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

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.

The importance of mold sensitivity in nonallergic rhinitis patients.

BACKGROUND: In recent studies, local specific immunoglobulin E (sIgE) production against allergens in nasal mucosa and a positive response to a nasal allergen provocation test (NAPT) have been demonstrated in some patients initially diagnosed as nonallergic rhinitis (NAR) or idiopathic rhinitis (IR). The aim of this study was to evaluate the presence of local allergic rhinitis (LAR) in patients who experience rhinitis symptoms in indoor and outdoor moldy conditions and to investigate the role of the NAPT in diagnosis. METHODS: A total of 40 NAR patients with a history of persistent rhinitis and who had negative skin-prick tests (SPTs) and serum sIgE levels to common aeroallergens, as well as 20 healthy subjects were included in the study. NAPTs were performed with Aspergillus fumigatus (group 1) or a mixture of Alternaria alternata and Cladosporium herbarum extracts (group 2). RESULTS: In patient nasal lavage fluids, tryptase and mold sIgE levels were not significantly different from the control group. NAPT with Aspergillus fumigatus was positive in 8 of 12 NAR patients (66.6%) in group 1 and NAPT with the mixture of extracts was positive in 9 of 13 NAR patients (69.2%) in group 2. CONCLUSION: This study suggests that LAR may exist in a significant number of the persistent rhinitis patients who were previously considered as NAR based on negative SPTs or serum sIgE tests. To the best of our knowledge, this is the first study evaluating a nasal local allergic response to both indoor and outdoor molds.

Oral nickel exposure may induce Type I hypersensitivity reaction in nickel-sensitized subjects.

BACKGROUND: Little is known about the clinical and immunological changes in the nickel allergic patients with systemic symptoms. We aimed to evaluate T helper cell responses of patients with different clinical presentations due to nickel. METHODS: Patients having various allergic symptoms and positive patch test results to nickel and 20 controls underwent skin prick tests with nickel. IL-10, IL-4, IL-5 and IFN-gamma were measured in the culture supernatants of PBMC stimulated by nickel during lymphocyte proliferation test (LTT). RESULTS: 69 patients (56 female, mean age: 49.2 ± 13.1), 97% having nickel containing dental devices and 20 controls (8 female, mean age 34.9 ± 12.06) were evaluated. Skin prick tests with nickel were positive in 70% of the patients (p<0.001), being significantly higher in the patients with urticaria/angioedema (p=0.02). The LTT stimulation index (p<0.0001), IL-4 (p=0.002), IFN-gamma (p=0.01), IL-5 (p=0.04) and IL-10 (p=0.003) were higher in the patient group. LTT stimulation index, IL-4 and IL-10 were significantly elevated in patients having urticaria, angioedema and respiratory symptoms when compared to those who had only oral symptoms or systemic dermatitis (p=0.004, p=0.002 and p=0.01, respectively). CONCLUSION: This study suggests the presence of Type I hypersensitivity in addition to a Type IV immune reaction in patients with chronic systemic symptoms related to nickel. Nickel containing dental alloys and oral nickel intake seem to trigger systemic symptoms in previously nickel sensitized patients.

The prevalence of Hymenoptera venom allergy in adults: the results of a very crowded city in Euroasia.

BACKGROUND: There are scarce data about the prevalence of Hymenoptera venom allergy in the general population. The aim of this study was to determine the prevalence of Hymenoptera venom allergy in the general adult population of Istanbul. METHODS: A total of 17,064 randomly selected telephone numbers were contacted and 11,816 (69.25%) individuals who agreed to participate completed a questionnaire. Those who disclosed hypersensitivity reactions due to Hymenoptera stings in this initial survey were called again and given another questionnaire. Those who were suspected of experiencing hypersensitivity reactions to Hymenoptera stings were invited for a clinical investigation with in vivo and in vitro diagnostic tests. RESULTS: According to the first questionnaire, a total of 1171 (9.9%; 95% CI: 9.38-10.47%) were suspected of having a hypersensitivity to Hymenoptera stings. 51.75% (n: 606) answered the second questionnaire and 21% (n: 128) of these were still suspected of having a hypersensitivity to Hymenoptera stings (1.1%; 95% CI: 0.9-1.29%). The confirmed prevalence of hypersensitivity to Hymenoptera stings according to skin tests and in vitro sIgE levels was 0.2% (95% CI: 0.14-0.30%). Nearly all of the participants with systemic reactions were admitted to the emergency department, although only one tenth of them received adrenaline in the emergency room. 2.3% carried an adrenaline injector, whereas none of the patients received venom immunotherapy. CONCLUSIONS: The prevalence of Hymenoptera sting reactions in our geographical region is comparable with other European studies. There is a need to increase the awareness of adrenaline in the emergency management of insect sting anaphylaxis and venom immunotherapy in the prophylaxis.

