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

During a career you hear many words of wisdom from your mentors who are with you seeing children in the office and from meetings, curbside conversations/consultations, and from the literature. The adage that allergic children get sick easier, more frequently, and have more severe illnesses has been out there for many years. There are a number of theories for this contention. Children with allergy tend to remedy their itchy nose with internal manipulation, otherwise known as nose-picking. The finger serves as the vector for direct inoculation of viral particles onto the respiratory tract. Also, a number of years ago a publication reported that allergic noses actually had more receptors for the cold virus than non-allergic noses.

The May issue of the  Journal of Allergy, Asthma, and Immunology (Volume 125 No 5.) has an article by Jaime Olenec, ‘Weekly monitoring of children with asthma for infections and illness during common cold seasons’ concluded that atopic (showing IgE antibodies) children with asthma do have more frequent and more severe asthma exacerbations due to the common cold. The bottom line for me is the impact that the specialty of allergy and the determination of sensitization to allergens can make on children with asthma. The study did not address allergen control measure effects on frequency/severity of asthma symptoms.

My review of the study-

The group who did this is excellent and has a long established research track record and publication record regarding the role of viruses and allergy in pediatric asthma.

The journal in which this was published is peer-reviewed and a top-notch allergy journal. Also of note is that the manuscript was submitted in September, 2010 and was accepted for publication four months later.

The support for the work was from the National Institutes of Health.

The purpose of the study was to look at the impact of viral infections and allergic sensitization on the loss of asthma control during the peak ‘cold’ season.

The study involved 58 children between the ages of 6-8 years who were known to have asthma. These children were followed for three years. Skin testing and specific IgE testing was performed on all. Nasal samples were collected and analyzed for human rhinovirus infection. Diary cards were kept for symptoms. Cold and asthma symptom scores were collected along with peak flow value recordings and notations of the frequency albuterol (rescue inhaler) usage.

There were 42 children who had at least one season of complete data. The average age was 6.5 years and there were 30 boys and 12 girls. In this group 50% had one or more positive skin prick test for an allergen. Of note is that 69% had one or more positive blood tests for an allergen. Additional baseline information included; daily asthma controller medications used by 88%, and oral corticosteroids were used by 57% in the past year. Fifty five percent of the mothers and 40% of the fathers had allergy.

The number of viral illnesses per season was higher in the allergen sensitized group; 47% more virus-associated illness per season. During documented viral infections (viral cultures were frequently performed), the non-atopic children commonly reported no or mild cold symptoms. In the sensitized (atopic) children symptoms tended to be more moderate or severe. Also, almost half of the viral infections in the sensitized children caused moderate or severe asthma symptoms.

The author’s conclusions were that respiratory tract illnesses (asthma symptoms) due to viruses were more severe and were more frequent in children who are atopic.

These were children with asthma who had a positive allergy test. The terms sensitized and atopy were used to describe the group. Asthma frequency and asthma severity was increased in those who have made at least one IgE antibody to something.

This was a small study which was done in only one site. Larger studies in a variety of populations need to be done to confirm these observations.

This work re-affirms my practice of being aggressive with my allergic asthmatic children when the first signs of a cold occur. I advocate stepping-up the treatment program and continuing it for up to 14 days. One of the charts shows that the average duration of cold symptoms was 8.1 +/- 5.6 days and the average duration of asthma symptoms was 7.2 +/- 7.8 days in those who had a documented rhinovirus infection. For me this fits nicely with what I advise- on the average cold symptoms may begin the day prior to asthma symptoms and at the extremes of the range, asthma symptoms may last 14 days in some children.

FEL

A message was forwarded to me about a news broadcast from Chicago that highlighted a tool that can be used to help with asthma diagnosis and management. The FDA has recently approved this according to the message. This tool is the measurement of exhaled nitric oxide (eNO). In allergic asthma  airway inflammation involves numerous inflammatory cells especially eosinophils. These inflammatory cells have a marker for their involvement and activation called nitric oxide. We are able to measure this by-product of airway inflammation in the breath. I also received another link on this measure of airway inflammation. In this second newsbroadcast Dr. Wolfe, an allergist, does a nice job in explaining this test, this measure, and allergic asthma.

This is not a new procedure. At Riley Hospital our group has been using this measurement in the care of children with asthma. It is nice to see that the concept of eNO is catching on and its value is appreciated.

