Publications by authors named "Asli Gelincik"

57 Publications

Adherence to subcutaneous immunotherapy with aeroallergens in real-life practice during the COVID-19 pandemic.

Allergy 2021 Apr 27. Epub 2021 Apr 27.

Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Background: The success of subcutaneous immunotherapy (SCIT) mostly depends on regular injections. Our aim was to investigate adherence to SCIT with aeroallergens during the COVID-19 pandemic and demonstrate clinical consequences of treatment disruptions in real life.

Methods: Visual analogue scale for quality of life (VAS-QoL), VAS for symptom scores (VAS-symptom), medication scores (MSs), and total symptom scores (TSS-6) were recorded during the pandemic in 327 adult allergic rhinitis and/or asthmatic patients receiving maintenance SCIT, and these scores were compared with the pre-pandemic data. Patients were grouped according to SCIT administration intervals; no delay (Group 1), <2 months (Group 2), and ≥2-month intervals (Group 3).

Results: A total of 104 (31.8%) patients (Group 3) were considered as nonadherent which was mostly related to receiving SCIT with HDMs and using public transportation for reaching the hospital. Median MS, VAS-symptom, and TSS-6 scores of Group 3 patients during the pandemic were higher than the pre-pandemic scores (p = 0.005, p < 0.001, p < 0.001, respectively), whereas median VAS-QoL scores of Group 3 during the pandemic were lower than the pre-pandemic scores (p < 0.001). Median TSS-6 and VAS-symptom scores were the highest in Group 3 compared with other groups (p < 0.001 for each comparison). Median VAS-QoL scores were the lowest in Group 3 compared with Group 1 and Group 2 (p < 0.001, p = 0.043, respectively).

Conclusion: When precautions in allergy clinics are carefully applied, adherence to SCIT can be high during a pandemic. Patients must be encouraged to regularly adhere to SCIT injections since delays in SCIT administration can deteriorate clinical symptoms.
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http://dx.doi.org/10.1111/all.14876DOI Listing
April 2021

Management of anaphylaxis due to COVID-19 vaccines in the elderly.

Allergy 2021 Apr 2. Epub 2021 Apr 2.

Regional Ministry of Health of Andalusia, Seville, Spain.

Older adults, especially men and/or those with diabetes, hypertension and/or obesity, are prone to severe COVID-19. In some countries, older adults, particularly those residing in nursing homes, have been prioritised to receive COVID-19 vaccines due to high risk of death. In very rare instances,the COVID-19 vaccines can induce anaphylaxis, and the management of anaphylaxis in older people should be considered carefully. An ARIA-EAACI-EuGMS (Allergic Rhinitis and its Impact on Asthma, European Academy of Allergy and Clinical Immunology, and European Geriatric Medicine Society)Working Group has proposed some recommendations for older adults receiving the COVID-19 vaccines. Anaphylaxis to COVID-19 vaccines is extremely rare (from 1 per 100,000 to 5 per million injections). Symptoms are similar in younger and older adults but they tend to be more severe in the older patients. Adrenaline is the mainstay treatment and should be readily available. A flowchart is proposed to manage anaphylaxis in the older patients.
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http://dx.doi.org/10.1111/all.14838DOI Listing
April 2021

Impaired endothelial function irrespective of systemic inflammation or atherosclerosis in mastocytosis.

Ann Allergy Asthma Immunol 2021 Mar 26. Epub 2021 Mar 26.

Division of Immunology and Allergic Diseases, Department of Internal Medicine, İstanbul Faculty of Medicine, İstanbul University, İstanbul, Turkey. Electronic address:

Background: Knowledge on endothelial dysfunction and its relation to atherosclerosis in mastocytosis is limited.

Objective: To investigate the endothelial function in mastocytosis by flow-mediated dilatation (FMD) and biomarkers related to vascular endothelia and to evaluate its relationship with the presence of subclinical atherosclerosis by carotid intima media thickness (CIMT).

Methods: A total of 49 patients with mastocytosis and 25 healthy controls (HCs) were included. The FMD and CIMT during transthoracic echocardiography biomarkers including endocan, endothelin-1, and vascular endothelial growth factor (VEGF) were measured in the sera of participants. Tumor necrosis factor-alpha, interleukin 6, and high-sensitive C-reactive protein were determined as inflammatory biomarkers.

Results: The mean FMD % was lower in the patients than HCs (11.26% ± 5.85% vs 17.84% ± 5.27% P < .001) and was the lowest in the advanced systemic mastocytosis and smoldering systemic mastocytosis group among the patients (P = .03). The median value of VEGF was considerably higher in patients than HCs (73.30 pg/mL; minimum-maximum 32.46-295.29 pg/mL vs 46.64 pg/mL; minimum-maximum, 11.09-99.86 pg/mL; P = .001) and it was the highest in the advanced systemic mastocytosis and smoldering systemic mastocytosis group (P = .01). The FMD was inversely correlated with endocan (r = -0.390; P = .006), endothelin-1 (r = -0.363; P = .01) and VEGF (r = -0.402; P = .004) but there were no correlations between FMD and tumor necrosis factor-alpha, interleukin 6, and high-sensitive C-reactive protein. No differences in CIMT values between patients and HCs and no correlation between CIMT and the biomarkers were observed.

Conclusion: Endothelial dysfunction in mastocytosis becomes evident with decreased FMD and elevated serum VEGF in the absence of atherosclerosis or systemic inflammation and is related to disease severity.
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http://dx.doi.org/10.1016/j.anai.2021.03.020DOI Listing
March 2021

COVID-19 pandemic and allergen immunotherapy - an EAACI survey.

Allergy 2021 Mar 2. Epub 2021 Mar 2.

Hacettepe University School of Medicine, Department of Pediatric Allergy, Ankara, Turkey.

Background: As in many fields of medical care, the coronavirus disease 2019 (COVID-19) resulted in an increased uncertainty regarding the safety of allergen immunotherapy (AIT). Therefore, the European Academy of Allergy and Clinical Immunology (EAACI) aimed to analyze the situation in different countries and systematically collect all information available regarding tolerability and possible amendments in daily practice of sublingual AIT (SLIT), subcutaneous AIT (SCIT) for inhalant allergies and venom AIT.

