Noninvasive methods for the detection of upper and lower airway inflammation in atopic children.

BACKGROUND: Exhaled nitric oxide (FE(NO)) and exhaled breath condensate (EBC) are noninvasive methods to assess inflammation. OBJECTIVE: To investigate the role of the FE(NO) and of the EBC pH and IL-5 levels in atopic children. METHODS: We evaluated oral and nasal FE(NO) and the pH and IL-5 of oral and nasal EBC in children with atopic dermatitis (AD; n = 18), allergic rhinitis (AR; n = 18), intermittent asthma (n = 21), moderate persistent asthma (n = 18), and healthy controls (HCs; n = 16). RESULTS: Oral FE(NO) was significantly increased in asthma, whereas the nasal values were increased in AR and asthma in comparison with HCs. The pH of oral EBC was lower in AD and asthma than in AR and HCs, whereas the nasal levels were lower in AD, AR, and asthma than in HCs. The oral IL-5 was higher in AD, AR, and asthma in comparison with HCs, whereas the nasal IL-5 concentrations were higher in asthma and AR than in HCs. In AR, the nasal FE(NO) correlated with the IL-5 values and with the disease duration. In intermittent asthma, oral and nasal pH inversely correlated with the exacerbations, whereas in moderate asthma, the nasal IL-5 positively correlated with exacerbations. In AD, the oral and nasal IL-5 positively correlated with the serum IgE. CONCLUSION: These markers of nasal and bronchial inflammation, accessible with noninvasive techniques, might be useful to identify patients with uncontrolled diseases and to verify the usefulness of new therapeutic approaches. CLINICAL IMPLICATIONS: These markers are useful tools to monitor the upper and lower airway inflammation in atopic children.

Methylation profile in tumor and sputum samples of lung cancer patients detected by spiral computed tomography: a nested case-control study.

We evaluated the aberrant promoter methylation profile of a panel of 3 genes in DNA from tumor and sputum samples, in view of a complementary approach to spiral computed tomography (CT) for early diagnosis of lung cancer. The aberrant promoter methylation of RARbeta2, p16(INK4A) and RASSF1A genes was evaluated by methylation-specific PCR in tumor samples of 29 CT-detected lung cancer patients, of which 18 had tumor-sputum pairs available for the analysis, and in the sputum samples from 112 cancer-free heavy smokers enrolled in a spiral CT trial. In tumor samples from 29 spiral CT-detected patients, promoter hypermethylation was identified in 19/29 (65.5%) cases for RARbeta2, 12/29 (41.4%) for p16(INK4A) and 15/29 (51.7%) for RASSF1A. Twenty-three of twenty-nine (79.3%) samples of the tumors exhibited methylation in at least 1 gene. In the sputum samples of 18 patients, methylation was detected in 8/18 (44.4%) for RARbeta2 and 1/18 (5%) for both RASSF1A and p16(INK4A). At least 1 gene was methylated in 9/18 (50%) sputum samples. Promoter hypermethylation in sputum from 112 cancer-free smokers was observed in 58/112 (51.7%) for RARbeta2 and 20/112 (17.8%) for p16, whereas methylation of the RASSF1A gene was found in only 1/112 (0.9%) sputum sample. Our study indicates that a high frequency of hypermethylation for RARbeta2, p16(INK4A) and RASSF1A promoters is present in spiral CT-detected tumors, whereas promoter hypermethylation of this panel of genes in uninduced sputum has a limited diagnostic value in early lung cancer detection.

Association between reduced bronchodilatory effect of deep inspiration and loss of alveolar attachments.

BACKGROUND: We have previously shown that the bronchodilatory effect of deep inspiration is attenuated in individuals with COPD. This study was designed to investigate whether the impairment in this effect is associated with loss of alveolar attachments. METHODS: We measured deep inspiration (DI)-induced bronchodilation in 15 individuals with and without COPD (67 +/- 2.2 yrs of age, mean +/- SEM) undergoing lobar resection for peripheral pulmonary nodule. Prior to surgery, we measured TLCO and determined the bronchodilatory effect of deep inspiration after constricting the airways with methacholine. The number of destroyed alveolar attachments, as well as airway wall area and airway smooth muscle area, were determined in tumor-free, peripheral lung tissue. RESULTS: The bronchodilatory effect of deep inspiration correlated inversely with the % destroyed attachments (r = -0.51, p = 0.05) and directly with the airway smooth muscle area (r = 0.59, p = 0.03), but not with the total wall area (r = 0.39, p = 0.15). CONCLUSION: We postulate that attenuation of airway stretch due to loss of alveolar attachments contributes to the loss of the bronchodilatory effect of lung inflation in COPD.

The bronchodilatory effect of deep inspiration diminishes with aging.

Deep inspirations have the ability to dilate constricted airways. The impairment of this function has been associated with the occurrence of asthmatic symptoms. We evaluated whether the bronchodilatory effect of deep inspiration (DI) is affected by aging. We tested 25 healthy subjects (median age: 54 yrs, range: 25-83 yrs). Single dose methacholine (Mch) provocations were performed in the absence of DI, which induced at least 15% reduction in inspiratory vital capacity (IVC) from baseline. The post-Mch IVC measurement was followed by 4 DIs and by another IVC (post-DI IVC). The fractional difference between post-DI IVC and post-Mch IVC represented the % bronchodilation by DI. The % bronchodilation significantly diminished with aging (r=0.65, P=0.0005). The bronchodilatory ability of DI was also positively associated with the degree of Mch-induced reduction in IVC (r=0.84, P<0.0001). In multiple regression analysis, where % bronchodilation was the dependent variable, both % reduction in IVC (P<0.0001) and age (P=0.02) entered the model. Our data raise the hypothesis that aging is associated with reduction in DI-induced bronchodilation.

