Pigeon tick bite: A neglected cause of idiopathic nocturnal anaphylaxis.

Anaphylaxis is a serious systemic allergic reaction with rapid onset and potentially life-threatening. We report in detail a case of severe nocturnal anaphylaxis due to pigeon tick bite showing the diagnostic value of the extract and the recombinant allergen in the diagnostic procedures (basophil activation test, IgE immunoblot, and experimental ImmunoCAP). Apart from the presented case, we describe that during the last 10 years, we have collected 28 cases of allergy to Argas reflexus from several European countries. We suspect that this allergy is underdiagnosed because of the lack of diagnostic reagents. Because of the growing number of pigeons in Middle and Southern Europe cities, some cases of idiopathic anaphylaxis could potentially be caused by A. reflexus in those countries. The identification of pigeon ticks as a trigger of anaphylaxis would greatly improve medical care and advice for these patients as the parasite can be exterminated by eradication measures to avoid further incidents.

Nasal IL-17F is related to bronchial IL-17F/neutrophilia and exacerbations in stable atopic severe asthma.

Severe asthma (SA) is associated with neutrophil recruitment and T helper (TH )17 chemokine overexpression in bronchial biopsies. We aimed to evaluate IL-17A and IL-17F expression in nasal/bronchial lamina propria of atopic mild-to-severe asthmatics and controls in relation to neutrophilia and asthma exacerbations. Cryostat sections of nasal/bronchial biopsies obtained from 14 SA and 14 mild asthma (MA) stable atopic patients with rhinitis, and seven healthy controls were analyzed by immunohistochemistry for neutrophils, IL-17A and IL-17F expression. Atopic SA showed an increase in asthma exacerbations number, IL-17F and IL-17A expression in nasal/bronchial lamina propria compared to MA and controls, and a higher expression of bronchial neutrophils in SA compared to MA and controls. In all asthmatics, significant relationships were found between bronchial IL-17F and neutrophils/FEV1 , nasal IL-17F and bronchial neutrophil/IL-17 markers and between the latter and exacerbations, suggesting that nasal IL-17F might be informative on bronchial IL17-driven neutrophilia in atopic SA.

Cypress pollen: an unexpected major sensitizing agent in different regions of Italy.

OBJECTIVES: In this multicenter survey, we assessed the impact of sensitization to cypress in atopic patients in Italy and determined whether cypress pollen concentration changed over time. METHODS: Allergists were required to collect the results of 100-200 consecutive skin prick tests (SPTs) performed during 2012. Seasonal symptoms were also recorded, as were airborne cypress pollen concentrations (data from the Italian Aerobiology Association) in 1998-2000 and 2010-2012. RESULTS: We examined 2258 atopic outpatients (56% females; age, 2-84 years) sensitized to at least 1 of the aeroallergens tested (Dermatophagoides species, grass, pellitory, olive, cypress, birch, Alternaria tenuis, and dog and cat dander). We found that 62.9%, 16.1%, and 32.7% of patients living in central, northern, and southern Italy, respectively, were sensitized to cypress (P < .0001). The cypress pollen concentration peak was delayed from February to March in 1998-2000 and 2010-2012 in all 3 regions, with a shift in pollination towards spring. Patients who were monosensitized to cypress reported mainly rhinitis (90.7%-97.6%) and conjunctivitis (38.1%-100%). In polysensitized patients, the prevalence of rhinitis, conjunctivitis, and asthma increased progressively (P < .0001) from southern to northern Italy. The same trend was observed for the prevalence of reported winter symptoms typical of cypress allergy (28%-65%). CONCLUSIONS: Today, cypress pollen is the most frequent sensitizing aeroallergen (assessed by SPT) in several areas of central Italy. Variations in the timing of the cypress pollination period may have favored this increased sensitization. Rhinitis and conjunctivitis are the predominant symptoms. The clinical impact of this allergy was poor in southern Italy and increased in central areas before reaching its peak in northern regions.

Effect of iron supplementation in women with chronic cough and iron deficiency.

