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Proton pump inhibitors (PPIs) are invaluable therapeutic options in a variety of dyspeptic diseases. In addition to their well-known risk profile, PPI consumption is related to food and environmental allergies, dysbiosis, osteoporosis, as well as immediate and delayed hypersensitivity reactions (HSRs). The latter, although a rare event, around 1%-3%, due to the extraordinarily high rate of prescription and consumption of PPIs are related to a substantial risk. In this Position Paper, we provide clinicians with practical evidence-based recommendations for the diagnosis and management of HSRs to PPIs. Furthermore, the unmet needs proposed in the document aim to stimulate more in-depth investigations in the topic., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Anaphylaxis, which is rare, has been reported after COVID-19 vaccination, but its management is not standardized., Method: Members of the European Network for Drug Allergy and the European Academy of Allergy and Clinical Immunology interested in drug allergy participated in an online questionnaire on pre-vaccination screening and management of allergic reactions to COVID-19 vaccines, and literature was analysed., Results: No death due to anaphylaxis to COVID-19 vaccines has been confirmed in scientific literature. Potential allergens, polyethylene glycol (PEG), polysorbate and tromethamine are excipients. The authors propose allergy evaluation of persons with the following histories: 1-anaphylaxis to injectable drug or vaccine containing PEG or derivatives; 2-anaphylaxis to oral/topical PEG containing products; 3-recurrent anaphylaxis of unknown cause; 4-suspected or confirmed allergy to any mRNA vaccine; and 5-confirmed allergy to PEG or derivatives. We recommend a prick-to-prick skin test with the left-over solution in the suspected vaccine vial to avoid waste. Prick test panel should include PEG 4000 or 3500, PEG 2000 and polysorbate 80. The value of in vitro test is arguable., Conclusions: These recommendations will lead to a better knowledge of the management and mechanisms involved in anaphylaxis to COVID-19 vaccines and enable more people with history of allergy to be vaccinated., (© 2022 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Chemotherapeutic drugs have been widely used in the treatment of cancer disease for about 70 years. The development of new treatments has not hindered their use, and oncologists still prescribe them routinely, alone or in combination with other antineoplastic agents. However, all chemotherapeutic agents can induce hypersensitivity reactions (HSRs), with different incidences depending on the culprit drug. These reactions are the third leading cause of fatal drug-induced anaphylaxis in the United States. In Europe, deaths related to chemotherapy have also been reported. In particular, most reactions are caused by platinum compounds, taxanes, epipodophyllotoxins and asparaginase. Despite their prevalence and relevance, the ideal pathways for diagnosis, treatment and prevention of these reactions are still unclear, and practice remains considerably heterogeneous with vast differences from center to center. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology organized a task force to provide data and recommendations regarding the allergological work-up in this field of drug hypersensitivity reactions. This position paper aims to provide consensus on the investigation of HSRs to chemotherapeutic drugs and give practical recommendations for clinicians that treat these patients, such as oncologists, allergologists and internists. Key sections cover risk factors, pathogenesis, symptoms, the role of skin tests, in vitro tests, indications and contraindications of drug provocation tests and desensitization of neoplastic patients with allergic reactions to chemotherapeutic drugs. Statements, recommendations and unmet needs were discussed and proposed at the end of each section., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Biologicals are crucial targeted therapeutic agents in oncological, immunological, and inflammatory diseases, and their use in clinical practice is broadening. In recent years, the spread of Personalized Precision Medicine has facilitated a proliferation of new treatment options, especially biologicals. Consequently, biologicals are now among the drugs that most frequently cause hypersensitivity reactions (HSRs). Patients can develop HSRs to these agents during the first-lifetime exposure or after repeated exposure, and these HSRs can be potentially life-threatening or limit therapeutic options. Despite the relatively high prevalence, the underlying mechanisms of these HSRs remain obscure, and the optimal management pathways are still a matter of discussion. In this Position Paper, the authors will provide evidence-based recommendations for diagnosing and managing HSRs to biologicals. Additionally, the document defines unmet needs as an opportunity to shape future research., (© 2021 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Immediate and nonimmediate hypersensitivity reactions to iodinated contrast media (ICM) have been reported to occur in a frequency of about 0.5%-3% of patients receiving nonionic ICM. The diagnosis and management of these patients vary among guidelines published by various national and international scientific societies, with recommendations ranging from avoidance or premedication to drug provocation test. This position paper aims to give recommendations for the management of patients with ICM hypersensitivity reactions and analyze controversies in this area. Skin tests are recommended as the initial step for diagnosing patients with immediate and nonimmediate hypersensitivity reactions; besides, they may also help guide on tolerability of alternatives. Re-exposition or drug provocation test should only be done with skin test-negative ICMs. The decision for performing either re-exposition or drug provocation test needs to be taken based on a risk-benefit analysis. The role of in vitro tests for diagnosis and pretreatment for preventing reactions remains controversial., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Biologicals have transformed the management of severe disease phenotypes in asthma, atopic dermatitis, and