Manlio Milanese

Nasal Obstruction in Patients with Seasonal Allergic Rhinitis: Relationships between Allergic Inflammation and Nasal Airflow

Background: Nasal obstruction is a typical symptom of allergic rhinitis. Allergic rhinitis is characterized by a Th2-dependent inflammation. The aim of this study was to evaluate the possible relationships between allergic inflammation, including inflammatory cells and cytokine pattern, and nasal airflow in patients with nasal obstruction due to seasonal allergic rhinitis. Methods: Fifty patients (31 males and 19 females, mean age 31.9 ± 4.8 years) with seasonal allergic rhinitis were evaluated during the pollen season. All of them had moderate to severe nasal obstruction. Total symptom score, rhinomanometry, nasal lavage, and nasal scraping were assessed in all subjects. Inflammatory cells were counted by conventional staining; IL-4, IL-5, IL-8, and IFNγ were measured by immunoassay on fluids recovered from nasal lavage. Results: Significant positive relationships were demonstrated between eosinophil infiltration and IL-4 levels (p < 0.0001), eosinophils and IL-5 levels (p < 0.0001), and eosinophils and IL-8 levels (p < 0.0001). Significant negative relationships were demonstrated between eosinophil infiltration and IFNγ levels (p < 0.0001) and eosinophil infiltration and nasal airflow (p < 0.001). Conclusions: This study demonstrates the close connection between Th2 cytokines and eosinophil infiltration. In addition, there is clear evidence concerning the relationship between eosinophil infiltration and nasal airflow. These findings constitute first evidence of the relationship between nasal airflow impairment and Th2-related inflammation in seasonal allergic rhinitis.

Improvement of clinical and immunopathologic parameters in asthmatic children treated for concomitant chronic rhinosinusitis

BACKGROUND Chronic rhinosinusitis is frequently associated with asthma. A Th2 cytokine pattern has been recently reported in chronic rhinosinusitis in asthmatic children. OBJECTIVE To evaluate the effects of treating concomitant chronic rhinosinusitis on respiratory symptoms and function and immunopathological parameters in asthmatic children. METHODS Eighteen children with moderate asthma (age range, 5 to 12 years) poorly controlled by high doses of inhaled corticosteroids and chronic rhinosinusitis were evaluated for symptoms, spirometry, and inflammation at baseline, after treatment, and 1 month after suspension of treatment. All of the children were treated with a combination of amoxicillin and clavulanate (20 mg/kg twice daily) and fluticasone propionate aqueous nasal spray (100 microg/d) for 14 days. A short course of oral corticosteroids was also prescribed (deflazacort, 1 mg/kg daily for 2 days, 0.5 mg/kg daily for 4 days, and 0.25 mg/kg daily for 4 days). Rhinosinusal lavage for cytokine measurements and a nasal scraping for cytologic analysis were performed in all patients before and after medical treatment. RESULTS A negative endoscopy result was demonstrated in 15 children after treatment. Symptoms and respiratory function significantly improved after treatment and 1 month later; 8 children had intermittent asthma and 10 had mild asthma. A significant reduction of inflammatory cell numbers was detected in all asthmatic children. Interleukin 4 levels significantly decreased (P < 0.001), whereas interferon-y levels increased (P < 0.001). CONCLUSION Treatment of chronic rhinosinusitis is able to improve symptoms and respiratory function in asthmatic children, reducing inflammatory cells and reversing the cytokine pattern from a Th2 toward a Th1 profile.

Fexofenadine reduces nasal congestion in perennial allergic rhinitis

Background: Nasal congestion is the predominant symptom in perennial allergic rhinitis (PAR), and it seems to be mainly related to the late‐phase inflammatory events. The present pilot study aimed to evaluate the therapeutic effect exerted by fexofenadine in patients with PAR due to mite allergy.

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.

