Acute Bacterial Sinusitis Addressed in New AAP Guidelines

Laurie Barclay, MD

Jun 24, 2013

Acute bacterial sinusitis may now be diagnosed in a child with upper respiratory infection (URI) and worsening symptoms after initial improvement, according to updated guidelines from the American Academy of Pediatrics (AAP), published online June 24 in Pediatrics. The new clinical practice guideline addresses diagnosis and judicious antibiotic use, updating the 2001 AAP guideline based on a review of the medical literature since publication of the previous recommendations.

"Acute bacterial sinusitis is a common complication of viral [URI] or allergic inflammation," write Ellen R. Wald, MD, and colleagues from the AAP. "Using stringent criteria to define acute sinusitis, it has been observed that between 6% and 7% of children seeking care for respiratory symptoms [have] an illness consistent with this definition."

Previous criteria for acute bacterial sinusitis in children were acute URI with either nasal discharge and/or daytime cough for longer than 10 days or severe onset of fever (≥39°C/102.2°F), purulent nasal discharge, and other respiratory symptoms for 3 or more consecutive days. A third criterion added to the 2013 guideline is URI with worsening symptoms such as nasal discharge, cough, and fever after initial improvement.

Another change in the updated guideline is that physicians may now observe children with persistent infection lasting longer than 10 days for an additional 3 days before prescribing antibiotics, whereas the 2001 guideline recommended antibiotics for all children diagnosed with acute bacterial sinusitis. However, antibiotics should still be given to children with severe onset or worsening symptoms.

Management Recommendations

First-line therapy for acute bacterial sinusitis is amoxicillin with or without clavulanate. If symptoms worsen or do not improve after 72 hours, another antibiotic may be substituted.

If the caregiver reports progression of initial signs and symptoms or appearance of new signs and symptoms, or if the child fails to improve within 72 hours of initial management, clinicians should reevaluate initial management and change or start antibiotics if indicated.

The AAP does not recommend imaging tests for children with uncomplicated acute bacterial sinusitis, based on their evidence review, because these tests do not distinguish acute bacterial sinusitis from viral URI. However, children with suspected orbital or central nervous system complications should undergo contrast-enhanced computed tomography scanning of the paranasal sinuses.

"Changes in this revision include the addition of a clinical presentation designated as 'worsening course,' an option to treat immediately or observe children with persistent symptoms for 3 days before treating, and a review of evidence indicating that imaging is not necessary in children with uncomplicated acute bacterial sinusitis," the guidelines authors conclude.

Underlying Evidence

In an accompanying technical report, coauthor Michael J. Smith, MD, MSCE, assistant professor of pediatrics, Division of Pediatric Infectious Diseases, University of Louisville School of Medicine, Kentucky, notes that data are limited regarding the diagnosis and management of acute bacterial sinusitis in children. Four placebo-controlled studies of antibiotic treatment in children with acute sinusitis yielded varying results, likely because of varying inclusion and exclusion criteria. Although heterogeneity precluded formal meta-analyses, qualitative analysis suggested that children presenting with greater severity of illness were more likely to benefit from antimicrobial therapy

"It is clear that some children with sinusitis benefit from antibiotic use and some do not," Dr. Smith writes. "Diagnostic and treatment guidelines focusing on severity of illness at the time of presentation have the potential to identify children who will benefit from therapy and at the same time minimize unnecessary use of antibiotics."

The AAP supported development of these guidelines. Dr. Smith has reported receiving financial support from Sanofi Pasteur and Novartis, and one coauthor is employed by McKesson Health Solutions. The remaining authors have disclosed no relevant financial relationships.

Pediatrics. Published online June 24, 2013. Guidelines full text, Technical report full text

Hand, Foot, and Mouth Disease: CVA6 Diagnostic Clues Found

Jenni Laidman

Jun 17, 2013

The unusual characteristics of hand, foot, and mouth disease (HFMD) caused by coxsackievirus A6 (CVA6) are easily confused with several other diseases, but the authors of an analysis of the 2011 to 2012 outbreak have characterized distinctive morphologies of this more severe enterovirus in a study published online June 17 inPediatrics.

Erin F. Mathes, MD, assistant clinical professor, Department of Dermatology and Department of Pediatrics, University of California, San Francisco, and colleagues examined the medical records of 80 children who tested positive for CVA6 (n = 17), using nucleotide sequencing, or who met clinical criteria for atypical HFMD between July 2011 and June 2012 at 7 academic pediatric dermatology centers around North America.

The authors found 4 morphologies that distinguished this coxsackievirus-associated outbreak from classic HFMD, including widespread vesiculobullous and erosive lesions extending beyond the palms and soles; eczema herpeticum-like eruptions in areas previously or currently affected by atopic dermatitis; eruptions similar to those in Gianotti-Crosti and focused in areas of previous skin injury, such as in areas of sunburn; and petechial or purpuric eruptions, frequently on acral sites, as in acral purpura.

