Age

Epidemiological studies in Tucson demonstrated the varying prevalence of positive immediate prick skin test reactions with age in their population. When tested with a battery of five allergens or mixes, only 22% of those who were 3 and 4 years old had at least one positive test. The peak prevalence of reactivity was seen in the first half of the third decade, when 52% reacted to at least one test. The prevalence of a positive skin test then declined slowly until the age of 50 years, following which there was a more rapid fall-off, reaching a low of 16% in the subjects over 75 years of age. Further studies in this population related the presence of prick skin test reactivity to the reactivity of the skin to histamine and to the serum total immunoglobulin E (IgE) levels. Dividing the population studied into four age groups, they found that total IgE was highest in those who were 9 to 19 years of age and declined progressively in the other three groups (20 to 34, 35 to 50, and over 50 years). Histamine reactivity in the skin was lowest in the 9- to 19-year-old group, however, and was higher in the three older groups. The prevalence of positive skin tests, reflecting in part the interaction of specific IgE and reactivity of the skin to histamine, was highest in the 20- to 34-year-old group.

The evolution of skin prick test reactivity was followed in a birth cohort on the Isle of Wight. The prevalence of a positive prick skin test to any allergen was 19.7% at age 4 years, 26.9% at age 10 years and 41.3% at age 18 years. In Sweden, 664 adults (age 20 to 60 years) were prick skin tested. The highest prevalence of positive prick skin tests was 55% in those 20–29 years of age and the lowest prevalence was 26% in those 50 to 60 years of age. When they repeated the prick skin tests 10 years later, the yearly incidence of any newly positive prick skin test was 0.5% while the rate of conversion of prick skin tests from positive to negative was 3.2% per year.

Supporting data for the above observations come from separate studies of levels of specific IgE and cutaneous reactivity to histamine by age. A retrospective review was conducted of results in 326 patients whose serum was analyzed for total and specific IgE. The highest levels for grass and house dust mite-specific IgE were observed in those who were 10 to 15 years of age. A prospective study of cutaneous reactivity to histamine was conducted in 365 subjects from 1 to 85 years of age. The size of the prick skin test to histamine increased progressively, peaking in those who were 21 to 30 years of age. There was then very little difference until the age of 50 years. Following this, there was a decline in the mean reaction size. Representative values with the 27 mg/mL concentration of histamine were: age 0 to 3 years, 3.8 mm; age 21 to 30 years, 6.2 mm; and age 61 to 70 years, 4.5 mm.

Reactivity of the skin to histamine and codeine was examined in children from infancy to the age of 2 years. Prick skin tests with both histamine and codeine (a nonimmunologic mast cell degranulating agent) were particularly small up to the age of 6 months, although after 1 month of age there was usually some reactivity to both reagents. Due to the reduced reactivity to histamine in children under 2 years, adjustment of the interpretation for the size of the positive histamine control is important.

Varying reactivity to histamine can have a significant effect on skin test reactions, even in adults. In an epidemiological study, 893 adult subjects were prick skin tested with 14 allergens and 10-fold dilutions of histamine, ranging from 1 mg/mL to 0.001 mg/mL. In those positive only to the highest concentration of histamine, 56% had all negative skin tests to allergens and only 15% had six or more positive skin tests. By comparison, of those responding to 0.01 and 0.001 mg/mL histamine concentrations, only 11% had all negative skin tests to allergens and 60% had six or more positive tests.

Physiologic Factors

The size of the reaction of the skin has been reported to vary with the time of day, the season of the year, the menstrual cycle, the subject’s handedness and with the part of the body used for testing. Although it had been reported that there was a circadian pattern to skin reactivity, a study of 20 children and 20 adults did not find any significant variation during the normal clinic hours. Subjects were tested in duplicate with serial dilutions of short ragweed and histamine at 8 a.m. and 4 p.m. No significant differences between the two sessions were observed at any dilution of either test material. The size of the skin reactions to histamine and allergens was examined over the course of a year. It was found that reactions to both allergens and histamine were greater in October and February than in July and August.

