Does improvement management of atopic dermatitis influence the appearance of respiratory allergic diseases? A follow-up study. Clinical and Molecular Allergy 2010 8:8 Published June 30, 2010. Authors- G Ricci, A Patrizi, A Giannetti, A Dondi, B Bendandi, and M Masi.

Background and purpose of the study

Atopic dermatitis (AD) is one of the most common skin conditions that affect children. AD is characterized by dry, itchy, rough, and flaky skin. Between 70-80% of children who have AD have an elevation of the antibody associated with allergy- IgE and antibodies to foods/inhalants.  Many children outgrow this condition and in some it persists into their adulthood. In some children AD is the first step along the allergic march; going on to have asthma and allergic rhinitis. Depending upon who you ask or quote, 25-80% go on to have asthma. That is a huge range. The authors of this study published a 10 year follow-up study in 2006 looking at this issue. They showed that the AD disappeared in 60%, 34% developed asthma, and 58% developed nasal allergy. So some, not all finish the allergic march with a better chance of having nasal allergy and about a 1/3 chance of developing asthma. This begs the question as to whether or not anything can be done about it.

This current study looked at the effect of clinical management on the subsequent development of other allergic conditions and they used more standardized and contemporary measures of the conditions in asking what are the risk factors in children who have AD that may predict the development of other allergic conditions.

This is a study from Italy. It was a retrospective analysis; children who had AD between 9-16 months of age were contacted for participation. They had to have been seen in the clinic between 1993-2002.

Methodology

The assessment included;

1. Diagnosis of AD based on Hanifin and Rajka criteria (well established for this condition)

2. AD was evaluated by the SCORAD index at the first visit ( a measure of disease severity)

The clinical management program involved;

1. Environmental management- house dust mite avoidance, high-filtration vacuum cleaning,

2. Skin care- emollients, topical corticosteroids, calcineurin inhibitors, oral steroids, immunosuppressants, biologicals, antibiotics, antihistamines, and leukotriene inhibitors

Allergy Assessment;

1. Skin prick tests (SPT), total IgE  and specific IgE tests- milk, egg, soybean, wheat, peanut, nut, codfish, apple, grass pollen, house dust mite, cat dander, and dog dander. A positive was any value >0.35 for the blood test and a wheal response on the SPT.

Telephone interviews

Results

Telephone interviews were conducted with the families of 176 children. Their ages ranged from 6-12 years. The average age at the time of the first evaluation was about 1 year.

One hundred of the 176 (57%) showed a sensitization by SPT to at least one of the foods/inhalants.

One hundred and three of the 176 (58.5%) had an elevation at least one specific IgE blood test.

After an average of 7.5 years 84 (48%) still had AD- it disappeared in 52%. In the group of children who still had AD, 44% had a single site involved (mostly on a limb) and 18% had multiple locations of AD.

When AD disappeared on the average, the child was 3.25 years old.

In this group of children, respiratory allergy conditions appeared in 66/176 (37.5%).The specific respiratory ailments were; 36 (20.5%) developed only nasal allergy, 18 (10%) developed only asthma, and 12 (7%) developed both.

The nasal allergy appeared at 4.8 years of age. The mean age of appearance of asthma was 3.33 years. Asthma tended to precede the development of the nasal allergy.

A mathematical model, logistic regression, was used to predict the occurrence of asthma. A child who developed nasal allergy or was positive to at least one inhalant (serum specific IgE >0.35) at the time of the first evaluation had a greater risk to develop asthma (odds ratio was 4.219).

Conclusions (authors’)

The results of this study were compared to their earlier study in which disease-specific management was not evaluated. In the current study, the use of integrated management of AD did not seem to influence the natural course of AD. However, the early diagnosis and improved management at specialty centers decreased the percentage of children who went on to develop respiratory allergic disease. The presence of early allergic sensitization at age 1 year may predict the development of respiratory allergy.

                                Percentage of Children with Allergic Conditions – Comparing the two studies

                                1981-1989 study                                                                               1993-2002 study

Resolved AD             60.5%                                                                                                  52%^*

Asthma                     34.1%                                                                                                  17%

Nasal Allergy            57.6%                                                                                                  27%

* not significantly different

In the present study at age 8 years (mean age of the children) 15% already had asthma. In the previous study, 29% had asthma by age 8 years. The management program accounted for a reduction in the appearance of asthma in this group. Similarly, the percentage with nasal allergy fell from about 35% to 17%. This could be due to better management of the AD.

This study used quantitative evaluations with determinations of specific IgE sensitivities and the use of improved clinical tools for assessing AD (SCORAD index, environmental prevention, integrated management) that helped with the early diagnosis, appropriate therapy, and monitoring of children with AD. This may have been  helpful in decreasing the numbers who go on to have respiratory allergy.