Method: Under the framework of the EAACI, a panel of experts in the field of AIT coordinated by the Immunotherapy Interest Group (IT IG) set-up a web-based retrospective survey (SurveyMonkey®) including 27 standardized questions on practical and safety aspects on AIT in worldwide clinical routine.

Results: 417 respondents providing AIT to their patients in daily routine answered the survey. For patients (without any current symptoms to suspect COVID-19), 60% of the respondents informed of not having initiated SCIT (40% venom AIT, 35% SLIT) whereas for the maintenance phase of AIT, SCIT was performed by 75% of the respondents (74% venom AIT, 89% SLIT). No tolerability concern arises from this preliminary analysis. 16 physicians reported having performed AIT despite (early) symptoms of COVID-19 and/or a positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Conclusions: This first international retrospective survey in atopic diseases investigated practical aspects and tolerability of AIT during the COVID-19 pandemic and gave no concerns regarding reduced tolerability under real-life circumstances. However, the data indicate an undertreatment of AIT, which may be temporary, but could have a long-lasting negative impact on the clinical care of allergic patients.
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http://dx.doi.org/10.1111/all.14793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013670PMC
March 2021

Impact of anxiety, stress and depression related to COVID-19 pandemic on the course of hereditary angioedema with C1 inhibitor deficiency.

Allergy 2021 Mar 1. Epub 2021 Mar 1.

Department of Internal Medicine, Division of Immunology and Allergic Diseases, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Background: Hereditary angioedema (HAE) attacks can be provoked with psychological factors. The aim of this study was to assess the effects of anxiety, depression and stress related to COVID-19 pandemic on disease activity of HAE patients during the quarantine period (QP) and the return to normal period (RTNP).

Methods: This study was conducted between March 2020 and September 2020 in four allergy centres. Demographic, clinical features and mental health status were evaluated in QP (from March to the beginning of June) and RTNP (from June to the beginning of September) applied by the government. The 10-point visual analogue scale (VAS10) was used to define the severity of HAE attacks. Depression-Anxiety- Stress Scale-21 (DASS-21) and Fear of COVID-19 (FC-19) scales were performed to assess mental health status.

Results: 139 HAE patients were included in the study. In QP, median attack numbers and median VAS10 scores were 5 (min-max: 0-45) and 6 (min-max: 0-10), respectively. HAE attack numbers, DASS-21 stress, anxiety, depression and total DASS-21 scores, as well as FC-19 scores were higher in QP than RTNP (p=0.001, p<0.001, p=0.001, p<0.001, p<0.001, p<0.001, respectively). However, there was no difference in attack severity scores between the two periods (p>0.05).

Conclusions: This study revealed that the restriction measures during COVID-19 outbreak causes an increase in the number of HAE attacks in relation to anxiety, depression, stress and fear of COVID-19 pandemic. Therefore, it is important to provide psychological support to HAE patients during the pandemic.
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http://dx.doi.org/10.1111/all.14796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014132PMC
March 2021

β-blockers and ACE inhibitors are not a risk factor for severe systemic sting reactions and adverse events during venom immunotherapy.

Allergy 2021 Feb 19. Epub 2021 Feb 19.

Department of Internal Diseases, Pulmonology and Allergology, Medical University of Wroclaw, Wroclaw, Poland.

Background: There is controversy whether taking β-blockers or ACE inhibitors (ACEI) is a risk factor for more severe systemic insect sting reactions (SSR) and whether it increases the number or severity of adverse events (AE) during venom immunotherapy (VIT).

Methods: In this open, prospective, observational, multicenter trial, we recruited patients with a history of a SSR and indication for VIT. The primary objective of this study was to evaluate whether patients taking β-blockers or ACEI show more systemic AE during VIT compared to patients without such treatment.

Results: In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. Of all patients included, 388 (27.2%) took antihypertensive (AHT) drugs (10.4% took β-blockers, 11.9% ACEI, 5.0% β-blockers and ACEI). Only 5.6% of patients under AHT treatment experienced systemic AE during VIT as compared with 7.4% of patients without these drugs (OR: 0.74, 95% CI: 0.43-1.22, p = 0.25). The severity of the initial sting reaction was not affected by the intake of β-blockers or ACEI (OR: 1.14, 95% CI: 0.89-1.46, p = 0.29). In total, 210 (17.7%) patients were re-stung during VIT and 191 (91.0%) tolerated the sting without systemic symptoms. Of the 19 patients with VIT treatment failure, 4 took β-blockers, none an ACEI.

Conclusions: This trial provides robust evidence that taking β-blockers or ACEI does neither increase the frequency of systemic AE during VIT nor aggravate SSR. Moreover, results suggest that these drugs do not impair effectiveness of VIT. (Funded by Medical University of Graz, Austria; Clinicaltrials.gov number, NCT04269629).
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http://dx.doi.org/10.1111/all.14785DOI Listing
February 2021

Evaluation of oxidative stress biomarkers and antioxidant parameters in allergic asthma patients with different level of asthma control.

J Asthma 2021 Jan 8:1-15. Epub 2021 Jan 8.

Department of Molecular Biology and Genetics, Istanbul University, Istanbul, Turkey.

Objective: There is evidence that reactive oxygen species, especially free radicals, produced during the immune and inflammatory response may play important roles in the development of asthma.We aimed to evaluate the levels of certain oxidative stress biomarkers and antioxidant capacity in asthma patients with different asthma control levels in comparison to healthy subjects.

Methods: A total of 120 adult allergic asthma patients and 120 healthy individuals were included in this study. Using spectrophotometric methods, we analyzed two oxidative stress markers, levels of malondialdehyde (MDA) and protein carbonyls (PC), as well as reduced glutathione (GSH), total antioxidant capacity (FRAP) and catalase activity as critical antioxidant defense parameters in the blood samples of allergic asthma patients and healthy controls. The patients were divided into 3 subgroups according to asthma control test (ACT) results: totally controlled (TCG), partially controlled (PCG) and uncontrolled (UCG) subgroups. All biomarkers were compared between the three patient subgroups, as well as between total asthma patients and control subjects.

