Allergies: A Leickly Story » Article Review

Skin Testing for Aeroallergens

fleickly — Wed, 30 Nov 2011 17:54:13 +0000

Position Paper:

Practical guide to skin prick tests in allergy to aeroallergens

I was alerted to this article by my partner Dr. Vitalpur. It comes from Allergy (European Journal of Allergy and Clinical Immunology) 2011 . The purpose of the article was to provide ‘pocket guidelines’ from a consensus report regarding the use of allergy skin prick tests for inhalant or aeroallergens.

The skin prick test (SPT) is a widely used, major diagnostic tool used for the diagnosis of allergy. The introduction of the article points out the many complexities in performing SPTs and recommends that they should be performed only by trained health professionals.

As for the methods used to create the guide; it was a combined effort from the Global Allergy and Asthma European Network (GA²LEN) and the Allergic Rhinitis and its Impact on Asthma (ARIA) task force. Once the document was created, it was reviewed by the membership of the networks. The authors point out that this is not an evidence-based guideline. It should be looked at as ‘…clear-cut answers to frequently asked questions by practitioners and patients.’ The evidence-based aspect follows the guide-in future reports.

The article is broken down into a series of 21 specific questions:

What are the indications for skin tests in clinical practice?
Which skin tests are recommended?
What role do intradermal tests play?
What is the recommended skin prick test technique?
Which treatments suppress skin tests?
Which diseases affect skin tests?
Which allergen extracts to choose?
Which allergen extracts should be tested?
What area of the body should be chosen and what is the ideal distance between tests?
Which negative and positive controls are recommended?
Which results are regarded as positive?
How do skin tests compare with serum-specific IgE?
How to interpret skin test results?
Which skin tests are recommended in adolescents and adults?
Which skin tests are recommended in the elderly?
Which skin tests are recommended in young children?
What is the role of skin tests in primary care?
How can skin tests be used in developing countries?
Are skin tests needed in allergen immunotherapy follow-up?
Can skin tests be used in research?
What are the future needs?

Each question has a short, concise answer. These are common concerns and questions. I would like to point out a few of them for this review. The link will direct the reader to questions not covered here.

1. What are the indications for skin tests in clinical practice?

Asthma and allergic rhinitis are the indications for aeroallergen testing. The SPTs can be used from infancy to old age. The repeating of SPTs is done to detect new sensitizations in children and when changes in symptoms have occurred.

2.Which skin tests are recommended?

Prick skin tests have a high degree of correlation with symptoms. There is high specificity (a negative test when you do not have the disease) and sensitivity (when the test is positive when you have the condition) with the skin pricks used for inhalant allergy.

Table 1 Performance of skin prick tests

Use standardized extracts when available (We have grass, house dust mites, and cat as standardized extracts.)
Include a positive and a negative control solution (histamine is the positive control)
Perform tests on normal skin (not on skin affected by severe eczema or urticaria)
Evaluate the patient for dermatographism (Means skin writing- pressure to the skin will cause a hive, this is a common reason for someone to allergic to everything including the negative control.)
Determine and record medications taken by the patient and the time of the last dose
Record the reactions after 15 minutes
Measure the longest wheal diameter

Skin prick testing may cause systemic reactions

The common errors in skin testing are listed in table 2

Tests are placed too close together and overlapping reactions cannot be separated visually.
Induction of bleeding, leading possibly to false-positive results.
Insufficient penetration of the skin by the puncture instrument, leading to false-negative results. This occurs more with plastic devices.
Spreading allergen solutions during the test or when the solution is wiped away.

3. What role do intradermal tests play?

Intradermal skin tests (when a needle is used to inject the extract- almost like a TB test) are not useful for allergy diagnosis with inhalant allergens. The clinical value is unknown in patients who only have positive intradermal tests. They are less safe to perform. There are practices where this is the only type of test done or they are performed when the SPTs are negative. We use this type of test ONLY in the ‘Bee Clinic’- the protocol for pursuing stinging insect allergy utilizes the intradermal test.

4. Which treatments suppress skin tests?

Drugs can suppress skin tests.

Antihistamines- have a significant impact on skin test results. They should be avoided for 7 days

Imipramine- anti-depressants, sometimes used for bed wetting- can affect skin test results for 21 days

Steroid ointments and creams- minimal if any effect on skin testing

UltraViolet light – used to treat skin condition, can effect skin test results for up to 4 weeks

Table 3 Inhibitory effect of various treatments on skin prick tests show other agents that may impact skin test results.