"The phenotypic variability and unusual skin eruptions can be confused with other infectious disease and inflammatory skin diseases," the authors write.

The current analysis could help sort out this confusion, Dean Morrell, MD, professor, director of pediatric and adolescent dermatology, University of North Carolina Department of Dermatology, Chapel Hill, told Medscape Medical News in an email. Dr. Morrell was not involved in the current study.

"This paper is an excellent and timely review of a new clinical entity," Dr. Morrell noted. "Eczema coxsackium was seen across the country and initially fooled many of us. The first case seen at [the University of North Carolina] was initially diagnosed as eczema herpeticum, but that diagnosis didn't really fit the clinical constellation of findings. This manuscript will further educate medical caregivers, who will certainly have the condition come through their practices."

The authors found that the most common symptoms of CVA6 were widespread vesicles, bullae, and/or erosions. Ninety-nine percent of patients had vesiculobullous and erosive eruptions. Infants younger than 1 year were more likely to have bullae than older children (38% of patients younger than 1 year compared with 7% aged 1 to 5 years and 18% of those older than 5 years; P = .039).

Although classical HFMD generally involves hands, feet, and occasionally the buttocks, with enanthem of small vesicles and eruptions of the oral mucosa, the exanthem differed in the CVA6 HFMD by frequently including the perioral area, extremities, and torso. Intraoral outbreaks also occur less frequently in the classic condition.

In most patients (61%), the vesicles, erosions, and bullae of various sizes covered more than 10% of body surface area, which has not been reported in previous HFMD outbreaks.

CVA6 often appeared in areas of previous trauma or inflammation, including diaper rash or healing lacerations, the authors report. Forty-four (55%) of the 80 patients had eruptions in areas of eczematous dermatitis, and 14 patients (18%) had eruptions in other areas of skin injury.

"Enteroviral infections, particularly CVA6, should now be considered in the differential diagnosis of patients presenting with new-onset vesicles and extensive erosions in preexisting areas of eczema," the authors write.

More than one third of the patients with CVA6 had Gianotti-Crosti-like distribution, with lesions on cheeks, extensor surfaces of extremities, and buttocks, but not on the trunk (28/76, 37%).

One coauthor is a consultant and has received payment for lectures and has a grant/pending grant from bioMérieux, which makes the enterovirus assay used in diagnosis at North Shore-Long Island Jewish Health Systems Laboratories. The other authors and Dr. Morrell have disclosed no relevant financial relationships.

Pediatrics. Published online June 17, 2013. Abstract

Trial Sheds New Light on Vesicoureteral Reflux in Children

Steven Fox

Jun 11, 2013

Data from the largest trial of its kind to date are shedding new light on the baseline clinical characteristics of children with vesicoureteral reflux (VUR).

Myra A. Carpenter, PhD, from the Department of Biostatistics, University of North Carolina, Chapel Hill, and colleagues, reported their results in an article published online June 10 in Pediatrics.

"The ideal management of children with [VUR] remains a source of debate," the researchers write. They add that in their view there is scant evidence to support many of the strategies used to manage VUR in children who have experienced 1 or 2 urinary tract infections (UTIs).

VUR is diagnosed in about a third of children who undergo imaging studies after having UTIs. It is associated with increased risk for renal scarring. However, the researchers note, scars are also seen in children who do not have VUR, and many children with higher-grade VUR never develop scarring.

Previous studies of VUR in children are limited by the lack of a placebo or observation group, according to the authors. To address that gap in knowledge, the researchers designed a new trial, the Randomized Intervention for Children with Vesicoureteral Reflux (RVUR) trial, to provide solid evidence about the use of antimicrobials to prevent recurrent UTIs in children with VUR.

The researchers recruited 607 children from 19 pediatric sites in the United States. All had experienced at least a single episode of UTI and had been diagnosed with grade 1 to 4 VUR.

The present article provides cross-sectional baseline data from the study population, including detailed clinical reports and imaging studies, as well as information provided by parents.

Among the findings so far, the authors report that most of the children enrolled are girls (558 girls, 49 boys). Ages range from 2 to 71 months, with a median age of 12 months.

About 11% of VURs were classified as grade 1, 42% as grade 2, 38% as grade 3, and 8% as grade 4.

More than 90% of the children were enrolled in the study after their first UTI.

In more than half the children (323 patients), the UTI that preceded enrollment was associated with fever and other symptoms, such as suprapubic, abdominal, or flank pain or tenderness; urinary urgency, frequency, or hesitancy; dysuria; and malodorous urine. In infants younger than 4 months, symptomology of UTI included failure to thrive, dehydration, or hypothermia.

Nearly a third of the cohort of children (197) presented with fever alone, and 86 had only other symptoms.

"Renal involvement at baseline...was uncommon with cortical defects identified in 89 (15%) children," the authors write. They identified bladder and bowel dysfunction in 71 (56%) of 126 children who were toilet-trained.

More data are expected. The researchers are following up the children for 2 years to assess recurrent febrile or symptomatic UTI, renal scarring, prophylaxis failure, antimicrobial resistance, medication adherence, and quality-of-life measures.

