Overview of asthma patients followed up in a tertiary clinic.

Summary: Background. Asthma is a disease that combines different biological mechanisms, inflammatory pathways, and phenotypic features. Our aim was to investigate the demographic and disease characteristics of patients with asthma and to reveal the distribution with different phenotypes according to endotype groups. Methods. Patients were identified as eosinophilic if the absolute eosinophil count was measured at least once ≥ 300/µL during the oral corticosteroid free period or ≥ 150/µL under oral corticosteroids. Patients sensitive to at least one inhalant allergen with skin prick test and/ or spIgE measurement were defined as allergic. They were categorized into four main endotypes. Results. Data of 405 asthma patients with a median age of 50.9 years were analyzed. The prominent clinical and phenotypic characteristics of the study group were being obese (43.2%) or overweight (32%), severe asthma (49.6%), adult-onset (56.1%) or late-onset asthma (35.3%). The distribution of the four main endotypes according to eosinophilic and/or allergic status, is as follows: 22.7% allergic-eosinophilic (AE), 27.9% nonallergic-eosinophilic (NAE), 22.9% allergic-noneosinophilic (ANE), 26.4% nonallergic-noneosinophilic (NANE). While most severe asthma patients were in the AE and NAE groups, those with early-onset asthma were in AE and ANE, and those with late-onset asthma were in the NAE and NANE groups. The proportion of uncontrolled patients was higher in the NAE group. Among the severe asthma patients, the rate of uncontrolled disease was higher in those with NANE asthma. Conclusions. Different phenotypes were more closely related to some endotypes. This may allow the clinicians to identify patients and predict appropriate treatment modalities and response for individualized care.

Can dose reduction be made in patients with allergic bronchopulmonary aspergillosis receiving high-dose omalizumab treatment?

Summary: Objective. To reduce the omalizumab dose in patients with allergic bronchopulmonary aspergillosis (ABPA) who were on long-term omalizumab treatment. Methods. Once asthma was controlled, two approaches were used to reduce total monthly omalizumab dose, 1) both extending dose intervals from 2 to 4 weeks and decrease omalizumab dose, 2) to reduce omalizumab dose while keeping dose intervals stable. Results. Thirteen patients with ABPA (8F/5M, mean age 53.4 ± 13.0 years) were included. Pre-omalizumab, mean blood eosinophil count was 723.1 ± 547.1 cells/mcL, mean numbers of attacks and hospitalizations were 2.5 ± 1.5 and 1.3 ± 0.8, respectively. Median total monthly omalizumab dose was 750 (min 300, max 900) mg. First and 2nd approach to reduce omalizumab dose was used in nine and four patients with a median time of reduction 32 (min 13, max 47) months. The 2nd dose reduction was made in four patients at median of 23.5 months. Pre-omalizumab, mean oral corticosteroid (OCS, as methylprednisolone) dose was 12.2 ± 10.4 mg daily, it decreased to 0.69 ± 0.95 mg (p = 0.001) in the 1st year of omalizumab and could be stopped in 11 patients. Attacks and hospitalizations decreased to 0.31 ± 0.86 (p less than 0.001) and 0 (p = 0.003), respectively, in the 1st year of omalizumab. Total omalizumab dose was reduced by median 40% (min 20, max 60) in 1st intervention and 50% (min 20, max 67) after 2nd intervention. After omalizumab reduction, asthma control did not deteriorate and there was no need to increase the omalizumab or OCS-dose. Conclusions. Decreasing the total omalizumab dose does not cause clinical deterioration in ABPA after the disease is controlled.

Economic burden of severe asthma in Turkey: a cost of illness study from payer perspective.

