third of 163 pediatricians and family practitioners recently surveyed were not aware of the choking game or the signs indicating that a patient might be participating in this activity.

Finally, to identify participating youths, health and mental health practitioners should consider adding a question about strangulation activities to clinical screening tools, especially for youths identified as having substance use or mental health risks

Friday, March 5, 2010

Oral Immunotherapy Induces Tolerance in Egg Allergic Children

From Medscape Medical News
Deborah Brauser

March 5, 2010 (New Orleans, Louisiana) — Oral immunotherapy (OIT) can induce clinical desensitization in children allergic to eggs, decrease egg IgE levels, and decrease egg-specific basophils, according to a new study presented here at the American Academy of Allergy, Asthma and Immunology (AAAAI) 2010 Annual Meeting.

"This was the first multicenter, randomized trial to examine the safety and efficacy of [OIT] for egg allergy," investigational team member Stacie M. Jones, MD, professor and chief of pediatric allergies and immunology at the University of Arkansas for Medical Sciences and the Arkansas Children's Hospital Research Institute in Little Rock, told meeting attendees during a late-breaking research session.

Investigators from Duke, Johns Hopkins, Mount Sinai, and National Jewish Health were also involved in this study, which was part of the Consortium of Food Allergy Research (CoFAR), established by the National Institute of Allergy and Infectious Diseases.

"Some of the most exciting research in allergy today focuses on possible treatments for patients with severe food allergy," said team member Robert A. Wood, MD, chief of pediatrics, allergy, and immunology at Johns Hopkins University School of Medicine, Baltimore, Maryland, in a press release.
"This important study ... provides further evidence that a real treatment for food allergy will soon be possible."

"In fact, a few of the kids from this study are now eating scrambled eggs without any problems," he told Medscape Allergy and Clinical Immunology during a presession press conference. "So some are cured of their allergy, but we're not yet ready to say what percent of those on active therapy are getting there."

OIT Group Shows Greater Tolerance

The estimated cumulative prevalence of egg allergy is 2.6% by the age of 2.5 years, which can cause serious problems after exposure, reported Dr. Jones.

In this study, the investigators enrolled 55 egg-allergic children between the ages of 5 and 18 years and randomized them to receive either a daily dose of egg white solid OIT (n = 40; 62% male; mean age, 7.13 years) or a placebo (n = 15; 60% male; mean age, 7.07 years). All patients underwent initial escalation, build-up, and maintenance (at 2000 mg) for a total of 44 weeks, followed by an oral food challenge.

"This was done to determine how many of the children had become desensitized, indicated by the ability to ingest 5 grams of egg," reported Dr. Jones.

Results at the end of the study showed that 21 of the 40 children who received the OIT passed the oral food challenge, whereas none of those who received the placebo did.

In addition, 33 of those treated with OIT ingested more than 2750 mg of the egg white solid compared with only 1 person in the placebo group.

The egg OIT group also showed significant decreases in both egg IgE levels (mean, −12.66 vs −1.26; P = .02) and egg percutaneous skin tests (−6.5 vs 0.1 mm; P = .001) compared with the placebo group, as well as a significant reduction in basophil activations (P < .001).

"Symptoms reported during the dosing phases were mild to moderate, with no symptoms reported in 11,802 of the doses consumed by the OIT group compared with only 4014 symptom-free doses consumed by the placebo group," said Dr. Jones.

The predominant dosing reactions were oropharyngeal at 15.46% vs 0.22% for the egg OIT and placebo groups, respectively.

"In conclusion, 10% to 15% of patients will not tolerate OIT in this protocol, but we didn't go in thinking this would be right for everyone," said Dr. Jones. "But for those who did tolerate it, the procedure was effective and safe for home use under supervision."

However, she added that more research is needed before it can be considered for clinical practice.