Results: There were remarkable differences between the control group and the combined patient group for all parameters. A significant increase in MDA and PC, especially in the UCG ( < 0.01 and  < 0.05, respectively) was detected in comparison to other subgroups. Additionally, increased MDA and PC levels, as well as decreased GSH levels were observed in all subgroups individually in comparison to the control ( < 0.001).

Conclusions: This research demonstrates the presence of severe oxidative stress, considering the increase in lipid peroxidation and protein oxidation, in patients with allergic asthma, even under controlled conditions.
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http://dx.doi.org/10.1080/02770903.2020.1870129DOI Listing
January 2021

Diagnostic workup including CD203c-based basophil activation test in immediate hypersensitivity due to metronidazole and ornidazole and evaluation of cross-reactivity in between.

Allergy 2021 03 27;76(3):842-852. Epub 2020 Aug 27.

Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Background: Little is known about the diagnostic approaches for immediate hypersensitivity reactions (IHRs) due to 5-nitroimidazole antibiotics. The aim was to evaluate the usefulness of in vivo tests and basophil activation test (BAT) for the diagnosis of IHRs due to metronidazole and ornidazole and to determine possible cross-reactivity in between.

Methods: Forty-nine patients with a clear history of IHRs due to these drugs and 20 healthy subjects who were known to tolerate these drugs were included. Skin tests (STs) and single-blind placebo-controlled drug provocation tests (SBPCDPTs) were performed with both drugs whereas BAT was applied only with the culprit drug.

Results: The most and least common reaction types were urticaria/angioedema (34.7%) and anaphylaxis (14.3%), respectively. SBPCDPTs were positive in 15 out of 47 patients, and only 7 had positive STs. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of STs for metronidazole/ornidazole were 33.3%/16.6%, 94.2%/97.3%, 60%/50%, and 84.6%/88.1%, respectively. BAT was positive in 12 out of 15 patients and negative in 10 control subjects, giving a sensitivity rate of 71.4% (CI, 29.0%-96.3%) for metronidazole and 83.3% (CI, 35.8%-99.5%) for ornidazole. The optimal concentration of both drugs for BAT was determined as 5 mg/mL. No cross-reactivity among two drugs was observed according to in vivo tests.

Conclusions: Our study showed that SBPCDPT and BAT are both useful diagnostic tools for IHRs due to 5-nitroimidazole antibiotics and can be used as supplementary to each other. No cross-reactivity between metronidazole and ornidazole in IHRs exists.
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http://dx.doi.org/10.1111/all.14542DOI Listing
March 2021

Not every angioedema following urticaria is histamine-mediated.

Ann Allergy Asthma Immunol 2020 11 1;125(5):603-605. Epub 2020 Jul 1.

Division of Immunology and Allergic Diseases, Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey.

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http://dx.doi.org/10.1016/j.anai.2020.06.035DOI Listing
November 2020

COVID-19 pandemic: Practical considerations on the organization of an allergy clinic-An EAACI/ARIA Position Paper.

Allergy 2021 03;76(3):648-676

Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

Background: The coronavirus disease 2019 (COVID-19) has evolved into a pandemic infectious disease transmitted by the severe acute respiratory syndrome coronavirus (SARS-CoV-2). Allergists and other healthcare providers (HCPs) in the field of allergies and associated airway diseases are on the front line, taking care of patients potentially infected with SARS-CoV-2. Hence, strategies and practices to minimize risks of infection for both HCPs and treated patients have to be developed and followed by allergy clinics.

Method: The scientific information on COVID-19 was analysed by a literature search in MEDLINE, PubMed, the National and International Guidelines from the European Academy of Allergy and Clinical Immunology (EAACI), the Cochrane Library, and the internet.

Results: Based on the diagnostic and treatment standards developed by EAACI, on international information regarding COVID-19, on guidelines of the World Health Organization (WHO) and other international organizations, and on previous experience, a panel of experts including clinicians, psychologists, IT experts, and basic scientists along with EAACI and the "Allergic Rhinitis and its Impact on Asthma (ARIA)" initiative have developed recommendations for the optimal management of allergy clinics during the current COVID-19 pandemic. These recommendations are grouped into nine sections on different relevant aspects for the care of patients with allergies.

Conclusions: This international Position Paper provides recommendations on operational plans and procedures to maintain high standards in the daily clinical care of allergic patients while ensuring the necessary safety measures in the current COVID-19 pandemic.
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http://dx.doi.org/10.1111/all.14453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323448PMC
March 2021

Diagnosis and management of the drug hypersensitivity reactions in Coronavirus disease 19: An EAACI Position Paper.

Allergy 2020 11 1;75(11):2775-2793. Epub 2020 Jul 1.

Allergy Unit, Regional University Hospital of Malaga-IBIMA-UMA-BIONAND-ARADyAL, Malaga, Spain.

Coronavirus disease 2019 (COVID-19), a respiratory tract infection caused by a novel human coronavirus, the severe acute respiratory syndrome coronavirus 2, leads to a wide spectrum of clinical manifestations ranging from asymptomatic cases to patients with mild and severe symptoms, with or without pneumonia. Given the huge influence caused by the overwhelming COVID-19 pandemic affecting over three million people worldwide, a wide spectrum of drugs is considered for the treatment in the concept of repurposing and off-label use. There is no knowledge about the diagnosis and clinical management of the drug hypersensitivity reactions that can potentially occur during the disease. This review brings together all the published information about the diagnosis and management of drug hypersensitivity reactions due to current and candidate off-label drugs and highlights relevant recommendations. Furthermore, it gathers all the dermatologic manifestations reported during the disease for guiding the clinicians to establish a better differential diagnosis of drug hypersensitivity reactions in the course of the disease.
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http://dx.doi.org/10.1111/all.14439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300843PMC
November 2020

Rapid drug desensitization for platinum-based chemotherapy drugs significantly increases peripheral blood IL-10 levels.