Summary: Objective. To estimate economic burden of severe asthma in Turkey from payer perspective based on expert panel opinion on practice patterns in clinical practice. Methods. This cost of illness study was based on identification of per patient annual direct medical costs for the management of sever easthma in Turkey from payer perspective. Average per patient direct medical cost was calculated based on cost items related to outpatient visits, laboratory and radiological tests, hospitalizations and interventions, drug treatment and equipment, and co-morbidities/complications. Results. Based on total annual per patient costs calculated for outpatient admission ($ 177.91), laboratory and radiological tests ($ 82.32), hospitalizations/interventions ($ 1,154.55), drug treatment/equipment ($ 2,289.63) and co-morbidities ($ 665.39) cost items, total per patient annual direct medical costrelated to management of severe asthma was calculated to be $ 4,369.76 from payer perspective. Drug treatment/equipment (52.4%) was the main cost driver in the management of severe asthma in Turkey, as followed by hospitalizations/interventions (26.4%) and co-morbidities (15.2%). Conclusions. In conclusion, our findings indicate that managing patients with severe asthma pose a considerable burden to health economics in Turkey, with medications as the main cost driver.

Successful desensitization to brentuximab after anaphylactic shocks

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Clinical approach on challenge and desensitization procedures with aspirin in patients with ischemic heart disease and nonsteroidal anti-inflammatory drug hypersensitivity.

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.

Drug allergy passport and other documentation for patients with drug hypersensitivity - An ENDA/EAACI Drug Allergy Interest Group Position Paper.

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.

Pharmacoeconomic and clinical implications of sequential therapy for metastatic renal cell carcinoma patients in Central and Eastern Europe.

INTRODUCTION: The incidence and mortality rates of kidney cancer in the Central and Eastern European (CEE) region are among the highest in the world. Access to second and subsequent lines of metastatic renal cell carcinoma (mRCC) therapies is highly varied in the region. Despite the increasing body of evidence supporting the clinical benefit of multiple lines of treatment, access to treatment beyond first line is restricted in many of these countries. AREAS COVERED: The adoption of targeted therapies for the first-line treatment of mRCC in the region was slow and faced many obstacles. In order to evaluate the current status of treatment beyond the first-line setting in the CEE region, this review examines the availability and reimbursement of mRCC drugs and clinical practice in institutions that treat patients with mRCC. EXPERT OPINION: This review highlights the need to raise awareness among physicians, payers and regulators on clinical trial and cost-effectiveness data regarding the treatment of mRCC beyond the first line. The obstacles to mRCC drug access highlighted in this review need to be overcome to ensure that patients are receiving the best treatment available.

Determinants of nocebo effect during oral drug provocation tests

BACKGROUND: A 'nocebo' effect is defined as troublesome symptoms after the administration of placebo. The aim of this study was to determine characteristics of nocebo responses and related factors. METHODS: Patients with a reliable history of drug-induced hypersensitivity reactions subjected to placebo-controlled oral drug provocation tests and reacted to placebo, were consecutively included in this case-control study. Controls consisted of the randomly selected subjects who had a history of drug hypersensitivity reaction but did not react to placebo. A structured questionnaire was performed by an allergy specialist. RESULTS: There were 137 subjects (mean age: 43.10 ± 12.65 years), with nocebo and 91 subjects (42.38 ± 12.18 years) without any reaction to placebo. Most nocebo reactions (71.5%, n = 98) were classified as subjective, with local pruritus as the most common finding. A minority of nocebo reactions (11.7%,n = 16) were objective as cutaneous reactions including flushing and urticaria. Factors related with nocebo risks were university graduation (OR: 2.96, 95% CI: 1.27-6.93, p = 0.012) and non-atopy (OR: 2.12, 95% CI: 1.02-4.40, p = 0.043). In terms of the time of first and last historical reaction to drugs, each 1-unit (a month) increase in first reaction time (OR: 1.008, 95% CI: 1.00-1.02, p = 0.001) and last reaction time (OR: 1.019, 95% CI: 1.01-1.03, p < 0.001) were associated with increased nocebo risk. CONCLUSION: In conclusion, subjects with high education, non-atopy, and older drug hypersensitivity reactions history seem to be more likely to experience nocebo effect during oral drug provocation tests. These risk factors should be considered and managed accordingly to complete the drug provocation procedure successfully

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Evaluation of vascular endothelial growth factor-A and Endostatin levels in induced sputum and relationship to bronchial hyperreactivity in patients with persistent allergic rhinitis monosensitized to house dust.