Increased eNOS levels in hereditary angioedema.

BACKGROUND: Hereditary angio-edema (HAE), characterized by recurrent episodes of angioedema involving the skin and the mucosa of the upper respiratory or the gastrointestinal tracts, results from heterozygosity for deficiency of the serine proteinase inhibitor (serpin), C1 inhibitor (C1-INH). OBJECTIVE: In this study, serum inflammatory cytokine levels and circulating endothelial cells collected from HAE patients during both acute attacks and asymptomatic periods were evaluated. METHOD: Twenty-four patients with Type I and 1 patient with Type II HAE in an asymptomatic period (Group I), 8 patients with Type I HAE during a mild to moderate acute attack (Group II) and 20 healthy subjects (13 females, mean age: 32.1±8.2years) were included. Serum IL-6, IL-8, IL-1ß, TNF-α, vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) levels were detected by ELISA. Circulating endothelial cells (CECs) and circulating endothelial progenitors (CEPs) were evaluated using Fluorescence Activated Cell Sorting (FACS). RESULTS: Serum eNOS levels of HAE patients were significantly higher than healthy subjects (p<0.006) while mean TNF-α levels in Group I were slightly lower (p<0.03) than Group II. There were no differences in terms of other inflammatory cytokines between the control subjects and HAE patients who were either in an asymptomatic period or experiencing an acute attack. CECs and CEPs were also similar. CONCLUSION: These results suggest that an inflammatory response is not necessary to trigger HAE attacks. On the other hand, increased eNOS levels might reflect a sustained hyperpermeability state in HAE patients.

Nickel dental alloys can induce laryngeal edema attacks: a case report.

Nickel is a strong immunological sensitizer and may result in contact hypersensitivity. Case reports of allergic reactions to intraoral nickel have occasionally been reported in the published work and these allergic reactions are generally of a delayed type (type IV). Here, we present a case of a nickel allergic patient displaying frequent laryngeal edema attacks which required treatment with epinephrine injections followed by parenteral corticosteroid doses. Her complaints ceased after the removal of the dental bridge and the foods containing nickel. In summary, we propose that in the case of recurrent laryngeal edema attacks without any explainable cause, an allergic reaction due to nickel exposure should be taken into consideration.

Anaphylaxis in a tertiary adult allergy clinic: a retrospective review of 516 patients.

BACKGROUND: Anaphylaxis is a life-threatening acute allergic reaction that can occur at any age. OBJECTIVE: To determine the frequency, triggering factors, and clinical features of anaphylaxis among adult patients who were referred to a tertiary health care facility. METHODS: A retrospective medical chart review was performed including all patients referred to the outpatient clinic of the adult allergy department in our university hospital between January 1, 2008 and December 30, 2011 to determine cases involving anaphylaxis. RESULTS: A total of 516 (2.11%) patients among 24,443 admissions were diagnosed with anaphylaxis. Although the second highest frequency of anaphylaxis cases took place in 2008, a gradual rise in the frequency was determined from 2009 to 2011. Drugs (90.7%) were the most frequent cause, followed by Hymenoptera stings (5.4%), foods (1.6%), latex (0.4%), and exercise (0.2%) respectively. The clinical manifestations during anaphylaxis reported by patients were cutaneous (n = 292, 56.6%), respiratory (n = 253, 49%), cardiovascular (n = 212, 41%), neuropsychiatric (n = 60, 11.6%), and gastrointestinal (n = 52, 10.1%), respectively. Approximately one fifth of the patients received epinephrine, whereas 43% of patients did not receive epinephrine during their treatment in the emergency room. An epinephrine auto-injector was prescribed to 42 patients (8.1%). CONCLUSION: In this study, the second pattern of National Institute of Allergy and Infectious Disease (NIAID) and the Food Allergy and Anaphylaxis Network (FAAN) diagnostic criteria for anaphylaxis predominated among adult patients. Drugs were the leading triggering factor, followed by Hymenoptera stings, foods, latex, and exercise, respectively. Atopy, asthma, and allergic rhinitis were rarely detected.