Supported by the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the Children's Hospital of Philadelphia Clinical, and the National Center for Research Resources/National Center for Advancing Translational Sciences. The authors have disclosed no relevant financial relationships.

Pediatrics. Published online June 10, 2013. Abstract

 

Medscape Medical News © 2013  WebMD, LLC 

Timing of Inhaled Adrenaline Matters in Infant Bronchiolitis

Jun 12, 2013

By Gene Emery

NEW YORK (Reuters Health) Jun 12 - When it comes to giving inhalation therapy to an infant with acute bronchiolitis, timing may be everything.

Doctors in Norway found that babies who periodically received inhaled racemic adrenaline did no better than those who inhaled aerosolized saline for the same amount of time.

Yet when the treatment was given on an as-needed basis -- whether it was the drug or saline -- it cut the in-hospital time by 23% (p=0.01). Babies assigned to on-demand inhalation also needed 21% less oxygen supplementation (p=0.04) and the benefits were most pronounced in infants aged three months and younger.

"The strategy of inhalation on demand appears to be superior to that of inhalation on a fixed schedule," Dr. Havard Ove Skjerven of Oslo University Hospital and colleagues concluded in a paper released online today by the New England Journal of Medicine.

In Norway, inhaled racemic adrenaline therapy "has been a standard treatment for the last 30 years or so. It's given between 14 and 15 times for each patient, on average, so it's a lot of treatments," Dr. Skjerven told Reuters Health in a telephone interview.

"Bronchodilators are overused in infants with bronchiolitis in spite of several trials and recommendations that it's not necessarily the best treatment to be used," said Dr. Alyssa Silver of The Children's Hospital at Montefiore Medical Center in New York, who was not connected with the study. "Having one more study to show that inhaled adrenaline is also ineffective is one more piece of evidence."

But Dr. Silver told Reuters Health she was surprised that the on-demand treatment produced such improvement.

Eight centers in southeastern Norway and 404 children under the age of one year participated in the randomized double-blind trial. Inhaled adrenaline, which reduces mucosal swelling, has been shown in outpatients to improve symptoms and lower the risk of hospitalization. It has not, however, been found to reduce hospital stay for inpatients. The Skjerven team wanted to test that, and whether on-demand care would be better than a fixed schedule.

"It's common to give it on a regular schedule, which would be every second or third hour, whether he seems to need it or not, and whether he's awake or not," said Dr. Skjerven.

With on-demand therapy, "the nurses continuously made the decision about whether the patient needed it or if it seemed to be helping," he said. "If the patient was stable or sleeping, you would not wake up that patient to give him a treatment."

Regardless of the schedule, when the researchers just looked at saline versus adrenaline, the length of hospital stay, supplemental oxygen use, clinical scores, and other measures were essentially the same.

Yet when they compared on-demand inhalation versus fixed-schedule treatment regardless of whether adrenaline was used, mean length of stay in the hospital went from 61.3 hours in the fixed-schedule group to 47.6 hours in the on-demand group.

The number of infants requiring oxygen supplementation went from 48.7% down to 38.3% with on-demand, and the average number of inhalation treatments was 17.0 in the fixed-schedule group but 12.0 in the on-demand group.

"The main reason for trying on-demand treatment was to see if we could give more individualized treatment" and fewer treatments," Dr. Skjerven said. "That it actually turned out better was a surprise for us."

"The effect was most predominant in the smallest children, those less than three months, and those are the ones causing the most trouble for us," he said. "It actually shortened hospital stay by 24 hours, which was a lot."

The treatment was discontinued in 20.5% of the children, mostly in the saline group and mostly because it appeared that the treatment had failed. But the difference in the discontinuation rates was not statistically significant between the groups.�

Why would on-demand therapy be better?

"Remember, we give it as 100% oxygen and a high dose of adrenaline with a tight mask fitting around the face up to every hour. It's very likely to give them a stress reaction. A lot of them start screaming and they're obviously not comfortable with this," Dr. Skjerven said.

"There's a concept called minimum handling in intensive care units where you try to cluster up procedures and give the longest periods of sleep as possible to help recovery as much as possible," he said. "We've hypothesized that this concept is transferable to small infants less than three months, which makes sense to us."

He said the results "are definitely causing a guideline change in Norway and we're waiting to see what kind of influence it might have globally."

Dr. Silver said bronchodilation therapy probably remains common "because we have no good treatment option. It's a disease process that affects a lot of babies. It's the number one reason for admission of infants less than one in the United States. You see these young babies struggling to breathe and people just want to do something."

SOURCE: http://bit.ly/12nmgr2

N Engl J Med 2013; 368:2286-2293.

Drug Therapy for Parents' ADHD Improves Kids' Behavior

Fran Lowry

May 31, 2013

HOLLYWOOD, Florida — Pharmacologic therapy for parents who have attention-deficit/hyperactivity disorder (ADHD) improves their parenting skills, especially if their children also have the disorder.