BACKGROUND: Studies about the pathogenesis of bronchial hyperreactivity (BHR) in patients with persistent allergic rhinitis (PAR) and its relationship with lower airway remodeling are extremely limited. OBJECTIVE: This study evaluated bronchial vascular remodeling via the measurement of angiogenic factor, vascular endothelial growth factor-A (VEGF-A), and anti-angiogenic factor, Endostatin, and evaluated their relationship with BHR in patients with PAR. METHODS: The study group consisted of 30 patients with PAR monosensitized to house dust mites and 14 non-allergic healthy controls. All subjects underwent induced sputum and methacholine (M) bronchial provocation tests. VEGF-A and Endostatin levels were measured by ELISA in induced sputum supernatants. RESULTS: The percentages of eosinophils in induced sputum were significantly increased in patients with PAR compared with healthy controls. There were no significant differences between patients with PAR and healthy controls in terms of levels of VEGF (37.9pg/ml, min-max: 5-373pg/ml vs. 24.9, min-max: 8-67pg/ml, p=0.8 respectively), Endostatin (532.5pg/ml, min-max: 150-2125pg/ml vs. 644, min-max: 223-1123pg/ml, p=0.2 respectively) and VEGF/Endostatin ratio (0.057 vs. 0.045, p=0.8 respectively). In addition, there were no significant differences between patients who are BHR positive (n=8), or negative to M (n=22) in terms of levels of VEGF, Endostatin and VEGF/Endostatin ratio and no correlations among value of PD20 to M and levels of VEGF, Endostatin and VEGF/Endostatin ratio. CONCLUSION: We conclude that VEGF-A and Endostatin did not differ between patients with PAR and healthy controls regardless of BHR to M.

EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders.

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-1ß, 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.

Determinants of nocebo effect during oral drug provocation tests.

BACKGROUND: A "nocebo" effect is defined as troublesome symptoms after the administration of placebo. The aim of this study was to determine characteristics of nocebo responses and related factors. METHODS: Patients with a reliable history of drug-induced hypersensitivity reactions subjected to placebo-controlled oral drug provocation tests and reacted to placebo, were consecutively included in this case-control study. Controls consisted of the randomly selected subjects who had a history of drug hypersensitivity reaction but did not react to placebo. A structured questionnaire was performed by an allergy specialist. RESULTS: There were 137 subjects (mean age: 43.10 ± 12.65 years), with nocebo and 91 subjects (42.38 ± 12.18 years) without any reaction to placebo. Most nocebo reactions (71.5%, n=98) were classified as subjective, with local pruritus as the most common finding. A minority of nocebo reactions (11.7%, n=16) were objective as cutaneous reactions including flushing and urticaria. Factors related with nocebo risks were university graduation (OR: 2.96, 95% CI: 1.27-6.93, p=0.012) and non-atopy (OR: 2.12, 95% CI: 1.02-4.40, p=0.043). In terms of the time of first and last historical reaction to drugs, each 1-unit (a month) increase in first reaction time (OR: 1.008, 95% CI: 1.00-1.02, p=0.001) and last reaction time (OR: 1.019, 95% CI: 1.01-1.03, p<0.001) were associated with increased nocebo risk. CONCLUSION: In conclusion, subjects with high education, non-atopy, and older drug hypersensitivity reactions history seem to be more likely to experience nocebo effect during oral drug provocation tests. These risk factors should be considered and managed accordingly to complete the drug provocation procedure successfully.

Insights into cancer surveillance in Central and Eastern Europe, Israel and Turkey.