Promising option in the prevention of idiopathic anaphylaxis: omalizumab.

Anaphylaxis is a serious and probably lethal systemic reaction which occurs instantaneously after exposure to an allergen. It can occur after exposure to various triggers including allergic and non-allergic factors. When a trigger cannot be determined, idiopathic anaphylaxis is considered. In idiopathic anaphylaxis presenting with frequent attacks, long-term prophylaxis with H(1) antihistamine and steroid treatment are recommended. Omalizumab, a humanized monoclonal antibody drug which decreases free immunoglobulin E molecules in the circulation, is approved for the treatment of chronic severe persistent allergic asthma. We report a 46-year-old female patient with severe uncontrolled allergic asthma and idiopathic anaphylaxis presenting with attacks of abdominal pain, generalized urticaria, feeling of strangulation in her throat and unconsciousness. Omalizumab at a dose of 375 mg once every 2 weeks was administrated and at the end of 3 months anaphylactic attacks had ceased. At the end of the sixth month of omalizumab therapy, her injection intervals were extended to 4 weeks. After she began experiencing moderate attacks of urticaria and hoarsening, however, initial treatment plan was reestablished. Currently, she has completed her first year of treatment without further attacks.

Omalizumab markedly improves urticaria activity scores and quality of life scores in chronic spontaneous urticaria patients: a real life survey.

Treatment of chronic urticaria consists of antihistamines as the first-line treatment. For more severe symptoms, combinations can be necessary as well as dose augmentations. The recent guidelines suggest the possibility of using omalizumab in resistant cases, but this therapy is still investigational. We treated two patients with idiopathic recurrent angioedema and 12 patients with chronic spontaneous urticaria (CSU) with omalizumab, who had not benefited from the recommended first-line, second-line and third-line treatments. To evaluate the efficacy of the omalizumab treatment, urticaria activity scores (UAS) and chronic urticaria quality of life (CU-Q2oL) scores were measured at baseline, and at the end of the first and sixth month of the therapy. The dosage and intervals of omalizumab therapy were determined according to the rules suggested for severe asthma treatment. CU-Q2oL scores and UAS displayed significant improvements in all 14 patients. None of the patients reported any adverse effect during the treatment until the submission of this data. Our results show that omalizumab apparently improves CU-Q2oL as well as UAS in treatment-resistant CSU in a real life setting.

There is an increased risk of atherosclerosis in hereditary angioedema.

BACKGROUND: Hereditary angioedema is associated either with a deficiency in the amount or in the function of the C1 inhibitor (C1 INH). OBJECTIVE: In this study the endothelial function of HAE patients was investigated to evaluate the impact of hereditary C1-INH deficiency on atherosclerosis, which has not yet been established before. METHODS: A total of 26 patients (14 female, 12 male. Mean age: 38±13) diagnosed with HAE and 30 healthy controls were enrolled in the study. Measurement of coronary flow reserve (CFR) in the left anterior descending coronary artery was performed using transthoracic doppler harmonic echocardiography at baseline and following dipyridamol infusion. The intima-media thickness (IMT) in the carotid artery was measured using an echocardiographic system equipped with 10 MHz linear transducer (Vingmed System Five). RESULTS: The mean CFR value for the HAE patient group was significantly lower than that of the control group (p<0.001). The mean IMT was not found to be significantly different between the two groups, although it was slightly higher in the HAE patient group. No correlation was found between the CFR and the disease severity scores, nor was it shown between the CFR values and the duration of danazol treatment. CONCLUSION: Our results indicate that there is a microvascular endothelial dysfunction in HAE patients. Although carotid intima media thickness of these patients was not significantly increased, the presence of microvascular endothelial dysfunction might be regarded as an early indicator of a premature atherosclerosis.

Coronary artery calcification and coronary flow velocity in haemodialysis patients.

