Paola Rottoli

An Official American Thoracic Society Clinical Practice Guideline: The Clinical Utility of Bronchoalveolar Lavage Cellular Analysis in Interstitial Lung Disease

BACKGROUND The clinical utility of bronchoalveolar lavage fluid (BAL) cell analysis for the diagnosis and management of patients with interstitial lung disease (ILD) has been a subject of debate and controversy. The American Thoracic Society (ATS) sponsored a committee of international experts to examine all relevant literature on BAL in ILD and provide recommendations concerning the use of BAL in the diagnosis and management of patients with suspected ILD. PURPOSE To provide recommendations for (1) the performance and processing of BAL and (2) the interpretation of BAL nucleated immune cell patterns and other BAL characteristics in patients with suspected ILD. METHODS A pragmatic systematic review was performed to identify unique citations related to BAL in patients with ILD that were published between 1970 and 2006. The search was updated during the guideline development process to include published literature through March 2011. This is the evidence upon which the committees conclusions and recommendations are based. RESULTS Recommendations for the performance and processing of BAL, as well as the interpretation of BAL findings, were formulated by the committee. CONCLUSIONS When used in conjunction with comprehensive clinical information and adequate thoracic imaging such as high-resolution computed tomography of the thorax, BAL cell patterns and other characteristics frequently provide useful information for the diagnostic evaluation of patients with suspected ILD.

Serum CC-Chemokine Ligand 18 Concentration Predicts Outcome in Idiopathic Pulmonary Fibrosis

RATIONALE Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a poor prognosis. There is great effort to find predictors of outcome. Conclusive data for any serum biomarker are lacking. We have recently documented that serum CCL18 concentrations correlate with the course of pulmonary function data in patients with pulmonary fibrosis of various causes. OBJECTIVES To test the value of serum CCL18 concentrations in IPF, we included 72 patients in a prospective study. METHODS IPF was defined according to the ATS/ERS criteria. Serum CCL18 concentrations were measured by a commercially available ELISA. Patients were followed for 24 months. Pulmonary function tests were performed at least every 6 months. MEASUREMENTS AND MAIN RESULTS Baseline serum CCL18 concentrations predicted the change in TLC and FVC at the 6-month follow-up. Receiver operating characteristics (ROC) revealed a significant relation between survival and baseline CCL18 concentrations. By ROC analysis, the cutoff value with the highest diagnostic accuracy was defined as 150 ng/ml (sensitivity, 0.83; specificity, 0.77). There was a significantly higher mortality in patients with serum CCL18 concentrations above 150 ng/ml (P < 0.0001). The hazard proportional ratio adjusted for age, sex, and baseline pulmonary function data was 8.0. There was a higher incidence of disease progression in the group with high serum CCL18 concentrations. CONCLUSIONS Our data demonstrate that serum CCL18 concentrations have a predictive value in IPF and may be a useful tool in the clinical management of patients with IPF and in clinical trials.

Bronchoalveolar lavage fluid protein composition in patients with sarcoidosis and idiopathic pulmonary fibrosis : a two-dimensional electrophoretic study

We used two‐dimensional (2‐D) electrophoresis to analyze the protein composition of fluid recovered by bronchoalveolar lavage (BALF) from patients with sarcoidosis and idiopathic pulmonary fibrosis, two forms of interstitial lung disease with different cellular composition and cytokine profile in BALF. They are also characterized by different pathogenesis and clinical evolution, idiopathic pulmonary fibrosis being less favorable than sarcoidosis due to rapidly progressive pulmonary fibrosis. Thirty‐eight proteins or protein fragments, never previously assigned in BALF samples, were identified by various methods including mass fingerprinting of tryptic digests. Comparison of the BALF protein maps of the two groups of patients showed 32 spots with statistically significant disease‐related variations in relative abundance. In sarcoidosis we found an increase in the amount of several plasma proteins, while in idiopathic pulmonary fibrosis we observed a statistically significant increase in low‐molecular‐weight proteins, many of which are involved in inflammatory processes (such as MIF and calgranulin) or antioxidant response (such as antioxidant peroxysomal enzyme and thioredoxin peroxidase 2). 2‐D electrophoresis allowed us to identify new BALF proteins and to characterize protein composition in patients with sarcoidosis and idiophatic pulmonary fibrosis. Comparison of the gels of the two diseases showed that they differ in BALF protein profiles as they do in type of immune response.

Prevention of corticosteroid-induced osteoporosis with alendronate in sarcoid patients.

