Impact of changed legislation on skin tests: the present and future.

PURPOSE OF REVIEW: To discuss the impact of current European Union regulations on the availability of commercially available skin test allergens in European member states. RECENT FINDINGS: European Union legislations now define diagnostic allergens to be medicine requiring market authorization of every individual diagnostic allergen with obligations including clinical trials, application dossiers, a regular update of the dossiers, handling of variation processes and ongoing stability testing of the source material and periodic safety update reporting. The financial expenses of the initiation and maintenance of approvals for diagnostic allergens far exceed their related revenues. Thus, the numbers of authorized test allergens are steadily decreasing. SUMMARY: The current European Union regulations are anticipated to have an immense impact on in-vivo allergy diagnosis in Europe. Available skin test allergens decreased to less than half of what has been before in recent years. EAACI has addressed both the EU and EMA to resolve this situation.

Skin Testing for Allergic Rhinitis: A Health Technology Assessment.

BACKGROUND: Allergic rhinitis is the most common type of allergy worldwide. The accuracy of skin testing for allergic rhinitis is still debated. This health technology assessment had two objectives: to determine the diagnostic accuracy of skin-prick and intradermal testing in patients with suspected allergic rhinitis and to estimate the costs to the Ontario health system of skin testing for allergic rhinitis. METHODS: We searched All Ovid MEDLINE, Embase, and Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, CRD Health Technology Assessment Database, Cochrane Central Register of Controlled Trials, and NHS Economic Evaluation Database for studies that evaluated the diagnostic accuracy of skin-prick and intradermal testing for allergic rhinitis using nasal provocation as the reference standard. For the clinical evidence review, data extraction and quality assessment were performed using the QUADAS-2 tool. We used the bivariate random-effects model for meta-analysis. For the economic evidence review, we assessed studies using a modified checklist developed by the (United Kingdom) National Institute for Health and Care Excellence. We estimated the annual cost of skin testing for allergic rhinitis in Ontario for 2015 to 2017 using provincial data on testing volumes and costs. RESULTS: We meta-analyzed seven studies with a total of 430 patients that assessed the accuracy of skin-prick testing. The pooled pair of sensitivity and specificity for skin-prick testing was 85% and 77%, respectively. We did not perform a meta-analysis for the diagnostic accuracy of intradermal testing due to the small number of studies (n = 4). Of these, two evaluated the accuracy of intradermal testing in confirming negative skin-prick testing results, with sensitivity ranging from 27% to 50% and specificity ranging from 60% to 100%. The other two studies evaluated the accuracy of intradermal testing as a stand-alone tool for diagnosing allergic rhinitis, with sensitivity ranging from 60% to 79% and specificity ranging from 68% to 69%. We estimated the budget impact of continuing to publicly fund skin testing for allergic rhinitis in Ontario to be between $2.5 million and $3.0 million per year. CONCLUSIONS: Skin-prick testing is moderately accurate in identifying subjects with or without allergic rhinitis. The diagnostic accuracy of intradermal testing could not be well established from this review. Our best estimate is that publicly funding skin testing for allergic rhinitis costs the Ontario government approximately $2.5 million to $3.0 million per year.

International guidelines for the in vivo assessment of skin properties in non-clinical settings: Part 2. transepidermal water loss and skin hydration.

