Elena Battistini

Dissociation between exhaled nitric oxide and hyperresponsiveness in children with mild intermittent asthma

BACKGROUND Bronchial hyperresponsiveness and airway inflammation are distinctive features of asthma. Evaluation of nitric oxide (NO) levels in expired air have been proposed as a reliable method for assessing the airway inflammatory events in asthmatic subjects. A study was undertaken to evaluate whether airway hyperresponsiveness is related to levels of exhaled NO. METHODS Thirty two steroid-naive atopic children with mild intermittent asthma of mean (SD) age 11.8 (2.3) years and 28 age matched healthy controls were studied to investigate whether baseline lung function or airway hyperresponsiveness is related to levels of exhaled NO. Airway responsiveness was assessed as the dose of methacholine causing a 20% decrease in forced expiratory volume in one second (FEV1) from control (PD20 methacholine) and exhaled NO levels were measured by chemiluminescence analysis of exhaled air. RESULTS At baseline asthmatic children had significantly higher NO levels than controls (mean difference 25.87 ppb (95% CI 18.91 to 32.83); p<0.0001) but there were no significant differences in lung function parameters (forced vital capacity (FVC), FEV1 (% pred), and forced expiratory flows at 25–75% of vital capacity (FEF25–75%)). In the asthmatic group exhaled NO levels were not significantly correlated with baseline lung function values or PD20 methacholine. CONCLUSIONS These results suggest that levels of exhaled NO are not accurate predictors of the degree of airway responsiveness to inhaled methacholine in children with mild intermittent asthma.

Exhaled nitric oxide levels in non-allergic and allergic mono- or polysensitised children with asthma

BACKGROUND Increased fractional exhaled NO concentrations (Feno) and blood/tissue eosinophilia are frequently reported in allergic children with mild asthma and are thought to reflect the intensity of the inflammation characterising the disease. The aim of this study was to investigate possible differences in Feno levels or in the intensity of the blood eosinophilia in allergic and non-allergic asthmatic children. METHODS 112 children with stable, mild, intermittent asthma with a positive bronchial challenge to methacholine were consecutively enrolled in the study; 56 were skin prick test and RAST negative (non-sensitised) while 56 were sensitised to house dust mites (23 only to house dust mites (monosensitised) and 33 were sensitised to mites and at least another class of allergens (pollens, pet danders, or moulds)). Nineteen sex and age matched healthy children formed a control group. RESULTS Compared with non-allergic patients, allergic children had a significantly higher rate of blood eosinophilia (p=0.0001) with no differences between mono- and polysensitised individuals. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), forced expiratory flow at 25–75% of vital capacity (FEF25–75%), and the degree of bronchial reactivity to methacholine were similar in non-atopic and atopic children, with no differences between mono- and polysensitised individuals. Feno levels measured by chemiluminescence analyser were higher in asthmatic children (15.9 (14.3) ppb) than in the control group (7.6 (1.6) ppb, p=0.04) and higher in allergic patients (23.9 (2.1) ppb) than in non-allergic patients (7.9 (0.8) ppb, p=0.0001), but there were no differences between mono- and polysensitised individuals (p>0.1). Significant correlations between blood eosinophilia and Feno levels were seen only in allergic (r=0.35, p<0.01) and in polysensitised individuals (r=0.45, p<0.05). CONCLUSIONS In children with mild asthma, a similar degree of functional disease severity may be associated with a higher inflammatory component in allergic than in non-allergic subjects.

Relationship between body mass index and asthma characteristics in a group of Italian children and adolescents

