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Featured researches published by Angelo De Lauretis.


Respirology | 2014

Rituximab in severe, treatment‐refractory interstitial lung disease

Gregory J. Keir; Toby M. Maher; Damien Ming; Reza Abdullah; Angelo De Lauretis; Melissa Wickremasinghe; Andrew G. Nicholson; David M. Hansell; Athol U. Wells; Elisabetta Renzoni

In patients with severe interstitial lung disease (ILD) progressing despite conventional immunosuppression, rituximab, a B‐lymphocyte depleting monoclonal antibody, may offer an effective rescue therapy.


The Journal of Rheumatology | 2013

Serum Interleukin 6 Is Predictive of Early Functional Decline and Mortality in Interstitial Lung Disease Associated with Systemic Sclerosis

Angelo De Lauretis; Piersante Sestini; Panagiotis Pantelidis; Rachel K. Hoyles; David M. Hansell; Nicole Goh; Christopher Zappala; Dina Visca; Toby M. Maher; Christopher P. Denton; Voon H. Ong; David J. Abraham; Peter Kelleher; Laureen Hector; Athol U. Wells; Elisabetta Renzoni

Objective. Biomarkers of progression of interstitial lung disease (ILD) are needed to allow early therapeutic intervention in patients with scleroderma-associated disease (SSc-ILD). Methods. A panel of 8 serum cytokines [interleukin 6 (IL-6), IL-8, IL-10, CCL2, CXCL10, vascular endothelial growth factor, fibroblast growth factor 2, and CX3CL1] was assessed by Luminex bead technology in exploratory cohorts of 74 patients with SSc and 58 patients with idiopathic pulmonary fibrosis (IPF). Mortality and significant lung function decline [forced vital capacity (FVC) ≥ 10%; DLCO ≥ 15%] from date of serum collection were evaluated by proportional hazards analysis. Based on these findings, the prognostic value of serum IL-6, evaluated by ELISA, was assessed in a larger test cohort of 212 patients with SSc-ILD. Results. In the exploratory cohort, only serum IL-6 was an independent predictor of DLCO decline in both IPF and SSc-ILD. The IL-6 threshold level most predictive of DLCO decline within a year was 7.67 pg/ml. In the larger test cohort, serum IL-6 > 7.67 pg/ml was predictive of decline in FVC (HR 2.58 ± 0.98, p = 0.01) and in DLCO (HR 3.2 ± 1.7, p = 0.02) within the first year, and predictive of death within the first 30 months (HR 2.69 ± 0.96, p = 0.005). When stratified according to severity (FVC < 70%), serum IL-6 > 7.67 pg/ml was predictive of functional decline or death within the first year in patients with milder disease (OR 3.1, 95% CI 1.4–7.2, p = 0.007), but not in those with severe ILD. Conclusion. In SSc-ILD, serum IL-6 levels appear to be predictive of early disease progression in patients with mild ILD, and could be used to target treatment in this group, if confirmed by prospective studies.


American Journal of Respiratory and Critical Care Medicine | 2016

Mucins MUC5B and MUC5AC in Distal Airways and Honeycomb Spaces: Comparison among Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia, Fibrotic Nonspecific Interstitial Pneumonitis, and Control Lungs

Caterina Conti; Angeles Montero-Fernandez; Elaine Borg; Tina Osadolor; Patrizia Viola; Angelo De Lauretis; Carmel Stock; Martina Bonifazi; Matteo Bonini; Gaetano Caramori; Gisela Lindahl; Francesco Blasi; Andrew G. Nicholson; Athol U. Wells; Piersante Sestini; Elisabetta Renzoni