BACKGROUND: There is an emerging perspective that it is not sufficient to just assess skin exposure to physical and chemical stressors in workplaces, but that it is also important to assess the condition, i.e. skin barrier function of the exposed skin at the time of exposure. The workplace environment, representing a non-clinical environment, can be highly variable and difficult to control, thereby presenting unique measurement challenges not typically encountered in clinical settings. METHODS: An expert working group convened a workshop as part of the 5th International Conference on Occupational and Environmental Exposure of Skin to Chemicals (OEESC) to develop basic guidelines and best practices (based on existing clinical guidelines, published data, and own experiences) for the in vivo measurement of transepidermal water loss (TEWL) and skin hydration in non-clinical settings with specific reference to the workplace as a worst-case scenario. RESULTS: Key elements of these guidelines are: (i) to minimize or recognize, to the extent feasible, the influences of relevant endogenous-, exogenous-, environmental- and measurement/instrumentation-related factors; (ii) to measure TEWL with a closed-chamber type instrument; (iii) report results as a difference or percent change (rather than absolute values); and (iv) accurately report any notable deviations from this guidelines. CONCLUSION: It is anticipated that these guidelines will promote consistent data reporting, which will facilitate inter-comparison of study results.

International guidelines for the in vivo assessment of skin properties in non-clinical settings: part 1. pH.

BACKGROUND: Skin surface pH is known to influence the dissolution and partitioning of chemicals and may influence exposures that lead to skin diseases. Non-clinical environments (e.g., workplaces) are highly variable, thereby presenting unique measurement challenges that are not typically encountered in clinical settings. Hence, guidelines are needed for consistent measurement of skin surface pH in environments that are difficult to control. METHODS: An expert workshop was convened at the 5th International Conference on Occupational and Environmental Exposure of Skin to Chemicals to review available data on factors that could influence the determination of skin surface pH in non-clinical settings with emphasis on the workplace as a worst case scenario. RESULTS: The key elements of the guidelines are: (i) minimize, to the extent feasible, the influences of relevant endogenous (anatomical position, skin health, time of day), exogenous (hand washing, barrier creams, soaps and detergents, occlusion), environmental (seasonality), and measurement (atmospheric conditions) factors; (ii) report pH measurements results as a difference or percent change (not absolute values) using a measure of central tendency and variability; and (iii) report notable deviations from these guidelines and other relevant factors that may influence measurements. CONCLUSION: Guidelines on the measurement and reporting of skin surface pH in non-clinical settings should promote consistency in data reporting, facilitate inter-comparison of study results, and aid in understanding and preventing occupational skin diseases.

Assessment of the current practice of antibiotic skin testing in a tertiary hospital in United Arab Emirates.

INTRODUCTION: Skin testing can be a useful diagnostic tool to identify patients who are allergic to penicillin. Procedures for skin testing in the United Arab Emirates have not been standardized. The aim of this study was to examine the current practice of antibiotic skin testing in a tertiary hospital in the United Arab Emirates (UAE). METHODOLOGY: This was a prospective cross-sectional study conducted in Al Qassimi Hospital, in which the medical records of all patients who were prescribed antibiotics over an eight-week period were screened to evaluate patients' history, indication for performing the test, results, and documentation of findings. RESULTS: During the study period 357 patients received parenteral antibiotics, of which 238 had one skin test, 21 had two skin tests, and one patient had four skin tests. Skin testing was performed without regard for patient history. Documentation of both positive and negative results was poor. There was no standard technique for skin testing used within the institution, and significant variations were noted between wards. In most cases the techniques used deviated from recommended procedures in the medical literature. CONCLUSIONS: Standardized guidelines for antibiotic skin testing should be established and implemented as soon as possible using recommended international guidelines.

Potency values from the local lymph node assay: application to classification, labelling and risk assessment.

Hundreds of chemicals are contact allergens but there remains a need to identify and characterise accurately skin sensitising hazards. The purpose of this review was fourfold. First, when using the local lymph node assay (LLNA), consider whether an exposure concentration (EC3 value) lower than 100% can be defined and used as a threshold criterion for classification and labelling. Second, is there any reason to revise the recommendation of a previous ECETOC Task Force regarding specific EC3 values used for sub-categorisation of substances based upon potency? Third, what recommendations can be made regarding classification and labelling of preparations under GHS? Finally, consider how to integrate LLNA data into risk assessment and provide a rationale for using concentration responses and corresponding no-effect concentrations. Although skin sensitising chemicals having high EC3 values may represent only relatively low risks to humans, it is not possible currently to define an EC3 value below 100% that would serve as an appropriate threshold for classification and labelling. The conclusion drawn from reviewing the use of distinct categories for characterising contact allergens was that the most appropriate, science-based classification of contact allergens according to potency is one in which four sub-categories are identified: 'extreme', 'strong', 'moderate' and 'weak'. Since draining lymph node cell proliferation is related causally and quantitatively to potency, LLNA EC3 values are recommended for determination of a no expected sensitisation induction level that represents the first step in quantitative risk assessment.