I feel that a measure of eNO offers a significant amount of information regarding the role of allergy and the level of control patients with asthma have. I use eNO measures frequently in my Allergy/Asthma practice.

FEL

Saints celebrate a Super Bowl win

I just returned from New Orleans where I attended the American Academy of Allergy, Asthma, and Immunology (AAAAI) annual meeting. It was very hard for an Indianapolis Colts fan to venture into the city that beat my team in the most recent Super Bowl. They still celebrate that victory – deservedly so. It’s just that everywhere you go you see ‘Who dat’ Saints stuff. 

At this meeting I had two major agendas; to update my understanding of the conditions I see and care for in my profession and to begin the process of recruiting our third full-time allergist for Riley Hospital. When I got to Riley in 1994, I was the first staff allergist there in 22 years. The allergy service has been up and running. We (Dr. Vitalpur and I) are looking to expand and we need to expand.  We interviewed a few current fellows in training and we look forward to their visits with us. It is exciting to interact with physicians currently in their training programs. These are young people eager and ready to embark on their career choice of patient care, teaching, and research in the field of allergy/clinical immunology. This is an exciting time for the allergy program at Riley. 

In a later posting I plan to include more material on food allergy. I have been invited to give an update from the meeting (food allergy topics only) at a food allergy support group this Tuesday (March 16) in Greenwood, In.  My thought is to have the group hear my presentation first then publish it on the web. The early preview of the update is for the support group. 

Food Allergy 

More on this later however, the meeting had many talks on the concept of ‘tolerance’. The is the condition by which despite a specific IgE (blood test/skin test) to a food that food has been ingested and continues to be ingested without any clinical symptoms. 

Now here is the clinical scenario that we need to think carefully about. Trail mix (made of peanut and tree nuts and other stuff) is ingested and an allergic reaction occurs. The child is treated in the office and the advice is to not eat peanuts or tree nuts. Blood is drawn and the specific IgE is positive to a number of tree nuts and to peanut. The history of food exposure before the reaction indicated that roasted peanut products are eaten every day by this child. Tree nut exposure has occurred in the past but very irregularly. So which food caused the reaction? Peanut which was a daily part of the child’s diet (you have exposure, constant ingestion, and an positive allergy test) or a tree nut (you have exposure, rare re-exposure, and a positive allergy test).  In this case, despite a positive IgE to peanut, the child was ‘tolerant’ to peanut. The history indicated that there was frequent exposure to peanut. The problem is that by avoiding peanut, tolerance may be lost and re-introduction of peanut may cause clinical symptoms. 

Food sensitization in children may be due to environmental exposures to the food (vs. ingestion). 

The Future of Inhalant Immunotherapy 

Currently we have subcutaneous (SQ) allergen immunotherapy (IT)- allergy shots, injections. This form of therapy has been well established for 100 years. It is somewhat crude/unrefined and reactions can occur. The advances in this field include; 

1.  Sublingual immunotherapy (SLIT)- not approved in this country 

2.  Peptide immunotherapy (PIT) 

3.  Allergen fusion proteins 

4.  Allergens attached to viruses 

Anaphylaxis 

Fatal allergic reactions may not always have skin manifestations. Low blood pressure was seen in 80% and 60% had respiratory effects. Skin reactions occurred in 60%. All too often there is a delay in recognizing anaphylaxis when skin reactions are absent. Not everyone experiencing an anaphylactic reaction will have a skin reaction. 

Asthma 

I was involved as a principle investigator in the first phase of the National Cooperative Inner-City Asthma Study (NCICAS). I attended a session on inner-city asthma given by Herman Mitchell. Dr. Mitchell has been involved with this issue for many years. He shared a number of observations that spanned almost two decades of investigation. 

            Asthma is not just one disease. It is many diseases. It is complex and multi-causal. There are many factors that interact that determine its development and its exacerbations. This would be true for all populations with asthma. 

            The inner-city asthma studies emphasized the importance of sensitization (having a positive allergy test) and exposure (measuring the allergen in the environment). 

            House dust mites were found more often and in greater amounts in detached, low-rise housing and less in high rise apartments. In evaluating a child with asthma, we need to know what type of building they live in. 