Medical treatment reverses cytokine pattern in allergic and nonallergic chronic rhinosinusitis in asthmatic children

A Th2 cytokine pattern has recently been reported both in allergic and nonallergic chronic rhinosinusitis in asthmatic children. The aim of the study was to evaluate the cytokine pattern in chronic rhinosinusitis in allergic and nonallergic asthmatic children before and after medical treatment. Thirty asthmatic children were evaluated, 18 males and 12 females (mean age 9.1 years). Sixteen were allergic and 14 were nonallergic. All children were asthmatic and suffered from chronic rhinosinusitis, whose diagnosis was confirmed by endoscopy. All of them were treated with amoxicilline‐clavulanate (20 mg/kg b.i.d.) and fluticasone propionate aqueous nasal spray (100 µg daily) for 14 days; a short course of oral corticosteroid was also prescribed (deflazacort 1 mg/kg daily for 2 days, 0.5 mg/kg daily for 4 days and 0.25 mg/kg daily for 4 days). Rhinosinusal lavage and nasal cytology were performed in all subjects before and after medical treatment. IL4 and IFNγ were measured by immunoassay and inflammatory cells were counted by conventional staining. Thirteen allergic children and 12 nonallergic children showed a negative endoscopy after the treatment. Allergic subjects showed a significant decrease of IL4 (p = 0.0002) and a significant increase of IFNγ (p = 0.03) after the treatment. Nonallergic children showed a significant decrease of IL4 (p = 0.0007) and a nonsignificant increase of IFNγ. A significant reduction of the inflammatory infiltrate was detected in all asthmatic children (p < 0.05). This study confirms a Th2 polarization in chronic rhinosinusitis both in allergic and nonallergic asthmatic children. Moreover, the medical treatment of chronic rhinosinusitis reversed the cytokine pattern from a Th2 towards a Th1 profile both in allergic and nonallergic children.

Cysteinyl-leukotrienes in the regulation of β2-adrenoceptor function: an in vitro model of asthma

BackgroundThe response to β2-adrenoceptor agonists is reduced in asthmatic airways. This desensitization may be in part due to inflammatory mediators and may involve cysteinyl-leukotrienes (cysteinyl-LTs). Cysteinyl-LTs are pivotal inflammatory mediators that play important roles in the pathophysiology of asthma, allergic rhinitis, and other inflammatory conditions. We tested the hypothesis that leukotriene D4 (LTD4) and allergen challenge cause β2-adrenoceptor desensitization through the activation of protein kinase C (PKC).MethodsThe isoproterenol-induced cAMP accumulation was evaluated in human airway smooth muscle cell cultures challenged with exogenous LTD4 or the PKC activator phorbol-12-myristate-13-acetate with or without pretreatments with the PKC inhibitor GF109203X or the CysLT1R antagonist montelukast. The relaxant response to salbutamol was studied in passively sensitized human bronchial rings challenged with allergen in physiological salt solution (PSS) alone, or in the presence of either montelukast or GF109203X.ResultsIn cell cultures, both LTD4 and phorbol-12-myristate-13-acetate caused significant reductions of maximal isoproterenol-induced cAMP accumulation, which were fully prevented by montelukast and GF109203X, respectively. More importantly, GF109203X also prevented the attenuating effect of LTD4 on isoproterenol-induced cAMP accumulation. In bronchial rings, both montelukast and GF109203X prevented the rightward displacement of the concentration-response curves to salbutamol induced by allergen challenge.ConclusionLTD4 induces β2-adrenoceptor desensitization in human airway smooth muscle cells, which is mediated through the activation of PKC. Allergen exposure of sensitized human bronchi may also cause a β2-adrenoceptor desensitization through the involvement of the CysLT1R-PKC pathway.