In a small trial of 38 parent-child dyads with ADHD, treatment of the parents with lisdexamfetamine dimesylate (LDX) enhanced their ability to help their children do homework and also caused them to interact with their children in a more positive, nurturing way.

This in turn improved the behavior of their children, according to the results of the study, presented here in a poster session at the New Clinical Drug Evaluation Unit (NCDEU) 53rd Annual Meeting.

Studies show that one quarter to one third of children with ADHD have a parent who meets some ADHD diagnostic criteria, and this may adversely affect the child's ability to improve, lead investigator James G. Waxmonsky, MD, from Florida International University College of Medicine, in Miami, told Medscape Medical News.

"Our center really focuses on pediatric ADHD, but for years, we would have parents come in with their children, and as their child gets assessed and treated, the parents would say, 'That sounds like me,' or, 'That sounds like my spouse, what can you do for adults?' " Dr. Waxmonsky said.

"We started to wonder, since so many children with ADHD will also have a parent with the disorder, what impact this would have on the child's improvement, because we are asking the parent to do things like give a daily medication, structure their child's day, be very consistent and persistent in the way they interact with their child, but if they have attention and organizational issues, this may be very difficult for them," he said.

Treatment Naive

The investigators recruited 38 parents who met the criteria for ADHD but had never been treated and who also had children with ADHD. "It took a while to find and enroll the families. We also had a higher attrition rate, in part because many of the adults had never been treated with stimulants before, and they did not like the side effects," Dr. Waxmonsky explained.

Of the 38 dyads enrolled, 26 finished the study.

All the adult participants met full Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for ADHD and had a child between the ages of 5 and 15 years with ADHD. The adults were first optimized on LDX (mean dose, 50 mg) during a 3-week period.

In the first phase of the study, the parent-child pairs completed 2 laboratory interactions, once with the parent on a blinded, optimal LDX dose, and once on placebo. The children were unmedicated for both interactions.

The interactions included doing homework, playing, and having family problem-solving discussions, as appropriate for the age of the children.

These activities were videotaped to record both negative and positive behaviors that parents and children exhibited.

Dr. James Waxmonsky

"For example, we wanted to see how many times did the parent repeat themselves, how many negative comments or positive comments did they make, how much did the child argue, whine, or complain," Dr. Waxmonsky explained.

In the second phase of the study, the parents were randomly assigned to continue blinded, optimized treatment with LDX or placebo for an additional month, and then the parent-children pairs were again brought in for a final interaction.

Improved Behavior in Kids

Significant reductions in ADHD symptoms in the parents were seen in the first phase, but despite this, they did not exhibit any changes in their parenting behavior. However, there were significant reductions in child negative behaviors during the homework task (P = .023).

In the second phase of the study, however, the parents who had undergone continuous treatment with LDX used significantly more praise (P = .013), were more verbally responsive to their child (P = .044), and reduced their verbalizations (P = .043) and commands (P = .018) compared with their behaviors during phase 1 of the study.

Additionally, the parents who were treated continuously with LDX increased their use of praise 3-fold (P = .003), whereas for the parents receiving placebo, rates of praise did not increase.

"The parents said less, especially in the homework task, and what they said had a more positive tone. If the child said something, the parents were more likely to respond in a shorter time period," Dr. Waxmonsky said.

"Interestingly, the child behaved much better. The kids were all unmedicated, but the improvement in the child behavior, just by adjusting the parent medication, was almost as much as if we had medicated the child."

It may be that treating parents' ADHD does something that allows the children to behave better, Dr. Waxmonsky speculated.

"The parents then react to their children's improved behavior and adjust their parenting, become more positive. They learn they don't have to repeat themselves and become more encouraging and nurturing in their interactions with their children."

The group plans to continue the study in hopes of reproducing these results in a larger sample.

"We're very interested now in seeing if giving adults with ADHD pharmacological treatment also helps them maximize the gain from behavioral parent training, so that if they go through such training sessions, do they get more out of them if their ADHD is under control? That is our next step," Dr. Waxmonsky said.

A Fine Study

"Previous research has shown that when depressed parents are treated, and their depression goes into remission, their children benefit, with improved health and well-being and fewer behavior problems," Alan J. Gelenberg, MD, Shively/Tan Professor and chair, Department of Psychiatry, Pennsylvania State University, in Hershey, commented to Medscape Medical News.

"Dr. Waxmonsky's fine study demonstrates that when parents suffer from ADHD, are treated, and improve, their children benefit. Building on previous work, this study shows that not only do parents report improved behavior in their children but that a laboratory simulation confirms that it is true."

The study was supported by an investigator-initiated grant from Shire. Dr. Waxmonsky reports a financial relationship with Shire. Dr. Gelenberg reports no relevant financial relationships.

New Clinical Drug Evaluation Unit 53rd Annual Meeting. Abstract 3. Presented May 29, 2013.

Probiotics and Prebiotics in Preventing Food Allergy and Eczema

Mikael Kuitunen

Curr Opin Allergy Clin Immunol. 2013;13(3):280-286. 