"Until we figure out the right dose and the right interval and can figure out what's going on with the reactions, we're just not quite there yet," said CoFAR team leader Hugh Sampson, MD, from the Department of Pediatrics and director of the Jaffe Food Allergy Institute at Mount Sinai Medical Center, New York City.

He reported that the researchers plan to continue following up the study participants to monitor dosing reactions and long-term tolerance.

Encouraging Results With Cautions

"This is a really important issue, and I was glad to see the consortium come together to work on this study," said John Oppenheimer, MD, associate clinical professor of medicine at New Jersey Medical School in Newark and past vice-chair of AAAAI's Clinical Therapeutics Committee.

"As a clinician, patients come to me every day with this problem, because it is a really common food," added Dr. Oppenheimer, who was not involved with the research. "With this study, we're beginning to get hope that we can diminish their level of sensitivity and induce tolerance levels."

He said that he will be interested to see the long-term results and to find out what converts these patients from true sensitization to true tolerance. "How long do they need to remain on immunotherapy and does it need to be continued the rest of their lives? These are the questions that remain. Overall, I'm excited but still cautious as I await further data."

"These findings are encouraging," agreed AAAAI president Mark Ballow, MD, professor of pediatrics and chief of the Division of Allergy, Immunology, and Rheumatology at State University of New York in Buffalo.
"For those who achieved a degree of tolerance to a certain amount of egg challenge, this is great because it can subsequently take their fear away from accidental exposure."

"That said, it's not yet ready for prime time, which I know is something this group also feels," added Dr. Ballow. "Looking at it over a longer time can make sure there aren't any hidden adverse events that may appear, which is always a concern."

This study was funded by the National Institute of Allergy and Infectious Diseases. The study authors have disclosed no relevant financial relationships.

American Academy of Allergy, Asthma and Immunology (AAAAI) 2010 Annual Meeting: Abstract L6. Presented March 2, 2010.

Thursday, March 4, 2010

Step-Up Therapy Improves Asthma Control in Children

From Medscape Medical News
Deborah Brauser

March 3, 2010 (New Orleans, Louisiana) — Children with asthma who continue to have symptoms while using low-dose inhaled corticosteroids (ICS) can benefit from "stepping up" treatment by increasing the dosage or adding either a long-acting beta agonist (LABA) or a leukotriene-receptor antagonist (LTRA), according to a new triple-crossover randomized study called BADGER (Best Add-On Therapy Giving Effective Responses).

In fact, 98% of the study participants showed a significant improvement in asthma control after the addition of at least 1 of these options, according to research presented here at the American Academy of Allergy, Asthma and Immunology (AAAAI) 2010Annual Meeting and published online simultaneously in The New England Journal of Medicine.

Although the overall best response was achieved by adding a LABA, many of the children had a best response with one of the other step-up treatments, "highlighting the need to regularly monitor and appropriately adjust each child's asthma therapy,"

He added that factors such as baseline Asthma Control Test (ACT) score, the absence of eczema, and race might also help clinicians to "better predict which of the 3 treatment options will help a patient the most."

Past Step-Up Evidence Lacking

Although clinicians usually agree on treatments going from step 1 (intermittent asthma) to step 2 (persistent), the few studies that have been conducted on how to best treat children whose asthma is poorly controlled while receiving low-dose ICS have shown inconsistent results, reported Dr. Lemanske.

"The evidence to guide step-up therapy is lacking," he told Medscape Allergy and Clinical Immunology. "So we wanted to answer the question: What is the best way to go from step 2 to step 3?"

Researchers from 5 centers (in 4 states), making up the National Heart, Lung, and Blood Institute–funded Childhood Asthma Research and Education Network, worked on the BADGER trial.

They sought to conduct a comparison study to establish not only which step-up therapy was best, but also "whether there are phenotypic or genotypic characteristics that can be used to predict whether a child will have a better response to one particular treatment than to another."

A total of 498 children between the ages of 6 and 17 years with mild to moderate asthma were enrolled between March 2007 and July 2008, with 157 (65.4% male; mean age, 10.8 years) receiving each of the 3 step-up treatments in random order for 16 weeks each.