Although the pathogenesis of idiopathic pulmonary fibrosis (IPF) remains elusive (1), one of the most intriguing aspects concerns the possible role of mucins. A strong association has been reported between the promoter polymorphism rs35705950 of MUC5B and the occurrence of familial/sporadic IPF (2–10), as well as with a more benign disease course (10, 11). Overexpression of MUC5B and of the other main airway mucin, MUC5AC, has been described in IPF lungs (12, 13), but the level of expression in other types of pulmonary fibrosis is unknown. In this study, we compare MUC5B and MUC5AC expression among IPF, idiopathic nonspecific interstitial pneumonitis (i-NSIP), systemic sclerosis–associated NSIP (SSc-NSIP), and control lungs. Some of the results of this study have been previously reported in the form of an abstract (14). Surgical lung biopsies from 23 patients with IPF/usual interstitial pneumonia (UIP) (17 men; mean6 SD age, 596 10 yr; 16 ever-smokers), 18 with i-NSIP (10 men; mean, age 466 23 yr; 11 ever-smokers), and 15 with SSc-NSIP (4 men; mean age, 526 11 yr; 11 ever-smokers) and normal lung tissue peripheral to resected cancer from 10 smoker and 10 nonsmoker control subjects (11 men; mean age, 686 14 yr) were selected from the Royal Brompton Hospital pathology archive with ethical approval. No significant differences in FVC, diffusing capacity of the lung for carbon monoxide (DLCO), or composite physiologic index (15) were observed between the different fibrotic patterns with the exception of patients with SSc-NSIP, characterized by a significantly higher DLCO (FVC, 796 22, 796 15, and 786 26% of the predicted value, respectively, in IPF, SSc-NSIP, and i-NSIP; DLCO, 516 9, 586 8, and 486 15% of the predicted value; composite physiologic index, 416 10, 386 7, 476 14). Sequential sections were immunolabeled with MUC5Band MUC5ACspecific antibodies (MUC5AC, Clone 45M1; Biocare Ltd., Concord, CA; and MUC5B, clone sc-20119, Santa Cruz Biotechnology, Dallas, TX; 1:100 dilution for both). Distal airways were defined as airways with no cartilage support or glandular elements, surrounded by smooth muscle bands and characterized by an undulating epithelium. Honeycomb cysts were defined as mucuscontaining areas with a less-wrinkled epithelium compared with the distal airways and surrounded by fibrosis (Figure 1). In each biopsy, three distal airways, and in the case of UIP biopsies, three honeycomb cysts, were evaluated. In each area, quantification of the proportion of MUC5Band MUC5AC-positive cells, respectively, was evaluated in six randomly selected fields, each containing 100 airway (or honeycomb cyst, as appropriate) epithelial cells, by an observer blinded to clinical details (C.C.). Positive cells were defined as brown-stained elements, a sign of the antibody reaction with MUC5B or MUC5AC. Preliminary experiments showed that this sample size minimized the coefficient of variation and that the manual readings did correlate well with image analysis (ImageJ Threshold Color plugin), with absolute intraclass correlation coefficients of 0.81 (95% confidence interval, 0.71–0.87) for MUC5AC and 0.72 (95% confidence interval, 0.57–0.81) for MUC5B. To compare manual counts of MUC5B and MUC5AC staining across patterns, multilevel mixed-effects linear regression was performed, using a model in which patients were analyzed as random effect variables, with airways (or honeycomb cysts) and fields nested into patients (Stata 12, College Station, TX). In IPF/UIP distal airways, the proportion of MUC5B cells was more than twofold higher compared with control, i-NSIP, and SSc-NSIP distal airways (P, 0.0001 for all comparisons), even after adjustment for age, sex, and smoking status on multivariate analysis, whereas the proportion of MUC5B cells in honeycomb cysts was similar to control airways (Table 1 and Figure 1). No significant differences were observed in MUC5B expression between distal airways of SSc-NSIP, i-NSIP, and controls. In contrast, the proportion of MUC5AC epithelial cells in IPF/UIP distal airways was similar to control biopsies, whereas both i-NSIP and SSc-NSIP distal airways were characterized by significantly lower percentages of MUC5ACpositive cells (P, 0.001 vs. controls and UIP), even after adjustment for age, sex, and smoking history. In IPF/UIP honeycomb cysts, the proportion of MUC5AC-positive cells was significantly lower than in distal airways of control biopsies (P = 0.004). The higher expression of MUC5B in IPF/UIP distal airways when compared with control lungs is in keeping with the findings of Seibold and colleagues (12). However, we did not observe increased expression of MUC5AC in IPF/UIP distal airways compared with controls as described by Seibold and colleagues, a discrepancy that could at least partially be related to differing staining techniques. The relative sensitivity of immunofluorescence, used by Seibold and colleagues, and immunoperoxidase, used in this study, in analyzing mucin staining in formalin-fixed paraffin-embedded lung biopsies is not known, but it may be that sensitivity differs between the two techniques. In summary, we report that MUC5B overexpression appears to be specific to IPF/UIP, with twice the number of MUC5B cells seen in IPF/UIP distal airways compared with idiopathic and SScassociated fibrotic NSIP patterns. Further, the distal airways, rather than honeycomb cysts, appear to be the primary site of MUC5B overexpression in IPF lungs. Although we did not assess whether this was related to the MUC5B variant rs35705950, an association between the single-nucleotide polymorphism and overexpression of MUC5B in the distal airways, but not in honeycomb cysts of IPF lungs, was reported by Nakano and colleagues (16), This research project was supported by the European Respiratory Society, with a short-term fellowship grant awarded to C.C., and by the National Institute of Health Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust.