AIMS: Chronic cough is more frequent and severe in women than in men. Women often have decreased iron stores, because of menses and pregnancies. We investigated if iron deficiency has a role in chronic cough by increasing airway sensitivity to inhaled irritants. METHODS: Twenty-two non-smoking women with chronic unexplained cough and iron deficiency (serum ferritin below 15 ng/ml) were examined in baseline, after 2 months empiric treatment with anti H1-histaminic drug and proton pump inhibitor, and after iron supplementation (330-660 mg iron sulphate tablets daily) for 2 months. Outcome measures were cough visual analogue scale (VAS), and histamine thresholds of the larynx (PC25MIF50, concentration causing 25% in MIF50), bronchi (PC20FEV1) and cough (PC5cough). RESULTS: Mean serum ferritin was 9.3 ng/ml (95% CI 7.7-10.9), 13 patients had mild anaemia. All the patients had laryngeal and cough hyperresponsiveness,12 had also bronchial hyperresponsiveness. Empiric treatment produced no significant effect, whereas iron supplementation improved cough VAS from 4.03 (3.6-4.47) to 2.6 (1.9-3.27), p < 0.0001, PC20FEV1 from 10.04 mg/ml (5.37-18.77) to 22.2 (11.7-41.8), p < 0.001, PC25MIF50 from 3.09 mg/ml (1.9-4.9) to 11.9 (7.3-19.4), p < 0.001 and PC5cough from 2.1 mg/ml (1.2-3.6) to 8.8 (5.2-15.1), p < 0.001. CONCLUSION: In women with unexplained chronic cough unresponsive to targeted treatment, airway and cough hyperresponsiveness may be sustained by iron deficiency. Healthy women with chronic cough should be checked for iron deficiency as iron repletion may resolve such disturbing symptom.

Clinical manifestations, co-sensitizations, and immunoblotting profiles of buckwheat-allergic patients.

BACKGROUND: Buckwheat allergy is a rare food allergy in Europe and North America, whereas it is often described and studied in Asia. The aim of this study was to describe a series of patients with proven buckwheat allergy evaluated in an Italian allergy clinic. Co-sensitization to other food and inhalant allergens and immunoblotting profiles of buckwheat-allergic patients were studied. METHODS: Patients with suspected buckwheat allergy who attended the allergy clinic between January 1, 2006, and September 30, 2008, were evaluated. All patients underwent skin prick tests for a standard panel of inhalant and food allergens, prick-by-prick with buckwheat flour, buckwheat-specific IgE determinations, and double-blind placebo-controlled food challenge (DBPCFC) with buckwheat flour. Immunoblotting with buckwheat flour extract was performed on sera from buckwheat-allergic patients. RESULTS: Among 72 patients with suspected buckwheat allergy, 30 (41.7%) were sensitized to buckwheat and 24 had a positive DBPCFC. The mean buckwheat IgE level was 6.23 kUA/l (range, 0.16 to >100 kUA/l). Several IgE-binding proteins were identified and grouped into three patterns: a 16-kDa band in patients with predominantly gastrointestinal symptoms with grass and wheat flour co-sensitization, a 25-kDa band in patients with predominantly cutaneous symptoms and a low frequency of co-sensitization, and a 40-kDa band in patients with anaphylaxis and a low frequency of co-sensitization. CONCLUSIONS: Buckwheat allergy is an emerging food allergy in Italy. We identified three distinct patterns of clinical and laboratory characteristics, suggesting that specific allergens could be more frequently associated with clinical manifestations of different severity.

Sensitization to horse allergens in Italy: a multicentre study in urban atopic subjects without occupational exposure.