Allergy 2020 11 21;75(11):2942-2945. Epub 2020 Apr 21.

Division of Allergy and Immunology, Istanbul Faculty of Medicine, Department of Internal Medicine, Istanbul University, Istanbul, Turkey.

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http://dx.doi.org/10.1111/all.14311DOI Listing
November 2020

An Update on the Management of Severe Cutaneous Drug Hypersensitivity Reactions.

Curr Pharm Des 2019 ;25(36):3881-3901

Department of Pediatric Allergy and Immunology, Mersin University, Faculty of Medicine, Mersin, Turkey.

Severe cutaneous drug hypersensitivity reactions involve of different mechanisms , some of which are life-threatening, such as Stevens-Johnson syndrome/toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, generalized bullous fixed drug eruptions, serum sickness and serum sickness-like reaction and drug-induced vasculitis. These reactions may have substantial morbidity and mortality. In the past years, successive studies have provided new evidence regarding the pathogenesis of some of these severe reactions and revealed that underlying mechanisms are highly variable. Since these reactions have unique presentations and distinct pathomechanisms, the treatment methods and response rates might be different among various entities. Although supportive and local therapies are sufficient in some of these reactions, targeted immunosuppressive treatments and even mechanistic therapies such as plasmapheresis may be required in severe ones. However, there is still insufficient evidence to support the best treatment options for these patients since number of patients and large-scale studies are limited. In this review, conventional and new treatment options for severe cutaneous drug hypersensitivity reactions are presented in detail in order to provide the contemporary approaches to lessen the morbidity and mortality relevant to these severe iatrogenic diseases.
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http://dx.doi.org/10.2174/1381612825666191106115556DOI Listing
June 2020

A practical 16-day desensitization protocol in lenalidomide-induced non-immediate hypersensitivity reactions.

Ann Allergy Asthma Immunol 2019 10 7;123(4):394-397. Epub 2019 Aug 7.

Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul University, Istanbul Faculty of Medicine, Turkey.

Background: Desensitization in immediate-type hypersensitivity reactions (HRs) caused by chemotherapeutics is well described and standardized for many drugs. However, there are no standardized protocols in non-immediate HRs.

Objective: To evaluate the effectiveness of a 16-day desensitization protocol in the non-immediate HRs induced by lenalidomide.

Methods: According to our previously published slow desensitization protocol, we desensitized patients who had experienced non-immediate HRs attributable to lenalidomide. The protocol was started with the 1/100 of the daily-prescribed dose in milligrams of the culprit drug; then the doses were slowly increased to complete the procedure in 16 days. Demographic and clinical features of the patients were further appraised.

Results: Ten patients (mean age was 64.7 ± 10.8 years; 7 male) were successfully desensitized to lenalidomide. The mean reaction time was 7.3 ± 3.9 days in the history, and the reaction types were delayed urticaria (n = 4), eczematous rash (n = 3), and maculopapular eruptions (n = 3). The desensitization was successfully completed in 16 days in 9 patients. In 1 patient, maculopapular eruptions developed on the 11th day, and the patient was treated with corticosteroids. We repeated the previous tolerated dose longer and completed with a slower dose increasement, and the targeted dose was achieved in 35 days.

Conclusion: The 16-day desensitization protocol seemed to be safe and effective in the non-immediate type drug HRs caused by lenalidomide.
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http://dx.doi.org/10.1016/j.anai.2019.07.031DOI Listing
October 2019

Validation of the Turkish version of the Urticaria Control Test: Correlation with other tools and comparison between spontaneous and inducible chronic urticaria.

World Allergy Organ J 2019 26;12(1):100009. Epub 2019 Jan 26.

Dermatological Allergology, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Germany.

Background: The urticaria control test (UCT) is a questionnaire designed to determine if chronic urticaria (CU) is controlled or not and to aid therapeutic decision-making. It collects retrospective information about the symptoms and quality of life impairment over the last 4 weeks. The current study aimed to investigate the validity, reliability and sensitivity to change of the Turkish version of the UCT. We also evaluated its correlation with other tools and compared the UCT results of patients with chronic spontaneous urticaria (CSU) and patients with chronic inducible urticaria (CINDU).

Methods: Following forward/backward translation and cognitive debriefing, the Turkish version of the UCT was used in 81 CSU and 78 CINDU patients. Dermatology life quality index (DLQI), Chronic urticaria quality of life questionnaire (CU-Q2oL), urticaria activity score (UAS), patients' and physicians' global assessment visual analog scores and Likert scales were used at baseline and after four weeks to assess quality of life impairment, disease activity and disease control. Statistical analysis to determine the validity and reliability of the Turkish version of the UCT as well as comparison between CINDU and CSU patients were performed.

Results: Duration of disease was longer, disease control was poorer and severe complaints were more frequent in CINDU patients (duration of disease: 36.3 (24) ± 49.1 vs 31.5 (9) ± 67.9, p = .007, UCT baseline: 8.4 (8) ± 3.4 vs 10.4 (11) ± 3.9, p = .001 and patient's global assessment Likert scale severe complaints: 6 vs 15, p < .001, respectively). The UCT showed excellent internal consistency for CSU and a minimally acceptable consistency for CINDU Cronbach's α 0.89 for CSU versus 0.68 for CINDU). It showed strong correlation with CU-Q2oL but a moderate correlation with DLQI (r = -0.649, P < .001 and r = -0.545, P < .001, respectively). It was able to discriminate between patients with different disease control and was sensitive to detect changes in the disease control in both groups. The minimally important difference of the UCT was found to be 3.

Conclusions: The Turkish version of the UCT is a valid and reliable tool for the management of CU patients and can be used both in CSU and CINDU patients to determine if the treatment is sufficient and if disease activity and quality of life impairment are under control or not.
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http://dx.doi.org/10.1016/j.waojou.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439411PMC
January 2019

Interleukin-10 is increased in successful drug desensitization regardless of the hypersensitivity reaction type.