chronic spontaneous urticaria. As a result, the number of approved biologicals for the treatment of atopic diseases is continuously increasing. Although atopic diseases are among the most common diseases in the reproductive age, investigations, and information on half-life, pharmacokinetics defining the neonatal Fc receptors (FcRn) and most important safety of biologicals in pregnancy are lacking. Given the complex sequence of immunological events that regulate conception, fetal development, and the intrauterine and postnatal maturation of the immune system, this information is of utmost importance. We conducted a systematic review on biologicals in pregnancy for indications of atopic diseases. Evidence in this field is scarce and mainly reserved to reports on the usage of omalizumab. This lack of evidence demands the establishment of a multidisciplinary approach for the management of pregnant women who receive biologicals and multicenter registries for long-term follow-up, drug trial designs suitable for women in the reproductive age, and better experimental models that represent the human situation. Due to the very long half-life of biologicals, preconception counseling and healthcare provider education are crucial to offer the best care for mother and fetus. This position paper integrates available data on safety of biologicals during pregnancy in atopic diseases via a systematic review with a detailed review on immunological considerations how inhibition of different pathways may impact pregnancy., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

The outbreak of the SARS-CoV-2-induced coronavirus disease 2019 (COVID-19) pandemic re-shaped doctor-patient interaction and challenged capacities of healthcare systems. It created many issues around the optimal and safest way to treat complex patients with severe allergic disease. A significant number of the patients are on treatment with biologicals, and clinicians face the challenge to provide optimal care during the pandemic. Uncertainty of the potential risks for these patients is related to the fact that the exact sequence of immunological events during SARS-CoV-2 is not known. Severe COVID-19 patients may experience a "cytokine storm" and associated organ damage characterized by an exaggerated release of pro-inflammatory type 1 and type 3 cytokines. These inflammatory responses are potentially counteracted by anti-inflammatory cytokines and type 2 responses. This expert-based EAACI statement aims to provide guidance on the application of biologicals targeting type 2 inflammation in patients with allergic disease. Currently, there is very little evidence for an enhanced risk of patients with allergic diseases to develop severe COVID-19. Studies focusing on severe allergic phenotypes are lacking. At present, noninfected patients on biologicals for the treatment of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, or chronic spontaneous urticaria should continue their biologicals targeting type 2 inflammation via self-application. In case of an active SARS-CoV-2 infection, biological treatment needs to be stopped until clinical recovery and SARS-CoV-2 negativity is established and treatment with biologicals should be re-initiated. Maintenance of add-on therapy and a constant assessment of disease control, apart from acute management, are demanded., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

NSAID-exacerbated respiratory disease (N-ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence-based recommendations for the diagnosis and management of N-ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N-ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N-ERD. Recommendations for the most effective management of a patient with N-ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub-phenotypes and emerging sub-endotypes of N-ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N-ERD and unmet needs, which should be addressed in the future., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Hypersensitivity to acetylsalicylic acid (ASA) constitutes a serious problem for subjects with coronary artery disease. In such subjects, physicians have to choose the more appropriate procedure between challenge and desensitization. As the literature on this issue is sparse, this study aimed to establish in these subjects clinical criteria for eligibility for an ASA challenge and/or desensitization., Methods: Collection and analysis of data on ASA challenges and desensitizations from 10 allergy centers, as well as consensus among the related physicians and an expert panel., Results: Altogether, 310 subjects were assessed; 217 had histories of urticaria/angioedema, 50 of anaphylaxis, 26 of nonimmediate cutaneous eruptions, and 17 of bronchospasm related to ASA/nonsteroidal anti-inflammatory drugs (NSAID) intake. Specifically, 119 subjects had index reactions to ASA doses lower than 300 mg. Of the 310 subjects, 138 had an acute coronary syndrome (ACS), 101 of whom underwent desensitizations, whereas 172 suffered from a chronic ischemic heart disease (CIHD), 126 of whom underwent challenges. Overall, 163 subjects underwent challenges and 147 subjects underwent desensitizations; 86 of the latter had index reactions to ASA doses of 300 mg or less. Ten subjects reacted to challenges, seven at doses up to 500 mg, three at a cumulative dose of 110 mg. The desensitization failure rate was 1.4%., Conclusions: In patients with stable CIHD and histories of nonsevere hypersensitivity reactions to ASA/NSAIDs, an ASA challenge is advisable. Patients with an ACS and histories of hypersensitivity reactions to ASA, especially following doses lower than 100 mg, should directly undergo desensitization., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The strongest and best-documented risk factor for drug hypersensitivity (DH) is the history of a previous reaction. Accidental exposures to drugs may lead to severe or even fatal reactions in sensitized patients. Preventable prescription errors are common. They are often due to inadequate medical history or poor risk assessment of recurrence of drug reaction. Proper documentation is essential information for the doctor to make sound therapeutic decision. The European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology have formed a task force and developed a drug allergy passport as well as general guidelines of drug allergy documentation. A drug allergy passport, a drug allergy alert card, a certificate, and a discharge letter after medical evaluation are adequate means to document DH in a patient. They are to be handed to the patient who is advised to carry the documentation at all times especially when away from home. A drug allergy passport should at least contain information on the culprit drug(s) including international nonproprietary name, clinical manifestations including severity, diagnostic measures, potential cross-reactivity, alternative drugs to prescribe, and where more detailed information can be obtained from the issuer. It should be given to patients only after full allergy workup. In the future, electronic prescription systems with alert functions will become more common and should include the same information as in paper-based documentation., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Biologic agents (also termed biologicals or biologics) are therapeutics that are synthesized by living organisms and directed against a specific determinant, for example, a cytokine or receptor. In inflammatory and autoimmune diseases, biologicals have revolutionized the treatment of several immune-mediated disorders. Biologicals have also been tested in allergic disorders. These include agents targeting IgE; T helper 2 (Th2)-type and Th2-promoting cytokines, including interleukin-4 (IL-4), IL-5, IL-9, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP); pro-inflammatory cytokines, such as IL-1β, IL-12, IL-17A, IL-17F, IL-23, and tumor necrosis factor (TNF); chemokine receptor CCR4; and lymphocyte surface and adhesion molecules, including CD2, CD11a, CD20, CD25, CD52, and OX40 ligand. In this task force paper of the Interest Group on Biologicals of the European Academy of Allergy and Clinical Immunology, we review biologicals that are currently available or tested for the use in various allergic and urticarial pathologies, by providing an overview on their state of development, area of use, adverse events, and future research directions., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hypersensitivity reactions to aspirin (acetylsalicylic acid) and other nonsteroidal anti-inflammatory drugs (NSAIDs) constitute only a subset of all adverse reactions to these drugs, but due to their severity pose a significant burden to patients and are a challenge to the allergist. In susceptible individuals, NSAIDs induce a wide spectrum of hypersensitivity reactions with various timing, organ manifestations, and severity, involving either immunological (allergic) or nonimmunological mechanisms. Proper classification of reactions based on clinical manifestations and suspected mechanism is a prerequisite for the implementation of rational diagnostic procedures and adequate patient management. This document, prepared by a panel of experts from the European Academy of Allergy and Clinical Immunology Task Force on NSAIDs Hypersensitivity, aims at reviewing the current knowledge in the field and proposes uniform definitions and clinically useful classification of hypersensitivity reactions to NSAIDs. The document proposes also practical algorithms for the diagnosis of specific types of NSAIDs hypersensitivity (which include drug provocations, skin testing and in vitro testing) and provides, when data are available, evidence-based recommendations for the management of hypersensitive patients, including drug avoidance and drug desensitization., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Data are limited about the value of skin tests in the diagnosis of proton pump inhibitor (PPI)-induced hypersensitivity reactions and the cross-reactivity between PPIs. We aimed to assess the role of skin testing in the diagnosis of PPI-related immediate hypersensitivity reactions and the cross-reactivity patterns among PPIs., Methods: The study was designed in a prospective, national, multicentre nature. Sixty-five patients with a suggestive history of a PPI-induced immediate hypersensitivity reaction and 30 control subjects were included. Standardized skin prick and intradermal tests were carried out with a panel of PPIs. Single-blind, placebo-controlled oral provocation tests (OPTs) with the PPIs other than the culprit PPI that displayed negative results in skin tests (n = 61) and diagnostic OPTs with the suspected PPI (n = 12) were performed., Results: The suspected PPIs were lansoprazole (n = 52), esomeprazole (n = 11), pantoprazole (n = 9), rabeprazole (n = 2), and omeprazole (n = 1). The sensitivity, specificity, and negative and positive predictive values of the skin tests with PPIs were 58.8%, 100%, 70.8%, and 100%, respectively. Fifteen of the 31 patients with a hypersensitivity reaction to lansoprazole had a positive OPT or skin test result with at least one of the alternative PPIs (8/52 pantoprazole, 6/52 omeprazole, 5/52 esomeprazole, 3/52 rabeprazole)., Conclusion: Considering the high specificity, skin testing seems to be a useful method for the diagnosis of immediate-type hypersensitivity reactions to PPIs and for the evaluation of cross-reactivity among PPIs. However, OPT should be performed in case of negativity on skin tests., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for 21-25% of reported adverse drug events which include immunological and nonimmunological hypersensitivity reactions. This study presents up-to-date information on pathomechanisms, clinical spectrum, diagnostic tools and management of hypersensitivity reactions to NSAIDs. Clinically, NSAID hypersensitivity is particularly manifested by bronchial asthma, rhinosinusitis, anaphylaxis or urticaria and variety of late cutaneous and organ-specific reactions. Diagnosis of hypersensitivity to a NSAID includes understanding of the underlying mechanism and is necessary for prevention and management. A stepwise approach to the diagnosis of hypersensitivity to NSAIDs is proposed, including clinical history, in vitro testing and/or provocation test with a culprit or alternative drug depending on the type of the reaction. The diagnostic process should result in providing the patient with written information both on forbidden and on alternative drugs., (© 2011 John Wiley & Sons A/S.)