            High humidity in the home is a factor. 

            Air pollution poses a conundrum. Overall air pollution levels have decreased, yet asthma prevalence has increased. Could this be a protective effect? Approximately 25% of children currently live in environments that exceed the standards for safe air. Things to consider in the child’s environment include how far away they live from a main road. 

            Asthma is a weighty problem. Inner-city asthma studies have shown 29% of the children with asthma are obese and 56% are over the 85%tile for weight. Between 85-90% of the child’s time is spent indoors where it would be difficult for active play/exercise. Safety concerns of the inner-city environment contributes to this problem. 

Human Genome Studies 

            This is a very hot topic. Most of it is research based however one of the anticipated outcomes would be to look at someone’s genetic profile and be able to predict susceptibility, expression, and severity of asthma and allergic diseases. We may be able to predict the kind of asthma someone will have and design very specific programs to prevent/treat. 

Asthma Treatment- Inhaled Corticosteroids 

            Not everyone responds to inhaled corticosteroids (ICS) given for asthma. Up to 50% of those on ICS may not respond. There are no biomarkers that we can use to determine in which patients a ICS will work; we depend on a clinical response. 

            The question is how long do you wait until it is determined that the ICS has made no difference? 

            This presentation posed many probing asthma management questions. It is important to set goals/outcomes when starting a program and to bring the patient back in a reasonable period of time to see if those goals/outcomes have been achieved. We also have to make sure that there was adherence to the therapeutic program (it is hard to tell if something was a failure/success if it was not used). In this situations it may be of benefit to start at a higher than anticipated dose looking for any response. 

Allergy Blood Testing 

            There are three companies that offer the blood tests for IgE and the results they provide are not equal. You cannot compare one with the other. 

            The future microarray technology will help us sort out relevant allergens. Skin testing and blood tests for allergy use very crude protein extracts that may have different and numerous proteins. The results obtained may be due to cross-reactivity with other substances or even binding to proteins that cause no clinical reactivity. 

            Of importance- the blood test result, the concentration of IgE antibody (kU/L) provides predictive power for a reaction it does not tell us anything about the severity of a reaction. 

            Do not use the term RAST- it is outdated, it refers to a technology no longer used. 

Urticaria- Hives 

            This is one of the most frustrating clinical conditions that we see. Parents, patients, and healthcare providers want the answer for the hives. I think the frustration of not knowing will continue. Idiopathic is the medical term used to describe something for which no cause has been determined. In some contexts it means the healthcare provider is the ‘idiot’ because they were unable to figure it out. 

            More than 80% of the time, chronic (more than 2 months) hives is idiopathic. The evaluation needs to consider the role of aspirin and other non-steroidal anti-inflammatory medications. Physical reasons for hives also need to be considered (light, pressure, water, heat, cold, or vibration). 

            The list of agents used to treat hives was described as ‘weird’. Frequently, a typical (H1) antihistamine has added to it an H2 antihistamine (commonly used to treat excess stomach acid). There are a variety of combinations used, however the definitive study that showed a positive effect was the used of hydroxyzine and cimetidine. The mechanism of action was the impact of the cimetidine on the liver metabolism of the hydroxyzine- cimetidine allowed the hydroxyzine to be around longer. 

            A somewhat new therapy for hives was the immunosuppressive agent cyclosporine. Adding a second H1 antihistamine may help. 

These are some of the highlights from the meeting. More specifically these comments come from the notes taken that I could read. 

Check-in next week – I plan to post my notes on the majority of food allergy topics after my presentation on March 16, 2010. 

FEL 

 The article did contain something that I strongly feel needs to be critiqued and clarified. The content expert for the quote was an associate professor of family practice at Michigan State University. Dr. Reinhardt is quoted as saying that the National Heart, Lung, and Blood Institutes (NHLBI) Guidelines for the Diagnosis and Management of Asthma 2007 advocates the use of the Phadia test to determine whether a person has allergies to common indoor allergens. He also states that too few clinicians are using this test.

 The first comment is out of context with other considerations that need to be addressed prior to ordering an expensive and perhaps unreliable laboratory test. The comment supports one commercially available product (fair balance). It assumes that this commercial product is the one the Guidelines recommend. As to the last comment regarding the use of the Phadia test for inhalant allergens, this is most probably because clinicians may be aware of the problems with this approach to allergy.