5. Which diseases affect skin tests?

Patients with widespread eczema or hives cannot be tested in areas of affected skin. Neurological disorders and infectious diseases (e.g. leprosy) can lead to false-negative results.

6. Which allergen extracts to choose?

The quality of the allergen extract is of key importance as variations in the quality and/or potency of commercially available extracts exists, in particular for animal mites, animal dander, and molds, but even pollens. Use standardized extracts if available.

7. Which allergen extracts should be tested?

This varies per region. This answer was relevant to Europe. I comment on this at the end of the review.

8. What area of the body should be chosen and what is the ideal distance between tests?

Usually, the skin tests are performed on the forearms depending on the age of the patient. The distance between tests should be 2 cm. We have used the child’s back for testing. There is a larger surface area to work with. If needed, more items could be evaluated using the larger space. It is also an area which would not be frequently treated with a topical steroid.

9. Which results are regarded as positive?

The wheal and erythema have been used to assess the positivity of the skin test. However, only the wheal is needed. The largest size of the wheal is considered to be sufficient. Wheal diameters equal to or larger than 3 mm are considered positive in SPTs.

Redness alone is not a significant response. There needs to be a wheal (swollen area) of proper size to be called significant. In our clinic, the physician who ordered the test reads them and decides on the significance. All too often, slight red marks are interpreted as positives.

10. How do skin tests compare with serum-specific IgE?

Serum-specific IgE, SPTs and allergen challenge do not have the same biological and clinical relevance and are not interchangeable. Low levels of serum-specific IgE are less often associated with symptoms than higher levels, but they do not exclude allergic symptoms particularly in very young children.

Note- the paper did not use the term RAST. The proper term is serum-specific IgE- that blood test for allergy. I thought that the answer to this question was not as complete as it should have been.

11. Are skin tests needed in allergen immunotherapy follow-up?

Skin test reactivity decreases with allergen-specific immunotherapy to inhalant allergens, but skin tests cannot be used to assess the efficacy of immunotherapy in practice. Moreover, skin tests cannot be used to decide the cessation of immunotherapy.

Reviewer’s Comments-From the original 21 questions, I chose 11 that tend to be more frequently brought up in our practice. Many of the questions that I omitted dealt with issues unique to Europe or to the adult population.

In a nutshell the skin prick tests for aeroallergens (inhalant allergens) are:

Indicated for respiratory tract symptoms
Can be done in very young children
Should be done with the proper extracts and application technique
Can be done if a few medications are out of the child’s system
There may be a problem finding clear skin to do them on a child who has eczema or hives
May be done on the arms,
Are considered positive if the wheal (swollen area) is of proper size (redness alone does not qualify)
Should not be used to monitor an allergy shot program.

This was a very neat, concise, and well done synopsis of how things are done in Europe. An additional tidbit was the answer to the question- Which allergens should be tested? The quick answer is that it depends on the allergen exposure for the area and that a common, standardized battery of tests should be recommended for Europe. The list was short;

Pollens- Birch, Cypress, Grass (one species or a mix), Mugwort, Olive (or Ash), Parietaria, Plane, and Ragweed
Mites- two species
Animals- Cat and Dog
Mold- Alternaria and Cladosporium (Aspergillus extract is not available in all countries).
Insects- Cockroach

That panel for respiratory tract allergens would contain only 15 aeroallergens plus the two controls- 17 skin tests done to assess allergen sensitization.

A reference was also made to the National Health and Nutrition Examination Survey (NHANES) performed in the United States (2005) – 10 allergens were used.

FEL

11-30-2011

Notable Articles on Skin, Food, Drug, Insect Allergy-JACI 2010

fleickly — Thu, 03 Mar 2011 15:13:02 +0000

In a very well done review article, Drs. Scott Sicherer and Donald Leung present the advances that were published in the premier allergy journal (the Journal of Allergy and Clinical Immunology, JACI) last year-2010. Reviews like this have appeared in the JACI at least since 2004. The topics included allergic skin disease, anaphylaxis, and hypersensitivity or foods, drugs, and insects. What follows is a summation of some of the highlights from that article. Some of these are for general interest, some show where the science is heading and what the future may hold, and others go over new twists on old problems.

