Chitotriosidase: a biomarker of activity and severity in patients with sarcoidosis.

BACKGROUND: Serum chitotriosidase is a promising biomarker that has shown high specificity and sensitivity in patients with sarcoidosis. The aim of this study was to investigate correlations between serum chitotriosidase, clinical phenotypes, disease localizations and different radiological lung involvement and to identify clinical features associated with over-expression of chitotriosidase in a large cohort of sarcoidosis patients. METHODS: Chitotriosidase activity was evaluated in a population of 694 consecutive patients (males 39%, age 55.8 ± 12.8 years). Clinical and respiratory functional characteristics, Clinical Outcome Scale (COS) classification, clinical phenotypes proposed by the GenPhenResA project, and radiological assessment, including CT scan, were collected. Serum sampling and clinical and functional assessments at follow-up were also included. RESULTS: Significantly higher chitotriosidase activity was observed in sarcoidosis patients than in healthy controls (p < 0.0001). Evidence of lung fibrosis with reticular abnormalities and traction bronchiectasis at High resolution CT, presence of multiple extrapulmonary sarcoid localizations and increased 24-h urinary excretion of calcium were associated with significantly higher chitotriosidase activity (p < 0.005). Patients with remitted or minimal disease had lower values of chitotriosidase than patients with persistent disease. At follow-up, patients who required an increase in steroid dose showed an increase in its activity. CONCLUSIONS: Chitotriosidase is a reliable biomarker of sarcoidosis. It is increased in patients with sarcoidosis correlating with disease activity, severity and multiorgan dissemination. Steroid therapy tended to reduce chitotriosidase expression, however it responded in cases of disease relapse.

Correction to: Chitotriosidase: a biomarker of activity and severity in patients with sarcoidosis.

After publication of our article [1] the authors have notified us that one of the names has been incorrectly tagged.

Bronchoalveolar lavage proteomic analysis in pulmonary fibrosis associated with systemic sclerosis: S100A6 and 14-3-3ε as potential biomarkers.

Objective: SSc is a rare severe connective tissue disorder. Its prognosis is mainly related to the development of pulmonary fibrosis (PF)-SSc and pulmonary arterial hypertension. No known therapy for PF-SSc modifies progressive lung fibrotic involvement. Research is therefore aimed at a deeper understanding of complex pathogenetic mechanisms and the possibility of new prognostic biomarkers and therapeutic targets. Methods: Towards the first of these aims, we conducted functional proteomic analysis of bronchoalveolar lavage samples from PF-SSc patients and smoker and non-smoker controls. Results: The differential expression pattern revealed by principal component analysis highlighted a specific protein profile of PF-SSc with respect to control samples, and enrichment analysis shed light on process networks involved in pathogenesis. The proteins identified are known to be involved in lung inflammation of PF-SSc-induced IL6 signalling, the complement system, innate immunity, Jak-STAT, the kallikrein-kinin system, blood coagulation, the immune response mediated by phagocytosis and phagosomes in antigen presentation. In particular, our MetaCore network suggested C3a, APOAI, 14-3-3ε, SPFA2 and S100A6 as potential biomarkers; these are upstream molecules involved in lung fibrosis, innate immunity and vascular damage occurring in PF-SSc. Conclusion: This report provides a molecular overview of pathological processes in PF-SSc, pinpointing possible new disease biomarkers and therapeutic targets.

Sarcoidosis: proteomics and new perspectives for improving personalized medicine.

INTRODUCTION: Through synergistic approaches integrating biomedical data from omics sciences to the clinical practice, precision medicine aims at more accurate identification of risk factors, characterization of endotypes, patient stratification, establishment of individualized therapy, and prediction of outcomes. Areas covered: This review evaluates the potential role of different omics approaches for the development and application of precision medicine to sarcoidosis patients. This systemic and heterogeneous inflammatory disease is of unknown etiology, affects people of any age, and requires genotypic and phenotypic characterization. The latter can be achieved through the integration of genomic (i.e. information about genes and their mutations potentially involved in sarcoidosis), transcriptomic (reflecting the dynamic state of a cell and measuring the transcribed genes over time), and proteomic data (i.e. proteins in bronchoalveolar lavage, lung tissues, lung cells, serum and immunity system). Expert commentary: Genomic studies have revealed numerous aspects of sarcoidosis; however, for precision medicine, it is necessary to implement genomics with other omic approaches. The improving reliability of omics data, their storage, and their bioinformatics processing represents the next step to recapitulate in silico biological systems, with the final aim to simulate potential molecular pathways involved in the pathology and useful for clinical purposes.

Calgranulin B and KL-6 in Bronchoalveolar Lavage of Patients with IPF and NSIP.

Idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) are the most frequent idiopathic interstitial pneumonias. The aim of this study was to evaluate concentrations of calgranulin B and Krebs von den Lungen 6 (KL-6) in bronchoalveolar lavage (BAL) fluid of patients with IPF and idiopathic NSIP (i-NSIP) with fibrotic pattern. Thirty patients with IPF (68.73 ± 8.63 years), 30 with i-NSIP (68.33 ± 7.45 years), and healthy controls were included in the study. Calgranulin B and KL-6 both proved to be significantly higher in BAL of IPF and i-NSIP patients than in healthy controls (p < 0.05). Calgranulin B showed several significant correlations with functional parameters (oxygen demand at rest, 6-min walking test (6MWT), and PFTs); KL-6 was correlated with oxygen demand at rest and during 6MWT. Patients with higher concentrations of both biomarkers (> 75th percentile) had more advanced disease with lower values of FEV1%, FVC%, RV%, TLC%, DLCO% of predicted, distance walked in 6MWT, and BAL neutrophil percentage. Calgranulin B and KL-6 in BAL proved to be reliable biomarkers of IPF and i-NSIP and to have prognostic meaning, discriminating severe and advanced patients. The combination of the two biomarkers can facilitate the stratification of severity.

Serum amyloid A in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Serum amyloid A (SAA) is an apo-lipoprotein (12-14 kDa) produced by the liver in response to proinflammatory cytokines from activated monocytes. The precursor of SAA is an acute-phase protein involved in the pathogenesis of sarcoidosis and has been found to be increased during exacerbation of chronic obstructive pulmonary disease and lung cancer. However, no data are available on SAA levels in patients with idiopathic pulmonary fibrosis (IPF), the most common and severe idiopathic form of interstitial pneumonitis associated with a usual interstitial histological and radiological pattern. The aim of this preliminary study was to evaluate SAA concentration in patients with IPF and to explore its potential use as a clinical biomarker. METHODS: SAA levels were determined by enzyme-linked immunosorbent assay in a population of 21 patients with IPF (14 male, aged 64.8 ± 8.1 years) and compared with those in 11 healthy controls (3 male, aged 55 ± 11.3 years). Clinical, functional, and immunological data were collected in a database. RESULTS: SAA levels were significantly higher in patients with IPF than in controls (p = 0.03). In patients with IPF, statistically significant correlations were found between SAA and HDL cholesterol levels (r = -0.62, p = 0.05) and FVC % predicted value (r = -0.52, p = 0.01). CONCLUSIONS: SAA is a promising marker of disease severity in patients with IPF. Our preliminary data suggest a potential pathogenetic role of alteration in lipid metabolism in this rare disease.

Macrophage activation in acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a common cause of disease acceleration in IPF and has a major impact on mortality. The role of macrophage activation in AE of IPF has never been addressed before. METHODS: We evaluated BAL cell cytokine profiles and BAL differential cell counts in 71 IPF patients w/wo AE and in 20 healthy volunteers. Twelve patients suffered from AE at initial diagnosis while sixteen patients developed AE in the 24 months of follow-up. The levels of IL-1ra, CCL2, CCL17, CCL18, CCL22, TNF-α, IL-1ß, CXCL1 and IL-8 spontaneously produced by BAL-cells were analysed by ELISA. RESULTS: In patients with AE, the percentage of BAL neutrophils was significantly increased compared to stable patients. We found an increase in the production rate of the pro-inflammatory cytokines CXCL1 and IL-8 combined with an increase in all tested M2 cytokines by BAL-cells. An increase in CCL18 levels and neutrophil counts during AE was observed in BAL cells from patients from whom serial lavages were obtained. Furthermore, high baseline levels of CCL18 production by BAL cells were significantly predictive for the development of future AE. CONCLUSIONS: BAL cell cytokine production levels at acute exacerbation show up-regulation of pro-inflammatory as well as anti-inflammatory/ M2 cytokines. Our data suggest that AE in IPF is not an incidental event but rather driven by cellular mechanisms including M2 macrophage activation.

Multivariate analysis of risk factors for pharyngocutaneous fistula after total laryngectomy.

The objective of this study was to identify, through multivariate analyses, the configuration of factors that most closely impact the development of pharyngocutaneous fistula (PCF). Incidence and treatment of PCF was also revisited. A retrospective longitudinal study of 218 patients who have undergone total laryngectomy (TL) was conducted in a tertiary academic referral center. There were 47 patients (21.6%) developing PCF within 1 month after surgery (median 14 days, range 2-26 days). Non-surgical closure of the PCF was achieved in 36 patients (76.6%) within a median of 16.5 days (range 8-27 days). Eleven patients (23.4%) required a surgical closure of the PCF. In nine patients the surgical approach consisted in resuturing of the pharyngeal mucosa. Major surgery with the use of flaps (pectoralis major myocutaneous flap and free forearm flap) was required in two patients. Multivariate analysis revealed that diabetes mellitus (odd ratio 23.41 [95% CI 8.46-64.78]), preoperative hypoalbuminemia (odd ratio 9.42 [95% CI 3.60-24.61]), chronic pulmonary diseases (odd ratio 6.64 [95% CI 1.97-22.56]) and chronic hepatopathy (odd ratio 3.26 [95% CI 1.19-9.96]) were independent predictors for PCF formation. PCF results in prolonged hospitalization with increased medical costs, delay of adjuvant postoperative therapy and potentially life-threatening complications such as carotid rupture. In order to reduce the risk of PCF and avoid a delayed TL, optimization of comorbidities and correction of nutritional deficiencies with enteral or parenteral nutritional supplements should be achieved as early as possible.