It has been proposed that aspirin (ASA) and other non-steroidal anti-inflammatory drug (NSAID)-induced urticaria (UR)/angioedema (AE) are mediated through inhibition of cyclooxygenase-1 (COX-1) enzymes. Therefore, drugs with COX-2 selectivity may be well tolerated in such patients. We investigated the safety of preferential COX-2 inhibitor meloxicam in subjects with UR or AE type intolerance reaction to classical ASA/NSAIDs. Subjects with reliable or documented history of UR/AE due to classical ASA/NSAIDs underwent a single-blinded, placebo-controlled oral challenge with a cumulative dose of 7.5 mg meloxicam on 2 separate days. One-quarter and three-quarter divided doses of placebo and the active drug were given at 1-h intervals. A total of 116 patients (86 women and 30 men, mean age 39.6 ± 12.7 years) were enrolled to the study. The rate of atopy was 25.9%. Mean duration of drug reaction was 87.4 ± 110.8 (1-720) months. Almost half of the patients were multi-reactors. The most comorbid disease was asthma and the two most frequent NSAIDs inducing UR/AE were paracetamol (19. 6%) and ASA (19%). No reaction to placebo was observed. Ten out of 116 patients (8.6%) developed mild UR/AE, or only erythema and pruritus at a one-quarter or cumulative dose of 7.5 mg of meloxicam. The remaining subjects (91.4%) tolerated perfectly meloxicam challenge. This study indicates that 7.5 mg meloxicam is a safe alternative for ASA/NSAID-intolerant UR/AE patients. Intolerance reactions to meloxicam are much milder forms of the patients' historical ASA/NSAID-induced cutaneous reactions., (© 2010 Japanese Dermatological Association.)

Background: Severe asthma puts enormous burden on patients. To evaluate asthma-related restrictions on patients' daily lives along with their expectations about future asthma care., Methods: A structured questionnaire was administered to severe asthma patients at 25 centers across Turkey. The patients were divided into; uncontrolled (n: 274) and controlled asthma (n: 177) according to the existence of symptoms despite the GINA step 4 or 5 treatment., Results: A total of 451 patients (F/M: 337/114, mean age: 47.6 +/- 13.2 years) were included; 93% were nonsmokers and 51.2% were atopic. Chronic rhino-sinusitis, ASA/NSAID sensitivity, and osteoporosis were significantly higher in uncontrolled patients. Nearly 70% of the uncontrolled asthmatics defined asthma as disturbing with significant restrictions in daily life. The most important role for medication was symptom relief. One inhaler or one tablet a month was the most preferred form of drug usage. In addition, 30.6% of the patients had tried alternative treatment with herbal remedies. Although patients were willing to become members of an asthma association, they expected the Turkish government to provide special asthma clinics and fund research into new treatments. Controlled patients achieved or were close to achieving asthma control goals. Uncontrolled patients seemed to be more pessimistic in this respect, but they reserved significant levels of hope for the future. Two-thirds of all the patients thought that they would receive better treatment in the next 5 years., Conclusions: In this study group, severe asthma patients face significant limitations in their daily lives, but they are optimistic about better asthma control and treatment options in the future.