 The 2007 asthma guidelines do not specific the Phadia test for determining allergy. On page 168 of the NHLBI Asthma Guidelines Key Points clearly indicate that there are more steps involved- a relevant history, skin testing or in vitro testing, and an assessment of the significance of the test results. The guidelines do not mention specifically the Phadia test in the Key Points. This test has value, but only in the context of a patient’s history. The Phadia test for inhalant allergens is frequently falsely positive. In a recent national survey (JACI 2009;123:1163-9) 20% had symptoms of allergic disease. The Phadia test for inhalants demonstrated that 50% of the population had a positive test (for more on this article see ‘Incidence of Allergy in Children: Using Allergy Testing Panels (Pharmacia ImmunoCap) or Symptoms?’ one of my earlier posts on this topic). It is very important to point out that any test used in allergy only tells us that antibodies are produced. It is the history of symptoms plus the results of the test together that fulfill the criteria for allergy. A test result alone makes no one allergic and is only as useful as the history that supports it.

 In my opinion the reason why the Phadia test is not being used is because clinicians are aware of the need of taking a history, they dislike the obligatory panel of analysis offered by the Phadia panel, there is worry about the cost, and the test declares many more positive than actually have symptoms.

 Do we let the laboratory test dictate the diagnosis/treatment or the patient’s history matched to relevant laboratory studies to decide how to manage asthma?

I am old school- I make sure that I understand the history of the condition and the environmental exposures. From this I decide what tests for allergy are relevant and use testing to verify my clinical impression. Sometimes we don’t need to test. Sometimes we have to take the test results and re-evaluate the history and exposures to make sense of it all. Health care is expensive, laboratory tests for specific IgE is expensive. The consequences of questionable results taken out of context can have a cost as well. Allergen-environmental control is a big business. Consider the hidden costs of extra work, alteration of living environments, and the status of pets. Seek out consultation of experts who can sort through both a medical and environmental history and make sense of what to test for. You also need to consider what the gold standard is for the assessment of allergic sensitization and that is the allergen skin prick test. Look also to the credentials of the providers that you are working with.

Fred Leickly

Your Indiana Joint Asthma Coalition (InJAC)  just put online a Continuing Medical Education (CME) offering on the most recent national asthma guidelines. As the chair of the Health Care Committee of InJAC it was my job to oversee the project. This gave me the opportunity to go over that 400+ document known as the “Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma”. The CME program can be viewed by anyone without registering for the credit. The online program is a slide set on the various sections of the guidelines. Each reviewer summarized the essential points and provided notes for each slide in the presentation. A shorter Summary report of the Asthma Guidelines (EPR-3) is also available.  This is the 3rd such report. The first came in 1991. Number two was 1997. There was a publication that dealt with 5 specific hot topics from the guidelines in 2002. In 2007 the most recent EPR was published.

As I reviewed the EPR-3 I noted how often allergy/atopy appears in the document. Consider a few of the following statements;

1. Atopy, the genetic predisposition for the development of immunoglobulin E (IgE)-mediated response to common aeroallergens, is the strongest identifiable predisposing factor for developing asthma (Key Point- page 11).
2. The onset of asthma for most patients begins early in life with the pattern of disease persistence determined by early, recognizable risk factors including atopic disease, recurrent wheezing, and a parental history of asthma (Key Point- page 12).
3. This working definition (of asthma) and its recognition of key features of asthma have been derived from studying how airway changes in asthma relate to the various factors associated with the development of airway inflammation (e.g. allergens, respiratory viruses, and some occupational exposures) and recognition of genetic regulation of these processes (page 14).
4. Sensitization and exposure to house-dust mites and Alternaria (mold) are important factors in the development of asthma in children (page 22).
5. The asthma predictive index…..identifies the following risk factors for developing persistent asthma among children younger than 3 years of age who had four or more episodes of wheezing during the previous year: either (1) one of the following: parental history of asthma, a physician diagnosis of atopic dermatitis, or evidence of sensitization to aeroallergens, or (2) two of the following: evidence of sensitization to foods, > 4 percent peripheral blood eosinophilia, or wheezing apart from colds (page 25).
6. Tests to consider in the differential diagnosis of asthma- allergy testing (page 45).
7. Key Points in the Initial Assessment of Asthma- identify precipitating factors (inhalant allergens…) and identify co-morbid conditions that may aggravate asthma (rhinitis –nasal allergy…) page 47.
8. Referral to an Asthma Specialist for Consultation and Co-management- ….for allergy skin testing (authors note- not RAST or blood specific IgE)…..for consideration of allergen immunotherapy (page 68).

