Ambroxol inhibits neutrophil respiratory burst activated by alpha chain integrin adhesion.

The purpose of the present study was to investigate the possible anti-oxidant effect(s) of Ambroxol on neutrophils activated by ligand-binding of the drug with membrane-associated adhesion integrin CD11a and to estimate dose-response changes in oxygen free radical production. The amount of free radical production by anti-CD11a- and anti-CD4-coated neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine (FMLP) and challenged with increasing concentration of Ambroxol, was evaluated within a time frame of 90 minutes. A significant dose-dependent effect response of Ambroxol on O2‾ production by cells coated with anti-CD11a antibody was observed. This preliminary study opens a new perspective on the therapeutic role of Ambroxol as an antioxidant drug and for its potential use in controlling oxidative stress, particularly in leukocyte-dependent inflammation.

Timing of introduction of solid food and risk of allergic disease development: understanding the evidence.

Strategies to prevent or reduce the risk of allergic diseases are needed. The time of exclusive breastfeeding and introduction of solid foods is a key factor that may influence the development of allergy. For this reason, the aim of this review was to examine the association between exposure to solid foods in the infant's diet and the development of allergic diseases in children. Classical prophylactic feeding guidelines recommended a delayed introduction of solids for the prevention of atopic diseases. Is it really true that a delayed introduction of solids (after the 4th or 6th month) is protective against the development of eczema, asthma, allergic rhinitis and food or inhalant sensitisation? In recent years, many authors have found that there is no statistically significant association between delayed introduction of solids and protection for the development of allergic diseases. Furthermore, late introduction of solid foods could be associated with increased risk of allergic sensitisation to foods, inhalant allergens and celiac disease in children. Tolerance may be driven by the contact of the mucosal immune system with the allergen at the right time of life; the protective effects seem to be enhanced by the practice of the breastfeeding at the same time when weaning is started. Therefore, recent guidelines propose a "window" approach for weaning practice starting at the 17th week and introducing almost all foods within the 27th week of life to reduce the risk of chronic diseases such as allergic ones and the celiac disease. Guidelines emphasize the role of breastfeeding during the weaning practice.

Unusual shift from IgE-mediated milk allergy to food protein-induced enterocolitis syndrome.

Food protein-induced enterocolitis syndrome (FPIES) is a potentially severe non-IgE-mediated food allergy usually caused by cow's milk or soy, and more rarely by solid foods such as rice, oats, barley, chicken, turkey, egg white, green peas and peanuts. In children with FPIES, the presence of specific IgE antibodies to the causative food, either at presentation or during follow-up, defines an "atypical form" of FPIES characterized by a lesser probability of developing tolerance and a potential progression to typical IgE-mediated hypersensitivity. Although it is uncommon, the shift from non-IgE-mediated milk-protein induced enterocolitis syndrome to IgE-mediated milk allergy has recently been described. We report the first case, to our knowledge, of a shift from IgE-mediated cow's milk allergy to pure non-IgE-mediated FPIES, in a 4-month-old male infant.

Bronchial and alveolar nitric oxide in exercise-induced bronchoconstriction in asthmatic children.

