Chronic Urticaria: Following Practice Guidelines.

Histamine is a key inflammatory player in the pathogenesis of urticaria, a mast-cell-driven disease characterized clinically by the development of wheals, angioedema, or both. Changes to the management of chronic spontaneous urticaria have recently been adopted due to increasing literature surrounding the efficacy and safety of up-dosing modern second-generation H1-antihistamines and the use of omalizamub, a biologic agent, as a third-line treatment. Given the prevalence of chronic urticaria and its impact on quality of life, this editorial aims to provide a summary of the proposed updated guidelines for the management of chronic urticaria as agreed upon at the 5th Consensus Conference on the Update and Revision of the EAACI/GA2LEN/EDF/WAO Guideline for Urticaria in Berlin in December 2016. The chronic urticaria treatment algorithm outlined here reflects the updates and revisions made by 43 international experts representing 40 societies from 25 countries. These guidelines have yet to be published and therefore will require approval by respective national and international boards before adoption.

Angioedema in chronic spontaneous urticaria is underdiagnosed and has a substantial impact: Analyses from ASSURE-CSU.

BACKGROUND: ASSURE-CSU revealed differences in physician and patient reporting of angioedema. This post hoc analysis was conducted to evaluate the actual rate of angioedema in the study population and explore differences between patients with and without angioedema. METHODS: This international observational study assessed 673 patients with inadequately controlled chronic spontaneous urticaria (CSU). Physicians abstracted angioedema data from medical records, which were compared with patient-reported data. Patients in the Yes-angioedema category had angioedema reported in the medical record and a patient-reported source. For those in the No-angioedema category, angioedema was reported in neither the medical record nor a patient-reported source. Those in the Misaligned category had angioedema reported in only one source. Statistical comparisons between Yes-angioedema and No-angioedema categories were conducted for measures of CSU activity, health-related quality of life (HRQoL), productivity and healthcare resource utilization (HCRU). Regression analyses explored the relationship between Dermatology Life Quality Index (DLQI) score and angioedema, adjusting for important covariates. RESULTS: Among evaluable patients, 259 (40.3%), 173 (26.9%) and 211 (32.8%) were in the Yes-angioedema, No-angioedema and Misaligned category, respectively. CSU activity and impact on HRQoL, productivity, and HCRU was greater for Yes-angioedema patients than No-angioedema patients. After covariate adjustment, mean DLQI score was significantly higher (indicating worse HRQoL) for patients with angioedema versus no angioedema (9.88 vs 7.27, P < .001). The Misaligned category had similar results with Yes-angioedema on all outcomes. CONCLUSIONS: Angioedema in CSU seems to be under-reported but has significant negative impacts on HRQoL, daily activities, HCRU and work compared with no angioedema.

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.

This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

The burden of chronic spontaneous urticaria is substantial: Real-world evidence from ASSURE-CSU.

BACKGROUND: Chronic spontaneous urticaria (CSU) can be debilitating, difficult to treat, and frustrating for patients and physicians. Real-world evidence for the burden of CSU is limited. The objective of this study was to document disease duration, treatment history, and disease activity, as well as impact on health-related quality of life (HRQoL) and work among patients with inadequately controlled CSU, and to describe its humanistic, societal, and economic burden. METHODS: This international observational study assessed a cohort of 673 adult patients with CSU whose symptoms persisted for ≥12 months despite treatment. Demographics, disease characteristics, and healthcare resource use in the previous 12 months were collected from medical records. Patient-reported data on urticaria and angioedema symptoms, HRQoL, and work productivity and activity impairment were collected from a survey and a diary. RESULTS: Almost 50% of patients had moderate-to-severe disease activity as reported by Urticaria Activity Score. Mean (SD) Dermatology Life Quality Index and Chronic Urticaria Quality of Life Questionnaire scores were 9.1 (6.62) and 33.6 (20.99), respectively. Chronic spontaneous urticaria markedly interfered with sleep and daily activities. Angioedema in the previous 12 months was reported by 66% of enrolled patients and significantly affected HRQoL. More than 20% of patients reported ≥1 hour per week of missed work; productivity impairment was 27%. These effects increased with increasing disease activity. Significant healthcare resources and costs were incurred to treat CSU. CONCLUSIONS: Chronic spontaneous urticaria has considerable humanistic and economic impacts. Patients with greater disease activity and with angioedema experience greater HRQoL impairments.