Reviewer’s comments

I was surprised at the wide range of children who go on from Atopic Dermatitis to Asthma to Allergic Rhinitis. More definitive epidemiologic work is needed to have a more precise estimate. I hear all too often from other allergists that it is an absolute fact; if the child has AD they will have…..This group of investigators had previously  looked at this evolution to other allergic conditions in the 1980s. This earlier study served as a nice comparison group for the current study.

Back in the80′s the tools and criteria differed. The current study tries to standardize the diagnosis of the allergic conditions. The entire group of children were evaluated with the same tools for AD severity and for respiratory allergy.

This study looks at the impact of early evaluation and the impact of management programs on the occurrence of detouring children who may have been on that allergic march. The first detour was asthma and the second change of course was allergic rhinitis.

Evaluation and management seems to re-direct some of these children away from respiratory allergy. it is not known if these conditions appear later in life. That will be a paper for review perhaps 10 years from now.

 The foods that were important were eggs and milk. A specific IgE level was >2.0KU/L to milk or egg was found to be predictive of sensitization to inhalants in late infancy.

Other considerations are that this is a group of children from Italy- the genetics may differ and certainly the environment differs. Such a study needs to done on our population of children to see if the results can be replicated.

As noted by the authors, demographic information was lacking making it a bit more difficult to describe and characterize the population.

Do we need to be more aggressive with our AD children? When should all these evaluations be performed. In this study many of the children had progressed and were very severe at the time they presented to the specialty clinic. The study did not look at how long treatment should be tried before embarking on a more Allergy/Dermatology Specialty oriented evaluation.

I like the selection of allergy tests here. Nut and apple were a surprise for a first evaluation for specific IgE to food at age 1 year. We did not see shrimp or scallops as a choice here.  Also, the evaluation for the inhalants was looking at sensitization- has the child begun to make antibodies towards these items? The study used these as associations and not necessarily as cause/effect items.

I think we need to re-think about the number of children who march from AD to other allergic conditions. It never was 100% – here is it about a third of children who do this. A take home message here is to consider being more aggressive with our evaluations, monitor more frequently, and carefully in hopes of halting that march from AD to Asthma to Allergic Rininits.

FEL

Animals and Asthma- to have or to have not?

  Photo by Bethany King

Recent research has challenged our previous recommendations regarding the role of a pet in the development of asthma and in the development of allergy. The hot topic today is a review of a publication by M. Kerkhof and colleagues titled ‘ Effects of pets on asthma development up to 8 years of age: the PIAMA study’ (Allergy 2009; 64: 1202-1208).

Background: four papers written between 1999-2003 found that a pet in the home during the early years of a child’s life prevented the development of allergy. Six reports between 1999-2004 gave mixed results as to whether or not a pet prevented the development of asthma. A meta-analysis (where the findings of a number of studies are combined) found a small (20%) increase in asthma with early pet exposure up to age 6 years. There have been no studies published regarding the relationship of pet exposure after the first few years of life and the development of asthma. This study fills that void.

Purpose: the study looked at the effect of the presence of cats and dogs in the home at any age during childhood and the incidence of asthma up to age 8 years.

Methods (how they studied this): This was a major survey performed in the Netherlands. There were 2951 children involved. Questionnaires were completed every year for 8 years.

Results (what they found): at age 3 months, 34 % of the children had a cat and 16% had a dog in the home.

1. When a dog was in the home, there was less allergy to house dust mites and to pollen at age 8 years.

2. The presence of a dog or cat in the home at 3 months of age was not associated with the presence of asthma or asthma symptoms when the child was 8 years old.

3. The occurrence of wheeze and a dry cough at night after age 2 years was higher in the children who had a dog in the home at the beginning of the study. The wheeze was more in boys and the dry nighttime cough favored the girls.

4. Removing a dog from the home was associated a higher incidence of wheezing (Odds Ratio = 2.59) and having a prescription for an inhaled steroid (Odds Ratio = 3.03). This was observed in the year after the removal of the animal. Note: a simple way of interpreting the Odds Ratio is that wheezing occurred 159% more and prescriptions for inhaled corticosteroids were 203% more in children where the dog was removed.

  Kita one of our Siberian Huskys- a real snow dog

Conclusions:

1. Pet exposure early in life may prevent the development of allergic sensitization to pollen and house dust mites at age 8 years.