These treatments were the standard low-dose ICS (100 µg of fluticasone twice daily) plus either the LABA salmeterol (50 µg twice daily) or the LTRA montelukast (5 or 10 mg daily), or 2.5 times the standard ICS dose (250 µg fluticasone twice daily) only. Each patient also received a metered-dose inhaler of albuterol and prednisone.

At the end of each 16-week period, the number of days that the asthma symptoms were under control, lung function, and the number of exacerbations and attacks were measured before the patient moved on to the next treatment option.

Methods used included the Pediatric Asthma Quality of Life Questionnaire, the ACT (with scores from 0 to 27), spirometry tests, and patient- or guardian-recorded diary entries.

A Place for All 3 Therapies

The results, concentrating on the 165 patients who completed at least 2 study periods, showed that "although our goal was for 25% of the patients to see a difference in their asthma symptoms after using at least 1 of the treatments, we were surprised to see that 161 showed substantial improvement [P < .001]," said Dr. Lemanske.

The best response was shown in almost 40% of the patients by adding the LABA, in 30% by adding the LTRA, and in 28% by increasing the dose of ICS.

Using rank-ordered logistic regression, the predicted response to the LABA addition was significantly better than to the addition of the LTRA (relative probability [RP], 1.6; 95% confidence interval [CI], 1.1 - 2.3; P = 0.004) and the ICS step-up (RP, 1.7; 95% CI, 1.2 - 2.4; P = .002).

"In other words, the LABA was more than one and a half times as likely to produce the best response," explained Dr. Lemanske.

"All 3 therapies clearly have a place in the management of kids with persistent asthma not well controlled on low-dose [ICS] alone," said investigational team member Leonard B. Bacharier, MD, from the Department of Pediatrics at Washington University in St. Louis, Missouri, in a press release. "Statistically, LABA therapy was most likely to help the most patients, but it's hard to look at an individual patient and know which one to choose."

Significant predictor factors included ACT score, eczema, and race.
LABA treatment was the best add-on therapy for patients with an ACT score greater than 19 (P = .009). However, "if it was 19 or under, there was no difference among the therapies in producing a differential response," reported Dr. Bacharier.

Although patients who had eczema did well on any of the 3 treatments, those who did not have eczema did better on the LABA.

The LABA was also most likely to give the best response in whites. The LABA and higher-dose ICS were equally likely to show the best response in African Americans, whereas the LTRA was least likely.

Factors that were not found to be significantly predictive of a drug's effectiveness included age, sex, allergies, bronchodilator response or reversibility, and number of recent exacerbations.

Dr. Lemanske said that although he was disappointed to not find more predictors, "we're not done analyzing and still have lots of genotyping to do."

A Ceiling Effect for Low-Dose ICS

"Overall, our findings suggest that there is a ceiling effect of low-dose [ICS] in many, though not all, children, and that the addition of a different class of medication is often required to achieve improvements in asthma control," said Dr. Lemanske. "The important take-home message is that if you choose something at step 3 and you're not happy with it, based on the control, instead of pushing it up to step 4, look to one of these other treatments."

He noted, however, that none of the study treatments provided perfect asthma control, and that there were still 120 asthma exacerbations or attacks among the patients who required rescue medication with prednisone. "We obviously still need to do more work."

When asked about the recent mandates of the US Food and Drug Administration (FDA) on the need to lower the use of LABAs in patients with controlled asthma, Dr. Lemanske said that that was like comparing apples and oranges.

"The FDA was talking about step-down treatment, and our study was on step-up therapy for patients who did not have control of their asthma. Also, BADGER was an efficacy trial and we were not powered to look at safety outcomes. The duration of our trial and the size of our sample precluded statements regarding long-term risks."

In the journal article, the authors write that "clinicians who prescribe LABAs (never to be used as monotherapy) in combination with [ICS] should continue to evaluate risk-benefit ratios."