BACKGROUND: Epidemiological studies have shown an association between the severity of exercise-induced bronchoconstriction (EIB) and fractional exhaled nitric oxide at the flow of 50 mL/s (FeNO(50)). However, no study has assessed the correlation between alveolar production (C(alv)) and bronchial flux (J(NO)) of nitric oxide (NO) and EIB in asthmatic children. OBJECTIVE: To identify the relationship between severity of EIB and bronchial or alveolar nitric oxide. METHODS: Our group included 36 allergic children with intermittent asthma. The EIB was determined by a standard exercise challenge and the severity was expressed as the maximum change in percentage from the baseline value of lung function (ΔFEV(1)%, ΔFEF(25-75)%) after exercising. A chemiluminescence analyser at multiple flows was used to calculate FeNO(50), J(NO) and C(alv,) which reflect large airways, J(NO) and alveolar concentration of NO respectively. RESULTS: Sixteen (44.4%) children presented a ∆FEV(1) ≥ 10%, eight (22.2%) had ∆FEV(1) ≥ 15% and nine (25%) children had a ∆FEF(25-75) ≥ 26%. A significant correlation was observed between severity of EIB and FeNO(50) , J(NO) and C(alv.) EIB was significantly more severe in children sensitive to indoor allergens compared with outdoor allergens only (P = 0.014); those children showed also higher levels of C(alv) (P = 0.003) and of J(NO) (P = 0.044). CONCLUSIONS AND CLINICAL RELEVANCE: Our results suggest that inflammation is present in the central and peripheral airways and that it is associated with the severity of EIB. Clinicaltrials.gov NCT00952835.

Severe chronic allergic (and related) diseases: a uniform approach--a MeDALL--GA2LEN--ARIA position paper.

Concepts of disease severity, activity, control and responsiveness to treatment are linked but different. Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow-up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria and atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as comorbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies.

Markers of oxidative stress are increased in exhaled breath condensates of children with atopic dermatitis.

BACKGROUND: Airway inflammation may be present in subjects affected by atopic dermatitis (AD) but still without asthma symptoms. Exhaled breath condensate (EBC) reflects the composition of bronchoalveolar extracellular lining fluid that contains a large number of mediators of airway inflammation and oxidative damage. OBJECTIVES: We assessed inflammatory markers in the EBC of patients with AD. Fifty-six children (34 girls and 22 boys) were enrolled: 33 affected by AD and 23 healthy controls. METHODS: EBC was collected using a condenser device. We measured EBC pH and concentrations of leukotriene B4 (LTB4), 8-isoprostane, H(2) O(2) , malondialdehyde and 4-hydroxynoneal. Respiratory resistance was also evaluated. RESULTS: EBC pH in patients with AD was significantly lower than in healthy children, median (range) being 8·02 (7·94-8·12) in AD vs. 8·11 (8·05-8·16) (P = 0·02). The values of exhaled 8-isoprostane and LTB4 were significantly increased in subjects with AD compared with normal controls (P < 0·01 and P < 0·001, respectively). There was increased 4-hydroxynoneal in patients with AD but this did not reach statistical significance. Evaluating respiratory resistance, no bronchoreversibility was demonstrated in the children with AD. CONCLUSIONS: pH, LTB4 and 8-isoprostane in EBC could be sensitive markers of airway inflammation in children with AD. Prospective studies would be of interest to evaluate if airway inflammation, not yet clinically evident, could predict the development of asthma later in life in children with AD.

Agenesis of paranasal sinuses and nasal nitric oxide in primary ciliary dyskinesia.

Agenesis of paranasal sinuses has only been described in case reports of patients with primary ciliary dyskinesia (PCD). As agenesis of paranasal sinuses may contribute to low nasal nitric oxide levels, a common finding in PCD, we speculated that this condition might frequently occur in PCD patients. Patients referred for PCD evaluation were consecutively recruited for 30 months. In addition to standard diagnostic testing for PCD, a computed tomography (CT) scan of paranasal sinuses was performed in all subjects. 86 patients (46 children aged 8-17 yrs) were studied. PCD was diagnosed in 41 subjects and secondary ciliary dyskinesia (SCD) was diagnosed in the remaining 45 subjects. Frontal and/or sphenoidal sinuses were either aplastic or hypoplastic on CT scans in 30 (73%) out of 41 PCD patients, but in only 17 (38%) out of 45 with SCD (p = 0.002). There was a significant inverse correlation between the score for aplasia/hypoplasia of each paranasal sinus and nasal NO values in the PCD patients (p = 0.008, r = -0.432) but not in SCD (p = 0.07, r = -0.271). The findings of aplasia/hypoplasia of the frontal and or sphenoidal sinuses may be part of the spectrum of PCD and this finding should prompt exclusion of this condition.