Asia Pac Allergy 2019 Jan 28;9(1):e9. Epub 2019 Jan 28.

Division of Immunology and Allergy, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Background: Little is known about the mechanism of desensitization in hypersensitivity drug reactions.

Objective: The aim of this study was to evaluate the effects of drug desensitization on some cytokine levels in patients desensitized for drug hypersensitivity reactions.

Methods: Patients with a hypersensitivity reaction to any drug for whom desensitization was planned with the culprit drug, patients who could tolerate the same drugs and healthy subjects who were not exposed to these drugs were enrolled. Bead-based Milliplex MAP multiplex technology was used to determine interleukin (IL)-4, IL-5, interferon-γ and IL-10 levels in the sera of the subjects as a baseline and 24 hours after desensitization had been completed in the patients.

Results: A total of 26 patients (16 female [61.5%]; mean age 48.46 ± 15.97 years old), 10 control patients (5 female [50%]; mean age 47.4 ± 15.4 years old) and 5 healthy subjects (3 female [60%]; mean age 34.2 ± 5.6 years old) were enrolled. Four of the 26 patients did not tolerate the procedure and were grouped as the 'unsuccessful desensitization group' whereas 22 patients successfully completed the procedure and formed the 'successful desensitization group.' Baseline cytokine levels in the 3 groups were not statistically different. Postdesensitization IL-10 levels in the successful desensitization group were significantly higher than their initial levels ( = 0.005) whereas none of the cytokine levels significantly changed in the unsuccessful desensitization group. The rise in IL-10 levels was greater in chemotherapeutic desensitizations when compared to other drugs ( = 0.006).

Conclusion: Successful desensitization independent of the hypersensitivity reaction type seems to be related to the increase of IL-10.
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http://dx.doi.org/10.5415/apallergy.2019.9.e9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365657PMC
January 2019

Analysis of the factors associated with diagnostic skin test positivity in immediate-type hypersensitivity reactions due to proton pump inhibitors.

Allergy 2019 06 29;74(6):1187-1190. Epub 2019 Jan 29.

Department of Chest Diseases, Division of Allergy and Immunology, Ankara University School of Medicine, Ankara, Turkey.

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http://dx.doi.org/10.1111/all.13715DOI Listing
June 2019

Evaluation of the Potential Risk Factors for Drug-Induced Anaphylaxis in Adult Patients.

Int Arch Allergy Immunol 2019;178(2):167-176. Epub 2018 Nov 16.

Division of Immunology and Allergic Diseases, Department of Internal Medicine, Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Aim: To investigate the potential risk factors in patients who have experienced anaphylaxis from drugs.

Method: The study included 281 adult patients (median age 40 years; 76.5% female) who experienced immediate types of hypersensitivity reaction to a drug. The patients were divided into an anaphylaxis group and a nonanaphylaxis group. The anaphylaxis group was diagnosed according to the criteria of the World Allergy Organization. Skin testing with culprit drugs was performed. In the nonanaphylaxis group, drug provocation tests were performed with culprit drugs, including aspirin or diclofenac, to determine nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. Atopy was determined by skin prick tests with the common inhalant allergens. Patients' demographics, clinical features, and baseline tryptase and total IgE levels were compared between the 2 groups.

Results: The median interval between the last reaction in the patient's history and the study evaluation was 7 months (range 1-120 months). In 52.3% of the patients, reactions were defined as anaphylaxis. The most common culprit drugs were NSAIDs (56.9%) and β-lactams (34.7%). The culprit drugs were used parenterally in 13.2% of the patients. 34.9% of the patients had comorbid diseases and 24.6% used additional drugs, the most common being antihypertensives (10%). Atopy was determined in 28.8% and 28.1% of the patients were smokers. The median serum level of baseline tryptase and total IgE was 3.5 µg/L and 77 kU/L, respectively. In 46.3% of the patients, skin tests with culprit drugs were positive and the positivity ratio was higher in the anaphylaxis group (p = 0.002). Anapyhlaxis was more common in patients who were: hypertensive, atopic, using angio-tensin-converting enzyme inhibitors/angiotensin receptor blockers, and received the culprit drug parenterally (p = 0.034, p = 0.04, p = 0.03, p = 0.035, p = 0.013, and p < 0.001). In the multivariate analysis, it was observed that the parenteral usage of the drug and the presence of atopy were significantly higher in the anaphylaxis group (p < 0.001, odds ratio [OR] = 20.05, confidence interval [CI] 4.75-88.64; p = 0.012, OR = 2.1, CI 1.17-3.74). Age, smoking, family history, and serum levels of baseline tryptase and total IgE did not differ between groups.

Conclusion: The parenteral route and atopy increase the risk of drug-induced anaphylaxis. IgE-mediated sensitivity to the culprit drug seems to facilitate anaphylaxis.
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http://dx.doi.org/10.1159/000494130DOI Listing
May 2019

Proteomic Identification of Allergenic Proteins of Morus alba L. Pollenexacerbation.

Asian Pac J Allergy Immunol 2019 Dec;37(4):205-211

Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, Istanbul, Turkey.

Background: Tree pollens are well-known aeroallergens all over the world. Little is known about the allergenicity of Morus alba (white mulberry) pollen.

Objecive: We aimed to explore the potential allergens of this pollen and its clinical relevance in tree pollen allergic patients living in Istanbul, Turkey.

Methods: Twenty three seasonal allergic rhinitis patients with a confirmed tree pollen allergy and 5 healthy control subjects underwent skin prick and nasal provocation tests with M.alba pollen extract. The pollen extract was then resolved by gel electrophoresis, and immunoblotted with sera from patients/control individuals to detect the potential allergenic proteins. The prevalent IgE binding proteins from 1D-gel were analyzed by MALDI-TOF/TOF.