The prevalence of asthma and obesity, two often associated conditions, is influenced not only by age and gender but also by lifestyle factors. This study aimed to determine whether, in a Mediterranean northern Italian region, Liguria, an increased prevalence of obesity could be detected in asthmatic children and adolescents and to evaluate the possible relationship between body mass index (BMI) and the characteristics and/or severity of asthma. BMI was determined in 554 asthmatic subjects (2.2-16.1 years) and 625 age-matched controls; BMI was expressed as a continuous variable in standard deviation score (SDS) units, determined as difference between the individual observed value and the reference mean for age and sex, divided by the corresponding standard deviation (BMI-SDS). Overweight/obesity was set at BMI-SDS of 2 or more. BMI-SDS was significantly higher in controls than in asthmatics (p = 0.04); however, the proportion of overweight/obesity subjects (BMI-SDS > or = 2) was similar in controls and in asthmatic patients (p = 0.08). Evaluation of the asthmatic group revealed that BMI-SDS was independent of gender (p = 0.57), atopic sensitization (p = 0.69), and comorbidity with other allergic symptoms (p = 0.60). By contrast, BMI-SDS was lower in preschool-age children than in school-age children and adolescents (p < 0.0001), in subjects with a high rate of acute respiratory tract infections (p = 0.04), and in those not treated with inhaled corticosteroids (IGCs) (p = 0.02). Although an increase in the prevalence of overweight/obesity was not detected in asthmatic children and adolescents, the results reported here suggest a preventive surveillance of calorie intake and a promotion of physical activity in children requiring long-term treatment with inhaled glucocorticosteroids.

Steroid-Naive Adolescents with Mild Intermittent Allergic Asthma Have Airway Hyperresponsiveness and Elevated Exhaled Nitric Oxide Levels

Although atopic asthma symptoms often seem to disappear around puberty, subjects in this age group may experience unexpected, often severe, asthma attacks. This may be related to persistence of untreated airway hyperresponsiveness/inflammation in a life period characterized by low perceptiveness of disease-related symptoms. This study was designed to evaluate the prevalence and the severity of bronchial hyperreactivity and the exhaled nitric oxide (FENO) levels in a group of steroid-naive asthmatic adolescents. Fifty-two patients with mild-intermittent asthma were studied, ages 12 to 16, sensitized to house dust mites; 22 age-matched controls, were also studied. Asthma patients showed FEV1, FEF25–75%, and FVC values not significantly different from controls, (p>0.05, each comparison). By contrast, although none of the control subjects showed bronchial hyperreactivity, increased airway responsiveness to methacholine (MCh) was demonstrated in the majority of the patients and found to be severe in 36.5% (MCh PD20 ≥ 400 µg or accumulative dose ≤1220 µg) and moderate in 32.7% (MCh PD20 400–1400 µg or accumulative dose 1220–4620 µg). In addition, FENO concentrations were significantly higher in asthmatics, as compared with controls (20.4 ± 5.3 ppb and 4.4 ± 0.7 ppb, respectively; p<0.01) and 83% of the patients had FENO levels higher than 8.9 ppb (i.e., >2 standard deviations of the mean in control subjects). A positive, statistically significant correlation was found between FEF25–75% values and MCh PD20 (r = 0.358; p<0.01) or MCh accumulative dose (r = 0.355; p<0.05). No correlations were demonstrated between MCh responsiveness and FVC or FEV1 values or FENO levels and between FENO levels and pulmonary function parameters (p>0.05). The high incidence of bronchial hyperresponsiveness to MCh and of airway inflammation (as demonstrated by the elevated FENO levels) in adolescents with mild asthma suggests the need for more accurate evaluation and, possibly, for early intervention with antiinflammatory drugs in a significant proportion of patients in this age group.

Time-dependent changes in orally exhaled nitric oxide and pulmonary functions induced by inhaled corticosteroids in childhood asthma