Serum vitamin D levels and exercise-induced bronchoconstriction in children with asthma.

Epidemiological studies have established a relationship between low levels of serum vitamin D and reduced lung function in healthy adults, and asthma onset and severity in children. However, no study has examined the relationship between vitamin D levels and exercise-induced bronchoconstriction in asthmatic children. We evaluated the relationship between 25-hydroxyvitamin D concentrations and baseline forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and change in FEV1 (ΔFEV1) after a standardised exercise challenge in 45 children with intermittent asthma. Only 11% of the children had desirable serum vitamin D levels (at least 30-40 ng·mL(-1)). A positive correlation was found between serum 25-hydroxyvitamin D and both FVC (r=0.34; p=0.037) and FEV1 (r=0.32; p=0.037). Subjects with a positive response to the exercise challenge (ΔFEV1≥10%) presented lower serum levels of 25-hydroxyvitamin D than children with a negative challenge (mean±sd 16.2±5.2 versus 23.4±7.0 ng·mL(-1), respectively; p=0.001). Our results indicate that hypovitaminosis D is frequent in asthmatic children who live in a Mediterranean country. In those children, lower levels of vitamin D are associated with reduced lung function and increased reactivity to exercise.

Nasal nitric oxide and nitric oxide synthase expression in primary ciliary dyskinesia.

No study has evaluated the correlation between different expression of nitric oxide synthase (NOS) isoforms in nasal epithelial cells and nasal NO (nNO) level in primary ciliary dyskinesia (PCD). Gene expression of endothelial (NOS3) and inducible NOS (NOS2) and their correlation with nNO level, ciliary function and morphology were studied in patients with PCD or secondary ciliary dyskinesia (SCD). NOS3 gene polymorphisms were studied in blood leukocytes. A total of 212 subjects were studied (48 with PCD, 161 with SCD and three normal subjects). nNO level correlated with mean ciliary beat frequency (p = 0.044; r = 0.174). The lower the nNO level the higher was the percentage of immotile cilia (p<0.001; r = -0.375). A significant positive correlation between NOS2 gene expression and nNO levels was demonstrated in all children (p = 0.001; r = 0.428), and this correlation was confirmed in patients with PCD (p = 0.019; r = 0.484). NOS2 gene expression was lower in PCD than in SCD (p = 0.04). The NOS3 isoform correlated with missing central microtubules (p = 0.048; r = 0.447). nNO levels were higher in PCD subjects with the NOS3 thymidine 894 mutation, and this was associated with a higher ciliary beat frequency (p = 0.045). These results demonstrate a relationship between nNO level, NOS mRNA expression and ciliary beat frequency.

Correlation between serum 25-hydroxyvitamin D levels and severity of atopic dermatitis in children.

BACKGROUND: Vitamin D deficiency could be associated with the prevalence of atopic dermatitis (AD). OBJECTIVES: We carried out a study to see whether deficient/insufficient levels of vitamin D correlate with the severity of atopic skin disease. METHODS: Using the SCORAD index, we evaluated the severity of disease in 37 children (17 girls and 20 boys) aged between 8 months and 12 years with AD, consecutively enrolled in the study. Serum levels of 25-hydroxyvitamin D [25(OH)D] were determined by a chemiluminescent method. Specific IgE (sIgE) to Staphylococcus aureus enterotoxins and sIgE to Malassezia furfur were assayed by the ImmunoCAP system. anova and the Pearson correlation test were used for statistical evaluation. RESULTS: We found severe, moderate and mild AD in nine (24%), 13 (35%) and 15 (41%) children, respectively. Mean ± SD serum levels of 25(OH)D were significantly higher (P < 0·05) in patients with mild disease (36·9 ± 15·7 ng mL(-1)) compared with those with moderate (27·5 ± 8·3 ng mL(-1)) or severe AD (20·5 ± 5·9 ng mL(-1)). The prevalence of patients with sIgE to microbial antigens increased in relation to vitamin D deficiency and AD severity. CONCLUSIONS: These data suggest that vitamin D deficiency may be related to the severity of AD and advocate the need for studies evaluating the use of vitamin D as a potential treatment in patients with this disease.