Results: Eleven out of 23 patients were reactive to the extract with skin prick tests. Seven of those patients also reacted positively to the nasal provocation tests. The most common IgE-binding pollen proteins were detected between 55-100 kDa, and also at molecular weights lower than 30 kDa for some patients. Mass spectrometry analyses revealed that the principal IgE-binding protein was methionine synthase (5-methyltetrahydropteroyltriglutamate homocysteine methyltransferase), which is then proposed as a novel allergen in M.alba pollen.

Conclusion: This study provides the first detailed information for the potential allergens of Morus alba pollen of Istanbul. Methionine synthase with an apparent molecular weight of 80 to 85 kDa has been recognized as one of the allergens in Morus alba pollen for the first time.
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http://dx.doi.org/10.12932/AP-120418-0296DOI Listing
December 2019

Evaluation of the left venticular systolic function with the measurement of global longitudinal strain by Speckle tracking echocardiography in anaphylaxis.

Asia Pac Allergy 2018 Oct 24;8(4):e40. Epub 2018 Oct 24.

Department of Internal Medicine, Division of Immunology and Allergic Diseases, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Background: It is not known how cardiac functions are affected during anaphylaxis.

Objective: Our aim was to measure the cardiac functions shortly after an anaphylaxis attack using a new technique that detects subclinical left ventricular dysfunction.

Methods: Patients in our hospital who experienced anaphylaxis and urticaria (control group) due to any cause were included in the study. Tryptase levels were measured on the third hour of the reaction and 6 weeks later. Left ventricular systolic functions were evaluated with global strain measurement using echocardiography, approximately 4 hours and 6-week post reaction.

Results: Twelve patients were included in the anaphylaxis group (83.3% female; mean age, 43.25 ± 9.9 years). The causes of anaphylaxis were drug ingestion (n = 11) and venom immunotherapy. Eight of the anaphylactic reactions (66.7%) were severe and in 9 reactions (75%) tryptase levels increased. In the anaphylaxis group, strain values measured shortly after anaphylaxis were significantly lower than those calculated 6 weeks later ( < 0.001) and tryptase levels significantly increased ( = 0.002). The strain values measured both shortly after anaphylaxis and 6 weeks later did not differ according to severity of anaphylaxis. In severe anaphylaxis, tryptase levels during anaphylaxis and 6 weeks later were significantly higher ( = 0.019, = 0.035). The control group evidenced no differences regarding strain and tryptase levels measured at reaction and 6 weeks later. At reaction, in the anaphylaxis group, the tryptase levels were higher and the strain values were lower than those in the urticaria group ( = 0.007, = 0.003).

Conclusion: Cardiac dysfunction may develop during an anaphylaxis independent of severity of reaction.
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http://dx.doi.org/10.5415/apallergy.2018.8.e40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209598PMC
October 2018

Role of Skin Tests in the Diagnosis of Immediate Hypersensitivity Reactions to Taxanes: Results of a Multicenter Study.

J Allergy Clin Immunol Pract 2019 03 5;7(3):990-997. Epub 2018 Oct 5.

Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.

Background: Immediate hypersensitivity reactions (HSRs) to taxanes have been increasing in recent years, but the importance of skin tests in allergological workup has not been established.

Objective: In our study we tried to evaluate the role of prick and intradermal tests in the diagnosis of HSRs to paclitaxel and docetaxel.

Methods: In this multicenter prospective study, we enrolled patients with immediate HSRs to the aforesaid agents. Skin tests were performed on these subjects and if results were negative, intradermal tests with the culprit drug were conducted. Patients with grade 1 reactions subsequently underwent graded challenge; in cases of grade 2 or 3 reactions and/or positive test results, the culprit drug was administered with a desensitization schedule. Skin tests were also performed in 30 control subjects exposed to the taxanes without HSRs.

Results: A total of 84 patients (63 with HSRs to paclitaxel and 21 to docetaxel) were recruited in the period July 2015 to July 2017 by 8 centers; 58 patients (69%) developed grade 2 or 3 reactions. Prick test results were negative in all the cases, whereas intradermal test results were positive in 14 patients (10 with paclitaxel [15.9%] and 4 with docetaxel [19%]). The positivity of skin tests significantly correlated with grade 3 reactions and cutaneous involvement during HSRs. Graded challenge was performed in 16 patients without problems and 58 subjects underwent desensitization, which was well tolerated in all but 2 cases. In the control group, skin test results were negative in all the patients.

Conclusions: Skin tests for taxanes seem useful and can be performed in the allergological workup of subjects with HSRs to these agents, especially in cases of severe reactions with cutaneous involvement.
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http://dx.doi.org/10.1016/j.jaip.2018.09.018DOI Listing
March 2019

Deletions in SERPING1 Lead to Lower C1 Inhibitor Function: Lower C1 Inhibitor Function Can Predict Disease Severity.

Int Arch Allergy Immunol 2019;178(1):50-59. Epub 2018 Oct 2.

Division of Allergy and Immunology, Department of Internal Medicine, Ege University Faculty of Medicine, Izmir, Turkey.

Background: How genotype affects phenotype in hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) has not been totally clarified. In this study, we investigated the relationship between different types of mutations and various phenotypic characteristics.

Methods: Clinical data from 81 patients from 47 families were recorded. Complement proteins were analyzed from 61 untreated patients. The coding exons and the exon-intron boundaries of the SERPING1 gene were sequenced, and deletion/duplication analysis with multiple ligation dependent probe amplification was performed. The relationship of complement protein with the mutation type was analyzed by using generalized estimating equations.

Results: Thirty-five different mutations (15 novel and 2/15 homozygous) were identified. There was no causative mutation in 6 patients (7.4%). Patients with deletion and large deletion had the lowest (5.05%, 0-18.7; 5.8%, 0-16.5%, respectively), and the none mutation group had the highest C1 inhibitor function (23.3%, 11-78%, p < 0.001). C1 inhibitor function levels decreased as the age of the disease progressed (r = -0.352, p = 0.005). Lower C1 inhibitor function levels caused severer disease (r = -0.404, p = 0.001) and more frequent annual attacks (r = -0.289, p = 0.024). In the off-attack period, C1q levels were lower than normal in 9.8% of the patients.