Abstract. Prolonged corticosteroid administration, as often required in the treatment of sarcoidosis, increases the risk of osteoporosis and fracture. The aim of the present study was to evaluate the usefulness of alendronate, a third generation bisphosphonate, in preventing corticosteroid-induced osteoporosis. Forty-three consecutive, previously untreated, sarcoid patients (17 men and 26 premenopausal women) were included in the study: 13 needed no treatment and served as controls (Group 1) and 30 needed glucocorticoids (prednisone) and were randomly selected to also receive either placebo (n = 15, Group 2) or alendronate 5 mg/day (n = 15, Group 3). Bone mineral density (BMD) at the ultradistal radius by dual photon absorptiometry (Osteograph 1000, NIM, Verona, Italy) and biochemical markers of bone turnover were measured at baseline and after 6 and 12 months of glucocorticoid therapy. No significant difference was found between Groups 2 and 3 in the mean cumulative dose of prednisone (4945 ± 1956 mg and 5110 ± 2013 mg, respectively). At the end of the study period, BMD increased by 0.8% in the alendronate-treated group; in the placebo-treated group, BMD decreased by 4.5%. The difference between groups was significant (P < 0.01, ANOVA). A significant decrease in markers of bone formation was found in all patients treated with prednisone (Groups 2 and 3), independently of alendronate. Alendronate, however, counteracted the increase in markers of bone resorption induced by glucocorticoid therapy. Our data suggest that alendronate is effective in preventing glucocorticoid-induced bone loss in sarcoid patients. Further studies on alendronate use in steroid-induced osteoporosis are needed.

Predicting survival in newly diagnosed idiopathic pulmonary fibrosis: a 3-year prospective study

The natural history of idiopathic pulmonary fibrosis (IPF) is not well defined and its clinical course is variable. We sought to investigate the survival and incidence of acute exacerbations (AEs) and their significant predictors in newly diagnosed patients. 70 patients newly diagnosed with IPF were prospectively followed for at least 3 yrs. Baseline evaluation included Medical Research Council dyspnoea score (MRCDS), 6-min walk test, pulmonary function tests, all of which were repeated at 6 months, and high-resolution computed tomography. A retrospective cohort of 68 patients was used for confirmation. Mean survival from the time of diagnosis was 30 months, with a 3-yr mortality of 46%. A Risk stratificatiOn ScorE (ROSE) based on MRCDS >3, 6-min walking distance ≤72% predicted and composite physiologic index >41 predicted 3-yr mortality with high specificity. 6-month progression of ROSE predicted rapid progression. 3-yr incidence of AE was 18.6%, mostly occurring in the first 18 months; risk factors for AE were concomitant emphysema and low diffusing coefficient of the lung for carbon monoxide. Results were confirmed in an independent cohort of patients. In newly diagnosed IPF, advanced disease at presentation, rapid progression and AEs are the determinants of 3-yr survival. The purpose of the multifactorial ROSE is to risk-stratify patients in order to predict survival and detect rapid disease progression.

Oxidative stress in the pathogenesis of diffuse lung diseases: A review

Oxidative stress is an imbalance between oxidants (reactive oxygen and nitrogen species) and antioxidants that may affect lipids, DNA, carbohydrates and proteins. The lung is continuously exposed to endogenous and exogenous oxidants (cigarette smoke, mineral dust, ozone, radiation). Reactive oxygen and nitrogen species are mainly produced by phagocytes as well as by polymorphonuclear, alveolar, bronchial and endothelial cells. A potential role of oxidative stress in the pathogenesis of diffuse lung diseases (particularly idiopathic pulmonary fibrosis) has been demonstrated. Increased oxidant levels and decreased antioxidant defences can contribute to the progression of idiopathic pulmonary fibrosis and other diffuse lung diseases. The growing number of papers on the different aspects of oxidant/antioxidant imbalance in diffuse lung diseases in the last decade reflects increasing interest in this topic and suggests that specific DLDs may be characterized by specific patterns of oxidation and antioxidant responses. The study of oxidative stress can provide insights into etiopathogenesis and favour the discovery of new treatments. In this review of the literature on oxidants and antioxidants in diffuse lung diseases, the focus is on idiopathic pulmonary fibrosis, sarcoidosis, pneumoconiosis and pulmonary fibrosis associated with systemic sclerosis.