FOOD ALLERGY

Of course the biggest event in 2010 was the publication of the National Institute of Allergy and Infectious Diseases (NIAID) sponsored ‘Guidelines for the diagnosis and management of food allergy in the United States’. Previous postings on this site go into more detail on those guidelines. The review states that these guidelines should provide tremendous guidance for improved diagnosis and management of food allergy. I think we as allergists may be very busy in the next few years making sure that food allergy was the correct diagnosis. Allergists will be performing more food challenges to test the relevance of test results.

Food Allergy Epidemiology and Risk Factors

For the United States the prevalence of specific food allergy was (percent of the population);

Peanut- 0.8%
Tree Nut- 0.6%
Sesame seed- 0.1%

These were from telephone surveys and are self-reports.

Food allergy in children has increased (self-reported survey data);

Food Year

1997 2002 2008

Tree nuts 0.6% 1.2% 2.1%

Peanut 0.4% 0.8% 1.4%

Rates of clinical food allergy risk (National Health and Nutrition Examination Survey 2005-2006)

Food Rate
Milk 0.4%
Egg 0.2%
Peanut 1.3%
Shrimp 1.0%

In this study, children 1-5 years of age, clinical allergy to milk, egg, and peanut was 1.8% for each.

It needs to be pointed out that this information was from surveys and/or from specific IgE levels. They were not the results of a food challenge. So there is the possibility that this represents sensitization only and may be an over-estimate.

Risk factors for food allergy

Food allergy may be due to deficiency in vitamin D.

Vitamin D has been a most popular topic over the past year. The standards for daily intake of vitamin D are changing; we may need more of this vitamin in our diets. Relative vitamin D deficiency has been reported in a number of clinical conditions.

Prolonged avoidance of certain foods to infants at risk of developing food allergy has been the standard advice, however two studies were published that shake this concept, at least for milk and egg allergy. When milk exposure was delayed beyond the 15^th day of life, the odds ratio for milk allergy was 19.3. (Odds ratios are the odds that an event will occur compared to the odds that it will not occur). The OR gives an idea of how strongly a variable is associated with an outcome. In this example the odds of milk allergy was 19.3 times more likely to have milk allergy.

When egg was introduced at 4-6 months of life compared to introduction beyond the first year of life, the odds ratio was 3.4 for allergy to egg with late introduction (after age 1 year). The comment was made that oral exposure may promote tolerance and that excessive delays in introducing food allergens may be counterproductive and may allow sensitization to occur via intermittent exposure to the food and possible environmental exposure.

A study from the Consortium of Food Allergy Research reported that mother’s ingestion of peanut during pregnancy had a positive dose-response association with the infant having increase peanut specific IgE antibodies to peanut. The more peanuts the mother ate, the higher the peanut- specific antibody levels. The reviewers point out that this is sensitization (the blood test only). The children are being followed to see if true peanut allergy appears over time.

Food Allergy Treatment

Now what about those food labels for allergens. Specifically, when it says may contain an allergen or when there are no warning labels at all on the product. The review commented on a study in which 401 foods were evaluated for egg, milk, and peanut. The foods either had no indication that it contained one of these foods or the label stated that the food may contain an allergen. Overall, just over 5% of the products that had an advisory label had detectable protein and almost 2% of the food products with no label were contaminated with the food. Food allergen levels were low, but this could still be an exposure risk.

Avoidance has been the mainstay of food allergy treatment, however that may be changing. A study on peanut oral immunotherapy was published in 2010. There were 23 children who participated in the study. If a peanut has 300 mg of protein, in this study 1 child tolerated 6 peanuts (2000 mg), 5 tolerated 3 peanuts (1000 mg), and 8 had a peanut and a half (500 mg). So 14 of the 23 tolerated peanut- they did not have a serious reaction up to their limit of tolerance.

A very important editorial appeared in the JACI about peanut oral immunotherapy. The editorial stated that this procedure is not ready for clinical use at this time. There are still concerns about safety, efficacy, and a number of other practical issues. Be excited about the prospects, but be patient as well.

ANAPHYLAXIS

An updated practice parameter appeared this year on this topic. The highlights stressed the importance of a medical history, the early use of epinephrine, and prevention strategies.

A very detailed epidemiologic study from England revealed the following;

Anaphylaxis is more common in those with asthma
Anaphylaxis is more common in women
Drug and food reactions were the most common causes

ATOPIC DERMATITIS

Mechanisms of barrier dysfunction

The presence of an abnormal skin barrier is a major feature of this condition. A protein called filaggrin may have abnormal function. Filaggrin defects can lead to the absorption of allergens or enhance the colonization of the skin with bacteria leading to chronic inflammatory changes in the skin.