Although chronic urticaria is the most common cutaneous disorder seen in our outpatient allergy clinics, to our knowledge, no study of psychiatric morbidity in allergy departments has been carried out in our country. For the present study, we used the Minnesota Multiphasic Personality Inventory (MMPI) to evaluate the personality traits and psychological status of patients with chronic idiopathic urticaria (CIU). Fifty-nine outpatients with CIU and 59 healthy control subjects were enrolled in the study. Patients were included if no specific cause for their urticaria could be identified by detailed history and appropriate investigations. Psychiatric evaluation for all patients and controls was conducted at the Department of Psychiatry by using MMPI. Analysis of the MMPI profile showed that the scores for hypochondriasis, depression, hysteria, psychopathic deviance, paranoia, psychasthenia, schizophrenia, and social introversion were higher in patients with CIU compared to the control group (P < 0.05). The mean score of hysteria was significantly higher in women. There were no significant correlations between the scores of MMPI and duration of the disease. These data indicate that our patients with CIU seem to have more depressive, hysteric, touchy and suspicious personality traits with hypochondriac tendencies and in more conflict with their social environment. Attitudes such as perfectionism, need for approval, external control and need to be loved were also characteristics of the patient group. We believe that psychological status should be considered for effective management of patients with CIU.

Background: Although the role of inhaled fungi in inducing asthma has been repeatedly confirmed, there are few reports about the association of asthma with dermatophyte sensitivity and the causal role of Trichophyton allergy in asthma. The objective was to investigate the presence of Trichophyton sensitivity among patients with allergic and nonallergic asthma in combination with tinea, and to compare the situation with several control groups in order to evaluate the factors determining Trichophyton sensitivity., Methods: A total of 86 subjects (55 female, 31 male) with a mean age of 38.6 +/- 11.1 years were included in the study. The patients were divided into five groups: 1) nonallergic asthma plus tinea (n = 19) 2) allergic asthma plus tinea (n = 15) 3) asthma without tinea (n = 22) 4) tinea without asthma (n = 17) 5) healthy controls (n = 13). Skin tests with standardized extracts of T. rubrum and specific IgE measurements were performed in all subjects. All patients were also subjected to microscopic evaluation and fungal culture for dermatophyte infection., Results: The skin test positivity rate to Trichophyton extract of groups 1 (63.1%), 2 (46.7%), and 4 (47.1%) was higher than that in groups 3 (4.4%) and 5 (7.7%) (P < 0.05). Although not significant, the rates of sensitivity to T. rubrum (63.1%) and of severe asthma (31.6%) were higher in the group with nonallergic asthma with tinea (group 1) than in other groups. Among 51 patients in whom direct microscopic evaluation revealed dermatophyte infection, 60.8% had positive fungal cultures for T. rubrum (58.1%), T. mentagrophytes (35.5%), and Candida (6.4%)., Conclusion: According to our data, the presence of fungal infection seems to be an important determinant in hypersensitivity to Trichophyton whether or not the subject is asthmatic and/or allergic. Since a greater proportion of patients with nonallergic asthma--in whom the rate of severe asthma was also higher - showed positive skin tests to Trichophyton extracts in this study, we believe that patients with severe, intrinsic asthma should be examined for signs of fungal infection and tested to determine immediate hypersensitivity to dermatophyte antigens.

Exposure to cockroach has been reported to cause asthma in many parts of the world. Although house-dust-mite is known to be the most important indoor allergen in Turkey, there are few data on the prevalence of allergy to cockroaches. Therefore, we evaluated the prevalence of cockroach sensitivity in asthmatic Turkish patients to see whether it is also an important source of asthma in addition to house-dust mites. A total of 206 patients demonstrating the characteristic features of asthma were included in the study. Sixty-three percent of the patients were considered atopic, and 37% were found to be nonatopic by skin prick tests. Mite allergens were the most common cause of indoor allergy (50%), while cockroach sensitivity was detected in 25.7% of all the asthmatics. Among all cockroach-sensitive patients, 70% were also positive for mites. A female predominance was observed in cockroach-sensitive patients, as 44% of atopic women and 34% of atopic men had positive skin tests with cockroach allergen. The average duration of asthma was 7.1+/-5.6 years in cockroach-sensitive asthmatics, and there was no difference between groups in average duration of asthma (P>0.05). Mild, moderate, and severe asthmatics constituted 73.6%, 20.7%, and 5.7% of the cockroach-sensitive patients, respectively. These data indicate that cockroach is also an important source of domestic infestation in Turkey. Thus, it seems reasonable to suggest the need for cockroach allergen in the routine battery of inhalant skin tests in this geographic location. However, possible cross-reactivity with mites has to be taken into consideration during the clinical evaluation of subjects with cockroach sensitivity, especially in our patient population with such high rates of house-dust-mite allergy.