The above excerpts came from section 2 (asthma definition, pathophysiology, pathogenesis, and natural history of asthma) and section 3 part one- Asthma Management- measures of asthma assessment and monitoring. These remaining sections comprise over 300 pages of material. 

The remaining sections of the EPR-3 cover education, environmental control, medications, long-term management, and managing exacerbations of asthma. These sections also include information on the significant role of allergy in asthma. These sections go over specifics on how to manage the allergens.

 Through the allergist’s eyes- Asthma is significantly intertwined with allergy. We should look at it as a manifestation of the allergic condition. It is not allergy and asthma anymore, in many children it is allergy showing itself as asthma! Asthma can be a manifestation of allergy.

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

In 2008 there was report of increased allergic sensitization in mice fed diets enriched with folic acid. Folic acid then was suspected as a risk factor for developing allergy, but that was in mice. A Norwegian study from 2009 found that high levels of folate were associated with a higher prevalence of respiratory illness in children. One study in mice and one published in humans. So why implicate folate?

Almost 20 years ago it was shown that taking folic acid before and during pregnancy significantly decreased the occurrence of neural tube defects (spina bifida). The impact of this was so great that by 1998 it was mandated by the FDA that cereal grain products be fortified with folic acid. The population has seen an increase in exposure to folic acid somewhat coincidental with the increase in allergic conditions. Is there an association?

The study ‘Higher serum folate levels are associated with a lower risk of atopy and wheeze’ by E.C. Matsui and W. Matsui (JACI 2009;123:1253-9) used the National Health and Nutrition Examination Survey (NHANES) 2005-2006. There were over 8,000 individuals (all greater than 2 years of age) who answered questions about allergy, had allergy tests performed, and had serum folate levels determined. The study found that high levels of folate were actually protective against atopy and wheeze. More folate = less atopy and less wheeze.

The editorial by Dr. Ownby (JACI 2009;123:1260-1) eloquently looked at the background studies and critiques the current study. As with many studies such as this, more needs to be looked at in the quest to find factors associated with developing allergy.

The second article looks at infection as a reason for developing asthma and allergy. The timing of the infection and the organisms involved was of great interest.

There have been a few studies that looked at the effect of infection in the mother and the use of antibiotics during pregnancy and at delivery as an allergic risk factor for the newborn. The antibiotic decreases normal bacterial immune stimulation and altered maturation of the immune system allowing allergic sensitization to occur. In the article entitled ‘ Intrauterine bacterial growth at birth and risk of asthma and allergic sensitization among offspring at the age of 15-17 years’ by L. Kesk-Nisula et al (JACI 2009;123:1305-11) children born to a group of  Finish women who delivered infants by cesarean section in 1990-1992 were evaluated for asthma and allergic sensitization. Intrauterine bacterial cultures were done on 460 children. Years later (at age 15-17 years) these children filled out a questionnaire about asthma and allergy (self-report) and underwent skin testing. The presence of a pathologic anaerobic bacteria or a Streptococcus species cultured at birth was associated with a tremendous risk (odds ratio = OR) of ever having asthma (OR = 4.51 for anaerobes/2.53 for Streptococcus) or of currently having asthma (OR =7.34 for the anaerobes/3.37 for Streptococcus). This study concluded that specific types of bacteria cultured from the mother at the time of birth may have a role in the development of asthma. The authors suggest that the study of maternal microflora to which the infant is exposed to may be a future target for prevention of asthma in children.

            In the development of allergy/asthma genetics is a major factor. Many other exposures work upon the genetic predisposition. When epidemiologic studies show increases in condition prevalence investigators look for associations and risk factors that may prove to be causative by performing more extensive investigation. Folic acid usage increased concurrent with an increase in the prevalence of allergy. The large epidemiologic did not find an association. The study of intrauterine microflora is unique. The authors note that it is the first study of its kind. I would guess that more studies like this will be done and in different populations to verify the findings. So for now, do not worry about the folic acid and keep posted about the intrauterine bacterial environment.