Can we manage demand for allergy testing by restricting requests to a small number of prime target allergens?

BACKGROUND: Demand for expensive tests such as allergen-specific IgE is expanding far faster than for cheaper tests: at Burton Hospital the annual growth rate is 24%. Different hospitals have different policies on allergen testing. We report a comparison of the effect of requesting policy on diagnostic yield. METHODS: All results from five years of allergen testing were downloaded from the data warehouse at Burton, and a representative sample of recent results was evaluated from Ipswich Hospital. Statistical analysis by chi(2) test and significance tests for differences of proportions were carried out. RESULTS: Ipswich hospital used a standard four-allergen panel for respiratory patients and demonstrated a statistically significantly lower positivity rate for three of those four allergens. No relationship between the number of allergens tested and the probability of a positive result was shown - the probability of a positive result was approximately 0.3. Number of allergen-specific IgE tests requested/patient have remained roughly constant over 5(1/2) years but total demand has increased. CONCLUSIONS: Selective requesting for allergen-specific IgE testing may be more effective than use of a standard panel but this cannot be conclusively proven. It is not appropriate to attempt to limit workload by specifying a maximum number of tests that are allowed for any individual patient.

Skin testing technique and precision in stinging insect allergy.

AIM: We report on quantitative analysis of skin tests in patients undergoing Hymenoptera venom immunotherapy. The need for accuracy, coupled with a sound manual technique, in performing this procedure is emphasized. Involuntary errors may occur and pose serious problems with interpretation of results. A revealing example is reported and the strategy devised to analyse the flaws and overcome the resulting problems is presented and discussed. BACKGROUND: Skin testing plays a key role in the diagnosis of most allergic disease and in the assessment of allergen immunotherapy. Particularly, insect sting allergy requires implementation of complex and demanding skin testing protocols and a competent nursing practice. METHODS: Sixteen patients were tested before starting the immunotherapy and after three years of treatment. Cutaneous response (expected to decline, following immunotherapy) was assessed as: (i) allergen-elicited wheal areas; (ii) ratios between allergen-elicited wheal areas and homologous histamine (positive controls) wheal areas. RESULTS: By using allergen-elicited areas, the paradoxical result was obtained that skin reactivity had increased instead of decreasing, upon immunotherapy. Histamine response analysis suggested that this paradox might rather be the result of a technical flaw. Analysis of written notes of routine clinical meetings revealed that an important manual flaw had been detected (and corrected) some years earlier, affecting the results of the baseline testing (viz. the allergen was injected deeper in the skin, yielding a weaker response). Skin reactivity evaluation in terms of allergen-histamine ratio confirmed this interpretation, as, when the baseline ratios were compared with the three years immunotherapy ratios, a distinct decline in skin reactivity was detected, as expected. CONCLUSIONS: Skin testing in insect sting allergy is a conceptually and manually complex procedure, which should be subjected to systematic quality control assessment, like a laboratory procedure. The personnel involved in the performance of this procedure should receive appropriate and extensive training. RELEVANCE TO CLINICAL PRACTICE: Diagnosis of allergic diseases and monitoring of immunotherapy largely rely on impeccable skin testing technique.

[Allergy in general practice in Arhus County. Quality assessment of diagnosis, treatment and instructions to patients. III. Allergy testing]. / Allergiudredning i almen praksis i Arhus Amt. Kvalitetsvurdering af diagnostik, behandling og patientinstruktion. III. Allergidiagnostik.