Perioperative allergy: clinical manifestations.

Adverse drug reactions or side effects are usually expected, dose dependent, and occur at therapeutic doses. Anaphylactic and anaphylactoid reactions are unexpected and dose independent and can occur at the first exposure to drugs used during anesthesia. Perioperative anaphylaxis is a severe and rapid clinical condition that can be lethal even in previously healthy patients. The initial diagnosis of anaphylaxis is presumptive. A precise identification of the drug responsible for the adverse reaction is more difficult to establish in the case of anaphylactoid reaction because the adverse reaction could result from additive side effects of different drugs injected simultaneously. The timing of the reaction in relation to events, e.g. induction, start of surgery, administration of other drugs, i.v. fluids, is essential for the diagnosis. Generally, reactions are predominant in the induction and recovery phases, and manifested mainly as cutaneous symptoms. Reactions to drugs coincide with the phases when they are administered. Reactions to antibiotics are more frequent in the induction phase, to neuromuscular agents in the initiation and maintenance phases and to non-steroidal anti-inflammatory agents in the recovery phase. The differential diagnosis of any adverse reaction during or following anesthesia should include the possibility of anaphylaxis.

Muscle relaxants allergy.

The most common agents that are responsible for intraoperative anaphylaxis are muscle relaxants. In fact, neuromuscular blocking agents (NMBAs) contribute to 50-70 percent of allergic reactions during anaesthesia. The main mechanism of hypersensitivity reactions to NMBAs is represented by acute type I allergic reactions and the most severe form is anaphylaxis. The rate of non IgE mediated immediate hypersensitivity reactions usually varies between 20 percent and 35 percent of the reported cases in most large series. In a recent report, non allergic suspected reactions to NMBAs occurred with almost the same frequency as did those with an allergic component. Although the precise mechanisms of these reactions remain difficult to ascertain, they usually result from direct non specific mast cell and basophil activation. After diagnostic procedures, regardless of the specific IgE results, NMBAs are contraindicated if the skin tests were positive. In view of the constantly evolving anesthesiologic practices, and of the complexity of allergy investigation, an active policy to identify patients at risk and to provide any necessary support to anaesthetists and allergologists should be promoted. The high frequency of IgE anaphylactic reactions and the feasibility of skin tests in children justify systematic allergy testing whenever hypersensitivity reaction occurs during general anaesthesia.

A comparison between IgE and IgG4 as markers of allergy in children: an experimental trial in a model of natural antigen avoidance.

IgG4 have been hypothesized to act as blocking antibodies capable of preventing IgE-mediated effector cell triggering. This study aims to evaluate the changes in IgG4 in children during a period of natural antigen avoidance. Serum IgE and IgG4 were evaluated in a group of asthmatic children, aged between 7 and 17 years, admitted to the residential house Istituto Pio XII (Misurina, BL, Italy), located at 1,756 m, in a natural model of antigen avoidance. All the patients were skin prick test positive to at least two of the following allergens: Dermatophagoides pteronissynus, Dermatophagoides farinae, cat epithelium, timothy grass pollen and Parietaria pollen. During the 180 days of hospitalization, serum specific IgE and IgG4 were measured six times. A significant decrease (p≤0.05) in serum specific IgE to house dust mite and pollen allergens was observed; by contrast, no significant variations were shown by IgG4 and IgG4/IgE ratio. No significant relationship was found between serum specific IgE, IgG4 and IgG4/IgE ratio variations and the re-exposure to house dust mite allergens during the Christmas holidays. A positive correlation between specific IgE and specific IgG4 was observed at each considered time (T0: r=0.57, p=0.08; T1: r=0.85, p=0.001; T3: r=0.76, p=0.01). The positive correlation between specific IgE and specific IgG4, enduring throughout the entire time of study, suggests a relationship between these classes of immunoglobulins.