Respiratory Medicine | 2018

Functional associations of pleuroparenchymal fibroelastosis and emphysema with hypersensitivity pneumonitis

Joseph Jacob; Arlette Odink; Anne Laure Brun; Claudio Macaluso; Angelo De Lauretis; Maria Kokosi; Anand Devaraj; Sujal R. Desai; Elisabetta Renzoni; Athol U. Wells

BACKGROUND Pleuroparenchymal fibroelastosis (PPFE) has been described in hypersensitivity pneumonitis (HP) yet its functional implications are unclear. Combined pulmonary fibrosis and emphysema (CPFE) has occasionally been described in never-smokers with HP, but epidemiological data regarding its prevalence is sparse. CTs in a large HP cohort were therefore examined to identify the prevalence and effects of PPFE and emphysema. Methods 233 HP patients had CT extents of interstitial lung disease (ILD) and emphysema quantified to the nearest 5%. Lobar percentage pleural involvement of PPFE was quantified on a 4-point categorical scale: 0 = absent, 1 = affecting <10%, 2 = affecting 10–33%, 3 = affecting >33%. Marked PPFE reflected a total lung score of ≥3/18. Results were evaluated against FVC, DLco and mortality. RESULTS Marked PPFE prevalence was 23% whilst 23% of never-smokers had emphysema. Following adjustment for patient age, gender, smoking status, and ILD and emphysema extents, marked PPFE independently linked to reduced baseline FVC (p = 0.0002) and DLco (p = 0.002) and when examined alongside the same covariates, independently linked to worsened survival (p = 0.01). CPFE in HP demonstrated a characteristic functional profile of artificial lung volume preservation and disproportionate DLco reduction. CPFE did not demonstrate a worsened outcome when compared to HP patients without emphysema beyond that explained by CT extents of ILD and emphysema. CONCLUSIONS PPFE is not uncommon in HP, and is independently associated with impaired lung function and increased mortality. Emphysema was identified in 23% of HP never-smokers. CPFE appears not to link to a malignant microvascular phenotype as outcome is explained by ILD and emphysema extents.