Questions and answers in chronic urticaria: where do we stand and where do we go?

This supplement reports proceedings of the second international Global Urticaria Forum, which was held in Berlin, Germany in November 2015. In 2011, a report of the GA(2) LEN task force on urticaria outlined important and unanswered questions in chronic urticaria (CU). These included, but were not limited to, questions on the epidemiology and course of chronic spontaneous urticaria (CSU) [also called chronic idiopathic urticaria (CIU)], the resources allocated for the diagnosis and treatment of CSU, whether patients with angioedema as an isolated symptom can be regarded as a subgroup of CSU, and the efficacy and long-term safety of therapies. Many of these questions have been addressed by recent studies. Some of the answers obtained raise new questions. Here, we summarize some of the key insights on CU obtained over recent years, and we discuss old and new unmet needs and how to address them with future studies. We need to analyze the influence of recent advances in understanding of the burden of CU on patients and society, disease management and the CU patient journey. Our increased understanding of urticarial pathophysiology and consideration of the patient as a whole will need to be translated to better treatment algorithms and protocols. Actions to address these challenges include the 5th International Consensus Meeting on Urticaria, which will take place later this year. The formation of a global network of Urticaria Centers of Reference and Excellence over the next few years has also been proposed, with the aim of providing consistent excellence in urticaria management and a clear referral route, furthering knowledge of urticaria through additional research and educating/promoting awareness of urticaria.

Controversies and challenges in the management of chronic urticaria.

This supplement reports proceedings of the second international Global Urticaria Forum, which was held in Berlin, Germany in November 2015. Despite the clear international guideline, there remain a number of controversies and challenges in the management of patients with chronic urticaria (CU). As a result of major advancements in urticaria over the past 4 years, the current EAACI/GA(2) LEN/EDF/WAO urticaria guideline treatment algorithm requires updating. Case studies from patients with chronic spontaneous urticaria (CSU) [also called chronic idiopathic urticaria (CIU)], chronic inducible urticaria (CIndU) or diseases and syndromes related to CU are useful in describing and exploring challenges in disease management. Case studies of specific CSU patient populations such as children with CU or patients with angio-edema but no hives also require consideration as potentially challenging groups with unmet needs. The current EAACI/GA(2) LEN/EDF/WAO urticaria guideline provides a general framework for the management of patients with CU but, as these cases highlight, a personalized approach based on the expert knowledge of the physician may be required.

Definition, aims, and implementation of GA(2) LEN Urticaria Centers of Reference and Excellence.

BACKGROUND: GA²LEN, the Global Allergy and Asthma European Network, has recently launched a program for the development, interaction, and accreditation of centers of reference and excellence in special areas of allergy embedded in its overall quality management of allergy centers of excellence. The first area chosen is urticaria. Urticaria is a common and debilitating condition and can be a challenge for both patients and treating physicians, especially when chronic. Centers of reference and excellence in urticaria (UCAREs) can help to improve the management of hard-to-treat conditions such as urticaria. AIMS: Here, we describe the aims, the requirements and deliverables, the application process, and the audit and accreditation protocol for GA²LEN UCAREs. RESULTS: The main aims of GA²LEN UCAREs are to provide excellence in urticaria management, to increase the knowledge of urticaria by research and education, and to promote the awareness of urticaria by advocacy activities. To become a certified GA²LEN UCARE, urticaria centers have to apply and fulfill 32 requirements, defined by specific deliverables that are assessed during an audit visit. DISCUSSION AND CONCLUSION: The GA²LEN UCARE program will result in a strong network of urticaria specialists, promote urticaria research, and harmonize and improve urticaria management globally.

Management and treatment of chronic urticaria (CU).

Developments increasing our understanding of chronic urticaria have resulted in the simplification and improvement of available treatments. Currently, many treatments target mast cell mediators, but we can now disrupt mast cell activation with the anti-IgE antibody omalizumab, which has markedly advanced the treatment landscape for patients with difficult-to-treat urticaria. Current guidelines provide a framework for the management and treatment of patients with CU but, as each patient is different, knowledge and experience of specialist dermatologists and allergists are key to effective pharmacotherapy. This article reviews the different therapeutic options for patients with chronic spontaneous urticaria (also called chronic idiopathic urticaria) or chronic inducible urticaria and discusses management of special populations or special circumstances related to CU.