INTRODUCTION: The aim of this study was to compare the allergy test with the skin prick test and the specific IgE by Phadiatop test to a purely clinical allergy diagnosis by an allergy specialist in adult patients previously tested in general practice. MATERIALS AND METHODS: A total of 103 patients suspected of having asthma and/or rhinitis were re-evaluated with a clinical diagnosis and the two allergy tests. Both the patient and the individual general practitioner were asked about existing allergy diagnosis. RESULTS: The two test systems showed large differences in a semiquantitative linear system with an explained variation (r2) of only 8%. In comparison to a purely clinical diagnosis, they were diagnostically equal with both tests, with an additional 15% positive reactions of which 25% were judged clinically active. Both tests resulted in about 33% false-positive tests classified as clinically inactive. In the case of a positive Phadiatop test and clinically active allergy, both the patient and the general practitioner reported identical specialist diagnoses in about 75% of cases, while in 20-50% of the cases an identical diagnosis was reported when the clinical diagnosis was qualitatively different from the result of Phadiatop. CONCLUSION: The results of the two test systems often differ, and they both detect extra positive tests, in which case they should be used in a serial manner. Both tests often result in a false-positive diagnosis, and identification of clinically relevant positive tests often requires an experienced medical evaluation.

Comparison of the biological activity of the most common sublingual allergen solutions made by two European manufacturers.

BACKGROUND: The clinical efficacy of sublingual immunotherapy has been documented in numerous studies and meta-analyses and is argued to be a favored alternative to the subcutaneous route if allergic symptoms are treated with a high-dose therapy. What is still lacking is a 'conversion rate' between the biological activities of different allergen solutions to determine the one with the higher concentration. METHODS: A randomized, double-blind, parallel-group study was done with three groups sensitized to the allergens birch, grass or house dust mite via skin prick test. Staloral in the concentrations 10, 100 and 300 IR and SLITone in the concentration of 1,000 STU per milliliter were used for a computer-based comparison of the geometric mean wheal sizes of the different solutions. For each patient, individual regression curves led to the calculation of a mean corresponding IR value for the SLITone solution. RESULTS: A total of 47 patients took part in this clinical trial, most of whom were sensitized to more than one allergen. Values for birch (30 patients) showed that 1,000 STU corresponded to 77 IR, for grass (29 patients) 1,000 STU matched 78 IR and for house dust mite (30 patients) 1,000 STU matched 27 IR based on dose-response relationships. The Wilcoxon test showed that for all allergens the allergenic activity of the SLITone solution was significantly higher than the 10 IR solution and significantly lower than the 100- and 300-IR solutions. CONCLUSION: We established a conversion rate between the two leading sublingual allergen solutions on the European market to compare different units of measurement.

In vivo assessment with prick-to-prick testing and double-blind, placebo-controlled food challenge of allergenicity of apple cultivars.

BACKGROUND: Apple cultivars have been reported to differ in allergenicity on the basis of in vitro and skin prick tests with apple extracts. OBJECTIVES: We sought to evaluate the efficacy of the prick-to-prick method in assessing differences in allergenicity of apple cultivars and to confirm differences by means of double-blind, placebo-controlled food challenge (DBPCFC). METHODS: Intra-assay and intracultivar variation of prick-to-prick test results were determined in 6 Dutch and 8 Spanish patients with apple allergy by using 5 apples of the cultivars Golden Delicious, Fuji, and Ecolette in duplicate. In addition, 21 cultivars were screened for allergenicity in 15 Dutch patients with birch pollen and apple allergy. Two selected cultivars (Golden Delicious and Santana) were tested with DBPCFCs. The influence of storage conditions on allergenicity was assessed in 5 cultivars. RESULTS: Intra-assay variation of skin prick testing was 3.9%, and intracultivar variation was 4.1%. A ranking of 21 cultivars was made on the basis of prick-to-prick tests in 9 patients. Apple cultivars were classified as of low, intermediate, and high allergenicity, with a significant difference between low and high allergenicity (P < .001). A significant difference in allergenicity determined between Golden Delicious and Santana cultivars (P < .05) was confirmed by means of DBPCFC. With 5 cultivars, controlled atmosphere (2.5% oxygen/1% carbon dioxide) was shown to reduce allergenicity (P < .001) by 15% compared with storage at 2 degrees C. CONCLUSIONS: Prick-to-prick testing with fresh apples is a reproducible method of assessing allergenicity. Apples can be classified as of low or high allergenicity for the majority of patients. This was confirmed by using DBPCFCs. Selection of cultivars and control of storage conditions are both viable strategies for reduction of symptoms in patients with apple allergy.