Fifteen allergic women with seasonal rhinitis and/or asthma and 15 nonallergic female controls were skin tested three times during their menstrual cycle. There were significantly greater reactions to histamine and morphine in both allergic and nonallergic women and to Parietaria extract in allergic women on days 12 to 16 of the cycle, corresponding to ovulation and peak estrogen levels. The size of the reaction to histamine on the forearms was compared with handedness in 176 subjects. Significant differences between the size of the wheal and flare on the two forearms were observed. Subjects who were right-handed, with only right-handed relatives, had significantly larger reactions on the left arm. Subjects who were either left-handed or ambidextrous had significantly larger reactions on the right arm.

Reactivity of the Skin in Different Areas of the Body

The back is commonly used for percutaneous testing, since it provides a large surface that can accommodate many tests. Although it may be acceptable to consider the back as homo­genous for clinical purposes, there is a significant gradient of reactivity, with the upper back being less reactive than the middle, which in turn is less reactive than the lower third. The wheal diameter with allergens was 30% less and with histamine 19% less on the upper compared with the lower back. Often the forearm is employed as an alternative site for percutaneous testing because there is no need for the patient to disrobe and testing may be done with the patient sitting in a chair rather than lying down. It has been long recognized that the forearm is not as reactive as the back. In one study, allergen-induced wheal diameter was 27% smaller and flare diameter 14% smaller. While the difference is not great, it is estimated that 2.3% of tests positive on the back would be negative if performed on the forearm.

Viral Infections

Skin testing with inhalant allergens was performed in 16 adults before and up to 21 days following experimental inoculation with respiratory syncytial virus (RSV). Even subjects with no measurable skin test reactions at baseline showed increased wheal and flare areas in response to histamine and allergen skin tests after RSV infection. The altered skin test response persisted for up to 21 days after RSV inoculation. It was suggested that up-regulation of pathways relating to neurogenic inflammation may have played a role.

Medication (see Table 19-1 )

Histamine is a major mediator of the immediate skin test, so drugs that have antihistaminic properties suppress skin test reactions. Studies have assessed the duration of this suppression after the medication is discontinued, since this is often an important consideration for diagnostic allergy skin testing. Persisting suppression after multiple doses of first generation antihistamines was studied. The mean time for skin reactivity to return to normal after stopping the drug was 3 days for chlorpheniramine and tripelennamine and 5 days for hydroxyzine. However, some patients remained suppressed for 6 to 8 days. After a single dose of the second-generation antihistamine, fexofenadine, skin reactivity had returned to normal after 24 hours. Single 25 mg doses of the tricyclic antidepressants, desipramine and doxepin, produced suppression which lasted an average of 2 and 6 days respectively. It was recommended that doxepin be withheld at least 7 days before skin testing. Multiple dosing of the H ₂ antagonist, ranitidine, produced significant suppression of both the wheal and flare of the histamine skin test. Suppression was only 18% of the mean diameter, so withholding the drug on the day of testing should be adequate.

In 15 subjects, the leukotriene receptor antagonist, montelukast, significantly reduced the flare reaction to histamine, codeine and allergen. There was a nonsignificant trend toward reduction in wheal size with all three agents. Other investigators found nonsignificant reductions in both wheal (9.6%) and flare (7.3%) following administration of montelukast.

There is no consensus regarding the effect of corticosteroids on allergy skin tests. In a prospective study, topical application of corticosteroids for 4 weeks reduced the area of the allergen-induced wheal by 72% and the flare by 62%. The reduction could at least, in part, be explained by an 85% reduction in the number of detectable skin mast cells in the treated skin. A prospective study of 1 week of oral corticosteroids, 24 mg daily of methylprednisolone, found no effect on reactivity to ragweed. A retrospective analysis of 25 patients who had been on oral steroids for longer, but varying periods, suggested that they had diminished skin reactivity to codeine, a nonimmunologic mast cell degranulating agent. However, a prospective study of 33 patients who received oral steroids for at least 1 year (median dose 20 mg of prednisone per day, median duration of 2 years) revealed no suppression of skin reactions to either codeine or allergen.