Fred Leickly

The meeting’s agenda covered a wide variety of clinical conditions. It would have been impossible to attend every session. I chose sessions on the allergic environment, eczema, immunotherapy, food allergy, re-certification, headaches, and asthma. There are a number of ideas that are evolving and a number of things currently done in allergy/asthma care that need to change. Each and every one of these topics is truly worthy of more extensive review. I would be happy to use this blog to delve into topics in more detail (per request).

Atopic Dermatitis (aka Eczema)

I still need to be convinced regarding what to call this condition. Dr. Jeff Travers (chief of Dermatology at the IU School of Medicine) and I go back and forth on this topic. During the meeting I heard the concept of extrinsic and intrinsic atopic dermatitis. Extrinsic means from the outside and intrinsic from the inside. These terms have also been used for years to describe two presentations of asthma: extrinsic asthma due to allergy, and intrinsic asthma when no allergy is found. The word atopic means 1) the tendency to come from families with allergy, 2) to make the antibody seen with allergy (IgE, which would be elevated) and 3) to have positive allergy tests. Thus, Intrinsic AtopicDermatitis means no allergy demonstrated (intrinsic) in a condition associated with allergic sensitization (atopic). This blending of terms leads to confusion–why not stick with the simpler term of eczema?

I learned about the use of silver impregnated clothing to decrease the amount of bacteria on the skin. Skin bacteria can cause flaring of atopic dermatitis.

A number of  genes associated with atopic dermatitis have been discovered. These discoveries should increase our understanding on how this condition starts and hopefully how we can manage it better.

There was information on allergens that contain enzymes called proteases and how these protease containing allergens aggravate the skin.

Probiotics have been used to treat allergic conditions especially conditions related to food allergy. A review of studies on probiotics have not shown them to be effective in preventing or treating atopic dermatitis.

I listened to debates about being proactive in skin care therapy vs. being reactive. Proactive would be trying to prevent and reactive being treating only when there is a problem. This idea was particularly interesting. Atopic Dermatitis Guidelines and package inserts for a variety of medications used for atopic dermatitis treatment stress short courses of use, the reactive approach. The proactive debater posed the problem of a chronic disease that will have episodic flaring. The abnormality of the skin is there all the time requiring the need for medication to be used perhaps twice a week to avoid flares (those times when the skin is more itchy, more inflamed, and more broken down). Pediatrics deals extensively with disease prevention. My pediatric perspectives are preventative- proactive. All too often we (as patients) tend to be crisis-oriented or reactive to chronic conditions. I am obviously on the proactive side of this argument.

Therapies emphasized moisture and more moisture. Keep these kids wet! This is clearly a major step that is contrary to previous approaches that recommended the avoidance of frequent soaking/bathing. The avoidance of baths is clearly one of those long established principles of atopic skin care that has fallen by the wayside in contemporary skin care.

Foods are an issue in atopic dermatitis. The protease containing allergens such as molds, pets, and mites may have a role in triggering flares.

In Boston a program that has had success includes insuring compliance with the medications (taking them as prescribed), addressing the parents concerns about medication side-effects (helps with compliance), decreasing the itch, and increasing sleep. These are all essential elements to help with control of the condition.

Of note, we need to re-think the role of a specific therapy and make adjustments. Antihistamines are frequently used in atopic dermatitis. In allergic rhinitis and in hives, these products help control itch. However, in atopic dermatitis, the antihistamines have little effect on itch. The role of the anti-histamine is to sedate. Most of the scratching happens at night. A sedating antihistamine used at night works best.

Asthma

There were a number of new ideas regarding asthma. Look for vitamin D to have a possible role in treatment.

Current recommendations from evidenced-based asthma guidelines point out a difference between adults and children and the use of the long-acting bronchodilators in the two populations. These agents are called long-acting broncho-dilators (LABAs). In children, we should increase the dose of the inhaled corticosteroid before adding a LABA. This recommendation appears in two major asthma guidelines with type A evidence used to support the recommendation. This type of evidence (A) means that there are a substantial number of studies that support this statement.