BACKGROUND: Decreased coronary flow reserve (CFR) is a marker of endothelial dysfunction, coronary artery calcification and inflammation, well-known cardiovascular risk factors in haemodialysis (HD) patients. In this study, we aimed to investigate the correlation of coronary artery calcification scores (CACS) with CFR in HD patients. METHODS: Sixty-four end-stage renal failure patients were enrolled in this study (38 males, 26 females). Thirty-nine healthy subjects (22 males, 17 females) were included in the control group. Biochemical parameters and acute-phase inflammation marker [high-sensitivity C-reactive protein (hs-CRP)] of patients were recorded before dialysis. The CACS were measured by electron beam computerized tomography method. CFR recordings were performed by trans-thoracic Doppler echocardiography. The relationship between CACS and CFR was evaluated. RESULTS: The mean CACS was 281 +/- 589 and 29 patients had CACS < 10. Patients with CACS > 10 had significantly lower CFR values compared to patients with CACS < 10 (1.56 +/- 0.38 vs 1.84 +/- 0.53, P = 0.024). However, there was no difference in hs-CRP values between the groups. CFR was negatively correlated with CACS (r = -0.276, P = 0.030). In multiple stepwise regression analysis, CACS was found to be an independent variable for predicting CFR (P = 0.048). During a follow-up of 18 months, 10 patients had experience of cardiovascular events. Patients with CACS > 10 had significantly higher event rate [34.5% (10/29) vs 0% (0/24)] compared to those with CACS < 10 (P = 0.001). Patients who developed cardiovascular events had significantly higher mean CACS and lower CFR values than the remaining group (P = 0.019 and P = 0.039). All of four patients who died during follow-up were in the CFR < 2 and CACS > 10 groups. CONCLUSIONS: CACS was associated with CFR in HD patients. However, we did not find any association of inflammation with CACS and CFR. This association between CFR and CACS might indicate two different (anatomical and functional) aspects of the common pathophysiology of the arterial system in HD patients.

Coronary flow reserve dysfunction in hemodialysis and kidney transplant patients.

BACKGROUND: The assessment of coronary flow reserve (CFR) by trans-thoracic echocardiography has recently been introduced into clinical studies. Impairment of coronary microvascular functions and decreased CFR detected by trans-thoracic Doppler harmonic echocardiography (TTDE) has recently been reported in hemodialysis (HD) patients, but there is no comparative study between HD patients and renal transplant recipients. METHODS: The aim of our study was to evaluate coronary microvascular circulation in chronic HD patients and renal transplant recipients. Forty-eight chronic HD patients, 27 renal transplant patients and 39 normotensive healthy controls were studied for the assessment of CFR by TTDE. The carotid artery intima media thickness (IMT) and areas of focal plaque formation were also evaluated in all subjects. RESULTS: CFR values were significantly lower in both the HD and renal transplant groups than in the control group (p = 0.00). CFR values (1.57 +/- 0.32 vs. 1.89 +/- 0.50, p = 0.01) were also significantly lower in the HD group than in the renal transplant group. In 43 of 48 (89.6%) HD patients, CFR was <2.0; however, in 16 of 27 (59.3%) renal transplant recipients it was <2.0 (p = 0.00). When the HD and renal transplant groups were divided into two subgroups, according to CFR measurements (CFR < 2 and > or =2), no significant differences were found with respect to coronary risk factors and left ventricular echocardiographic measurements. The IMT of the control group (0.586 +/- 0.163 mm) was significantly lower than the HD (0.799 +/- 0.218 mm) and renal transplant groups (0.681 +/- 0.148 mm; p = 0.00). The IMT of the HD patients (0.799 +/- 0.218 mm) was significantly higher than the renal transplant recipients (0.681 +/- 0.148 mm; p = 0.01). CONCLUSIONS: Renal transplant and HD patients had lower CFR values detected by TTDE, which may be regarded as an early finding of an affected cardiovascular system. CFR is more impaired in HD patients than renal transplant recipients. Uremia-associated microvascular disease may be responsible for CFR impairment in HD patients.

Endothelial nitric oxide synthase intron 4a/b polymorphism and early atherosclerotic changes in hypopituitary GH-deficient adult patients.