American Journal of Respiratory and Critical Care Medicine | 2018

Predicting Outcomes in Idiopathic Pulmonary Fibrosis Using Automated Computed Tomographic Analysis

Joseph Jacob; Brian J. Bartholmai; Srinivasan Rajagopalan; Coline H.M. van Moorsel; Hendrik W. van Es; Frouke van Beek; Marjolijn Hl Struik; Maria Kokosi; Ryoko Egashira; Anne Laure Brun; Arjun Nair; Simon Walsh; Gary Cross; Joseph Barnett; Angelo De Lauretis; Eoin P. Judge; Sujal R. Desai; Ronald A. Karwoski; Sebastien Ourselin; Elisabetta Renzoni; Toby M. Maher; Andre Altmann; Athol U. Wells

Rationale: Quantitative computed tomographic (CT) measures of baseline disease severity might identify patients with idiopathic pulmonary fibrosis (IPF) with an increased mortality risk. We evaluated whether quantitative CT variables could act as a cohort enrichment tool in future IPF drug trials. Objectives: To determine whether computer‐derived CT measures, specifically measures of pulmonary vessel‐related structures (VRSs), can better predict functional decline and survival in IPF and reduce requisite sample sizes in drug trial populations. Methods: Patients with IPF undergoing volumetric noncontrast CT imaging at the Royal Brompton Hospital, London, and St. Antonius Hospital, Utrecht, were examined to identify pulmonary function measures (including FVC) and visual and computer‐derived (CALIPER [Computer‐Aided Lung Informatics for Pathology Evaluation and Rating] software) CT features predictive of mortality and FVC decline. The discovery cohort comprised 247 consecutive patients, with validation of results conducted in a separate cohort of 284 patients, all fulfilling drug trial entry criteria. Measurements and Main Results: In the discovery and validation cohorts, CALIPER‐derived features, particularly VRS scores, were among the strongest predictors of survival and FVC decline. CALIPER results were accentuated in patients with less extensive disease, outperforming pulmonary function measures. When used as a cohort enrichment tool, a CALIPER VRS score greater than 4.4% of the lung was able to reduce the requisite sample size of an IPF drug trial by 26%. Conclusions: Our study has validated a new quantitative CT measure in patients with IPF fulfilling drug trial entry criteria—the VRS score—that outperformed current gold standard measures of outcome. When used for cohort enrichment in an IPF drug trial setting, VRS threshold scores can reduce a required IPF drug trial population size by 25%, thereby limiting prohibitive trial costs. Importantly, VRS scores identify patients in whom antifibrotic medication prolongs life and reduces FVC decline.


The Lancet Respiratory Medicine | 2018

Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial

Dina Visca; Letizia Mori; Vicky Tsipouri; Sharon E. Fleming; Ashi Firouzi; Matteo Bonini; Matthew J Pavitt; Veronica Alfieri; Sara Canu; Martina Bonifazi; Cristina Boccabella; Angelo De Lauretis; Carmel Stock; Peter Saunders; Andrew J. Montgomery; Charlotte Hogben; Anna Stockford; Margaux Pittet; Jo Brown; Felix Chua; Peter M. George; Philip L. Molyneaux; Georgios A Margaritopoulos; Maria Kokosi; Vasileios Kouranos; Anne Marie Russell; Surinder S. Birring; Alfredo Chetta; Toby M. Maher; Paul Cullinan