Conclusion: Deletion mutations may represent the most unfavorable effect on C1 inhibitor function. The earlier disease onset age could be a sign for lower C1 inhibitor function levels in adult life. C1q levels could also be low in C1-INH-HAE patients, as in acquired angioedema. Lower C1 inhibitor function can predict disease severity and may have negative impacts on the course of C1-INH-HAE.
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http://dx.doi.org/10.1159/000492583DOI Listing
April 2019

An unusual dual hypersensitivity reaction to moxifloxacin in a patient.

Asia Pac Allergy 2018 Jul 17;8(3):e26. Epub 2018 Jul 17.

Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Both immediate and nonimmediate type hypersensitivity reactions (HRs) with a single dose of quinolone in the same patient have not been previously reported. A 47-year-old female patient referred to us because of the history of a nonimmediate type HR to radio contrast agent and immediate type HR to clarithromycin. She experienced anaphylaxis in minutes after the second dose of 50 mg when she was provocated with moxifloxacin. She was treated immediately with epinephrine, fluid replacement and methylprednisole and pheniramine. On the following day she came with macular eruptions, and she was treated with methylprednisolone. The positive patch test performed with moxifloxacin as well as the lymphocyte transformation test proved the T-cell mediated HR. In order to prove the immediate type HR, basophil activation test was performed but was found negative. This case report presents for the first time the 2 different types of HRs in a patient with a test dose of quinolone.
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http://dx.doi.org/10.5415/apallergy.2018.8.e26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073183PMC
July 2018

Generalized Fixed Drug Eruption Induced by Fluconazole Without Cross-Reactivity to Itraconazole: Lymphocyte Transformation Test Confirms the Diagnosis.

Drug Saf Case Rep 2018 Jan 2;5(1). Epub 2018 Jan 2.

Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Millet Street, Capa, Istanbul, Turkey.

We present a rare case of generalized fixed drug eruption caused by fluconazole. A 45-year-old female patient was referred to our outpatient clinic because of suspicious drug eruptions that occurred 5 months earlier and resolved within a month. The patient had sequela of hyperpigmentation on her arms, legs, back, and abdomen after oral administration of the fourth dose of 150 mg of fluconazole once daily because of vaginal candidiasis. Patch tests with the culprit drug applied both on unaffected skin areas and over one of the lesions were negative. A lymphocyte transformation test was performed and in response to fluconazole, CD4 T cells significantly proliferated. Because the patient needed a safe antifungal drug for her recurrent vaginal candidiasis symptoms, a single-blind placebo-controlled drug provocation test was performed with itraconazole and was negative. Accordingly, 200 mg of itraconazole once daily was given for 10 days safely.
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http://dx.doi.org/10.1007/s40800-017-0067-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750325PMC
January 2018

Endocan: A Novel Marker of Endothelial Dysfunction in C1-Inhibitor-Deficient Hereditary Angioedema.

Int Arch Allergy Immunol 2017 24;174(2):104-107. Epub 2017 Oct 24.

Immunology and Allergy Unit, Yedikule Education and Training Hospital, Istanbul University, Istanbul, Turkey.

Background: Hereditary angioedema (HAE) related to C1-inhibitor deficiency is a rare autosomal dominant disorder. Vascular cell adhesion molecules (VCAM) are known as endothelial activation markers. Endocan (also called ESM-1) is proposed as an endothelial dysfunction indicator. We aimed to investigate endothelial activation in attack-free periods in HAE patients by measuring their levels of endocan and VCAM-1.

Methods: Twenty-six HAE patients (22 female, mean age 40 ± 13 years) and 38 healthy control patients (13 female, mean age 36.9 ± 12 years) were included in the study. Peripheral blood samples were collected from HAE patients during symptom-free periods and control subjects. Endocan and VCAM-1 levels were measured using the enzyme-linked immunosorbent assay method.

Results: The median serum levels of endocan (647 ± 101 ng/mL) and VCAM-1 (500 ± 79 ng/mL) in the HAE patients were significantly higher than in the control patients (391 ± 41 and 325 ± 4; p < 0.001 for both).

Conclusion: The increased endocan and VCAM-1 levels may reflect an endothelial activation even in attack-free periods in HAE patients.
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http://dx.doi.org/10.1159/000481256DOI Listing
December 2017

High adherence to subcutaneous immunotherapy in a real-life study from a large tertiary medical center.

Allergy Asthma Proc 2017 Nov;38(6):78-84

Background: Studies on real-life adherence to subcutaneous allergen immunotherapy (SCIT) for respiratory allergy are scarce. The aim of this study was to evaluate adherence to SCIT.

Methods: The patients prescribed SCIT for allergic rhinitis and/or asthma in 2009-2011 were contacted in 2014 and asked whether they completed at least the 3 years of SCIT and/or whether they suspended the treatment for at least 2 months. The Total Symptom Score-6, visual analog scale (VAS), asthma control test (ACT), medication scores, quality of life (QoL) scores, and immunotherapy satisfaction scores with VAS obtained before the initiation of SCIT in the first year and at the end of SCIT were compared.

Results: A total of 204 patients (136 female [66.7%]; mean age, 38.83 ± 12.02 years) were included; 73% (149/204) were both compliant and persistent; 14% (29/204) were only persistent; and, overall, 87.3% (178/204) were considered adherent. Adherence was more frequent in female patients (95% CI, 62.3-76.3%; p = 0.018). Medication, symptom, ACT, and QoL scores in the first year and at the end of the treatment were significantly lower than the initial scores, and the immunotherapy satisfaction scores at the end of treatment were higher than the scores in the first year in the patients who were adherent (p < 0.001 for each score).

Conclusion: The adherence rate to SCIT in our study was relatively high, in contrast to previous real-life data. Results of our study indicated that a close relationship between allergists and their patients during SCIT and the follow-up period in the same center improved the outcome of SCIT.
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http://dx.doi.org/10.2500/aap.2017.38.4091DOI Listing
November 2017

Diagnostic Value of Oral Challenge Testing in the Diagnosis of Macrolide Hypersensitivity.