Serum levels of chitotriosidase as a marker of disease activity and clinical stage in sarcoidosis

Grosso S, Margollicci MA, Bargagli E, Buccoliero R, Perrone A, Galimberti D, Morgese G, Balestri P, Rottoli P. Serum levels of chitotriosidase as a marker of disease activity and clinical stage in sarcoidosis. 2004; 64: 57-62. Background: Sarcoidosis is a systemic granulomatous disease characterized by T-lymphocyte activation and lymphocyte migration into involved organs, usually the lungs. The amounts of a number of biochemical markers, such as angiotensin converting enzyme (ACE) activity, increase in the serum of patients with sarcoidosis. Chitotriosidase is an enzyme secreted by activated macrophages able to catalyze the hydrolysis of both chitin and chitin-like substrates. Chitotriosidase is involved in defense against, and in degradation of chitin-containing pathogens such as fungi, nematodes, and insects. Methods: Forty-three patients affected by chronic sarcoidosis, in active (23 patients) or inactive (20 patients) phase, were studied. Serum levels of chitotriosidase and ACE activity were evaluated and compared with those of 32 healthy subjects. Serum chitotriosidase concentration and ACE activity were also correlated with radiographic stage of disease. Results: Individuals with chronic sarcoidosis have higher serum chitotriosidase concentrations and ACE activity than those of normal subjects. Sarcoidosis patients in the active phase of the disease had significantly higher chitotriosidase and ACE levels than those in the inactive phase. In contrast to serum ACE activity, a significant relationship between serum levels of chitotriosidase and the four radiographic stages of the disease was observed. Conclusion: Although the data need to be validated by further investigation, the observations made in this study seem to indicate that serum chitotriosidase concentrations may be a useful marker for monitoring sarcoidosis disease activity and prognosis.

Chitotriosidase and soluble IL‐2 receptor: Comparison of two markers of sarcoidosis severity

Background. Sarcoidosis is a multisystemic granulomatous disease with an unpredictable clinical course characterized by accumulation of activated proliferating T lymphocytes and mononuclear phagocytes in affected organs. Aims and methods. The aims of this study were to describe the clinical, radiological and immunological features of a population of sarcoidosis patients followed at the Sarcoidosis Regional Centre in Siena and to analyse chitotriosidase and sIL‐2R concentrations in serum of these patients in order to understand their potential as disease markers. Results. Chitotriosidase and sIL‐2R concentrations in serum of sarcoidosis patients were found to be significantly higher than in healthy controls (p<0.01) and a positive correlation between the two markers was documented for the first time. Moreover, chitotriosidase and sIL‐2R were expressed differently in different radiographic stages of the disease. Conclusion. Chitotriosidase and sIL‐2R are two markers of sarcoidosis of different origin, the values of which show a correlation in these patients; they are easily detectable in serum and could be useful clinical markers of progression.

Infliximab treatment in a patient with rheumatoid arthritis and pulmonary fibrosis

To the Editors: Infliximab is a chimeric human-mouse anti-tumour necrosis factor-α (anti-TNF-α) immunoglobulin G monoclonal antibody that binds the soluble and transmembrane forms of TNF-α. Its efficacy in the treatment of chronic inflammatory diseases, such as rheumatoid arthritis (RA) and Crohns disease, is well documented 1, 2, and recent reports indicate a possible use in the treatment of psoriasis, giant cell arteritis, spondyloarthropaties and sarcoidosis 3–6. As conventional treatments of idiopathic pulmonary fibrosis and lung fibrosis associated …

Chitotriosidase Activity in the Serum of Patients with Sarcoidosis and Pulmonary Tuberculosis

Background: Human chitotriosidase is a chitinase selectively expressed by activated macrophages. An increase in chitotriosidase activity was previously described by us in the serum and bronchoalveolar lavage of sarcoidosis patients. Objective: The aim of the present study was to analyze serum chitotriosidase activity in a larger number of sarcoidosis patients to verify the reported increase with respect to controls and to compare serum chitotriosidase levels in patients with sarcoidosis and tuberculosis, two granulomatous disorders of different etiology. Methods: Chitotriosidase activity was measured in the serum of 96 sarcoidosis patients, 15 pulmonary tuberculosis patients and 30 healthy controls. Results: We found significantly higher serum chitotriosidase activity in sarcoidosis patients than controls (p < 0.01) and in sarcoidosis patients than tuberculosis patients (p < 0.01), confirming a striking elevation of chitotriosidase activity (>10 times greater than normal) in pulmonary sarcoidosis patients. This is the first time that chitotriosidase activity has been analyzed in the serum of patients with pulmonary tuberculosis; it was found to be significantly lower than in sarcoidosis patients and not significantly greater than in controls. Conclusion: Although the mechanisms leading to the increase in chitotriosidase activity in sarcoidosis are still unknown, this enzyme may be specifically involved in the pathogenesis of the disease. Further studies with a greater number of patients are needed to confirm these results and to determine whether chitotriosidase could be a marker with diagnostic or prognostic value in sarcoidosis.