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:

1. What are the indications for skin tests in clinical practice?
2. Which skin tests are recommended?
3. What role do intradermal tests play?
4. What is the recommended skin prick test technique?
5. Which treatments suppress skin tests?
6. Which diseases affect skin tests?
7. Which allergen extracts to choose?
8. Which allergen extracts should be tested?
9. What area of the body should be chosen and what is the ideal distance between tests?
10. Which negative and positive controls are recommended?
11. Which results are regarded as positive?
12. How do skin tests compare with serum-specific IgE?
13. How to interpret skin test results?
14. Which skin tests are recommended in adolescents and adults?
15. Which skin tests are recommended in the elderly?
16. Which skin tests are recommended in young children?
17. What is the role of skin tests in primary care?
18. How can skin tests be used in developing countries?
19. Are skin tests needed in allergen immunotherapy follow-up?
20. Can skin tests be used in research?
21. 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

1. Use standardized extracts when available (We have grass, house dust mites, and cat as standardized extracts.)
2. Include a positive and a negative control solution (histamine is the positive control)
3. Perform tests on normal skin (not on skin affected by severe eczema or urticaria)
4. 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.)
5. Determine and record medications taken by the patient and the time of the last dose
6. Record the reactions after 15 minutes
7. 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

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

I swear that I have not been cultivating ragweed. It grows naturally and loves fields, upturned sole, the sides of the road and developing land. Some of our Giant Ragweed plants are more that 9 feet tall! It is a bumper crop this year.

Giant ragweed has a very typical leave and those large anthers (?) from which that yellow pollen falls and becomes airborn. The species is called  ambrosia- for those allergic to ragwee, truly not a drink of the gods but a real source of respiratory and ocular misery.

Short ragweed is the most problematic for allergic individuals. The specific proteins in each species does vary, but they do share a number of allergenic proteins.

                                                 Short Ragweed                                                   Ragweed pollen

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