The current cancer landscape within transitional economies in central and Eastern Europe and the Mediterranean area is not particularly optimistic. Current perceptions are often based on extrapolations from other countries and regions; and hence the authors collaborated with the South Eastern Europe Oncology Group (SEEROG) to collect information on cancer registration in Central and Eastern Europe, Israel and Turkey. Healthcare authorities and specialist oncology centres in 21 countries in the region were contacted for information on cancer registries in their countries. Based on this information, the authors believe that the recording and reporting of data on cancer in the region is at an acceptable level. The authors discuss and compare institution- and population-based registries, and present opinions on elements of an 'ideal registry' based on the survey replies and comparisons with other registries. A comparison with the sources used for GLOBOCAN 2008 illustrates the need for consistent data to be communicated, published and utilised throughout the region and the oncology community. The authors conclude by considering the potential value of collaboration between health authorities across the region, as well as between the clinical and epidemiological communities, to ensure that cancer data are consistently collected, verified and made public.

First case report of acute generalized exanthematous pustulosis due to intravenous iopromide

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Prognostic factors associated with the response to sunitinib in patients with metastatic renal cell carcinoma.

OBJECTIVE: We investigated the prognostic clinicopathologic factors associated with overall survival (os) and progression-free survival (pfs) in the once-daily continuous administration of first-line sunitinib in a consecutive cohort of Turkish patients with metastatic renal cell carcinoma (rcc). METHODS: The study enrolled 77 Turkish patients with metastatic rcc who received sunitinib in a continuous once-daily dosing regimen between April 2006 and April 2011. Univariate analyses were performed using the log-rank test. RESULTS: Median follow-up was 18.5 months. In univariate analyses, poor pfs and os were associated with 4 of the 5 factors in the Memorial Sloan-Kettering Cancer Center (mskcc) score: Eastern Cooperative Oncology Group performance status of 2 or higher, low hemoglobin, high corrected serum calcium, and high lactate dehydrogenase. In addition to those factors, hypoalbuminemia, more than 2 metastatic sites, liver metastasis, non-clear cell histology, and the presence of sarcomatoid features on pathology were also associated with poor pfs; and male sex, hypoalbuminemia, prior radiotherapy, more than 2 metastatic sites, lung metastasis, nuclear grade of 3 or 4 for the primary tumour, and the presence of sarcomatoid features were also associated with poorer os. The application of the mskcc model distinctly separated the pfs and os curves (p < 0.001). CONCLUSIONS: Our study identified prognostic factors for pfs and os with the use sunitinib as first-line metastatic rcc therapy and confirmed that the mskcc model still appears to be valid for predicting survival in metastatic rcc in the era of molecular targeted therapy.

Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs.

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.

Impaired coronary flow reserve in metastatic cancer patients treated with sunitinib.

PURPOSE: Hypertension is one of the major side effects of sunitinib, an angiogenesis inhibitor used in the treatment of metastatic renal cell carcinomas (mRCC) and gastrointestinal stromal tumors (GIST). Endothelial dysfunction, an early and reversible event in the pathogenesis of atherosclerosis, is suggested to be one of the possible underlying mechanisms of hypertension caused by angiogenesis inhibitors. Coronary flow reserve (CFR) measurement by trans-thoracic Doppler echocardiography (TTDE) reflects coronary microvascular and endothelial functions, as a cheaper and an easy screening test. We have used TTDE to evaluate endothelial function and coronary microvascular function in mRCC and GIST patients under sunitinib treatment. METHODS: Eighteen metastatic cancer patients (16 mRCC and 2 GIST) on sunitinib treatment and 27 healthy subjects were enrolled in this cross-sectional study. Thyroid stimulating hormone (TSH), lipid profile, creatinine, hemoglobin, glucose, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anthropometric and physical parameters of patients were recorded. CFR recordings were performed by the Vivid 7 echocardiography device. RESULTS: CFR was significantly lower in patients when compared with controls (1.82±0.4 vs 2.71±0.8, respectively; p < 0.001). Impaired CFR was found in 13 (72%) patients whereas all controls had normal CFR values. CFR was inversely correlated with the duration of sunitinib treatment (r=-0.36, p =0.01), high sensitivite (hs) CRP (r = -0.574, p =0.01) and ESR (r = - 0.5, p = 0.02). CONCLUSION: Our findings indicate that CFR is significantly impaired in cancer patients on sunitinib treatment. There is an inverse correlation between CFR and duration of sunitinib treatment and inflammation markers.