2. Exposure to pets at any age in childhood did not affect the development of asthma up to age 8 years.

3. Exposure to dogs after the first two years of life increased the transient symptoms of wheeze and dry cough.

4. Dog removal increases the risk of wheeze and the need for an inhaled steroid.

Comments: the authors point out weaknesses in their study. One weakness is the problem with having a clear definition of asthma. This is a problem for many studies like this. The authors were able to examine 1132 of the 2951 children and validated the presence of asthma with specialized tests. This becomes an issue when trying to understand the transient wheeze and dry cough. Was this truly asthma or symptoms due to a viral illness? In the discussion it was thought that this was a response to the endotoxin in the environment from the dog that stimulates immune processes away from allergy.

Another potential weakness identified by the authors is that the measurement for allergy was done in only 1248 of the children.

Studies like this start us thinking about what advice to give to families on this subject. It is important to note that this work was done in the Netherlands and not done  in this country. This concept needs to be proven in the United States.  The differences in the populations  may limit our ability to extend the findings to current clinical practices here.

When evaluating a child for asthma, I think we have to be sure of the relationship of the symptoms to the skin test findings. All too often a family is told to get rid of the pets based on the results of an initial set of allergy tests. I am not sure this is an immediate way to proceed and we need to think of other family dynamics that are involved. I have frequently taken advantage of a more sophisticated measure used in asthma care/diagnosis to help figure out the relationship between triggering events and the clinical relevance of an allergy test result. At Riley we can measure exhaled nitric oxide. eNO is a by-product of allergic airway inflammation. When it is elevated there is most probably an allergic trigger causing the symptoms. I may not consider that a positive allergy test to dog relevant when there is significant exposure and the eNO is normal during an event. The asthma episode may be triggered by something else that requires investigation.

No, I am not ready to tell all my families to obtain an array of pets in anticipation of having children. I wonder what to do for those families who do not want the expense of feeding/picking up after pets. Ccould they purchase a ‘Bag o Pet’. This would contain all those things that are responsible for preventing sensitization and the development of asthma and not the live creature. Just a quick thought.

  Loki- (Brandon and Amanda’s cat- name for the Norse god of mischief)

Fred Leickly

One of the most commonly asked questions by young families is how to possibly prevent the development of allergy in the next child. In fact you can see such a question asked on my last post. This is an agonizing question for a pediatric allergist. The specialty of pediatrics and of allergy is very focused on prevention. We immunize to prevent illness, we educate to prevent injury, and we identify allergens relevant to allergic illnesses to direct avoidance measures. When we have identified an allergic child we advocate secondary or tertiary prevention. Specifically we advocate staying away from things that you are sensitized to and things that have caused problems. What is needed is primary prevention of allergy.

Primary prevention would be stopping allergy before it develops in a young child. There are a number of thoughts and ideas on what works best, however for the most part there is no failsafe way to prevent the development of allergy. Most of the time recommendations involve rather drastic elimination/avoidance measures which all too often may have an adverse effect on the quality of life for the child and the family. The medical evidence to support these recommendations is continuously changing. In some instances it never existed. A recent article in the Journal of Allergy Clinical Immunology provides an update on these primary efforts to prevent allergy in young children and in the mothers during pregnancy. This paper focused on the effect of the mother’s immune status on the development of allergy in the child.

The article looked at risk factors for the increase in allergy in the mother during pregnancy, risk factors for sensitizing the child to an allergen, and preventative measures to avoid allergy induction. There is a succinct summation and a few notes on what the future looks like at the end of the article. My reviewer’s prerogative allows me to be selective. I will forgo a discussion on the development of allergy in the mothers and focus on the children.

Risk Factors for Sensitization in the Child:

Remember a risk factor is an association only. It does not determine cause. The establishment of a relative risk directs a search for the cause.

There were 11 topics reviewed;

1. Diet of the mother during pregnancy
2. Exposure to tobacco smoke
3. Exposure to alcohol
4. Treatment with antibiotics
5. Insufficient exposure to environmental bacteria
6. Diet of the mother during lactation
7. Prematurity and low birth weight
8. Exposure route to antigens
9. Breast-feeding, formula diet, and introduction of solid food
10. Mode of birth
11. Epigenetic influences (gene-environment interactions)

1. Diet of the mother during pregnancy- The article has a table of references dealing with a wide variety of food associations-maternal ingestion and outcomes in children. The number in parentheses is the number of references that claimed the association. The use of these foodstuffs was associated with…..

n-6 Polyunsaturated Fatty Acids (PUFA) – increased risk of eczema (2)

Celery and citrus fruits- increased risk of food sensitization (1)

Vegetable oil, raw sweet pepper, citrus fruit- more inhalant sensitization (1)

Nuts – more wheezing, steroid use, asthma (1)

Overall high energy and lipid intake- more sensitization, asthma (2)

Probiotics- No effect on atopic dermatitis at 2 yrs, increased wheezing (1)

As you can see, there is not a substantial literature on this topic. The authors point out that for children without a first-degree relative (parent or sibling) with allergy there is no benefit from special nutritional interventions during pregnancy, during lactation, or during the first year of life

2. Exposure to tobacco smoke- Four articles support the finding that smoke exposure of the mother during pregnancy leads to higher IgE levels (the antibody associated with allergy), eosinophils (an inflammatory cell associated with allergy), airway disease and wheezing episodes in the child.  Of note is the observation that the risk of causing specific IgE to inhalant or food allergens was especially increased in children born to non-allergic parents who were exposed to cigarette smoke in the first two months of life. Usually allergy follows a family history of allergy, however cigarette smoke exposure appears to trigger sensitization in those children not genetically predisposed.