BACKGROUND: Horses play a significant role in people's leisure time in Italy and other countries, but few data are available on IgE-mediated sensitization to horse allergens in patients without occupational exposure. We assessed, in a multicentric survey, the prevalence of horse sensitization in atopic subjects and its clinical characteristics. METHODS: Allergists from the whole Italian territory were required to collect the results of skin prick tests from at least 100 consecutive subjects. Those patients with a positive skin test to horse dander underwent a detailed interview concerning clinical history, pet ownership and possible exposure. RESULTS: Data from 3,235 outpatients were collected and 2,097 had at least 1 skin positivity. Among them, 113 (5.38%) were sensitized to horse dander (9 monosensitized). Thirty patients reported direct horse contact (4 owners and 26 for riding or occasional contact), 23 patients were sometimes in contact with horse owners and 60 subjects denied any direct or indirect exposure. Among 9 horse monosensitized patients, 6 had intermittent and mild rhinitis and 3 persistent moderate/severe rhinitis plus asthma. Three of them were horse owners or riders and the remaining had no contact with the animal. CONCLUSIONS: Our data evidence that the rate of sensitization to horse dander is not negligible and probably underestimated. In susceptible, not occupationally exposed individuals, horse contact, but also indirect or no apparent exposure, may induce sensitization. We recommend inclusion of horse allergen in the routine panel for the diagnosis of respiratory allergy.

The expression of TSLP receptor in chronic rhinosinusitis with and without nasal polyps.

Chronic Rhinosinusitis with or without Nasal Polyps (CRSwNP and CRSsNP) may be characterized by different cytokine profiles. Generally, Th2 cytokines and eosinophilic infiltration have been reported to be more specific of CRSwNP compared to CRSsNP, where neutrophils seem to play a major role. The epithelial cell-derived thymic stromal lymphopoietin (TSLP) has been recently identified as a key factor in Th2-inflammatory response. The aim of this study is to investigate the expression of TSLP Receptor (TSLP R) in surgical specimens obtained from patients affected by CRSwNP (n=10) and CRSsNP (n=5) by immunohistochemical techniques (immunostaining score, IS). TSLP R expression was significantly higher in the inflammatory infiltrate and in the epithelial cells of CRSwNP, CRSsNP patients compared to the control group (IS 4.5±0.68, 4.4±1.44 and 0.43±0.3 respectively, p=0.0024 for inflammatory infiltrate and IS 5.8±0.92, 7.8±2.06 and 0.86±0.55 respectively, p=0.0018 for epithelial cells). No significant difference was observed in IS of inflammatory infiltrate and epithelial cells in CRSwNP compared to CRSsNP. Very low IS for TSLP R was found in connective tissue of all the samples, with no difference among the groups. TSLP receptor is highly expressed in CRS compared to controls and independently from the polyps suggesting an early common inflammatory pathway in the two CRS phenotypes.

Oxidative stress and airway inflammation after allergen challenge evaluated by exhaled breath condensate analysis.

BACKGROUND: Allergen exposure may increase airway oxidative stress, which causes lipid membrane peroxidation and an increased formation of 8-isoprostane. OBJECTIVE: The aim of the study was to investigate oxidative stress induced by allergen challenge in mild asthmatics, by measuring 8-isoprostane in exhaled breath condensate (EBC), and to examine their relationship with mediators derived from arachidonic acid. Methods 8-isoprostane, cysteinyl leukotrienes (cys-LTs) and prostaglandin E2 (PGE(2) ) concentrations in EBC were measured at baseline and after allergen challenge in 12 patients with mild allergic asthma sensitized to cat allergen. RESULTS: At 24 h after allergen challenge, compared with baseline values, EBC 8-isoprostane increased [48.64 pg/mL (44.14-53.61) vs. 21.56 pg/mL (19.92, 23.35), P<0.001], cys-LTs increased [27.37 pg/mL (24.09-31.10) vs. 13.28 pg/mL (11.32, 15.57), P<0.001] and PGE(2) decreased [18.69 pg/mL (12.26, 28.50) vs. 39.95 pg/mL (34.37, 46.43), P<0.001]. The trend of increasing 8-isoprostane after allergen challenge was significantly correlated with the trend of increasing cys-LTs (R(2) =0.85, P<0.001) whereas the trend of decreasing PGE(2) after allergen challenge was significantly correlated with the trend of increasing cys-LTs (R(2) =0.52, P=0.001). CONCLUSIONS AND CLINICAL RELEVANCE: The increase in EBC 8-isoprostane observed after allergen challenge indicates that allergen exposure increases airway oxidative stress in allergic asthma. The strict correlation between cys-LTs and 8-isoprostane underlines the relationship between allergic inflammation and oxidative stress. A shift of arachidonic acid metabolism towards lipoxygenase pathway is induced by the allergen challenge. Airway oxidative stress occurs after allergen challenge even in patients with mild intermittent allergic asthma.