PDE4 inhibitors in COPD--a more selective approach to treatment.

Chronic obstructive pulmonary disease (COPD) is a serious and mounting global public health problem. Although its pathogenesis is incompletely understood, chronic inflammation plays an important part and so new therapies with a novel anti-inflammatory mechanism of action may be of benefit in the treatment of COPD. Cilomilast and roflumilast are potent and selective phosphodiesterase (PDE)4 inhibitors, with an improved therapeutic index compared with the weak, non-selective PDE inhibitor, theophylline. Unlike theophylline, which is limited by poor efficacy and an unfavourable safety and tolerability profile, the selective PDE4 inhibitors are generally well tolerated, with demonstrated efficacy in improving lung function, decreasing the rate of exacerbations and improving quality of life, with proven anti-inflammatory effects in patients with COPD. Theophylline is a difficult drug to use clinically, requiring careful titration and routine plasma monitoring due to the risk of toxic side effects, such as cardiovascular and central nervous system adverse events, with dose adjustments required in many patients, including smokers, the elderly and some patients on concomitant medications. In contrast, the selective PDE4 inhibitors are convenient medications for both patient and physician alike. Hence these agents represent a therapeutic advance in the treatment of COPD, due to their novel mechanism of action and potent anti-inflammatory effects, coupled with a good safety and tolerability profile.

Bronchodilatory effect of deep inspiration is absent in subjects with mild COPD.

STUDY OBJECTIVES: To investigate whether the bronchodilatory effect of deep inspiration is impaired in subjects with COPD. METHODS: We measured deep inspiration-induced bronchodilation in 19 patients with COPD and 17 healthy subjects (mean age, 67.8 +/- 7.1 years vs 62.5 +/- 9.3 years, respectively [+/- SEM]). Each subject underwent a series of single-dose methacholine provocations to induce at least a 15% reduction in inspiratory vital capacity (IVC). When this was achieved, subjects were asked to perform four consecutive deep inspirations, after which the IVC measurement was repeated and the percentage of bronchodilation by deep inspiration was calculated. RESULTS: The percentage of reduction in IVC from baseline prior to the deep inspirations did not differ between the two groups (COPD, 20.1 +/- 1.6%; healthy, 22.7 +/- 2.4%; p = 0.38); median single methacholine doses employed were 20 mg/mL (range, 0.025 to 75 mg/mL) and 25 mg/mL (range, 10 to 75 mg/mL), respectively (p = 0.19). Deep inspirations were not able to reverse bronchoconstriction in patients with COPD (bronchodilation, 3.9 +/- 2.6%; p = 0.15 by one-sample t test). Bronchodilation by deep inspiration was present in healthy subjects (13.7 +/- 3.0%, p = 0.0003), and was significantly higher than that of patient with COPD (p = 0.02). In patients with COPD, deep inspiration-induced bronchodilation correlated with the percentage of predicted transfer factor of the lung for carbon monoxide (r = 0.53, p = 0.05), but not with airway obstruction, as assessed by FEV(1) or FEV(1)/FVC. CONCLUSIONS: The bronchodilatory ability of deep inspiration is lost in mild COPD. We speculate that the absence of deep inspiration-induced bronchodilation contributes to the development and severity of chronic respiratory symptoms in patients with COPD.

Clinical and biological heterogeneity in children with moderate asthma.

To evaluate the relationship between inflammatory markers and severity of asthma in children, the amount of interleukin-8 (IL-8) and granulocyte/macrophage colony-stimulating factor (GM-CSF) released by peripheral blood mononuclear cells, exhaled nitric oxide (FE NO) levels, p65 nuclear factor-kappaB subunit, and phosphorylated IkBalpha expression by peripheral blood mononuclear cells were assessed in six control subjects, 12 steroid-naives subjects with intermittent asthma, and 17 children with moderate asthma. To investigate their predictive value, biomarker levels were correlated with the number of exacerbations during a 18-month follow-up period. We found that GM-CSF release was higher in moderate and intermittent asthmatics than in control subjects, whereas IL-8 release was higher in moderate than in intermittent asthmatics and control subjects. FE NO levels were similar among study groups. In moderate asthmatics, IL-8, GM-CSF, and FE NO significantly correlated with the exacerbation numbers. Moreover, p65 and phosphorylated IkBalpha levels were greater in moderate than in intermittent asthmatics and control subjects. According to GM-CSF, IL-8, and FE NO levels, two distinct subgroups of moderate asthmatics (low and high producers) were identified. High producers experienced more exacerbations than low producers. This study shows ongoing inflammation associated with biological and clinical heterogeneity in moderate asthmatics despite regular treatment and proposes that large prospective studies confirm the importance of biomarkers to assess inflammation and asthma control in children with asthma.