Davide Biondini

Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis

The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or ≥10% predicted) was used to define “slow” or “rapid” disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression.

Clinical and Pathologic Factors Predicting Future Asthma in Wheezing Children. A Longitudinal Study.

Abstract Wheeze is a common symptom in infants, but not all wheezers develop asthma. Indeed, up to 50% of wheezing children outgrow their symptoms by school age. How to predict if early wheeze will become asthma is still a matter of vivid debate. In this work, we sought to assess the clinical and pathological factors that might predict the future development of asthma in children. Eighty children (mean age 3.8 ± 1 yr) who underwent a clinically indicated bronchoscopy were followed prospectively for a median of 5 years. At baseline, clinical characteristics with a particular focus on wheezing and its presentation (episodic or multitrigger) were collected, and structural and inflammatory changes were quantified in bronchial biopsies. Follow‐up data were available for 74 of the 80 children. Children who presented with multitrigger wheeze were more likely to have asthma at follow‐up than those with episodic wheeze (P = 0.04) or without wheeze (P < 0.0001). Children with asthma also had lower birth weights (P = 0.02), a lower prevalence of breastfeeding (P = 0.02), and a trend for increased IgE (P = 0.07) at baseline than those with no asthma. Basement membrane thickness and airway eosinophils at baseline were increased in children who developed asthma at follow‐up (P = 0.001 and P = 0.026, respectively). Multivariate analysis showed that among all clinical and pathological factors, multitrigger wheezing, basement membrane thickening, and reduced birth weight were predictive of future asthma development. We conclude that multitrigger wheeze and reduced birth weight are clinical predictors of asthma development. Basement membrane thickening in early childhood is closely associated with asthma development, highlighting the importance of airway remodeling in early life as a risk factor for future asthma.

Pretreatment rate of decay in forced vital capacity predicts long-term response to pirfenidone in patients with idiopathic pulmonary fibrosis

Pirfenidone reduces functional decline in patients with Idiopathic Pulmonary Fibrosis (IPF). However, response to treatment is highly heterogeneous. We sought to evaluate whether response to pirfenidone is influenced by the pretreatment rate of forced vital capacity (FVC) decline. Fifty-six IPF patients were categorized as rapid (RP) or slow progressors (SP) based on whether their FVC decline in the year preceding pirfenidone treatment was > or ≤ 10% predicted. Following pirfenidone treatment patients were followed-up every 6 months and up to 24 months. In the entire population, pirfenidone reduced significantly FVC decline from 231 to 49 ml/year at 6 months (T6) (p = 0.003) and this effect was maintained at the 12-, 18- and 24-month time points (p value for trend n.s.). In RP, the reduction of FVC decline was evident at 6 months (36 vs 706 ml/year pretreatment; p = 0.002) and maintained, though to a lesser degree, at 12 (106 ml/year), 18 (176 ml/year) and 24 months (162 ml/year; p value for trend n.s). Among SP, the reduction in FVC decline was not significant at any of the time points analyzed. In conclusion, pirfenidone reduces FVC decline in IPF patients. However, its beneficial effect is more pronounced in patients with rapidly progressive disease.

α1-Antitrypsin Polymerizes in Alveolar Macrophages of Smokers With and Without α1-Antitrypsin Deficiency

BACKGROUND: The deficiency of &agr;1‐antitrypsin (AAT) is secondary to misfolding and polymerization of the abnormal Z‐AAT in liver cells and is associated with lung emphysema. Alveolar macrophages (AMs) produce AAT; however, it is not known whether Z‐AAT can polymerize in AMs, further decreasing lung AAT and promoting lung inflammation. Our intention was to investigate whether AAT polymerizes in human AMs and to study the possible relation between polymerization and degree of lung inflammation. METHODS: Immunohistochemical analysis with 2C1 monoclonal antibody specific for polymerized AAT was performed in sections of the following: nine lungs from individuals with AAT deficiency (AATD) and severe COPD; 35 smokers with normal AAT levels, of whom 24 had severe COPD and 11 did not have COPD; and 13 nonsmokers. AMs positive for AAT polymers were counted and expressed as the percentage of total AMs in the lungs. RESULTS: AAT polymerization was detected in 27% (4%‐67%) of AMs from individuals with AATD but also in AMs from smokers with normal AAT with (24% [0%‐70%]) and without (24% [0%‐60%]) COPD, but not in AMs from nonsmokers (0% [0%‐1.5%]) (P < .0001). The percentage of AMs with polymerized AAT correlated with pack‐years smoked (r = 0.53, P = .0001), FEV1/FVC (r = −0.41, P = .005), small airways disease (r = 0.44, P = .004), and number of CD8+ T cells and neutrophils in alveolar walls (r = 0.51, P = .002; r = 0.31, P = .05, respectively). CONCLUSIONS: Polymerization of AAT in alveolar macrophages occurs in the lungs of individuals with AATD but also in smokers with normal AAT levels with or without COPD. Our findings highlight the similarities in the pathophysiology of COPD in individuals with and without AATD, adding a potentially important step to the mechanism of COPD.