Treatment dilemmas in chronic urticaria.

The European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA(2) LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) recently published updated recommendations for the classification, diagnosis and management of chronic urticaria (CU). This article discusses several case histories that provide examples of how these recommendations can be implemented in the treatment of CU in a variety of real-life patients.

The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update

This guideline is the result of a systematic literature review using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2) LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The life-time prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria do not only cause a decrease in quality of life, but also affect performance at work and school and, as such, are members of the group of severe allergic diseases. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS).

Methods report on the development of the 2013 revision and update of the EAACI/GA2 LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria

This methods report describes the process of guideline development in detail. It is the result of a systematic literature review using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2) LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS) and is published in Allergy 2014; 69:868-887

Methods report on the development of the 2013 revision and update of the EAACI/GA2 LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria.

This methods report describes the process of guideline development in detail. It is the result of a systematic literature review using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2) LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS) and is published in Allergy 2014; 69:868-887.

The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update.

This guideline is the result of a systematic literature review using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2) LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The life-time prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria do not only cause a decrease in quality of life, but also affect performance at work and school and, as such, are members of the group of severe allergic diseases. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS).

Post-treatment efficacy of discontinuous treatment with 300IR 5-grass pollen sublingual tablet in adults with grass pollen-induced allergic rhinoconjunctivitis.

BACKGROUND: Sustained efficacy over three pollen seasons of pre- and co-seasonal treatment with 300IR 5-grass pollen sublingual tablet has been demonstrated in adults with moderate-severe grass pollen-associated allergic rhinoconjunctivitis. OBJECTIVE: To assess the efficacy of discontinuous treatment with 300IR 5-grass pollen sublingual tablet during the post-treatment pollen season of this long-term study. METHODS: Adults aged 18-50, sensitized to grass pollen, with a history of allergic rhinoconjunctivitis for more than two pollen seasons, and a retrospective rhinoconjunctivitis total symptom score ≥ 12 (0-18 scale), were randomized to receive Placebo or a 300IR tablet daily beginning either 4 months (4M) or 2 months (2M) prior to each pollen season and continuing for its duration for three consecutive years. They were followed over the subsequent immunotherapy-free pollen season. Post-treatment efficacy was evaluated using the Average Adjusted Symptom Score (AAdSS, adjusting the Rhinoconjunctivitis Total Symptom Score for rescue medication usage) during the post-treatment pollen period. Secondary endpoints included Average Rhinoconjunctivitis Total Symptom Score (ARTSS), Average Rescue Medication Score (ARMS), overall Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score and safety evaluation. Efficacy variables were analysed using ancova. RESULTS: Overall, 435 patients contributed to the Year 4 efficacy analyses. The Least-Squares (LS) mean differences (95% confidence interval) in AAdSS between active treatment and Placebo over the fourth pollen period were -1.14 (-2.03; -0.26) (P = 0.0114) and -1.43 (-2.32; -0.53) (P = 0.0019) in the (4M) and (2M) groups, corresponding to -22.9% and -28.5% relative LS mean differences (vs. Placebo) respectively. The active groups also showed statistically significant differences compared to Placebo in ARTSS, ARMS and overall RQLQ score. No safety risk was identified during the post-treatment period. CONCLUSIONS AND CLINICAL RELEVANCE: Pre- and co-seasonal treatment with 300IR 5-grass pollen sublingual tablet administered discontinuously for three consecutive years is efficacious post-treatment, safe and well tolerated. Benefits of treatment were meaningful to patients.

Identification of phenolic dermal sensitizers in a wound closure tape.