Exhaled nitric oxide levels are elevated in asthmatic children and decrease after inhaled steroid treatment. We evaluated the time-dependent changes in fractional exhaled nitric oxide concentration (FENO) and pulmonary function parameters following inhaled steroid therapy. Thirty-nine steroid-naive atopic patients (age 11.92 ± 0.48 years) with mild intermittent asthma and 22 age-matched healthy controls were enrolled in the study; pulmonary functions and FENO levels were measured. Low doses of inhaled steroids were prescribed to all asthmatic patients who were reevaluated in a second visit (between 10 and 40 days after the beginning of the treatment). At the enrolment, asthmatic patients had similar forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) values (p > 0.05) but reduced forced expiratory flows at 25–75% of the vital capacity (FEF25–75%) values, as compared to controls (p < 0.05). In addition, FENO levels were significantly higher in asthmatics with respect to control subjects (30.8 ± 3.0 and 4.0 ± 0.5 ppb, respectively; p < 0.01). All asthmatics had FENO levels higher than 8.8 ppb (i.e., >2 standard deviations of the mean in controls). After steroid treatment, patients showed significant improvement of FEV1, FVC, and FEF25–75% (p = 0.0001; each comparison) and a reduction of FENO levels (p = 0.0001). A weak significant correlation was found between percent decrease in FENO levels and percent increase in FEV1 (r = 0.33, p = 0.04) or in FEF25–75% (r = 0.4, p = 0.01) after treatment. When changes in FENO levels and in pulmonary function parameters were corrected for days of treatment, significant correlations were still present between percent decrease in FENO levels and percent increase in FEV1 (r = 0.57, p = 0.0004) or percent increase in FEF25–75% (r = 0.45, p = 0.006). Sixteen of the 39 asthmatic patients were evaluated on two occasions after the beginning of treatment, at days 10 and 40. The significant reduction in FENO levels (p < 0.01) and the significant increase in FEV1 and FEF25–75% values observed (p < 0.05) after 10 days did not further improve at day 40. These data show that it is possible to demonstrate early effects of low-dose inhaled steroids in asthmatic children using objective measurements of airway caliber and inflammation.

IgE in childhood asthma: relevance of demographic characteristics and polysensitisation

Background Despite the therapeutic efficacy of the anti-IgE monoclonal antibody, the role of IgE in allergic asthma is still a matter of debate. This may be mostly relevant in childhood, where a wide range of total serum (s) IgE levels is often detected. Aim To evaluate whether the relationships between total or allergen-specific sIgE levels and the clinical markers of allergic inflammation and the pulmonary function values might be affected by the demographic characteristics of the patients or by the presence of multiple sensitisations to allergens. Methods 64 asthmatic children sensitised to house dust mites (HDM) were evaluated. The role of age, sex and multiple sensitisations was evaluated by multiple regression model (MRM) analysis. Results Total and HDM-specific sIgE levels (Log) showed similar moderate-to-strong correlations with exhaled nitric oxide (FENO) and blood eosinophilia (Log) (p<0.0001) but not with forced vital capacity, forced expiratory volume in 1 s (FEV1), %FEV1 change after salbutamol. The positive associations between total sIgE levels and Log FENO levels or Log blood eosinophilia were also detected by MRM analysis. Age brought a negative, although limited, contribution to FENO levels and blood eosinophilia (p<0.043). Positive similar associations were also detected between HDM-specific sIgE levels and FENO levels or blood eosinophilia; however, no significant contribution of age or of other covariates was detected. Conclusion In childhood allergic asthma, total and HDM-specific sIgE levels are tightly linked to markers of allergic inflammation but not to pulmonary functions. These relationships are weakly affected by age but not by sex or by the presence of multiple sensitisations.

Gastroesophageal reflux and its clinical manifestation at gastroenteric and respiratory levels in childhood: physiology, signs and symptoms, diagnosis and treatment

Gastroesophageal reflux (GER) is a physiological process occurring with different frequency and characteristics in healthy infants, children and adults, most episodes being brief and asymptomatic. By contrast, GER disease (GERD) occurs when this normal event results in the occurrence of symptoms/signs or complications involving the upper portion of the gastroenteral tract and the respiratory system. Transient relaxations of the lower esophageal sphincter represent the major mechanism responsible for reflux episodes, possibly associated with gastroesophageal dysfunctional motility, excessive gastric acid secretion or anatomic abnormalities. The diagnosis of GERD, that is, a causal relationship between reflux and GERD symptoms, may be difficult to determine and make clinically, with support needed from diagnostic evaluations, and final confirmation by response to treatment. Management of GER/GERD should follow a stepwise approach: lifestyle modifications, pharmacologic therapy and surgical procedures; some of these steps may occur simultaneously. In children with mild symptoms and without anatomic abnormalities, the initial choice should be lifestyle modifications and pharmacologic therapy with prokinetic agents, antacids and histamine-2-receptor antagonists. For severe GERD, therapeutic options include proton pump inhibitors and antireflux surgery. In determining the best approach for each individual patient, efficacy, safety, morbidity, compliance and cost must be considered.