Abstract and Introduction

Abstract

Purpose of review To describe the current literature on clinical trials of probiotics for eczema and food allergy prevention in view of recent new approaches and long-term follow-ups.

Recent findings Attempting allergy prevention by probiotic administration has been most successful when assessing atopic eczema, the most prevalent allergic disease at an early age. More than half of the published studies demonstrate a decrease in eczema prevalence until 2 years, whereas the remaining studies fail to show an effect. Effects have been most consistent with combined prenatal and direct postnatal supplementation of the infant and appear strain-specific, with Lactobacillus rhamnosus most often showing an effect. Prenatal-only and postnatal-only studies often fail to show effects. Recent long-time follow-ups have shown promising but not consistent results. A very recent follow-up of a large well conducted cohort shows that long-term effects of eczema prevention persists until age 4 and prevention of respiratory allergies might also be possible.

Summary Prevention of eczema with probiotics seem to work until age 2 years and extended effects until 4 years have been shown in high-risk for allergy cohorts. Effects are strain-specific, with L. rhamnosus showing the most consistent effects especially when combining pre and postnatal administration.

Introduction

The increase in allergic diseases has been linked to the relative lack of microbial stimulation,^[1] especially in early childhood when the permeability of the gut is higher^[2]and the gut immune system is not fully developed.^[3] A recent understanding is the coevolution of the human species and the metagenome.^[4] The diversity of the microbiome and its contribution to the development of allergic and autoimmune diseases has gained much attention.^[5] The body's largest immune system residing in the gut is complexly stimulated by the gut microbiome, which is considered central when evaluating the hygiene hypothesis, now rephrased as the micoflora hypothesis of allergic diseases.^[6,7] New molecular techniques enable broader analysis of microbiota and the microbiome.

Development of oral tolerance requires contacts with microbes.^[8] A low diversity of gut microbiota during the first months has been associated with development of atopic eczema.^[9,10] Mice reared in germ-free environments do not develop tolerance, but this can be reconstituted with the administration of bifidobacteria.^[11] Further, less lactobacilli and bifidobacteria have been shown in the gastrointestinal tract of infants developing allergy later.^[12,13] This led to the probiotic concept.

Supplementing microbes using probiotics, health-promoting nonpathogenic bacteria in an attempt to prevent allergies is a well tolerated alternative.^[14–16] Twenty-three randomized, placebo-controlled intervention studies regarding the clinical effect of probiotic supplementation on development of allergy and eczema in particular have been published. Eczema is the most prevalent allergic disease in early childhood and fairly easy to diagnose reliably using well defined validated criteria and a reliable marker of allergic disease being a significant risk factor for developing respiratory allergies later.^[17] Many studies also report on the prevention of food allergy, but its prevalence is significantly less than that of eczema. Around 60% of the studies show a favourable effect decreasing the risk of eczema during the first years of life. The remaining studies fail to show an effect. Most investigators have chosen high risk for allergy cohorts to study the probiotic preventive capacity. This review highlights recent work on prevention of eczema and food allergy using probiotics. Since the publication of earlier reviews on prevention and treatment of allergic diseases,^[18,19]several large prevention studies have been published that are the focus of this review.

Clinical Probiotic Studies on Prevention of Eczema and Food Allergy

The main probiotic prevention studies are summarized in .^[20–42] In the largest cohort reported (n = 1223), supplementing pregnant women from week 36 with a mixture of four probiotics [Lactobacillus rhamnosus GG (LGG), L. rhamnosus LC705, bifidobacterium lactis Bb12 and propionibacterium] and infants receiving the same probiotics and a prebiotic oligosaccharide from birth to 6 months with 925 infants followed until age 2 years after showed a 20% reduction of eczema [32.3 to 26.0%, odds ratio (OR) 0.69 (0.52–0.93), P = 0.015] and a 30% reduction of atopic eczema [17.7 to 12.4%, OR 0.61 (0.42–0.90), P = 0.012] compared with the placebo group.^[25] Long-term follow-up until age 5 of 891 infants showed no effect in reducing eczema or any allergic disease in the whole cohort, but a significantly diminished cumulative incidence of IgE-associated eczema and food-specific IgE-sensitization in caesarean-delivered children (17% of the cohort).^[26] They showed a delayed colonization with bifidobacteria compared with vaginally delivered children, which was corrected with probiotic supplementation. A good retention of children was shown, with 88% attending at the 5-year visit. The second largest cohort from New Zealand is unique in comparison of two different probiotic strains. Pregnant women (n = 474) were treated with Lactobacillus rhamnosus HN001, bifidobacterium animalis subsp lactis HN019 or placebo 1 month prenatally and until 6 months to the breastfeeding mother and directly to infants from birth until 2 years. A 50% reduction of eczema in the lactobacillus group [26.8 vs. 14.8%, hazard ratio 0.51 (0.30–0.85)], but no change in the bifidobacteria group was found.^[32] The study highlights the importance of the bacterial strain; not every probiotic strain is efficient. The probiotic intervention was prenatal combined with postnatal both to the lactating mother and directly to the infant and with a longer intervention than in most studies. Very recently, their 4-year follow-up was reported^[33] showing sustained eczema reduction with L. rhamnosus. Interestingly, this is also the first study to show a reduction in respiratory allergies with less rhinoconjunctivitis, indicating that by preventing early onset eczema, it is possible to stop the atopic march. These two largest cohorts show an eczema preventive effect from L. rhamnosus alone or in a mixture with other strains, but not all studies do so.