Bronchodilator effects of exercise hyperpnea and albuterol in mild-to-moderate asthma

In asthmatic patients, either bronchodilatation or bronchoconstriction may develop during exercise. In 18 patients with mild-to-moderate asthma, we conducted two studies with the aims to 1) quantify the bronchodilator effect of hyperpnea induced by incremental-load maximum exercise compared with effects of inhaled albuterol (study 1, n=10) and 2) determine the time course of changes in airway caliber during prolonged constant-load exercise (study 2, n=8). In both studies, it was also investigated whether the bronchodilator effects of exercise hyperpnea and albuterol are additive. Changes in airway caliber were measured by changes in partial forced expiratory flow. In study 1, incremental-load exercise was associated with a bronchodilatation that was approximately 60% of the maximal bronchodilatation obtainable with 1,500 microg of albuterol. In study 2, constant-load exercise was associated with an initial moderate bronchodilatation and a late airway renarrowing. In both studies, premedication with inhaled albuterol (400 microg) promoted sustained bronchodilatation during exercise, which was additive to that caused by exercise hyperpnea. In conclusion, in mild-to-moderate asthmatic individuals, hyperpnea at peak exercise was associated with a potent yet not complete bronchodilatation. During constant-load exercise, a transient bronchodilatation was followed by airway renarrowing, suggesting prevalence of constrictor over dilator effects of hyperpnea. Finally, the bronchodilator effect of hyperpnea was additive to that of albuterol.

Choosing wisely: practical considerations on treatment efficacy and safety of asthma in the elderly

The prevalence of asthma in the most advanced ages is similar to that of younger ages. However, the concept that older individuals may suffer from allergic asthma has been largely denied in the past, and a common belief attributes to asthma the definition of “rare” disease. Indeed, asthma in the elderly is often underdiagnosed or diagnosed as COPD, thus leading to undertreatment of improper treatment. This is also due to the heterogeneity of clinical and functional presentations of geriatric asthma, including the partial loss of reversibility and the lower occurrence of the allergic component in this age range. The older asthmatic patients are also characterized the coexistence of comorbid conditions that, in conjunction with age-associated structural and functional changes of the lung, may contribute to complicate the management of asthma. The current review addresses the main issues related to the management of allergic asthma in the geriatric age. In particular, the paper aims at revising current pharmacological and non pharmacological treatments for allergic asthmatics of advanced ages, primarily focusing on their safety and efficacy, although most behaviors are an arbitrary extrapolation of what has been tested in young ages. In fact, age has always represented an exclusion criterion for eligibility to clinical trials. Experimental studies and real life observations specifically testing the efficacy and safety of therapeutic approaches in allergic asthma in the elderly are urgently needed.

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.

Airway responses to methacholine and exercise at high altitude in healthy lowlanders

Peribronchial edema has been proposed as a mechanism enhancing airway responses to constrictor stimuli. Acute exposure to altitude in nonacclimatized lowlanders leads to subclinical interstitial pulmonary edema that lasts for several days after ascent, as suggested by changes in lung mechanics. We, therefore, investigated whether changes in lung mechanics consistent with fluid accumulation at high altitude within the lungs are associated with changes in airway responses to methacholine or exercise. Fourteen healthy subjects were studied at 4,559 and at 120 m above sea level. At high altitude, both static and dynamic lung compliances and respiratory reactance at 5 Hz significantly decreased, suggestive of interstitial pulmonary edema. Resting minute ventilation significantly increased by approximately 30%. Compared with sea level, inhalation of methacholine at high altitude caused a similar reduction of partial forced expiratory flow but less reduction of maximal forced expiratory flow, less increments of pulmonary resistance and respiratory resistance at 5 Hz, and similar effects of deep breath on pulmonary and respiratory resistance. During maximal incremental exercise at high altitude, partial forced expiratory flow gradually increased with the increase in minute ventilation similarly to sea level but both achieved higher values at peak exercise. In conclusion, airway responsiveness to methacholine at high altitude is well preserved despite the occurrence of interstitial pulmonary edema. We suggest that this may be the result of the increase in resting minute ventilation opposing the effects and/or the development of airway smooth muscle force, reduced gas density, and well preserved airway-to-parenchyma interdependence.