Health-related quality of life and unmet needs in patients with primary ciliary dyskinesia.

Few studies have evaluated the quality of life of patients with primary ciliary dyskinesia (PCD). We sought to determine the health impact of the disease as well as the unmet needs in a large group of patients. Questionnaires were either posted or e-mailed to known patients with PCD and published online. Questionnaires included the St George's Respiratory Questionnaire, the Medical Outcomes Study Short Form-36 and a questionnaire that we produced to obtain information on age of diagnosis, symptoms and likely PCD-specific problems of these patients. 78 subjects (96% of those invited) answered all the questionnaires. Patients were diagnosed at a mean age of 9.4 yrs. Progressive worsening of the disease was observed and adherence to physiotherapy was found to be poor, particularly in adolescents and adults. Patients with the highest treatment burden had a worse quality of life. Over time patients become progressively less interested in treating their disease and adherence to treatment modalities decreases. PCD is associated with a progressive and continuous impact on the physical and mental health of the patients. Earlier identification of the patients and better strategies aimed at improving compliance with care are urgently needed.

Asthma and obesity in childhood: on the road ahead.

Epidemiological data show a link between asthma and obesity, suggesting many different mechanisms that may underlie the association. However, diagnosis of asthma is often self-reported by patients or caregivers. Definition of asthma is crucial, particularly in childhood. Obesity can be associated with symptoms commonly attributed to asthma, such as wheezing, dyspnoea and sleep apnoea. Obese subjects are less fit and may have more frequent bouts of breathlessness on exertion accompanied by an exaggerated symptom perception. Therefore, the link between the two diseases should be analysed by focusing not only on reported diagnosis of asthma but also on objective markers that can better characterize the asthma phenotype. These markers should include lung function parameters, bronchial hyper-reactivity, atopic sensitization and indices of lung inflammation. As we look back and move forward, a multidisciplinary approach is increasingly necessary to understand the complexity of obesity and asthma, keeping in mind that diet and exercise could influence both diagnosis and treatment. In the meantime, in clinical settings, physicians should be cautious about diagnosing asthma in obese children on the basis of self-reported symptoms alone and should confirm the diagnosis by using objective measurements and marker evaluations that can better identify asthma phenotype and exclude overdiagnosis.

Nasal nitric oxide levels in healthy pre-school children.

The evaluation of nasal nitric oxide (nNO) has been proposed as a screening tool in children with clinically suspectable primary ciliary dyskinesia. Nevertheless, normal values have been reported for school-aged children. This study was designed to identify normal nNO levels in pre-school children. nNO was assessed in 300 healthy children aged between 1.5 and 7.2. Two hundred and fifty of them were unable to fulfill the guideline requirements for nNO measurement and were assessed by sampling the nasal air continuously with a constant trans-nasal aspiration flow for 30 s during tidal breathing. For those children who were able to cooperate, the average nNO concentration was calculated according to guidelines. A statistically significant relationship between nNO level and age was demonstrated in this study group of pre-school children (p < 0.001). An increase in nNO of about 100 ppb was observed in children older than 6 yr vs. those aged < 3. This study presents a description of normal nNO values in pre-school children. The effect of the age and the eventual presence of rhinitis and snoring need to be considered whenever nNO is evaluated in the clinical practice, in particular in non-cooperative children.

Upper respiratory tract infections and atopy.

Upper respiratory tract infections and allergic diseases are particularly common in children. It seems that atopy may predispose to more severe symptoms during infections and may facilitate together with other genetic factors and with adverse environmental conditions the occurrence of chronic rhinosinusitis (CRS) and chronic otitis media with effusion (OME). The initial event in CRS is the obstruction of the osteomeatal complex, while obstruction and dysfunction of the Eustachian tube may be the preliminary event for the development of OME.