The monoclonal antibody against IgE, omalizumab, has been reported to reduce skin test reactions. In 19 subjects with perennial allergic rhinitis, 3 months of treatment with omalizumab 0.030 mg/kg/IU/mL reduced free IgE levels >98% and the cumulative whealing response to titrated prick skin tests (150–10 000 AU/mL of house dust mite extract) by 78–83%.

Allergy immunotherapy has been observed to reduce the immediate reaction to allergen skin testing. The reductions in the immediate skin test are accompanied by reductions in nasal and conjunctival sensitivity. Allergen immunotherapy reduces the late cutaneous reaction even more than the immediate.

Quantity and Quality of Extracts

The size of the reaction is a function of the patient’s sensitivity and the amount of the relevant allergen injected. The relationship between dose and response is best expressed as a log : log relationship. The slope is steeper when the size of the reaction is expressed as the log of the area, as opposed to the log of the diameter. When log-linear dose responses are calculated, the resulting curve is S-shaped, but linear in the midrange. A 10-fold increase in the concentration of allergen or histamine will produce approximately a 1.5-fold increase in mean diameter or a doubling of the area of the wheal.

In the USA, standardized extracts are available for several grasses, ragweed, Dermatophagoides pteronyssinus and farinae , and cat. In general, other pollen extracts, although not standardized, are of good potency. Most extracts of dog dander, probably most or all fungi and all extracts of cockroach are relatively weak. In the case of fungi and cockroach, proteases in the extracts may degrade susceptible proteins within the extract. One exception to the low potency of most dog extracts is the acetone-precipitated dog extract manufactured by Holister-Steir (Spokane, WA). This extract contains 30 to 40 times as much major allergen as the other commercially available dog extracts. The increased allergen content has been shown to result in an increased number of positive prick skin tests in comparative skin testing.

A unique problem appears to exist with extracts of some foods. Many patients with documented food sensitivity will fail to react to commercial extracts or in vitro tests prepared from these extracts but will react to testing with fresh extracts of the foods. Reactions to fresh foods, but not commercial food extracts, have been reported with fruits and celery, with shellfish and fish, and even with peanuts and walnuts. This report notwithstanding, peanut extracts have been reported to be reliable in other studies. In 76 children aged 5 months to 15 years, there were 31 positive blinded food challenges out of 96 foods which yielded positive prick skin tests. All the positive challenges were to peanuts, eggs, milk or soy. There were no positive open feeding challenges to foods that had not been positive on prick skin testing.

Prick Versus Intradermal Testing

There are two approaches to allergen skin testing. One is percutaneous introduction of the allergen through a break in the skin by pricking, puncturing or scratching. In the last of these, a linear scratch is made without drawing blood. The scratch may be performed first with the extract then dropped on the abraded skin, or the scratch may be made through a drop of extract. The scratch test has now largely been abandoned due to greater discomfort, poorer reproducibility and the possibility of leaving multiple linear depigmented areas for some time afterward. The prick test is performed by introducing the tip of the device into the epidermis at approximately a 45-degree angle through a drop of extract; the tip is then lifted, creating a small, transient break in the epidermis. Prick testing can be performed with either solid needles or hollow hypodermic needles. Puncture testing is performed by pressing the tip of the device at a 90-degree angle to the skin. Usually the device employed has a sharp point approximately 1 mm long, with a widening above to limit penetration into the skin.

The alternative to percutaneous testing is intracutaneous testing. A hypodermic syringe and needle is employed. The needle is threaded into the dermis where, typically, 0.01 to 0.02 mL of extract is injected. Intradermal testing is more sensitive than prick/puncture. For equivalent reactions at threshold-sized reactions, the extract for prick/puncture testing must be 1000-fold more concentrated. Also, direct comparisons indicate that intradermal testing is more reproducible than percutaneous testing. Nevertheless, there are many arguments in favor of the percutaneous test as the routine for allergy testing. These include economy of time, patient comfort and safety. These apply to percutaneous versus intracutaneous, no matter what relative concentrations of extract are employed. If, in addition, the intradermal test is performed with a concentration greater than 1 : 1000 that of the percutaneous test, in order to increase its sensitivity, additional considerations arise as to whether this increased sensitivity is clinically necessary or useful.