N Engl J Med. Published online March 2, 2010.

Even Low-Level Smoke Exposure Increases Atherosclerosis and Lipid Changes in Adolescents

From Heartwire
Sue Hughes

March 4, 2010 (Turku, Finland) — Healthy adolescents frequently exposed to tobacco smoke have arterial changes associated with preclinical atherosclerosis and increased apolipoprotein B (apoB) levels, a new study has shown [1].

The study, published online March 2, 2010 in Circulation: Cardiovascular Quality and Outcomes, was conducted by a group led by Dr Katariina Kallio (University of Turku, Finland).

"Our findings suggest that children should not face exposure to tobacco smoke at all," Kallio said in a press statement. "Even a little exposure to tobacco smoke may be harmful for blood vessels. We need to provide children with a smoke-free environment."

In the paper, the authors explain that passive smoking has been associated with increased carotid intima-media thickness (IMT) in adults, but no studies have previously examined the impact of exposure to tobacco smoke on IMT in healthy children or adolescents.
In addition, it is known that exposure to environmental tobacco smoke may lead to alterations in serum lipid profile in adults, but there are no data on the relation of tobacco-smoke exposure and lipoprotein levels in children.

The current study involved 494 healthy 13-year-old children who were recruited as infants into Finland's Special Turku Coronary Risk Factor Intervention Project (STRIP), which began in 1990 and is aimed at lowering children's risks of heart disease by controlling their exposure to known environmental dangers.

Maximum carotid and aortic IMT and brachial-artery flow-mediated dilation were measured using high-resolution ultrasound. Serum lipid, lipoprotein, and apoA-I and B concentrations were also determined.
Long-term exposure levels to secondhand smoke were estimated by measuring blood levels of cotinine, a byproduct of nicotine that indicates how much tobacco smoke was encountered over the past few days.
Most study participants had six annual blood tests for cotinine levels. These results were averaged, and the participants were divided into three levels of tobacco exposure: high (163 participants), intermediate (171), and low (160).

Results showed that maximum IMT in both the carotid and aorta increased as exposure to cigarette smoke increased, and endothelial function as measured by brachial artery flow-mediated dilation was decreased in the highest-exposure group compared with the lowest. In addition, apoB and apoB/apoA-I ratio increased with increases in cotinine level.

The authors comment: "The present study suggests that even modest exposure to tobacco smoke is associated with increased IMT. As thickness of the arterial wall is a marker of early atherosclerosis, our data suggest that exposure to tobacco smoke may play a role in the development of atherosclerosis."

They note that the results also confirm previous findings reported in 11-year-old children showing an association between secondhand-smoke exposure and endothelial dysfunction. They suggest that endothelial dysfunction may be the first phenomenon in subclinical atherosclerosis preceding the thickening of the vascular wall.

Mechanisms by which exposure to tobacco smoke increases IMT are put forward, including direct toxic effects of cigarette-smoke constituents on endothelial permeability and structure, enhanced platelet activity so that they bind to injured areas and promote growth of smooth-muscle cells, and increased lipid peroxidation in combination with accelerated uptake of LDL cholesterol by macrophages.

On the apoB and apoB/apoA-I ratio results, they note that the concentration of apoB provides a direct measure of the number of circulating atherogenic lipoproteins, the apoB/apoA-I ratio represents the balance of proatherogenic and antiatherogenic lipoproteins, and childhood levels of apoB/apoA-I ratio predict carotid IMT and endothelial function in adulthood. They point out that the apoB/apoA-I ratio in adults is a strong predictor of coronary events and that it may be the best single lipoprotein variable related to coronary risk.

They add that in the present study, exposure to tobacco smoke had an independent association with apoB, but this did not confound the association between passive smoking and IMT.
Thus, although exposure to tobacco smoke can promote atherosclerosis in part by the effects on apoB metabolism, this did not fully explain the relation between smoke exposure and IMT shown in this study.