Table 1.  Main probiotic prevention studies

Ref.	Population active, placebo	Probiotic and daily dose	Intervention prenatal	Postnatala	Follow-up, years	Result for eczema
Kalliomaki et al. [20]	FHA+ 159 randomized, 132 completed A=64P=68	Lactobacillus rhamnosus GG (LGG) 2×1010	1 month	6 months to BF mother or infant if not BF (56%)	2	RR of eczema 0.51 (0.32–0.84) in probiotic vs. placebo
Kalliomaki et al.b [21]	107 completed A=53P=54				4	RR of eczema 0.57 (0.33–0.97)
Kalliomaki et al.b [22]	116 completed A=53P=62				7	RR of eczema 0.64 (0.45–0.92)
Rautava et al. [23]	FHA+ 62 randomized, 57 completed A=27,P=30	LGG 2×1010	2–4 weeks	3 months BF mother only	2	RR of eczema 0.32 (0.12–0.85)
Rautava et al[24]	FHA+ 81 randomized, 72 completed A=32,P=40	LGG 1×1010, B. lactis Bb12 1×1010	No	From start of infant formula to 12 months	1	NS eczema decrease 20 to 13% in placebo vs. probiotic group
Kukkonen et al. [25]	FHA+ 1223 randomized, 925, completed A=461P=464	LGG: 5×109, L. rhamnosus LC705: 5×109,B breve Bb99 : 2×108, propionibactfreund: 2×109 mothers 2 × dose	1 month	6 months	2	OR of eczema 0.69 (0.52–0.93) and of IgE+eczema 0.61 (0.42–0.90)
Kuitunenc et al. [26]	891 completed A=445P=446				5	No difference in eczema in whole cohort; OR 0.43 (0.19–0.95) in probiotic caesarean delivered
Taylor et al. [27]	FHA+ 226 randomized, 178 completed A=89P=89	L. acidophilus 3×109	No	6 months	1	No eczema difference between groups; more IgE+ eczema in probiotic group (26 vs. 14%),P=0.045
Prescottd et al. [28]	153 completed A=77,P=76				2.5	No eczema difference between groups
Jensend et al. [29•]	123 completed (54%) A=66, P=57				5	No eczema difference between groups
Abrahamssonet al. [30]	FHA+ 232 randomized, 188 completed A=95P=93	L. reuteri 1×108	1mo	12 months	2	Eczema no difference, less IgE+ eczema 2nd year in probiotic group (8 vs. 20%), P=0.02
Kopp et al. [31]	FHA+ 105 randomized, 94 completed A=50P=44	LGG 1×1010	1 month	0–3 months BF mother only, 3–6 months direct to infant	2	No eczema difference between groups
Wickens et al. [32]	FHA+ 512 randomized, 446 completed A1=144 A2=152 P=150	L. rhamnosus HN001 6×109, B. animalisHN019 9×109	1 month	Until 6 months if BF + direct to infants 2 years	2	HR 0.51 (.30–.85) of eczema in lactobacillus group; no difference to placebo in bifidogroup
Wickense et al. [33•]	425 completed A1=136, A2=146, P=143				4	HR 0.57 (0.39–0.83) of eczema in lactobacillus group; no difference to placebo in bifido group
Huurre et al. [34]	Unselected 171 randomized, 140 completed A=72 P=68	LGG 1×1010, BifidoBb12 1×1010	From 1st trimester	End of BF to mother only	1	No significant eczema difference between groups
Soh et al. [35]	FHA+ 253 randomized, 245 completed A=124P=121	B. longum BL999 & L. rhamnous LPR sum 2.8×108	No	6 months	1	No significant eczema difference between groups
West et al. [36]	Unselected 179 randomized, 171 completed A=84 P=87	Lactobacillus F19 1×108	No	Age 4–13 months in cereals	1	Eczema lower in probiotic 11% vs. placebo 22%, P<0.05
Niers et al. [37]	FHA+ 156 randomized, 98 completed A=50P=48	B. bifidum W23 1×109, B. lactis W52 1×109, Lc. lactis W58 1×109	1 month	12 months	2	Parent reported eczema lower at 3 mo, later no difference between groups
Dotterud et al. [38]	Unselected 415 randomized, 278 completed A=138P=140	LGG 5×1010, L. acidopLa–5 5×1010, Bifido Bb–12 5×109	1 month	3 months to BF mother only	2	OR of eczema 0.51 (0.30–0.87) in probiotic group vs. placebo
Kim et al. [39]	FHA+ 112 randomized, 68 completed A=33P=35	B. bifidum BGN4 1.6×109, B. lactis AD011 1.6×109, L. acidoph 1.6×109	1–2 months	3 months to BF mother, then age 4–6 months to infant	1	Less eczema in probiotic 36% vs. placebo 62%, P=0.029
Boyle et al. [40]	FHA+ 250 randomized, 210 completed A=108P=102	LGG 1.8×108	1 month	No	1	No significant eczema difference between groups
Rautava et al. [41]	FHA+ 241 randomized, 205 completed A1=62, A2=73, P=70	A1: L. rhamnosus LPR+ B. longum BL999, A2: L. paracasei ST11+ BL999, 1×109each	2	2 months BF mother	2	OR of eczema 0.17 (0.08–0.35) in A1 and 0.16 (0.08–0.35) in A2
Ou et al. [42]	FHA+ 191 randomized, 128 completed A=65,P=63	LGG 1×1010	From 2ndtrimester	6 months BF mother or non-BF infant	3	No significant eczema difference between groups