Skin sensitization testing in potency and risk assessment.

The purpose of this article is to review, and make recommendations for, the use of relevant skin sensitization test methods, for the purposes of determination of relative potency and the threshold dose necessary for the induction of skin sensitization, and for risk assessment. In addressing the first area, the utility of three guinea pig tests (the guinea pig maximization test, the occluded patch test, and the open epicutaneous test) of the local lymph node assay (LLNA) and of human volunteer testing for the assessment of relative potency and identification of thresholds for sensitization were considered. The following conclusions were drawn. (1) Although attempts have been made to modify the guinea pig maximization test for the purposes of deriving dose-response relationships, this method is usually unsuitable for determination of relative sensitizing potency. (2) Guinea pig methods that do not require the use of adjuvant and which employ a relevant route of exposure (the occluded patch test and the open epicutaneous test) are more appropriate for the assessment of relative skin-sensitizing potency. (3) The LLNA is suitable for the determination of relative skin sensitizing potency, and the adaptation of this method for derivation of comparative criteria such as EC3 values (the estimated concentration of test chemical required to induce a stimulation index of 3 in the LLNA) provides an effective and quantitative basis for such measurements. (4) For all the methods identified above, potency is assessed relative to other chemical allergens of known skin sensitizing potential. The estimation of likely threshold concentrations is dependent upon the availability of suitable benchmark chemicals of known potency for human sensitization. (5) Human testing (and specifically, the Human Repeat Insult Patch Test) can provide information of value in confirming the absence of skin sensitizing activity of formulations and products under specific conditions of use and exposure. Based on the above, the following recommendations are made. (1) If results are already available from suitable guinea pig tests, then judicious interpretation of the data may provide information of value in assessing relative skin sensitizing potency. This option should be explored before other analyses are conducted. (2) The LLNA is the recommended method for new assessments of relative potency, and/or for the investigation of the influence of vehicle or formulation on skin sensitizing potency. (3) Whenever available, human skin sensitization data should be incorporated into an assessment of relative potency. With respect to risk assessment, the conclusion drawn is that all the available data on skin-sensitizing activity in animals and man should be integrated into the risk-assessment process. Appropriate interpretation of existing data from suitable guinea pig studies can provide valuable information with respect to potency, as the first step in the development of a risk assessment. However, for de novo investigations, the LLNA is the method favored for providing quantitative estimations of skin-sensitizing potency that are best suited to the risk assessment process. Finally, human testing is of value in the risk assessment process, but is performed only for the purposes of confirming product safety.

A skin sensitization risk assessment approach for evaluation of new ingredients and products.