Management and Natural History

The initial step is to make the correct diagnosis. Hyper-IgE syndrome can look and act like atopic dermatitis.

Treatment includes skin barrier repair, allergen avoidance, infection control, and the use of anti-inflammatory agents. Keeping the skin well hydrated and preventing skin water loss is important. Betamethasone was great at decreasing symptoms but did cause thinning of the skin. The topical steroids are of help in gaining control followed by topical calcineruin inhibitors for long-term therapy.

Using probiotics to treat atopic dermatitis is a very controversial area. A study from Europe suggested that formula supplementation with a very specific prebiotic helped to reduce the occurrence of atopic dermatitis in ‘low-atopy-risk infants’.

URTICARIA and ANGIOEDEMA

Anti-histamines are the first line treatments for urticaria. Higher doses of an anti-histamine may be required for symptom relief. In one report, levocetirizine (Xyzal) or desloratidine (Clarinex) were increased by 5 mg a week to a maximum dose of 20 mg or 20 mg of the other agent was used if there was no relief of symptoms. This increase of the dose did relief symptoms with 75% responding. The authors of this anti-histamine study suggested up to a 4-fold increase may be needed for symptom control and this can be achieved without safety issues.

Another study looked at cyclosporine at low-dose as an option.

In pursuit of a cause for chronic urticaria, low vitamin D levels may be causative and supplementing with vitamin D may help.

This was a nice review that summarized 113 articles that appeared in the JACI in 2010.

FEL

Does allergic rhinitis exist in infancy?

fleickly — Sat, 15 Jan 2011 15:43:54 +0000

Does the baby have ‘allergies’?

How often has this question been asked? Better yet, how often are infants and young children subjected to extensive/ expensive testing and related therapies based on the idea that they are struggling with nasal allergy? This is a common concern and a common diagnosis. I am not sure it is always the correct diagnosis.

A diagnosis should lead to a treatment program. The consequences of (mis)diagnosing nasal allergy in infants may include an altered diet, removal of pets, medications (and the struggles of administering them), and even immunotherapy (a real issue in children less than 5 years of age, may even be contraindicated, and there are no studies regarding safety or efficacy of allergen immunotherapy in this age group). The medical literature has precious few published studies on this problem of infants having nasal allergy. Recently a study has appeared in the literature that takes a hard look at this problem.

So, can infants have nasal allergy (allergic rhinitis- AR) and if they can (and do) what are risk factors associated with the condition? Note that in the study the authors are calling the condition ‘Allergic Rhinitis-like’ .

In the February 2011 issue of Allergy (Allergy 2011; 66: 214–221) Herr and colleagues have the following article, ‘Does allergic rhinitis exist in infancy? Findings from the PARIS birth cohort‘. This article has a few things that excite me; allergy, allergy in young children, and epidemiology (from all the extra schooling for my Masters of Public Health). Here is my review of that article.

Purpose of the Study

The purpose of the paper was to look at the prevalence of AR-like symptoms and to study potential risk factors for atopy in a population of infants. The study was performed in Paris, France.

How they did it (Methods)

Participating children/families were part of the PARIS birth-cohort. All participants responded to a standardized questionnaire. Laboratory studies included tests for markers of allergy. The allergens that were evaluated included house dust mite (limited to the species common in Europe), pets, grass pollen, weed pollen, tree pollen, and mold spores. The foods that were tested included egg, milk, peanut, mustard, fish, wheat, soy, hazelnut, sesame seed, shrimp, beef, and kiwi.

What they found (Results)

The entire cohort numbered 4,177 children. From that number, 1,850 were analyzed for this study. The children were evaluated at 18 months of age.

AR-like symptoms occurred in 169/1850 (9%). AR-like symptoms were nasal congestion, nasal discharge, and sneezing.

There was no significant difference between the AR-like group (169) when compared to the non-AR children (1,681) for the following;

Male sex (no sex predisposition)
Socioeconomic status (household income)
Number of siblings
Tobacco smoke exposure
Breast feeding
Parental history of asthma or eczema
Total IgE level
Food allergen sensitization
Having only one marker of atopy

The one maker of atopy was one of the following; elevated blood eosinophil count, a total IgE > 45 U/ml (this is determined by a blood test), or sensitization to inhalant allergens only (eosinophils are cells that are associated with allergic reactions). So these factors did not sort out the group with vs. the group without AR-like symptoms. They were not risk factors.