FHA, family history of atopy positive; HR, hazard ratio; OR, odds ratio; RR, relative risk.

^aProbiotic directly to the child, if not otherwise specified.

^bSame cohort as Kalliomäki 2001 ref [20].

^cSame cohort as Kukkonen 2007 ref [25].

^dSame cohort as Taylor 2007 ref [27].

^eSame cohort as Wickens 2008 ref [32].

Some studies used postnatal-only probiotic supplementations. In an Australian study, Lactobacillus acidophilus or placebo was administered from birth to 6 months in 231 newborns. Their long-term follow-up study until 5 years has just been published in which no significant difference in prevalences of eczema, food allergy or respiratory allergies were found^[29] consistent with earlier reported 1^[27] and 2.5 years^[28] of follow-up. Another postnatal-only study by Soh et al.[35] in Asian infants stated that infants were given Bifidobacterium longum and L. rhamnosus during 6 months in two logs lower concentrations than other studies, and they found no allergy-preventive effects. Nonhydrolyzed fermented milk with or without heat-killed Bifidobacterium breve and Streptococcus thermophilus was given from birth until 1 year and children followed at 4, 12 and 24 months. No difference in cow's milk allergy prevalence was found, but decreased positive skin prick test to cow's milk and incidence of digestive and respiratory potentially allergic events emerged.^[43] Hence, postnatal-only supplementation appears less effective in allergy prevention.

All aforementioned studies assessed allergy-preventive capacity of probiotics in high risk for allergy cohorts. Three studies used unselected cohorts. An easy-to-implement approach was used in a Swedish study,^[36] in which supplementation with Lactobacillus F19 during weaning from 4 to 13 months resulted in halved eczema frequencies at 13 months. In a Norwegian study,^[38] a probiotic mixture (LGG, L. acidophilus La-5 and Bifidobacterium animalis) given 1 month prenatally and 3 months to the breastfeeding mother showed less atopic eczema in the children at 2 years in the actively treated group [OR 0.51 (0.30–0.87)]. Supplementing the mother pre and postnatally without infant supplementation can possibly work and would be an easy way of supplementation. Boyle et al.[40] assessed whether prenatal administration without supplementing infants would suffice for allergy prevention. Using LGG from 36 weeks of gestation until delivery had no effect on eczema prevalence by age 1 year, however. A recent study evaluated the effects of maternal supplementation of L. rhamnosus LPR and B. longum BL999, Lactobacillus paracasei ST11 and BL999 or placebo 2 months before delivery and during breastfeeding from birth to 2 months. Eczema risk very efficiently decreased in both probiotic groups until 2 years [OR 0.17; 95% confidence interval (CI) 0.08–0.35, P < 0.001 and 0.16; 95% CI 0.08–0.35, P < 0.001, respectively].^[41] This study shows an effect from two combinations of bifidobacteria and lactobacilli, an unusual finding in probiotic studies. In a similar study, LGG or placebo was given to atopic mothers from the second trimester of pregnancy. After delivery, LGG was given to the breastfeeding mother or to nonbreastfeeding infants for 6 months. No effects on prevalences of allergic diseases including eczema were detected. However, the mothers' own allergic disease symptoms were relieved.^[42]

Taken together, prenatal maternal supplementation appears important for allergy-preventive effects, leading to faster infant colonization, but prenatal-only supplementation seems insufficient.^[40] Further changes in the breastmilk composition can be important for the preventive effects.^[40,44–46]

Two studies have evaluated the eczema-preventing effect of prebiotics. Moro supplemented with a galacto-oligosaccharide (GOS)/fructo-oligosaccharide (FOS) vs. maltodextrin in extensively hydrolysed formula in high-risk infants from birth to 6 months showed a significantly reduced risk of eczema at 6 months in the GOS/FOS group (9.8%; 5.4–17.1 vs. 23.1%; 16.0–32.1, P = 0.014),^[47] an effect that was sustained until 2 years.^[48] An increase in faecal bifidobacteria was evident in the GOS/FOS group.^[47] A multicentre study from five European countries randomized 830 low-risk for allergy infants to receive a regular formula with or without prebiotics before the age of 2 months. At 1 year, the prevalence of atopic dermatitis was 44% lower in the prebiotic group.^[49]