OBJECTIVE: Endothelial nitric oxide synthase (eNOS) intron 4a/b polymorphism is associated with plasma NO concentrations and coronary artery disease/hypertension in various populations. GH deficiency in adulthood predisposes to reduced NO concentrations and premature atherosclerosis. Our aim was to determine whether intron 4a/b polymorphism of eNOS gene influences endothelial function and early atherosclerotic changes in GH-deficient hypopituitary patients. DESIGN: Thirty-three hypopituitary GH-deficient patients on conventional replacement therapy other than GH and 43 age-, sex-, and body mass index (BMI)-matched controls were studied in this cross-sectional case-control study. METHODS: Early atherosclerotic changes were determined by flow-mediated dilation (FMD) of brachial artery and carotid artery intima-media thickness (IMT). eNOS4a/b polymorphism was detected by PCR. RESULTS: Hypopituitary patients had significantly higher total/low-density lipoprotein cholesterol and fat mass and lower IGF-I concentrations compared with controls. IMT was significantly higher in patients (0.777+/-0.23 vs 0.639+/-0.17 mm, P<0.01). No significant difference was observed with respect to FMD measurements. eNOS4a/b genotype frequencies were similar between patients and controls. Patients carrying 'a' allele (a/a and a/b) had significantly higher IMT compared with controls carrying 'a' allele and bb genotype (P<0.05). However, logistic regression analysis revealed that presence of hypopituitarism, age> or =45 years, and BMI> or =27.9 kg/m(2) were significant independent predictors of IMT> or =0.65 mm. CONCLUSION: No compelling data are evident to suggest that eNOS4a/b polymorphism modifies the atherosclerotic process in GH-deficient situations. A large case-control study is needed to confirm our findings.

Coronary flow reserve is impaired in patients with adult growth hormone (GH) deficiency.

OBJECTIVE: Relationship between adult growth hormone deficiency (AGHD) and increased cardiovascular disease risk is very well known in hypopituitary patients treated with conventional hormone replacement therapy other than growth hormone (GH) administration. Endothelial dysfunction, an early and reversible event in pathogenesis of atherosclerosis, is associated with increased vascular smooth muscle tone, arterial stiffening and intima-media thickness (IMT). Coronary flow reserve (CFR) measurement by transthoracic 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 AGHD. DESIGN: Cross-sectional observational study. PATIENTS: A total of 10 GH-deficient adults on conventional replacement therapy other than GH (4 males, 6 females; mean age 37 +/- 11 years) and 15 healthy subjects (7 males, 8 females; mean age 41 +/- 11 years) were studied. Patients and controls were all nonsmokers, normotensive and nondiabetic. MEASUREMENTS: IGF-1, free T4, lipid profile, insulin, glucose, insulin resistance (IR), anthropometrical and physical parameters were recorded. CFR recordings and IMT measurements were performed using the Vivid 7 echocardiography device. RESULTS: IMT were significantly higher in patients than controls (0.70 + 0.19 mm and 0.53 + 0.13 mm, respectively; P = 0.02). CFR was significantly lower in patients than in controls (1.96 +/- 0.35 and 2.62 +/- 0.45, respectively; P < 0.001). CFR was positively correlated with IGF-1 levels (r = 0.54, P = 0.005). CONCLUSION: CFR is significantly lower in adults with GH deficiency than in controls. Direct correlation between CFR and IGF-1 concentrations suggests GH replacement could improve microvascular function and thereby could decrease cardiovascular morbidity and mortality in AGHD.

Coronary flow reserve is also impaired in patients with subclinical hypothyroidism.

The diagnosis of subclinical hypothyroidism and detection of its effects on cardiovascular system is important. Also, the patients with subclinical hypothyroidism even at the very early stage are at increased risk for developing atherosclerosis. We evaluated coronary microvascular circulation and endothelial dysfunction of epicardial coronary arteries by the measurement of coronary flow velocity reserve via a non invasive technique, transthoracic Doppler echocardiography in subclinical hypothyroidism. Coronary flow reserve in patients with subclinical hypothyroidism such as in overt hypothyroidism was lower than that of euthyroid subject. As a conclusion, endothelial and microvascular dysfunction, which are early harbingers of atherosclerosis, are shown in overt and subclinical hypothyroidism.