Airway inflammatory profile is correlated with symptoms in stable COPD: A longitudinal proof-of-concept cohort study.

BACKGROUND AND OBJECTIVE: Symptoms negatively impact the quality of life and long-term prognosis of patients with chronic obstructive pulmonary disease (COPD). Little is known about the relationship linking airway inflammation and symptoms in stable COPD. In this study, we evaluated whether respiratory symptoms in COPD are related to sputum inflammatory cellular profile and whether symptom changes are associated with changes in airway inflammation. METHODS: A total of 40 patients with stable COPD with moderate-to-severe airflow obstruction were enrolled. Patients were visited weekly over 4 weeks. At each visit, patients underwent clinical assessments, lung function tests and sputum induction. Patients recorded daily dyspnoea, sputum and cough scores. RESULTS: The changes between two consecutive visits in the percent of sputum neutrophils and eosinophils were related to the changes in the cough (P < 0.001; r = 0.63) and dyspnoea scores (P < 0.001; r = 0.58) of the prior week. Furthermore, using regression analyses, we were able to demonstrate that changes in the cough score were specifically associated to the change in neutrophils, while changes in the dyspnoea score and use of rescue medications were associated with changes in eosinophils numbers. CONCLUSION: Our study showed an association between symptoms and the sputum inflammatory profile. In particular, changes in symptoms (cough and dyspnoea) were correlated with changes in the specific sputum inflammatory cell components of airway inflammation (neutrophils and eosinophils, respectively), providing novel information on the mechanisms of disease manifestation.

Long-term effects of inhaled corticosteroids on sputum bacterial and viral loads in COPD.

Inhaled corticosteroid-containing medications reduce the frequency of COPD exacerbations (mainly infectious in origin) while paradoxically increasing the risk of other respiratory infections. The aim was to determine the effects of inhaled corticosteroids on airway microbial load in COPD patients and evaluate the influence of the underlying inflammatory profile on airway colonisation and microbiome.This is a proof-of-concept prospective, randomised, open-label, blinded endpoint study. Sixty patients with stable moderate COPD were randomised to receive one inhalation twice daily of either a combination of salmeterol 50 µg plus fluticasone propionate 500 µg or salmeterol 50 µg for 12 months. The primary outcome was the change of sputum bacterial loads over the course of treatment.Compared with salmeterol, 1-year treatment with salmeterol plus fluticasone was associated with a significant increase in sputum bacterial load (p=0.005), modification of sputum microbial composition and increased airway load of potentially pathogenic bacteria. The increased bacterial load was observed only in inhaled corticosteroid-treated patients with lower baseline sputum or blood eosinophil (≤2%) levels but not in patients with higher baseline eosinophils.Long-term inhaled corticosteroid treatment affects bacterial load in stable COPD. Lower eosinophil counts are associated with increased airway bacterial load.

Reducing agents decrease the oxidative burst and improve clinical outcomes in COPD patients: a randomised controlled trial on the effects of sulphurous thermal water inhalation.

BACKGROUND: Inhalation of thermal water with antioxidant properties is empirically used for COPD. AIMS: To evaluate the effects of sulphurous thermal water (reducing agents) on airway oxidant stress and clinical outcomes in COPD. METHODS: Forty moderate-to-severe COPD patients were randomly assigned to receive 12-day inhalation with sulphurous thermal water or isotonic saline. Patients were assessed for superoxide anion (O2 (-)) production in the exhaled breath condensate and clinical outcomes at recruitment, the day after the conclusion of the 12-day inhalation treatment, and one month after the end of the inhalation treatment. RESULTS: Inhalation of reducing agents resulted in a significant reduction of O2 (-) production in exhaled breath condensate of COPD patients at the end of the inhalatory treatment and at followup compared to baseline. A significant improvement in the COPD assessment test (CAT) questionnaire was shown one month after the end of the inhalatory treatment only in patients receiving sulphurous water. CONCLUSION: Thermal water inhalation produced an in vivo antioxidant effect and improvement in health status in COPD patients. Larger studies are required in order to evaluate whether inhalation of thermal water is able to modify relevant clinical outcomes of the disease (the study was registered at clinicaltrial.gov-identifier: NCT01664767).

Deficient antiviral immune responses in childhood: distinct roles of atopy and asthma.