Systematic Reviews on Probiotics for Allergy Prevention

Several systematic reviews addressing probiotics for allergy prevention have been published and a more analytical approach was used in two meta-analyses.^[50,51] A recent review summarized the publications on probiotics and prebiotics for preventing allergic disease including six randomized controlled studies. It concluded that an effect on development of eczema could be supported, with the strongest effect when supplementation started prenatally, in which seven out of 10 studies showed a decrease in eczema frequency until 2 years [OR for eczema 0.76 (95% CI 0.64–0.91) and atopic (IgE-associated) eczema 0.70 (95% CI 0.56–0.88)].^[51] However, due to the heterogeneity of study design using different populations in diverse environments, various strains and study designs, especially time and length of intervention, it is difficult to perform stringent meta-analyses and hence conclusions should be cautious.

In summary, results from studies on primary prevention of allergies using probiotics should be limited to used strain(s) and time (pre and/or postnatal) and length of intervention as well as populations (high-risk, normal risk) and setting (hygienic conditions in study environment). The use of prebiotics should also be taken into account.

Mechanisms of Action in Allergy Prevention

The prenatal exposure to a farming environment has also pointed to the importance of prenatal exposure for allergy-preventive effect.^[52] By colonizing the mother prenatally, the transfer of favourable bacteria to the infant starts during birth. Also, immunomodulation of the mother and changes in her breastmilk composition could benefit the infant with regard to allergy development.^[45,46] It appears that the prenatal immunomodulation is insufficient for a change in the child's immunologic response to the nonallergic phenotype and needs to be followed by stimulation of the infant's gut immune system, preferably directly to the infant.

The preventive mechanism by which probiotics operate might be the modification of the gut microbiota and immunomodulation. In-vitro and in-vivo immunologic effects have been shown from probiotic administration.^[53,54] We showed an inverse association of C-reactive protein (CRP) and development of eczema. Probiotics induced a low-grade inflammation characterized by increased IgE, IgA, interleukin (IL)-10 and CRP.^[53] We propose that a chronic low-grade inflammation may be the link between probiotics and development of allergic diseases similar to the inflammation induced by people with helminth infestation. Probiotic administration has resulted in demonstrable changes in the levels of the given strains in faecal samples in reported studies and supplementation has been successful in all studies^{[25–27,31,35,37]} in which colonization has been reported. However, there is no good evidence for a permanent colonization of the supplemented probiotic in infants or children and in adults given probiotics, which can be found in faeces only for weeks after stopping the intervention.^[55] A short prenatal supplementation of LGG modulated the infants' intestinal colonisation with Bifidobacteria towards that of a healthy breastfed infant^[56] but did not affect microbial diversity.^[57] Administering only one or few probiotic bacteria cannot affect the gut microbial diversity. Further, supplying one bacteria leads to bacterial antigen exposure of the host's immune system, that after a specific mucosal IgA-response develops, diminishes.^[58] Pakistani children have a higher turnover of Escherichia coli strains than Swedish children.^[59] An interesting approach would be to constantly change the supplemented probiotic bacteria to achieve a stronger and long-lasting immune stimulation. This would be a surrogate for the diminished microbial diversity in our westernized societies.

Conclusion

No proven effective way of primary prevention of allergic disease has been found, despite intensive research on environmental and dietary factors assessed, including breastfeeding, maternal diets and dietary restrictions, during pregnancy and lactation.^[60] The most promising allergy-preventive alternative is administration of probiotic bacteria. However, giving recommendations on allergy prevention is difficult because the studies have used different probiotic strains and timing.^[61] The majority of studies have evaluated eczema as the main outcome rather than food or other allergies. There is a growing body of evidence that primarily L. rhamnosus strains can be effective in preventing eczema. Recent studies show that an effect can be seen until at least 2 years, a good result already, and further some new studies show a longer effect until 5 years. By preventing development of food allergy and eczema, it is hoped that stopping the allergic march would be possible. Combined pre and direct infant postnatal supplementation has demonstrated most consistent effects. Choosing the most effective strains or combination of strains and the mode and length of the supplementation needs to be settled. We still need long-time follow-ups of the rigorous large preferably multicentre studies. We have seen in-vivo immunologic actions related to administration of probiotics, one attractive mechanism relating to low-grade inflammation, but we still have a lack of understanding of the mechanisms behind the allergy-preventive effects afforded by probiotic bacteria. There is also a potential for prebiotics in allergy prevention, but more studies are needed. There is a variation among probiotic studies related to several factors, including probiotic strain/combination of strains, dose, duration, host factors such as allergy risk profile, mode of delivery and type of feeding.