Asthma may be related to bacterial colonization at birth and to the occurrence of the common cold virus later in life. Evidence was also presented regarding the observation from large population studies that the process of airway inflammation starts well before actual symptoms. We heard about diet, viruses, stress, ozone, and endotoxin having a role in the development of asthma. The gene or genes for asthma need to be present. These genes then need to be activated or expressed for the child to show the signs and symptoms of disease. Bacterial colonization and a variety viruses may have a role in activating the genes.

Headaches

This was a great session. The audience heard from an ENT surgeon, an allergist, and a neurologist regarding their approach to headaches. The consensus was that migraine is the biggest player in these situations. The connection of allergy to headache has always been a concern. However, headache is not a manifestation of allergy. There are many studies that have looked at this. People with headaches can have positive allergy tests but does that make the allergen the cause of the headache? Think about other conditions or associations. Could there be an allergic cause for an appendicitis?

I heard of the concept of ‘allergic appendicitis’ during this presentation. It was very odd to hear about this in a headache session, but a valid point was made. This concept of the allergic appendix was compared to allergic headaches. Follow along; data from a national health survey from 1994 indicated that 50% of the population reported that they had allergy. So if someone who had problems with the appendix was allergy tested, the chances are very high that allergy would be found. This however does not make the inflammation of the appendix due to allergy. You can find a significant number of positive allergy tests, be sure of why the tests are being ordered. Think migraine more often as a reason for headache. Allergy is not a major reason for headaches.

Food Allergy

The biggest news from the meeting was the work done by Wes Burks at Duke on peanut allergy. This is exciting and long awaited for those who have peanut allergy and for the families who have someone with peanut allergy. Immunotherapy for peanut trials have allowed the equivalent of about 12 peanuts to be eaten without any problems/reactions. This would certainly take the fear from accidental exposure to peanut especially from tabletops at school cafeterias. I have to check my note again, but I had written down the treatment would be a suppository(?).

There was a very popular abstract (a quick presentation of work in progress prior to it being published in a journal) on food allergy and the over- use of panels for food allergy (pet peeve). A New York Times article a few months ago reported that food allergies were being over diagnosed. Dr. Sears at National Jewish Hospital in Denver, Colorado reported on over one hundred children seen at their center who had food allergy as determined by blood test panels. The average number of food allergies reported were six. After undergoing food challenges the number decreased to only 2 foods. 88% of the foods this group of children were told to avoid based on RA ST panels were added back into the diet. Using a food challenge, no one with meat ‘allergy’ had a positive food challenge (where meat caused a problem), 88% of the grain ‘allergic’ children were negative on challenge, and 83% of the fruit and vegetable group were also negative after a food challenge. Bottom line- the use of these panels is giving falsely positive information and leading to a misdiagnosis of food allergy.

Allergy Testing

I learned that I should no longer use the word RAST. The term is outdated and refers to a technology not used. The blood tests for allergens should no longer have a 0-6 grading scale and should only be reported in what is actually measured kU/l of serum. The test measures a concentration of a specific antibody in the blood. The relationship of that concentration to clinical activity needs to be determined by the clinician. I predict that the interpretation of the blood test results may be a huge issue.

A new in vitro or blood test for specific IgE in the blood is called an ISAC chip. This technology will help with cross-reacting proteins. We see the problem of cross-reactivity with multiple positive allergy tests to legumes (peanut, soy, beans, and peas). I think this will be a very worthwhile test in allergy.

There are three blood tests out there for detecting specific IgE. These are the Immunolite, ImmunoCap, and Hytec. Each of these measure something different. They measure a different population of IgE antibodies and may not be comparable. Caution was advised regarding the blood tests for specific IgE. The physician should know the method used, the validity of the assay, the performance of the laboratory in doing the assay, and realize that no test for allergy is infallible.

Conclusions

Each and every one of these topics could stand alone for more detail and interpretation and I would be most happy to elaborate in more detail. Let me know if you would like more information by adding a comment. If there continues to be an increase in the use of specific IgE panels (as advocated by those who market these tests) we will be doing significantly more food challenges in our office. Usually we are doing food challenges for those who may have outgrown a food allergy. We certainly can offer a food challenge for a child who has been told that food allergy exists based on blood test results. One of my tasks upon my return to the office is to look at our track record of doing food challenges. I hope to report on our successes and failures for our food challenge experience with milk, egg, soy,wheat, and of course peanut.