Diagnostic Usefulness of the Percutaneous Test

The prick skin test has served well in epidemiological studies. Prick skin test reactivity to indoor allergens, but not pollens, has been shown to be a risk factor for asthma in children and adolescents and adults. Prick skin test reactivity in asymptomatic freshmen in college carried an increased risk for development of allergic rhinitis. Three-year follow-up revealed that 18.2% of those with positive prick skin tests had developed allergic rhinitis compared to 1.8% of those with negative prick skin tests. At 7-year follow-up, 31.9% of those with positive prick skin tests and 7.7% of those with negative skin tests had developed allergic rhinitis. The larger the prick skin test as a freshman, the more likely the development of allergic rhinitis. Furthermore, after 7 years, new-onset asthma had developed in 5% of the prick skin test positive group, versus 1.5% in the skin test negative group.

Diagnostic Usefulness of the Intracutaneous Test

Although the intracutaneous test, at the strength customarily performed, is more sensitive, it may be questioned whether this increased sensitivity is clinically necessary. The prick skin test, performed with good quality extracts, is positive in many subjects who do not have a personal or even a family history of allergy. A number of studies have addressed the clinical usefulness of intracutaneous testing. In the Tucson epidemiological study, 311 subjects had prick skin testing followed, if negative, by intracutaneous testing with 1 : 1000 w/v extract to 14 common allergens. Subjects were divided, by history, into allergic and nonallergic groups. Prick test reactivity correlated with the presence of allergy symptoms. Conversely, positive reactions to intracutaneous testing, which followed a negative prick test for that allergen, showed no correlation with either the patient’s clinical allergic status or the level of total serum IgE. Studies in smaller groups of patients have supported these epidemiological data.

Two studies examined the intracutaneous test as a predictor of symptoms with natural exposure to the allergen. In a study of the clinical usefulness of intradermal skin tests to grass, four groups were compared: three of the groups had a history of seasonal allergic rhinitis, one with positive prick skin tests to timothy, one with negative prick but a positive intradermal test to timothy, and one with both prick and intracutaneous tests to timothy negative. The fourth group was a nonallergic control. On the basis of nasal challenge with timothy, grass pollen allergic reactions were present in 68% of those with positive prick skin tests to timothy and none of the nonallergic controls. In both the group with positive and those with negative intracutaneous tests to timothy, 11% were positive. Subjects were then followed through the grass pollen season. Their symptom scores, recorded in a diary, were examined for a correlation with grass pollen counts. A positive correlation was present in 64% of those with positive skin prick tests and none of the nonallergic controls. A positive correlation of symptoms and pollen count was present in 22% of those with a positive intracutaneous test and 21% of those with a negative intracutaneous test to timothy. Both criteria for allergy to timothy, a positive nasal challenge and a correlation between symptoms and grass pollen counts, were met in 46% of those with positive prick skin tests, but in none in the other three groups. Thus, under the conditions of this study, the presence of a positive intradermal skin test response to timothy in the presence of a negative prick skin test response to timothy did not indicate the presence of clinically significant sensitivity to timothy grass.

In the second study, subjects were challenged with cat exposure for 1 hour. Both positive prick skin tests and RASTs to cat were highly predictive of development of symptoms on exposure to the cat room. Subjects with a negative prick skin test were just as likely to have a positive challenge result if they had a negative (31%) as if they had a positive intracutaneous skin test to cat (24%). The authors concluded that, at least with regard to cat allergy, these results strongly suggest that major therapeutic decisions such as environmental control or immunotherapy should never be based on a positive intracutaneous skin test result alone.