BACKGROUND In fibrotic interstitial lung diseases, exertional breathlessness is strongly linked to health-related quality of life (HRQOL). Breathlessness is often associated with oxygen desaturation, but few data about the use of ambulatory oxygen in patients with fibrotic interstitial lung disease are available. We aimed to assess the effects of ambulatory oxygen on HRQOL in patients with interstitial lung disease with isolated exertional hypoxia. METHODS AmbOx was a prospective, open-label, mixed-method, crossover randomised controlled clinical trial done at three centres for interstitial lung disease in the UK. Eligible patients were aged 18 years or older, had fibrotic interstitial lung disease, were not hypoxic at rest but had a fall in transcutaneous arterial oxygen saturation to 88% or less on a screening visit 6-min walk test (6MWT), and had self-reported stable respiratory symptoms in the previous 2 weeks. Participants were randomly assigned (1:1) to either oxygen treatment or no oxygen treatment for 2 weeks, followed by crossover for another 2 weeks. Randomisation was by a computer-generated sequence of treatments randomly permuted in blocks of constant size (fixed size of ten). The primary outcome, which was assessed by intention to treat, was the change in total score on the Kings Brief Interstitial Lung Disease questionnaire (K-BILD) after 2 weeks on oxygen compared with 2 weeks of no treatment. General linear models with treatment sequence as a fixed effect were used for analysis. Patient views were explored through semi-structured topic-guided interviews in a subgroup of participants. This study was registered with ClinicalTrials.gov, number NCT02286063, and is closed to new participants with all follow-up completed. FINDINGS Between Sept 10, 2014, and Oct 5, 2016, 84 patients were randomly assigned, 41 randomised to ambulatory oxygen first and 43 to no oxygen. 76 participants completed the trial. Compared with no oxygen, ambulatory oxygen was associated with significant improvements in total K-BILD scores (mean 55·5 [SD 13·8] on oxygen vs 51·8 [13·6] on no oxygen, mean difference adjusted for order of treatment 3·7 [95% CI 1·8 to 5·6]; p<0·0001), and scores in breathlessness and activity (mean difference 8·6 [95% CI 4·7 to 12·5]; p<0·0001) and chest symptoms (7·6 [1·9 to 13·2]; p=0·009) subdomains. However, the effect on the psychological subdomain was not significant (2·4 [-0·6 to 5·5]; p=0·12). The most common adverse events were upper respiratory tract infections (three in the oxygen group and one in the no-treatment group). Five serious adverse events, including two deaths (one in each group) occurred, but none were considered to be related to treatment. INTERPRETATION Ambulatory oxygen seemed to be associated with improved HRQOL in patients with interstitial lung disease with isolated exertional hypoxia and could be an effective intervention in this patient group, who have few therapeutic options. However, further studies are needed to confirm this finding. FUNDING UK National Institute for Health Research.


Clinical Radiology | 2017

Predicting time to decline in FVC using baseline visual and computer-based CT analysis and baseline functional indices

Joseph Jacob; Brian J. Bartholmai; Andre Altmann; Angelo De Lauretis; Srinivasan Rajagopalan; Maria Kokosi; Arjun Nair; Ryoko Egashira; Anne Laure Brun; Simon Walsh; Ronald A. Karwoski; Sebastian Ourselin; Athol U. Wells


american thoracic society international conference | 2010

Serum Markers Of Disease Progression In Idiopathic Pulmonary Fibrosis And In Interstitial Lung Disease Associated With Systemic Sclerosis

Angelo De Lauretis; Panagiotis Pantelidis; Piersante Sestini; Nicole Goh; Rachel K. Hoyles; Chris Zappala; Christopher P. Denton; David J. Abraham; Peter Kelleher; Roland M. du Bois; David M. Hansell; Athol U. Wells; Elisabetta Renzoni


Archive | 2018

Effect of Ambulatory Oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a randomised mixed-method cross-over controlled clinical trial.

Dina Visca; Letizia Mori; Vicky Tsipouri; Sharon E. Fleming; Ashi Firouzi; Matteo Bonini; Matthew J Pavitt; Veronica Alfieri; Sara Canu; Martina Bonifazi; Cristina Boccabella; Angelo De Lauretis; Carmel Stock; Peter Saunders; Andrew J. Montgomery; Charlotte Hogben; Anna Stockford; Margaux Pittet; Jo Brown; Felix Chua; Peter M. George; Philip L. Molyneaux; Georgios A Margaritopoulos; Maria Kokosi; Vasileios Kouranos; Anne Russell; Surinder S. Birring; Alfredo Chetta; Toby M. Maher; Paul Cullinan


European Respiratory Journal | 2017

Predictors of continuous positive airway pressure adherence in obstructive sleep apnea syndrome

Veronica Leoni; Dina Visca; Angelo De Lauretis; Antonio Spanevello

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Athol U. Wells

National Institutes of Health

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Dina Visca

Catholic University of the Sacred Heart

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Elisabetta Renzoni

National Institutes of Health

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Toby M. Maher

National Institutes of Health

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Piersante Sestini

Catholic University of the Sacred Heart

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