A latex-allergic patient presented with a severe local reaction to a non-latex wound closure bandage following surgery. Extracts of the bandage were analyzed by gas chromatograph-electron impact-mass spectrometry (GC EI-MS) in the total ion monitoring mode. Components were identified by their ion mass fingerprint and elution time as a corresponding standard from the GC column. The chemicals identified were 4,4'-thiobis-(6-tert-butyl-m-cresol) (TBBC), 6-tert-Butyl-m-cresol (BC), 2,4-di-tert-butylphenol (BP) and erucamide (EA). Sensitization potential of these chemicals was evaluated using two quantitative structure-activity relationship (QSAR) programs. The phenol 2,6-di-tert-butyl-4-(hydroxymethyl)phenol (BHP) was also included in the test series. It was initially thought to be present in the bandage but detectable levels could not be confirmed. The potential for TBBC to induce a sensitization response was predicted by both Derek for Windows and TOPKAT 6.2. The potential for BC and BP to induce a sensitization response was predicted by Derek for Windows, but not TOPKAT. BHP and EA were not predicted to be sensitizers by either QSAR program. Local lymph node assay (LLNA) analysis of the chemicals identified TBBC, BP, and BC as potential sensitizers with EC3 values between 0.2 and 4.5%. None of the animals exhibited body weight loss or skin irritation at the concentrations tested. In agreement with the toxicological modeling, BHP did not induce a sensitization response in the LLNA. Following a positive LLNA response, TBBC, BP, and BC were further characterized by phenotypic analysis of the draining lymph nodes. A positive LLNA result coupled with a lack of increase in B220(+)IgE(+) cell and serum IgE characterize these chemicals as Type IV sensitizers. These studies used a multidisciplinary approach combining clinical observation, GC-EI-MS for chemical identification, QSAR modeling of chemicals prior to animal testing, and the LLNA for determination of the sensitization potential of chemicals in a manufactured product.

Substance abuse policy and peace in the Middle East: a Palestinian and Israeli partnership.

This paper describes the working exchange between Israelis, Palestinians and international experts who engaged in a process to promote communications, cooperation and coordination of efforts directed toward peace as well as the prevention and treatment of drug abuse in the region. From 1997 to 1999, a program of training workshops and courses, drug prevention and treatment skills development and collaborative research was conducted on the basis of mutual respect and cooperation among Palestinians and Israelis. By tapping into the issue of substance abuse and by focusing on its professional and academic dimensions, this initiative engaged representative delegations of the police force, academia, treatment centers and various government ministries. While events of this period underscored the dependence of "bottom-up" peace initiatives on the prevailing political situation, the experience revealed the vital role of NGO frameworks in providing a safety net for promoting and sustaining relations as well as addressing an issue of common concern. This case study shows that addiction professionals, both clinicians and researchers, can be instrumental in conflict resolution as well as the prevention and treatment of drug abuse.

Mutational analysis of the IgE epitopes in the latex allergen Hev b 5.

BACKGROUND: Hev b 5 is a major latex allergen and potential candidate for an immunotherapy reagent. OBJECTIVE: The purpose of this study was to produce a hypoallergenic form of Hev b 5. METHODS: We used SPOTs analysis with alanine substitution to identify amino acids (AAs) critical for IgE binding and used site-directed mutagenesis to produce recombinant proteins with altered IgE-binding activity. RESULTS: Eleven epitopes were identified (5.1-5.11) in Hev b 5. Individual patients demonstrated variable epitope recognition, with the most intense reactivity to epitopes 5.4 and 5.7. IgE inhibition assays with synthetic peptides indicated that mutating a single epitope would not reduce IgE binding, but rather a combination of epitopes was required. After alanine substitutions to identify the important AAs, site-directed mutagenesis was used to replace the crucial AAs with alanine. Twenty clones with different combinations of altered epitopes were evaluated by means of IgE inhibition assays. Clones with mutations in single epitopes failed to reduce IgE binding, but changes to 8 epitopes (14 AAs) resulted in a 4500-fold reduction in IgE binding. Epitopes 5.7 and 5.9 were found to be cross-reactive, making Hev b 5 a multivalent allergen. CONCLUSIONS: We produced a recombinant Hev b 5 protein with significantly reduced IgE-binding activity. Changing a minimum of 3 immunodominant epitopes was required to cause a 100-fold reduction in IgE binding. Changes in 8 epitopes, particularly the cross-reactive epitopes 5.7 and 5.9, were needed to maximize the reduction in IgE binding. Mutants with reduced IgE-binding activity may prove to be valuable reagents for immunotherapy.

Latex protein: a hidden "food" allergen?