The Gene-Environment Interactions in Respiratory Diseases (GEIRD) Project.

The role of genetic and environmental factors, as well as their interaction, in the natural history of asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD) is largely unknown. This is mainly due to the lack of large-scale analytical epidemiological/genetic studies aimed at investigating these 3 respiratory conditions simultaneously. The GEIRD project is a collaborative initiative designed to collect information on biomarkers of inflammation and oxidative stress, individual and ecological exposures, diet, early-life factors, smoking habits, genetic traits and medication use in large and accurately defined series of asthma, allergic rhinitis and COPD phenotypes. It is a population-based multicase-control design, where cases and controls are identified through a 2-stage screening process (postal questionnaire and clinical examination) in pre-existing cohorts or new samples of subjects. It is aimed at elucidating the role that modifiable and genetic factors play in the occurrence, persistence, severity and control of inflammatory airway diseases, by way of the establishment of a historical multicentre standardized databank of phenotypes, contributed by and openly available to international epidemiologists. Researchers conducting population-based surveys with standardized methods may contribute to the public-domain case-control database, and use the resulting increased power to answer their own scientific questions.

Both allergic and nonallergic asthma are associated with increased FE(NO) levels, but only in never-smokers.

BACKGROUND: Allergic asthma is consistently associated with increased FE(NO) levels whereas divergence exists regarding the use of exhaled nitric oxide (NO) as marker of inflammation in nonallergic asthma and in asthmatic smokers. The aim of this study is to analyze the effect of having allergic or nonallergic asthma on exhaled nitric oxide levels, with special regard to smoking history. METHODS: Exhaled NO measurements were performed in 695 subjects from Turin (Italy), Gothenburg and Uppsala (both Sweden). Current asthma was defined as self-reported physician-diagnosed asthma with at least one asthma symptom or attack recorded during the last year. Allergic status was defined by using measurements of specific immunoglobulin E (IgE). Smoking history was questionnaire-assessed. RESULTS: Allergic asthma was associated with 91 (60, 128) % [mean (95% CI)] increase of FE(NO) while no significant association was found for nonallergic asthma [6 (-17, 35) %] in univariate analysis, when compared to nonatopic healthy subjects. In a multivariate analysis for never-smokers, subjects with allergic asthma had 77 (27, 145) % higher FE(NO) levels than atopic healthy subjects while subjects with nonallergic asthma had 97 (46, 166) % higher FE(NO) levels than nonatopic healthy subjects. No significant asthma-related FE(NO) increases were noted for ex- and current smokers in multivariate analysis. CONCLUSIONS: Both allergic and nonallergic asthma are related to increased FE(NO) levels, but only in never-smoking subjects. The limited value of FE(NO) to detect subjects with asthma among ex- and current smokers suggests the predominance of a noneosinophilic inflammatory phenotype of asthma among ever-smokers.

Exhaled nitric oxide and nitric oxide synthase expression in Hodgkin's disease.

Hodgkin's disease (HD) is a malignant lymphoma with frequent mediastinal involvement, characterized by a significant inflammatory infiltration. Exhaled nitric oxide (FENO), is present in healthy humans, and has been proven to be increased in eosinophilic diseases such as allergic asthma. We investigated whether FENO is increased in mediastinal HD and whether NO is produced by lymphoma tissue. To this aim FENO was measured in 56 HD patients, 17 with and 39 without bulky mediastinal involvement, in the period from January 2007 to December 2008. Thirty-seven patients were reassessed after remission. Lymph node biopsies of 10 patients were evaluated for inducible (iNOS) and constitutive (eNOS) nitric oxide synthase expression by immunohistochemistry. FENO resulted significantly related to the mediastinal mass maximum diameter (p=0.009) and was significantly higher in patients with as compared to those without bulky mediastinal disease (38.7 ppb, CI 95% 19.3-58.0, versus 20.7 ppb, CI 95% 16.6-24.7; p=0.009). iNOS and eNOS immunoreactivity was observed in tumour and inflammatory cells (eosinophils and histiocytes). Only in patients with bulky mediastinal HD there was a significant decrease in FENO (from 50.4 ppb CI 95% 18.0-82.8 to 11.1 ppb CI 95% 4.4-17.8, p=0.011). In conclusion, high FENO and NOS expression in lymph-nodes indicate that NO is a component of the inflammatory network of HD. FENO may be proposed for the assessment and follow up of bulky mediastinal HD patients.