BACKGROUND: Impaired immune response to viral infections in atopic asthmatic patients has been recently reported and debated. Whether this condition is present in childhood and whether it is affected by atopy per se deserves further investigation. OBJECTIVE: We sought to investigate airway interferon production in response to rhinovirus infection in children who are asthmatic, atopic, or both and its correlation with the airway inflammatory profile. METHODS: Bronchial biopsy specimens and epithelial cells were obtained from 47 children (mean age, 5 ± 0.5 years) undergoing bronchoscopy. The study population included asthmatic children who were either atopic or nonatopic, atopic children without asthma, and children without atopy or asthma. Rhinovirus type 16 induction of IFN-λ and IFN-ß mRNA and protein levels was assessed in bronchial epithelial cell cultures. The immunoinflammatory profile was evaluated by means of immunohistochemistry in bronchial biopsy specimens. RESULTS: Rhinovirus type 16-induced interferon production was significantly reduced in atopic asthmatic, nonatopic asthmatic, and atopic nonasthmatic children compared with that seen in nonatopic nonasthmatic children (all P < .05). Increased rhinovirus viral RNA levels paralleled this deficient interferon induction. Additionally, IFN-λ and IFN-ß induction correlated inversely with the airway T(H)2 immunopathologic profile (eosinophilia and IL-4 positivity: P < .05 and r = -0.38 and P < .05 and r = -0.58, respectively) and with epithelial damage (P < .05 and r = -0.55). Furthermore, total serum IgE levels correlated negatively with rhinovirus-induced IFN-λ mRNA levels (P < .05 and r = -0.41) and positively with rhinovirus viral RNA levels (P < .05 and r = 0.44). CONCLUSIONS: Deficient interferon responses to rhinovirus infection are present in childhood in asthmatic subjects irrespective of their atopic status and in atopic patients without asthma. These findings suggest that deficient immune responses to viral infections are not limited to patients with atopic asthma but are present in those with other T(H)2-oriented conditions.

Nothing but lung and bones: Longitudinal evolution and quantitative analysis in a case of idiopathic diffuse pulmonary ossification.

A 77-year-old Caucasian man, a former surveyor in a chemical company, underwent a chest X-ray (CXR) as a follow-up exam for a melanoma of the back, surgically removed. CXR showed interstitial thickening in both lower lobes; then, a high-resolution computed tomography of the chest (HRCT) was performed to further investigate these findings, revealing multiple small, calcified nodules with branching appearance at both lung bases. Clinical examination and exposure history were negative, except for a decrease in diffusing capacity for carbon monoxide resulting from pulmonary function tests. Surgical lung biopsy was performed; histology revealed numerous nodules and branching tubules of bone tissue, some of which with marrow elements. After multidisciplinary discussion of the case, a diagnosis of idiopathic diffuse pulmonary ossification (DPO) was considered. Clinical status of the patient was stable over time, despite the increase in extent of calcifications. DPO is an uncommon condition that should be considered in different clinical-radiological settings; multidisciplinary discussion is essential for the final diagnosis.

Fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease: 5-year follow-up.

BACKGROUND: Both smokers and patients with asthma can experience fixed airflow obstruction, which is associated with distinctive patterns of airway pathology. The influence of fixed airflow obstruction on the prognosis of these patients is unknown. OBJECTIVE: We sought to investigate lung function decline and exacerbations in a 5-year prospective study of subjects with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease (COPD). We also sought to explore correlations between functional, pathological, and clinical features. METHODS: Patients with fixed airflow obstruction due to asthma (n = 16) or COPD (n = 21) and a control group of asthmatic patients with fully reversible airflow obstruction (n = 15) were followed for 5 years. RESULTS: The rates of decline in FEV(1) were similar in patients with fixed airflow obstruction caused by asthma (-49.7 +/- 10.6 mL/y) or COPD (-51.4 +/- 9.8 mL/y) and were higher than in asthmatic patients with reversible airflow obstruction (-18.1 +/- 10.1 mL/y, P < .01). Exacerbation rates were also higher in patients with fixed airflow obstruction caused by asthma (1.41 +/- 0.26 per patient-year) or COPD (1.98 +/- 0.3 per patient-year) compared with those seen in asthmatic patients with reversible airflow obstruction (0.53 +/- 0.11 per patient-year, P < .01). Baseline exhaled nitric oxide levels and sputum eosinophil counts correlated with the FEV(1) decline in asthmatic patients with fixed airflow obstruction. By contrast, baseline sputum neutrophil counts, emphysema scores, comorbidities, and exacerbation frequency correlated directly and pulmonary diffusion capacity correlated inversely with the FEV(1) decline in patients with COPD. CONCLUSION: In both patients with asthma and those with COPD, fixed airflow obstruction is associated with increased lung function decline and frequency of exacerbations. Nevertheless, the decline in lung function entails the specific pathological and clinical features of the underlying diseases.

Diffuse panbronchiolitis as parathymic syndrome in a Caucasian man previously treated for thymoma.