Skin sensitization risk assessment of new ingredients or products is critical before their introduction into the marketplace. The risk assessment process described in this article involves evaluation of skin sensitization hazard, consideration of all potential human exposures, comparative ingredient/product benchmarking, and, when appropriate, the management of the risk. In this article, a risk assessment process is reviewed along with a description of the risk assessment tools that are employed for evaluating a new ingredient or product. The basic process we use for evaluating the skin sensitization risk of a new product or ingredient is considered a no effect/safety factor approach. The tools used for conducting a risk assessment include structure activity relationship analysis, exposure assessment, preclinical testing (e.g., local lymph node assay [LNNA]) and clinical testing (e.g., human repeat insult patch testing [HRIPT]). The skin sensitization risk assessment process described in this paper has been used successfully for many years for the safe introduction of new products into the marketplace. This process is dynamic--it can be applied to a diversity of product categories (e.g., shampoo, transdermal drug). In summary, the skin sensitization risk assessment process described in this article allows one to carefully assess the skin sensitization potential of a new ingredient or product so that it can be safely introduced into the marketplace.

Local lymph node assay: validation assessment for regulatory purposes.

For the prediction of skin sensitization potential of substances, the murine local lymph node assay (LLNA) is an alternative to the widely used guinea pig tests. For more than 10 years, this method has undergone extensive development, evaluation, and validation. In this review, the validation status of the LLNA is considered, specifically with regard to its use for regulatory identification of skin sensitization hazards. The LLNA is a method for the predictive identification of chemicals that have a potential to cause skin sensitization. Activity is measured as a function of lymph node cell proliferative responses stimulated by topical application of test chemicals. The LLNA has successfully passed all reasonable validation stages. It provides a reliable and relevant source of predictive skin sensitization data, which unlike results from guinea pig tests, are reproducible from laboratory to laboratory. In summary, the LLNA is now ready for acceptance as a viable and complete alternative to traditional methods, offering a substantial reduction in animal numbers and refinement opportunities without compromising the standards for the identification of important skin sensitizers.

A hand immersion test under laboratory-controlled usage conditions: the need for sensitive and controlled assessment methods.

Exaggerated test conditions were frequently used to investigate the cutaneous tolerance of detergent products in the past. As the sensitivity of newly designed biometric methods is steadily improving, the trend towards more realistic test conditions should be encouraged. A hand immersion test under laboratory-controlled usage conditions is presently described, fulfilling such principles. Panelists soaked their hands in 2 different hand dishwashing liquids, 2x daily for 10 min each (with successive in-solution/out-of-solution cycles) for 4 consecutive days. Products were at usual dilution for dishwashing liquids and were randomized between the dominant and non-dominant hands of panelists. Visual scoring of erythema and dryness developing on the whole hands (scoring scales including interdigital areas and joints) during the week did not allow discrimination between the 2 products. However the dominant hands were significantly more susceptible to alterations than the non-dominant hands, regardless of product attribution. In contrast, skin electrical measurements (Corneometer CM800 and Skicon 200) on the dorsum of the hands (muscle mass between thumb and index) and squamometry analysis of tape stripping (harvested from the same site) yielded significant differences between the 2 products. In conclusion, a hand immersion test under realistic conditions has been described, which discriminates between products when sensitive assessment methods are used to explore skin sites partially protected from daily-life skin aggressions.

In vitro and skin testing for allergy: comparable clinical utility and costs.

Controversy exists concerning the appropriate use of skin testing and in vitro testing for the diagnosis of allergy, particularly inhalant allergy. Earlier comparisons of skin testing and in vitro testing concluded that skin testing had superior accuracy at lower expense. In light of new developments with in vitro allergy testing, however, this issue should be reconsidered. A review of the recent scientific literature indicates that in vitro and skin testing are highly correlated. However, without the existence of an independent gold standard for inhalant allergy, it is not possible to determine which test is more accurate. The accuracy of either test can be compromised if conducted using different protocols or having insufficient quality control. Given their respective trajectories for technological advancement, quantification, and quality control, in vitro testing may offer the more standardized approach. Although the cost per test of in vitro testing remains greater than that of skin testing, the per-patient costs of the two modalities appear to be comparable, given the greater number of allergens typically used in skin testing. In summary, both skin testing and in vitro testing are acceptable as frontline diagnostic tools.