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.

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.

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.

A case of work-related donkey milk allergy

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Th-17 cytokines and interstitial lung involvement in systemic sclerosis.

The two phenotypes of both limited and diffuse systemic sclerosis (SSc) have different forms of pulmonary involvement: pulmonary arterial hypertension (limited phenotype) or interstitial lung disease (ILD) (diffuse phenotype). We aimed to investigate whether Th17-related cytokines, as measured in exhaled breath condensate (EBC) and in serum were connected to ILD in diffuse SSc patients. We found that for both limited and diffuse SSc, the EBC levels of all cytokines and most of the cytokine serum levels were significantly higher in patients than in controls, while, the EBC levels of Th-17 cytokines and the serum levels of IL-10 and TNF-α were significantly higher in diffuse than in limited SSc. Moreover, the thoracic CT-scan score of ILD was significantly associated with the EBC levels of IL-1 beta and with the serum IL-23, TNF-α and IL-10 levels, whereas lung carbon monoxide diffusing capacity was negatively related to the EBC levels of IL-1 beta, IL-17 and serum IL-10. Serum IL-23 was also inversely correlated with vital capacity. In conclusion, in diffuse SSc patients our results show a clear link between Th-17 cytokines measured both in EBC and in serum with interstitial lung involvement. This highlights how important it is to target Th-17 cytokines when developing new treatments for lung fibrosis.

Effects of omalizumab in severe asthmatics across ages: A real life Italian experience.

BACKGROUND: This retrospective study aimed at evaluating long-term effects of Omalizumab in elderly asthmatics in a real-life setting. METHODS: 105 consecutive severe asthmatics (GINA step 4-5; mean FEV1% predicted:66 ± 15.7) treated with Omalizumab for at least 1 year (treatment mean duration 35.1 ± 21.7 months) were divided into 3 groups according to their age at Omalizumab treatment onset: 18-39, 40-64 and ≥ 65 years. RESULTS: Comorbidities, number of overweight/obese subjects and patients with late-onset asthma were more frequent among older people. A similar reduction of inhaled corticosteroids dosage and SABA on-demand therapy was observed in all groups during Omalizumab treatment; a similar FEV1 increased was also observed. Asthma Control Test (ACT) improved significantly (p < 0.001) in the three groups, increasing from 15 [IQR:12-18] to 24 [IQR:22-25] in younger subjects, from 14 [IQR:10-16] to 21 [IQR:20-23] in the 40-64-year-group and from 15 [IQR:12-16] to 20 [IQR:18-22] in elderly patients where improvement was lower (p = 0.039) compared to younger people. Asthma exacerbations decreased significantly after Omalizumab but the percentage of exacerbation-free patients was higher in younger people (76.9%) compared to middle aged patients (49.2%) and the elderly (29%) (p = 0.049). After Omalizumab treatment, the risk for exacerbations was lower in subjects aged 40-64 (OR = 0.284 [CI95% = 0.098-0.826], p = 0.021) and 18-39 (OR = 0.133 [CI95% = 0.026-0.678], p = 0.015), compared to elderly asthmatics. Also, a significantly reduced ACT improvement (ß = -1.070; p = 0.046) passing from each age class was observed. CONCLUSION: Omalizumab improves all asthma outcomes independently of age, although the magnitude of the effects observed in the elderly seems to be lower than in the other age groups.

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.

Asthma control in elderly asthmatics. An Italian observational study.

BACKGROUND: The exponential increase of individuals aged >64 yrs is expected to impact the burden of asthma. We aimed to explore the level of asthma control in elderly subjects, and factors influencing it. METHODS: A multicenter observational study was performed on consecutive patients >64 years old with a documented physician-diagnosis of asthma. Sixteen Italian centers were involved in this 6-month project. FINDINGS: A total of 350 patients were enrolled in the study. More than one-third of elderly asthmatic patients, despite receiving GINA step 3-4 antiasthmatic therapy, had an Asthma Control Test score ≤19, with a quarter experiencing at least one severe asthma exacerbation in the previous year. Twenty-nine percent of patients (n = 101) were classified as having Asthma-COPD Overlap Syndrome (ACOS) due to the presence of chronic bronchitis and/or CO lung diffusion impairment. This subgroup of patients had lower mean Asthma Control Test scores and more exacerbations compared to the asthmatic patients (18 ± 4 compared to 20 ± 4, p < 0.01, and 43% compared to 18%, p < 0.01, respectively). Modified Medical Research Council dyspnea mMRC scores and airway obstruction, assessed on the basis of a FEV(1)/FVC ratio below the lower limit of normal, were more severe in ACOS than in asthma, without any difference in responses to salbutamol. In a multivariate analysis, the mMRC dyspnea score, FEV(1)% of predicted and the coexistence of COPD were the only variables to enter the model. INTERPRETATION: Our results highlight the need to specifically evaluate the coexistence of features of COPD in elderly asthmatics, a factor that worsens asthma control.

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.

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 (AU)

Antecedentes: Se trata de una encuesta multicéntrica realizada en Italia para evaluar el impacto de la sensibilización a polen de ciprés en sujetos atópicos y establecer si la concentración de este polen en el aire ha cambiado a lo largo del tiempo. Métodos: El estudio fue realizado por alergólogos que recopilaron 100-200 sujetos consecutivos con pruebas cutáneas positivas (Prick) realizadas en 2012. Se recogieron los síntomas estacionales, junto con la concentración de polen de ciprés (obtenida por la asociación italiana de aerobiología) en 1998-2000 y 2010-2012. Resultados: En cuanto a los resultados obtenidos fueron examinados 2258 pacientes atópicos (56% mujeres; edad 2-84), sensibilizados frente al menos uno de los aeroalérgenos testados (Dermatophagoides, gramíneas, parietaria, olivo, cipres, abedul, Alternaria tenuis y epitelio de gato). El 62.9%, 16.1% y 32.7% de los pacientes que vivían en el centro, norte y sur de Italia, respectivamente, mostraron sensibilización a polen de ciprés (p<0.0001). Observamos un pico de concentración de polen de ciprés de febrero a marzo en los años 1998-2000 y 2010-2012, en todas las áreas. Los pacientes monosensibilizados a ciprés mostraron de forma prevalente rinitis (90.7-97.6%) y conjuntivitis (38.1-100%). La prevalencia de rinitis, conjuntivitis y asma se incrementa progresivamente (p<0.0001) del sur hacia el norte de Italia en los sujetos polisensibilizados. La misma tendencia se observó en los síntomas invernales típicos de la alergia al ciprés. Conclusiones: En conclusión, actualmente el polen de ciprés es el aeroalérgeno sensibilizante más frecuente (según resultados de prueba cutánea) en varias áreas de Italia central. Las variaciones del periodo de polinización pueden favorecer el incremento observado en la sensibilización a este polen. Los síntomas predominantes son rinitis y conjuntivitis. El impacto clínico de esta alergia es pobre en áreas del sur de Italia, siendo alto en las áreas del norte (AU)

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.

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.

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.

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.

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.