Diffuse panbronchiolitis (DPB) is a rare disease characterized by bronchiolitis and chronic sinusitis. Being largely restricted to East Asia, its actual incidence in Caucasian patients is probably underestimated. DPB has been described in association with thymic neoplasms, mainly arising as a consequence of immune dysregulation. We present a rare case of DPB diagnosed in a 69-year-old Caucasian man who had undergone surgery for stage 2A thymoma a year before. The patient came to our hospital complaining of exertional dyspnea and productive cough, with a persistent lung consolidation described at chest X-rays. High resolution computed tomography (CT) showed diffuse centrilobular micronodules and solid nodules, tree-in-bud opacities, peripheral consolidations and cylindrical bronchiectasis. Sinus disease was also demonstrated by CT. Analysis of bronchoalveolar lavage showed marked granulocyte inflammation and allowed the isolation of Haemophilus Influenzae. Consequently, the diagnosis of DPB was reached by integrating clinical, and radiological data. Long-term therapy with azithromycin was prescribed, and was found to be effective in controlling symptoms and reducing radiological abnormalities at 6-month clinical and CT follow-up. Confidence with the radiological presentation and clinical significance of DPB is necessary, since the condition is responsive and reversible to long-term macrolide treatment, the effect of which is mainly attributed to an anti-inflammatory, and immunoregulatory action.

Regular versus as-needed budesonide and formoterol combination treatment for moderate asthma: a non-inferiority, randomised, double-blind clinical trial.

BACKGROUND: Treatment guidelines for patients with moderate persistent asthma recommend regular therapy with a combination of an inhaled corticosteroid and a longacting ß2 agonist plus as-needed rapid-acting bronchodilators. We investigated whether symptom-driven budesonide and formoterol combination therapy administered as needed would be as effective as regular treatment with this combination plus as-needed symptom-driven terbutaline for patients with moderate asthma. METHODS: In this non-inferiority randomised clinical trial, we recruited adult patients (18-65 years of age) with stable moderate persistent asthma, according to 2006 Global Initiative for Asthma guidelines. Patients were recruited from outpatient clinics of secondary and tertiary referral hospitals and university centres. After a 6-week run-in period of inhaled regular budesonide and formoterol plus as-needed terbutaline, the patients were randomly assigned in a 1:1 ratio to receive placebo twice daily plus as-needed treatment with inhaled 160 µg budesonide and 4·5 µg formoterol (as-needed budesonide and formoterol therapy) or twice-daily 160 µg budesonide and 4·5 µg formoterol combination plus symptom-driven 500 µg terbutaline (regular budesonide/formoterol therapy) for 1 year. Randomisation was done according to a list prepared with the use of a random number generator and a balanced-block design stratified by centre. Patients and investigators were masked to treatment assignment. The primary outcome was time to first treatment failure measured after 1 year of treatment using Kaplan-Meier estimates, and the power of the study was calculated based on the rate of treatment failure. Analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00849095. FINDINGS: Between April 20, 2009, and March 31, 2012, we screened 1010 patients with moderate asthma and randomly assigned 866 eligible patients to the two treatment groups (424 to as-needed budesonide and formoterol therapy and 442 to regular budenoside and formoterol therapy). Compared with regular budesonide and formoterol therapy, as-needed budesonide and formoterol treatment was associated with a lower probability of patients having no treatment failure at 1 year (Kaplan-Meier estimates 53·6% for as-needed treatment vs 64·0% for regular treatment; difference 10·3% [95% CI 3·2-17·4], at a predefined non-inferiority limit of 9%). Patients in the as-needed budesonide and formoterol group had shorter time to first treatment failure than those in the regular therapy group (11·86 weeks vs 28·00 weeks for the first quartile [ie, the time until the first 25% of patients experienced treatment failure]). The difference in treatment failures was largely attributable to nocturnal awakenings (82 patients in the as-needed treatment group vs 44 in the regular treatment group). Both treatment regimens were well tolerated. INTERPRETATION: In patients with moderate stable asthma, as-needed budesonide and formoterol therapy is less effective than is the guideline-recommended regular budesonide and formoterol treatment, even though the differences are small. FUNDING: Italian Medicines Agency.

Asthma: a chronic infectious disease?

There are increasing data to support the "hygiene" and "microbiota" hypotheses of a protective role of infections in modulating the risk of subsequent development of asthma. There is less evidence that respiratory infections can actually cause the development of asthma. There is some evidence that rhinovirus respiratory infections are associated with the development of asthma, particularly in childhood, whereas these infections in later life seem to have a weaker association with the development of asthma. The role of bacterial infections in chronic asthma remains unclear. This article reviews the available evidence indicating that asthma may be considered as a chronic infectious disease.