3. Exposure to alcohol- elevated IgE levels in the children.

4. Treatment with antibiotics – two studies have shown that there is more wheezing, more allergy skin test reactivity, and more specific IgE in children who were exposed to antibiotics early in life. The theory here is that there is a disturbance of the good bacteria in the gut by the antibiotics which leads to altered develop of the gut’s immune system.

5. Insufficient exposure to environmental bacteria- this concept is part of the hygiene hypothesis for the development of allergy and yes it is insufficient or not enough exposure to bacteria. When there is not enough environmental bacterial exposure early in life, the immune system develops towards allergic responses. In this model, more frequent acute respiratory tract infections in the first 9 months of age reduces asthma, eczema, hay fever, allergic sensitization, and total IgE levels. More environmental bacteria exposure is good (at least for not going on to develop allergy).

6. Diet of the mother during lactation- contrary to the usual dogma, food exposure may be necessary to develop tolerance (vs. sensitization) to a food. The reference for this statement is an evidence-based review of the literature published in 2006. This review did not find any strong evidence for allergen avoidance during lactation (or pregnancy) in preventing the development of allergy in young children. Clearly more work is necessary in this area.

7. Prematurity and low birth weight- there is no association with an increased risk of developing food allergy. The risk for inhalant allergens has not been studied.

8. Exposure route to antigens- skin exposure is an excellent way to cause sensitization. Environmental skin contact to a food can lead to allergic sensitization whereas oral intake could induce tolerance. This is a fascinating concept. If the food sensitizations are occurring due to skin contact, then where/when/how is this happening?

9. Breast-feeding, formula diet, and introduction of solid food- less breast feeding and the early introduction of solid foods had been a confounder in the development of allergy. Only in high-risk babies did breast feeding for 4-6 months, the use of extensively hydrolyzed formula, and the avoidance of solid foods and cow’s milk worked to prevent atopic dermatitis and cow’s milk allergy until age 2 years. This did not work beyond 4-6 months of age. The negative effect of early introduction of solid food has not been confirmed by an evidence-based review of the literature.

10. Mode of birth- two studies suggest that birth by caesarian section increases the risk for nasal allergy, wheezing episodes, and having food-specific IgE.

11. Epigenetic influences (gene-environment interactions)- a number of risk factors have been discovered. These include diesel exhaust, wood smoke particles, road traffic, and tobacco smoke. More work has been done looking at xenobiotic chemicals, endocrine disruptors, heavy metals, and low-dose irradiation.

Suggestions to decrease the risk of developing allergic sensitization-

Avoidance of tobacco smoke by the mother and the child

Avoidance of alcohol during pregnancy and lactation

Eat a well-balanced diet; no special diet is needed unless there is a known food allergy

Avoidance of animals and dust only if allergy already exists

Avoidance of solid food until 4 months of age

Avoidance of nonprescription drugs, self-medication, and dietary supplements

Summary

The list of what should be avoided for a growing child has shortened due to the appearance of more controversial studies and a re-asking of the critical questions. What has stood the test of time is the continued recommendation to avoid tobacco smoke and alcohol. No special diet is needed by the mother during pregnancy or lactation unless the mother or the child already has a known sensitization/food allergy. The avoidance of pets, house dust, contact allergens, or medications is only recommended for those known to be already sensitive to these things. Exclusive breast feeding is recommended for at least 4 months but no longer than 9 months. The special hypo-allergenic formulas, those that have extensively hydrolyzed protein or are amino acid-based should be used for high-risk children to prevent atopic dermatitis or in one who already has this condition.

This is a tough area. We all want to do anything we can to prevent the development of allergy. The recommendations have changed over time. The allergist needs to keep track of these advances in our understanding of allergy prevention. The new recommendations follow the trend of using evidence-based medicine. These reviews have shown us no substantial evidence to support previous recommendations regarding the prevention of allergy in children. This is a very rich area of interest for many families and for research. I am confident that we will be seeing better studies. When these finally arrive be ready for more changes in what we recommend.

Fred Leickly