Determinants of Exhaled Nitric Oxide Levels (FeNO) in Childhood Atopic Asthma: Evidence for Neonatal Respiratory Distress as a Factor Associated With Low FeNO Levels

Background. In allergic asthmatic children exhaled nitric oxide (FeNO) levels are related to eosinophilic inflammation by correlation analysis. Whether FeNO can be modified by factors potentially influencing the natural history of asthma in early life is not known. Objective. To evaluate the frequency of anamnestic factors influencing the natural history of asthma and to identify potential determinants for elevated or low FeNO levels by multivariate analysis. Methods. One hundred seventy-one children with mild-moderate asthma were stratified according to their FeNO levels into three groups: low (<20 ppb), mid (20–40 ppb), and high (>40 ppb). The frequency of nine anamnestic factors together with indices of allergic sensitization (total and allergen-specific immunoglobulin E [IgE], blood eosinophil counts) and of airflow limitation (forced expiratory volume in one second [FEV1]% predicted) were evaluated. Results. Among factors related to the patient history, neonatal respiratory distress was reported only in children with low FeNO levels, whereas this factor was never reported in children with mid-to-high FeNO levels (p = .008). As compared with low FeNO group, mid and high FeNO groups showed higher eosinophil counts and a tendency to have lower FEV1 values. By multivariate analysis, four factors (eosinophils >300 cells/mm3, cat-specific IgE, house dust mites [HDM]-specific IgE, FEV1 ≤86% predicted) turned out to be significantly associated with mid-high FeNO levels and two factors (eosinophils >600 cells/mm3, total IgE >355 kU/L) with high FeNO levels. Conclusions. Besides confirming the well-known tight association between blood eosinophilia and/or allergic sensitization and FeNO, these data provide new evidence for neonatal respiratory distress as potential factor associated with low FeNO levels in childhood atopic asthma.

Intermittent gaseous bowel distention: atypical sign of congenital tracheoesophageal fistula.

Three girls, 5‐, 9‐, and 15‐year‐old, were evaluated for recurrent airway infections and pneumonia. Chest X‐rays, which included the upper portion of the abdomen, showed marked gaseous bowels distention, while computed tomography scans of the chest demonstrated the presence of tracheoesophageal fistula (TEF), confirmed by fiberoptic bronchoscopy. Abdominal gaseous distension, a known possible clinical manifestation of TEF in the neonatal period generated by airflow through the fistula into the oesophagus, has not been reported as a clue to the diagnosis in older children. When detected in patients with recurrent respiratory infection, should raise the suspicion of unrecognized TEF. Pediatr Pulmonol. 2009; 44:244–248.

e-NO peak versus e-NO plateau values in evaluating e-NO production in steroid-naive and in steroid-treated asthmatic children and in detecting response to inhaled steroid treatment.

Summary. Airway nitric oxide (NO) production can be measured by chemiluminescence analyzer in children able to perform a single low exhalation. The aim of the present study was to evaluate whether exhaled NO (e‐NO) peaks (first part of the exhalation) were as useful as e‐NO plateaus (last part of the exhalation) in evaluating e‐NO production in asthmatic children and in detecting responses to inhaled steroid treatment. E‐NO peak, plateau, and rate of production values were measured in 100 atopic asthmatic children using a chemiluminescence analyser. Thirty‐seven patients (mean age, 11.1 ± 0.7 years) were receiving inhaled steroids (flunisolide, 0.8–1 mg daily) or beclomethasone (0.2–0.4 mg daily), while the remaining 63 (mean age, 12.0 ± 0.4 yrs) were‐steroid naive and treated only with inhaled β2‐agonists on an as‐needed basis. Fifteen out of the 63 steroid‐naive patients were reevaluated after a short course (3 weeks) of inhaled corticosteroid treatment (flunisolide, 0.8–1 mg daily, or beclomethasone, 0.2–0.4 mg daily).