Simplified cell culture method for the diagnosis of atypical primary ciliary dyskinesia.

BACKGROUND: The diagnosis of primary ciliary dyskinesia (PCD) can be challenging, and it may be particularly difficult to distinguish primary ciliary disease from the secondary changes after infections. OBJECTIVES: The purpose of the study was to evaluate if nasal epithelial cells, obtained with nasal brushing instead of a biopsy, could be used in a culture system for the diagnosis of PCD in difficult cases. METHODS AND MAIN RESULTS: Ciliary motion analysis (CMA) and transmission electron microscopy (TEM) were performed on 59 subjects with persistent or recurrent pneumonia. These investigations allowed the diagnosis of PCD in 13 (22%) patients while the defect of the cilia was considered secondary to infections in 37 (63%) subjects. In the remaining nine (15%) patients the diagnostic evaluation with CMA and TEM remained inconclusive. Ciliogenesis in culture allowed the diagnosis of PCD in four of these patients, it was indicative of a secondary defect in two subjects, and it was not helpful in the remaining three patients. CONCLUSIONS: Culture of cells obtained with brushing of the nasal turbinate is not a perfect test, nevertheless it may offer diagnostic help in doubtful cases of PCD.

Medicines used in respiratory diseases only seen in children.

Detailed literature searches were carried out in seven respiratory disease areas. Therapeutic evidence for efficacy of medicinal products was assessed using the Grades of Recommendation, Assessment and Evaluation (GRADE) methodology, as well as an assessment of safety and side-effects. Systemic corticosteroids may reduce the development of bronchopulmonary dysplasia but have serious side-effects. Antioxidants need further study to demonstrate whether they have long-term benefits. Treatments for acute bronchiolitis have shown little benefit but new antiviral and monoclonal antibodies need further assessment. Well-constructed studies are needed to confirm the value of inhaled corticosteroids and/or montelukast in the management of viral-induced wheeze. Corticosteroids are the treatment of choice in croup. Minimal or no information is available for the treatment of congenital lung abnormalities, bronchiolitis obliterans and interstitial lung disease.

Childhood Asthma Control Test and airway inflammation evaluation in asthmatic children.

BACKGROUND: The Childhood Asthma Control Test (C-ACT) has been proposed as a tool in assessing the level of disease control in asthmatic children. To evaluate the position of C-ACT in the clinical management of asthmatic children, in relationship to the level of airway inflammation as assessed by fractional exhaled nitric oxide (FeNO) and with lung function. METHODS: A total of 200 asthmatic children were included in the study: 47 children with newly diagnosed asthma ('New') and without any regular controller therapy; and 153 children with previously diagnosed asthma, treated according to GINA guidelines, and evaluated during a scheduled follow-up visit ('Follow-up'). Childhood Asthma Control Test, FeNO and lung function [forced expiratory volume 1 (FEV1) and forced vital capacity (FVC)] were evaluated. RESULTS: In New vs Follow-up participants, C-ACT score (P < 0.001), FVC (P < 0.005) and FEV1 (P < 0.05) were significantly lower, and FeNO (P = 0.011) were significantly higher. In New, but not in Follow-up participants, significant correlations were observed between C-ACT score and FeNO (r = -0.51; P < 0.001), FEV1 (r = 0.34; P = 0.022) and FEV1/FVC (r = 0.32; P = 0.03). This lack of correlation in Follow-up visits seemed attributable to dissociation between inadequately controlled asthma by C-ACT ratings with normalization of other measures such as FeNO levels. CONCLUSIONS: This study confirms and expands the concept that C-ACT is complementary to, but not a substitute for, other markers of disease control in asthmatic children, especially in the context of follow-up visits.