Respectfully submitted,

Fred Leickly

Now think about asthma. You are out there and because this is an unpredictable condition, trouble starts. Where is your life preserver? Where is your inhaler? Should it be on your person just as that life jacket? This is a real concern and an issue that affects life and the quality of that life for those with asthma.

In the world of managing asthma we have two basic categories of medications: the long-term controller medications and fast-acting rescue medications. I like the use of the term ‘rescue’. These agents work fast and when used in a rescue fashion they help open the airways. The rescue medication will work  usually within 15 minutes of application. A few examples of what would be considered asthma rescue medications frequently used for children include:

1. Albuterol- available as ProAir, Proventil, and Ventolin HFA
2. Pirbuterol- available as Maxair
3. levo-albuterol- available as Xopenex

These agents can be effectively given by a metered dose inhaler (puffer) or through nebulization. Everyone who has asthma, regardless if it is intermittent or one of the three types of persistent asthma (mild, moderate, or severe), must have a rescue inhaler! This has been spelled out since the first edition of asthma guidelines (1991) and is an important part of the most recent NHLBI Guidelines for the Diagnosis and Management of Asthma. This is a well established recommendation, but how do we see it in real life situations?

I have always wondered where the rescue medication is kept, and how long it would take for someone to find and use their rescue medication when symptoms began. Recently, I had a chance to investigate that question.

I just  finished a Masters in Public Health program at Indiana University Purdue University Indianapolis (IUPUI). (As an aside, anyone interested in conditions that affect the health of the population would find the pursuit of this type of a masters program most rewarding.) Some courses  required doing field projects, especially in the epidemiology and biostatistics courses. I decided to do a project that involved the use of rescue medications by children with asthma.

In biostatistics you need to have a hypothesis, i.e., a statement that will be supported or found to not be true. My hypothesis was that all children with asthma have a rescue medication with them (or have immediate access). I was also interested whether or not a number of variables such as age, severity, or duration of asthma had any relationship to rescue medication availability. The questionnaire was answered by 124 children with asthma. I found that only 28% either carried their inhaler with them or had immediate (within 2-3 minutes) access to rescue medication. That means 72%, over two-thirds may have had to hustle to find rescue medication.

I asked this question of children who were about 10 years old. Just over half were boys. The group was representative of a suburban population. They severity of the asthma was as follows:

1. Intermittent 10%
2. Mild persistent 29%
3. Moderate persistent 55%
4. Severe persistent 6%

These children were asthma-experienced: the duration of having asthma was 6.6 years. This is where the inhalers were with this asthma-savvy group:

1. Inhaler in a pocket (on them) – 14%
2. Inhaler with a parent – 15%
3. Inhaler at home – 55%
4. Inhaler at school – 14%
5. No inhaler - 2%

The next question was how long would it take to find and use your rescue medication?

1. Immediately (optimal response) – 28%
2. At 5 minutes – 40%
3. At 15 minutes – 18%
4. At 30 minutes – 7%
5. Longer than 30 minutes 7%

The perfectionist in me felt that 5 minutes may be a concern, however there is a real issue with the 32% that needed 15 or more minutes.

There are a number of possible reasons for what I would consider a delay in rescue medication application. Our habits are that when things are going well, we tend to not be as vigilant. A well-controlled child with asthma would have very little additional need for a rescue medication so the lack of  immediate access may be due to the success of other therapies. In fact, only 25% had used their rescue inhaler within the preceding month.

I was surprised by the results of my biostatistics project (not the grade, but the findings). As a specialist in the area of asthma care I learned something new and something that will help me to help my patients with asthma. I did not have to read this in a journal about some other population of children, this was a group of kids here at home, in my own backyard. My lesson learned is to be sure to ask the question and to use that basic principle of pediatrics- prevention. Prevent disasters but emphasize the concept of rescue and support any opportunity for the easy and quick access of that life preserver. I do not hesitate in writing those permission slips so medications can be carried at school. Yes there is concern about ‘medications’ and the possibility of misuse/abuse I fully understand that. I also hear about and see children who are very scared with these sudden, acute attacks of respiratory distress. Acute asthma events are not predictable, they are serious, and they need to be addressed urgently. The rescue inhaler needs to be readily available.

Respectfully submitted,

Fred Leickly

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