Th1- and Th17-Related Cytokines in Venous and Arterial Blood of Sclerodermic Patients with and without Digital Ulcers.

The earliest clinical manifestation of SSc is usually Raynaud's phenomenon, a small-arteries vasospasm driven by vascular tone dysregulation and microcirculatory abnormalities, resulting in digital ulcers (DU) in up to 50% of patients. Many cytokines as well as growth factors have been shown to play a role in promoting vascular smooth muscle cell proliferation and fibroblast activation, leading to ischemic damage as well as skin fibrosis. We aim to investigate a possible difference in venous and arterial blood levels of many cytokines (Th1- and Th17-related), GM-CSF, and endothelin-1 (ET1) in patients with and without DU. In the same patients, the correlations between capillary damage, evaluated by nailfold videocapillaroscopy (NVC), extension of skin fibrosis, calculated by modified Rodnan skin score (mRSS), and cytokines, ET-1, and GM-CSF levels were also measured. Patients with DU showed venous levels of IL-1ß (p=0.024), IL-6 (p=0.012), IL-22(p=0.006), and TGF-ß (p=0.046) significantly higher compared to arterial levels and arterial levels of GM-CSF and TNF-alpha significantly higher compared to venous levels (p < 0.001). NVC abnormalities were correlated with arterial TNFa and venous IL22, IL23, and IL17 levels and negatively correlated with venous ET-1 levels, whereas mRSS showed a negative correlation with IL-21(ρ = -0.427, p=0.050). The increased Th17-cytokine levels in venous compared to arterial blood of patients with DU suggest local cytokine production on ulcer site. The higher TNFa and GM-CSF levels in arterial blood of DU patients support the attempt to mitigate the hypoxic damage, and the correlation between Th17-cytokines, mRSS, NVC, and ET1 agrees with the potent profibrotic stimulus at the onset of the disease, which decreases as the SSc progresses.

Breath analysis in patients with end-stage renal disease: effect of haemodialysis.

BACKGROUND: There is no agreement about exhaled nitric oxide (FE(NO)) and its change after haemodialysis (HD) in end-stage renal disease (ESRD) patients. To comprehensively assess NO production in the respiratory system, NO metabolites in exhaled breath condensate (EBC) needs to be measured in addition to FE(NO), taking into account the influence on these markers of airway pH, which may be regulated by ammonia (NH3+), present in large amounts in the breath of ESRD patients and removed by HD. STUDY DESIGN: FE(NO) and NO metabolites (NOx, NO2-,NO3- ), pH and NH3+ in EBC were measured in 12 ESRD patients, before and after HD. Twelve healthy subjects acted as controls. RESULTS: FE(NO )values of ESRD patients were similar to normals, while EBC-NOx, NO2-, NH3+ and pH were significantly higher in ESRD patients compared to normals (EBC-NOx 12.3, range 11.1-41.9 microm vs. 9.4, range 4.6-10.9 microm, P = 0.007; NO2- 4.70, range 1.17-8.22 microm vs. 0.90, range 0.72-1.17 microm, P = 0.023; NH3+ 2340, range 1325-3922 microm vs. 660, range 406-872 microm, P < 0.001; pH 7.16, range 6.82-7.44 vs. 6.60, range 6.42-6.76, P = 0.004, respectively). HD caused a mild significant decrease of FE(NO), and normalization of NH3+, NOx, NO2- and pH. A significant positive relationship between EBC-pH and EBC-NH3+ before and after HD (r(2) = 0.65, P = 0.000) was observed, explaining higher than normal EBC-pH before HD, while no relationship was found between EBC-pH and FE(NO) or NO metabolites. CONCLUSION: Oxidative stress, and not EBC-pH, is the most probable cause of increased NO metabolites in ESRD patients before HD.