It is clear from these studies that the intradermal skin test adds little to the diagnostic evaluation of allergy when allergy extracts of reasonable quality are available for skin testing. This probably includes almost all pollen extracts, house dust mite, cat and acetone-precipitated dog extracts. What of the extracts of poorer quality, particularly cockroach, fungi and some dander extracts? A study of the diagnosis of allergy to mouse extract is informative in this regard. In this study, 49 workers reported symptoms on mouse exposure. The mouse extract contained only 2.37 µg of Mus m 1 per mL, about 6% the major allergen content in cat extract. Using a nasal challenge as the gold standard, sensitivity was only 47% for measurement of mouse IgE (mIgE), 67% for the prick skin test, and 100% for an intradermal test at a 1 : 100 dilution of the extract. On the other hand, specificity was 91% for mIgE, 94% for prick skin test, but only 65% for intradermal testing. The prick skin test performed best, but with this weak extract, intradermal testing was required to identify some clinically sensitized workers.

Expressing the Results of Skin Testing

The results of both percutaneous and intracutaneous skin tests are often reported in only semi-quantitative terms. Results may be recorded only as positive or negative, or graded 0 to 4+ without any indication of what size reactions these numbers represent. At the very least, a record of skin testing should indicate certain information that will allow another physician to interpret the results. In addition to the concentration of extract employed, the form should indicate whether the tests are percutaneous or intracutaneous and, if the former, which device was employed for testing, whether testing was performed on the back or the arm, and the size of the positive and negative reactions. Finally, if an arbitrary grading system is employed, the range of reaction for each grade should be clearly indicated on the form (see Table 19-2 ).

A superior method of expressing results is to measure and record actual size of the reaction. This need not be excessively time consuming. Although the area of the wheal is the most accurate, measurements of the product of the orthogonal diameters, the sum of the orthogonal diameters and even the longest diameter correlate very well with area, with r values greater than 0.9. In fact, the longest diameter has been reported to correlate better with the wheal area than the mean of two perpendicular diameters. An additional advantage of measuring the diameter of the wheal is the observation that, with 17 of 18 standardized extracts, the risk of having allergic symptoms increased significantly with larger wheal diameter.

The Scandinavian Society of Allergology recommended that skin test results be standardized in relation to the size of the reaction to histamine, employing 0.1 mg/mL of histamine for intradermal testing and 1 mg/mL of histamine for prick skin testing. If the diameter of the reaction to allergen was the same size as the histamine reaction, the grade was 3+, if half that size 2+, and if twice as large 4+. A subsequent study suggested that the histamine control should be 10 mg/mL, because of the small reactions with high coefficient of variation with the 1 mg/mL histamine prick skin test. Even the 20–30% coefficient of variation for reactions to 10 mg/mL raises questions regarding the desirability of basing grading on a histamine control, which, if used for this purpose, should be performed at least in duplicate.

The reliability of different means of expressing the results of prick skin testing was compared in patients sensitive to dogs. A determination of sensitivity to dog was made in 202 children based on a composite score from history, RAST and bronchial or conjunctival allergen challenges. The results with the three common means of expressing results (wheal diameter, wheal diameter compared to the histamine control and titrated prick skin tests) were compared for sensitivity, specificity and overall efficacy. Although the overall efficacy of the histamine reference was greatest in this study, most allergists would prefer to have the maximum sensitivity, which was provided by a wheal ≥3 mm diameter, in order not to miss any truly sensitive patients. Other methods, or clinical judgment, should then be used to distinguish between those who are only sensitized and those who are clinically allergic.

Devices for Percutaneous Skin Testing

Intracutaneous skin tests are performed using a hypodermic syringe and needle. Percutaneous tests are performed with an ever-increasing variety of devices. Some devices have a single stylus with a single or several points and are used either to prick or puncture through a drop of extract or to carry a drop of extract from the extract bottle, so that application of extract and the puncture occur in one step. The puncture technique may be combined with twisting, which generally results in more pain and a greater chance of a false positive test. Increasingly, devices are being introduced which have multiple heads, so that up to 10 tests can be accomplished with one application ( Figure 19-1 ). Generally the multiple-headed skin test devices are designed to first be dipped into the extract bottles, then applied to the skin so that testing is accomplished in one step. Both the single and multiple test devices for percutaneous testing vary in the degree of trauma that they impart to the skin, therefore they vary in the size of positive reactions and also in the likelihood of producing a reaction at the site of the negative control. Thus, different devices require different criteria for what is the minimum wheal diameter that constitutes a positive reaction.

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