J Allergy Clin Immunol Pract 2018 Mar - Apr;6(2):521-527. Epub 2017 Sep 8.

Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Background: Hypersensitivity reactions (HRs) to macrolides are rare.

Objective: The aim of this study was to evaluate the diagnostic value of in vivo tests in the diagnosis of HRs to macrolides and also to assess cross-reactivity between 4 different macrolides (clarithromycin, dirithromycin, spiramycin, and azithromycin) belonging to 3 different groups.

Methods: Twenty-five patients with a history of immediate or delayed-type HRs to at least 1 macrolide and 20 healthy control subjects underwent skin testing for both the culprit and alternative macrolides. Then, all subjects underwent single-blind drug provocation tests (SBDPTs) with these drugs.

Results: Twenty-one patients (84%) described an early reaction, whereas the remaining 4 (16%) had delayed-type reactions. Skin prick test results with culprit macrolides were positive in only 2 patients who had experienced anaphylaxis. These 2 and another 4 patients with anaphylaxis history and 6 patients with negative skin test results who did not give consent were not challenged. A total of 13 patients with negative skin test results were challenged with the culprit drugs and all of them experienced HRs during the SBDPTs. Skin test results with alternative drugs were positive in only 2 patients with negative SBDPT results. Conversely, 5 patients with negative skin test results reacted to SBDPTs with alternative macrolides. In healthy control subjects, the skin test results were positive in 3 patients (1 positivity with clarithromycin, 2 positivity with spiramycin) whereas all DPT results were negative.

Conclusions: Our results suggested that DPT is the only reliable method to predict macrolide hypersensitivity as well as to detect cross-reactivity between macrolides.
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http://dx.doi.org/10.1016/j.jaip.2017.06.036DOI Listing
November 2019

Usefulness of In Vivo and In Vitro Diagnostic Tests in the Diagnosis of Hypersensitivity Reactions to Quinolones and in the Evaluation of Cross-Reactivity: A Comprehensive Study Including the Latest Quinolone Gemifloxacin.

Allergy Asthma Immunol Res 2017 Jul;9(4):347-359

Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey.

Purpose: Reports evaluating diagnosis and cross reactivity of quinolone hypersensitivity have revealed contradictory results. Furthermore, there are no reports investigating the cross-reactivity between gemifloxacin (GFX) and the others. We aimed to detect the usefulness of diagnostic tests of hypersensitivity reactions to quinolones and to evaluate the cross reactivity between different quinolones including the latest quinolone GFX.

Methods: We studied 54 patients (mean age 42.31±10.39 years; 47 female) with 57 hypersensitivity reactions due to different quinolones and 10 nonatopic quinolone tolerable control subjects. A detailed clinical history, skin test (ST), and single-blind placebo-controlled drug provocation test (SBPCDPT), as well as basophil activation test (BAT) and lymphocyte transformation test (LTT) were performed with the culprit and alternative quinolones including ciprofloxacin (CFX), moxifloxacin (MFX), levofloxacin (LFX), ofloxacin (OFX), and GFX.

Results: The majority (75.9%) of the patients reported immediate type reactions to various quinolones. The most common culprit drug was CFX (52.6%) and the most common reaction type was urticaria (26.3%). A quarter of the patients (24.1%) reacted to SBPCDPTs, although their STs were negative; while false ST positivity was 3.5% and ST/SBPCDPTs concordance was only 1.8%. Both BAT and LTT were not found useful in quinolone hypersensitivity. Cross-reactivity was primarily observed between LFX and OFX (50.0%), whereas it was the least between MFX and the others, and in GFX hypersensitive patients the degree of cross-reactivity to the other quinolones was 16.7%.

Conclusions: These results suggest that STs, BAT, and LTT are not supportive in the diagnosis of a hypersensitivity reaction to quinolone as well as in the prediction of cross-reactivity. Drug provocation tests (DPTs) are necessary to identify both culprit and alternative quinolones.
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http://dx.doi.org/10.4168/aair.2017.9.4.347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446950PMC
July 2017

Impact of high serum Immunoglobulin E levels on the risk of atherosclerosis in humans.

Asia Pac Allergy 2017 Apr 7;7(2):74-81. Epub 2017 Apr 7.

Division of Immunology and Allergic Diseases, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34015, Turkey.

Background: Epidemiological studies show that immunoglobulin E (IgE) levels were higher in subjects with acute coronary events. However, it is unknown if the increased IgE level is a marker of future coronary incidents and whether it may be regarded as a risk factor of an ischemic heart disease.

Objective: Our aim was to investigate the relationship between IgE levels and some atherosclerotic markers in patients without known atherosclerotic disease.

Methods: Fifty patients (mean age, 40.96 ± 10.8 years) with high serum IgE levels due to various conditions who did not display evidence of an atherosclerotic disease and 30 healthy control subjects (mean age, 47 ± 8.27 years) were included in the study. Atherosclerotic disease markers including adhesion molecules like vascular cell adhesion molecule-1, intercellular adhesion molecule-1, proinflammatory cytokines such as interleukin-6, endothelin-1, and systemic inflammatory markers such as high sensitivity C-reactive protein were determined by enzyme-linked immunosorbent assay (ELISA). Endothelial functions of the coronary arteries were determined by coronary flow reserve (CFR) measurements and carotid intima media thickness using transthoracic Doppler echocardiography.

Results: CFR was significantly lower in the patient group when compared with the control group (<0.001; 95% confidence interval, -0.79 to-0.20) while carotid media thicknesses were not different between 2 groups. There were no differences in ELISA test results between the 2 groups.

Conclusion: Our results showed that CFR as an early marker of endothelial dysfunction was significantly lower in patients with high IgE levels. This finding seems to support the role of IgE in the vascular pathology of atherosclerosis.
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http://dx.doi.org/10.5415/apallergy.2017.7.2.74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410414PMC
April 2017