Eosinophils Target Therapy for Severe Asthma: Critical Points.

Asthma is a chronic and heterogeneous disease, which is defined as severe disease whenever it requires treatment with a high dose of inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming ''uncontrolled" or if it remains ''uncontrolled" despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma, which is characterized by sputum eosinophilia, associated with mild to moderate increase in blood eosinophil count, frequently adult-onset, and associated with chronic rhinosinusitis with nasal polyps in half of the cases. Eosinophilic asthma is driven by T2 inflammation, characterized, among the others, by interleukin-5 production. IL-5 plays a key role in the differentiation, survival, migration, and activation of eosinophils, and it has become an appealing therapeutic target for eosinophilic asthma. In recent years two monoclonal antibodies (mepolizumab and reslizumab) directed against IL-5 and one monoclonal antibody directed against the alpha-subunit of the IL-5 receptor (benralizumab) have been developed. All these IL-5 target drugs have been shown to reduce the number of exacerbation in patients with severe asthma selected on the basis of peripheral blood eosinophil count. There are still a number of unresolved issues related to the anti-IL5 strategy in eosinophilic asthma, which are here reviewed. These issues include the effects of such therapy on airway obstruction and asthmatic symptoms, the level of baseline eosinophils that predicts a response to treatment, the relationship between blood and airway eosinophilia, and, perhaps most importantly, how to elucidate the pathogenetic role played by eosinophils in the individual patient with severe eosinophilic asthma.

Intercellular adhesion molecule-1 is upregulated on peripheral blood T lymphocyte subsets in dual asthmatic responders.

To examine the role of adhesion molecules in T cell recruitment and activation during allergen-induced late asthmatic response (LAR), we evaluated the expression of lymphocyte function-associated antigen-1 alpha (LFA-1 alpha) and intercellular adhesion molecule-1 (ICAM-1) on peripheral blood T lymphocyte subsets from atopic asthmatic patients and their changes following allergen inhalation challenge. 12 atopic asthmatic patients were studied. Six patients showed only a single early response after allergen challenge, and six developed a dual response. At baseline, dual responders (DR) had a significantly higher expression of ICAM-1 on CD4+ and CD8+ T lymphocytes as compared with both single early responders (P < 0.005 and P < 0.02, respectively) and controls (P < 0.001, both comparisons). Allergen challenge was followed by a decrease of CD8+ ICAM-1+ T lymphocytes in all DR (P < 0.05) and of CD4+ ICAM-1+ T lymphocytes in four out of six DR, at the time of the LAR. At the same time, a significant rise in serum levels of the soluble form of ICAM-1 was observed in DR. These results suggest that peripheral blood immunoregulatory T lymphocytes are in a higher state of activation in DR as compared with early responders. The upregulation of ICAM-1 on these cells may be important in enhancing airway inflammation in patients with LAR.

Anaphylaxis after eating Italian pizza containing buckwheat as the hidden food allergen.

A 20-year-old woman developed anaphylaxis after eating pizza on 4 different occasions in 2 restaurants. Both restaurants made their pizza dough with a mixture of wheat and buckwheat flours. A prick-to-prick test with buckwheat flour was positive. Skin prick tests and specific immunoglobulin E responses to soybean and peanut were weakly positive while the response to buckwheat was negative. We ruled out a pathogenic role for peanut and soybean because the patient usually eats both with no signs of allergic reaction. Double-blind, placebo-controlled food challenges with buckwheat flour were positive after the administration of a cumulative dose of 2.3 g of the culprit flour. To our knowledge, our report describes the first case of anaphylaxis after intake of buckwheat flour as the hidden allergen in pizza dough.