The factors that were significantly different between the groups were;

A parent’s history of nasal allergy
Increased eosinophils in the blood (> 470/mm³)
Inhalant allergen sensitivity (any positive)
House dust mite sensitivity (Dermatophagoides pteronyssinus)
Sensitization only to inhalant allergens
Having >2 of the markers of allergy

This information was entered into a mathematical model which provided an odds-ratio for the risk factors. The factors that increased the odds-ratios were;

Mother having allergic rhinitis (OR =1.54)
Both parents having allergic rhinitis ( OR = 2.09) (Dad’s history adds a little more risk)
Elevated blood eosinophil counts (OR = 1.54)
Inhalant allergen sensitization (OR = 2.21)
Sensitization to house dust mite (D.p.) (OR = 2.91)
>2 markers of allergy (OR = 2.16)

(Reviewers note-an Odds-Ratio is the odds of developing the condition when the factor is present divided by the odds of that factor in those who do not have the condition. If the Odds-Ratio is 1.0 there is identity and there is no difference at all. If the OR is negative, there may be a protective effect. If the OR is significantly greater than 1.0 then there is a greater chance of having AR-like symptoms with that risk factor.)

Conclusions (Authors’)

The prevalence of AR-like symptoms was 9.1% by age 18 months in this population of French children. The significant associations for having AR-like symptoms were having both parents with nasal allergy or the child having a marker of atopic disease. Allergic rhinitis can occur as soon as the first year of life.

There is a strong genetic component- there is a twofold increased risk of AR if both parents have AR. This was not seen if the parent had asthma or eczema.

The authors concluded that the total blood IgE level was of borderline significance.

One of the major findings was the association of AR-like symptoms with sensitization to the house dust mite. There was no association found with food sensitization. Pollen, mold, or pet sensitization was not a factor (reference is made to the need for at least two seasons of exposure prior to sensitization to pollen).

The authors point out that one of the strengths of this study is the objective measure of atopy in a very large sample of children <2 years of age.

One of the limitations is the <50% participation rate by the PARIS cohort.

Reviewer’s Comments

I struggled somewhat with cohort studies, relative risks, case-controlled studies and odds-ratios and how they are used. I concluded that this was a cohort for which case-controlled analyses were used. I had to dig up my epidemiology books as I went over the tables/results. Cohort studies and case-control studies lend themselves to different epidemiologic evaluations.

As with many studies, the conclusions are relative to the population which was studied. This is from Europe, the findings may not be valid here. However, the uniqueness of the study is the use of a large population of young children. We have not seen studies of this intensity in a young pediatric population.

Also consider the condition was AR-like. AR-like included symptoms seen in nasal allergy- congestion, discharge, and sneezing. As a long time sufferer from grass pollen triggered AR, I have sneezing fits, runny nose, itchy nose, congestion, as well as the ocular symptoms of red, watery, and very itchy eyes. These respond to an antihistamine. It would have been interesting to know if antihistamines were ever used and what the response was to this standard form of treatment. That may have helped solidify the diagnosis.

As I look at the significant levels of association for risk factors and odds-ratios I see the following risk factors of value when considering nasal allergy in a child with AR-like symptoms-

The presence of nasal allergy in both parents
An elevated blood eosinophil count (if a blood draw is needed)
Evidence of sensitization to the house dust mite

Those things that this study that I found not associated (based on statistical test results)

Total IgE
Allergy tests to foods, pollens, molds, and pets at this age.

So about 10% of children at 18 months of age who have nasal allergy-like symptoms. If allergy is at work in these children then you would have both parents with nasal allergy and/or evidence of sensitization to a house dust mite and/or an elevation of their blood eosinophil count.

Perhaps information like this with help sort out which young children may have allergy accounting for their nasal symptoms and it may help in limiting items for allergy testing.

The other issue comes from forward thinking the problem. Infants usually sleep on plastic encased mattresses, at least here in the USA. So can house dust mites live in such a mattress. Stuffed animals are a huge reservoir of house dust mites. The admittance of a stuffed animal to a baby’s crib may be time dependent with very young children not having such a thing in there sleeping environment due to safety concerns. So did the house dust mite sensitive population have exposure and if so, when in their lives.

As with many good studies, this one gets you to thinking and gets you to ask more questions.

FEL

Increased Asthma Frequency and Asthma Severity in Children: The Asssociation with Atopy

fleickly — Thu, 10 Jun 2010 11:40:19 +0000

Asthmatic children with atopy have more frequent and more severe virus-induced illnesses.

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