Avoidance of latex allergens is the primary method to prevent adverse reactions. Natural rubber latex is found in many different products in both the health care industry and in modern society, and consequently results in unexpected exposures of sensitized individuals. The use of latex gloves by food handlers provides one potential route for inadvertent exposure to latex allergens. In this study we have used two immunological methods to determine whether latex proteins are transferred to foods following contact with latex gloves. Direct transfer of latex protein to cheese was visualized using a modified immunoblot method. Sliced cheese was touched with a gloved finger. A nitrocellulose membrane was applied to lift the potential fingerprints and a rabbit anti-latex antiserum was used to visualize the transfer of any latex finger-prints. After handling lettuce with gloves, transferred protein was recovered by extracting the lettuce and quantified using an inhibition ELISA for latex proteins. Fingerprints of latex protein were readily detectable on cheese after contact with powdered latex gloves, but not with vinyl gloves. Furthermore, powdered latex glove use resulted in measurable amounts of latex protein on lettuce with an exposure-dependent increase in the latex protein levels. Lettuce alone or lettuce handled with vinyl gloves was negative for latex protein. The use of latex gloves by food handlers is the source of an indirect food additive in the form of latex proteins. It is recommended that food handlers avoid the use of latex gloves to eliminate inadvertent exposure of latex-sensitive individuals.

Latex allergy in the workplace.

While less than 1% of the general population is sensitized to latex, the U.S. Occupational Safety and Health Administration estimates that 8-12% of health-care workers are sensitized. The major source of workplace exposure is powdered natural rubber latex (NRL) gloves. NRL is harvested from HEVEA: brasiliensis trees and ammoniated to prevent coagulation resulting in the hydrolysis of the latex proteins. Prior to use in manufacturing, the latex is formulated by the addition of multiple chemicals. Thus, human exposure is to a mixture of residual chemicals and hydrolyzed latex peptides. Clinical manifestations include irritant contact dermatitis, allergic contact dermatitis (type IV), and type I immediate hypersensitivity response. Type I (IgE-mediated) NRL allergy includes contact urticaria, systemic urticaria, angioedema, rhinitis, conjunctivitis, bronchospasm, and anaphylaxis. Taking an accurate history, including questions on atopic status, food allergy, and possible reactions to latex devices makes diagnosis of type-I latex allergy possible. To confirm a diagnosis, either in vivo skin prick testing (SPT) or in vitro assays for latex-specific IgE are performed. While the SPT is regarded as a primary confirmatory test for IgE-mediated disease, the absence of a U.S. Food and Drug Administration-licensed HEVEA: brasiliensis latex extract has restricted its use in diagnosis. Serological tests have, therefore, become critically important as alternative diagnostic tests. Three manufacturers currently have FDA clearance for in vitro tests, to detect NRL-specific IgE. The commercially available assays may disagree on the antibody status of an individual serum, which may be due to the assay's detecting anti-NRL IgEs to different allergenic NRL proteins. Sensitized individuals produce specific IgE antibody to at least 10 potent HEVEA: allergens, Hev b 1-Hev b 10, each of which differs in its structure, size, and net charge. The relative content and ratios of Hevs in the final allergen preparation most probably could effect diagnostic accuracy. The Hev proteins have been cloned and expressed as recombinant proteins. Sequencing demonstrates both unique epitopes and sequences commonly found in other plant proteins. Sequence homology helps to explain the cross reactivity to a variety of foods experienced by latex allergic individuals. The development of recombinant allergens provides reagents that should improve the diagnostic accuracy of tests for latex allergy. Although clinical and exposure data have been gathered on the factors affecting response in latex-allergic individuals, less is known regarding the development of sensitization. Coupled with in vitro dermal penetration studies, murine models have been established to investigate the route of exposure in the development of latex sensitization. Time-course and dose-response studies have shown subcutaneous, intratracheal, or topical administrations of non-ammoniated latex proteins to induce IgE production. Both in vitro penetration and in vivo studies highlight the importance of skin condition in the development of latex allergy, with enhanced penetration and earlier onset of IgE production seen with experimentally abraded skin. The diagnosis of latex allergy is complicated by these variables, which in turn hinder the development of intervention strategies. Further epidemiological assessment is needed to more explicitly define the scope, trends, and demographics of latex allergy. Diagnostic accuracy can be improved through greater knowledge of proteins involved in the development of latex allergy, and better documentation of the presently available diagnostic tests. In vivo and in vitro models can elucidate mechanisms of sensitization and provide an understanding of the role of the exposure route in latex allergy-associated diseases. Together, these efforts can lead to intervention strategies for reducing latex allergy in the workplace.