Dominique Valeyre

Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor

FoxP3 is a key transcription factor for the development and function of natural CD4(+) regulatory T cells (Treg cells). Here we show that human FoxP3(+)CD4(+) T cells were composed of three phenotypically and functionally distinct subpopulations: CD45RA(+)FoxP3(lo) resting Treg cells (rTreg cells) and CD45RA(-)FoxP3(hi) activated Treg cells (aTreg cells), both of which were suppressive in vitro, and cytokine-secreting CD45RA(-)FoxP3(lo) nonsuppressive T cells. The proportion of the three subpopulations differed between cord blood, aged individuals, and patients with immunological diseases. Terminally differentiated aTreg cells rapidly died whereas rTreg cells proliferated and converted into aTreg cells in vitro and in vivo. This was shown by the transfer of rTreg cells into NOD-scid-common gamma-chain-deficient mice and by TCR sequence-based T cell clonotype tracing in peripheral blood in a normal individual. Taken together, the dissection of FoxP3(+) cells into subsets enables one to analyze Treg cell differentiation dynamics and interactions in normal and disease states, and to control immune responses through manipulating particular FoxP3(+) subpopulations.

Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials.

BACKGROUND Idiopathic pulmonary fibrosis is a progressive and fatal lung disease with inevitable loss of lung function. The CAPACITY programme (studies 004 and 006) was designed to confirm the results of a phase 2 study that suggested that pirfenidone, a novel antifibrotic and anti-inflammatory drug, reduces deterioration in lung function in patients with idiopathic pulmonary fibrosis. METHODS In two concurrent trials (004 and 006), patients (aged 40-80 years) with idiopathic pulmonary fibrosis were randomly assigned to oral pirfenidone or placebo for a minimum of 72 weeks in 110 centres in Australia, Europe, and North America. In study 004, patients were assigned in a 2:1:2 ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo; in study 006, patients were assigned in a 1:1 ratio to pirfenidone 2403 mg/day or placebo. The randomisation code (permuted block design) was computer generated and stratified by region. All study personnel were masked to treatment group assignment until after final database lock. Treatments were administered orally, 801 mg or 399 mg three times a day. The primary endpoint was change in percentage predicted forced vital capacity (FVC) at week 72. Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, numbers NCT00287729 and NCT00287716. FINDINGS In study 004, 174 of 435 patients were assigned to pirfenidone 2403 mg/day, 87 to pirfenidone 1197 mg/day, and 174 to placebo. In study 006, 171 of 344 patients were assigned to pirfenidone 2403 mg/day, and 173 to placebo. All patients in both studies were analysed. In study 004, pirfenidone reduced decline in FVC (p=0·001). Mean FVC change at week 72 was -8·0% (SD 16·5) in the pirfenidone 2403 mg/day group and -12·4% (18·5) in the placebo group (difference 4·4%, 95% CI 0·7 to 9·1); 35 (20%) of 174 versus 60 (35%) of 174 patients, respectively, had a decline of at least 10%. A significant treatment effect was noted at all timepoints from week 24 and in an analysis over all study timepoints (p=0·0007). Mean change in percentage FVC in the pirfenidone 1197 mg/day group was intermediate to that in the pirfenidone 2403 mg/day and placebo groups. In study 006, the difference between groups in FVC change at week 72 was not significant (p=0·501). Mean change in FVC at week 72 was -9·0% (SD 19·6) in the pirfenidone group and -9·6% (19·1) in the placebo group, and the difference between groups in predicted FVC change at week 72 was not significant (0·6%, -3·5 to 4·7); however, a consistent pirfenidone effect was apparent until week 48 (p=0·005) and in an analysis of all study timepoints (p=0·007). Patients in the pirfenidone 2403 mg/day group had higher incidences of nausea (125 [36%] of 345 vs 60 [17%] of 347), dyspepsia (66 [19%] vs 26 [7%]), vomiting (47 [14%] vs 15 [4%]), anorexia (37 [11%] vs 13 [4%]), photosensitivity (42 [12%] vs 6 [2%]), rash (111 [32%] vs 40 [12%]), and dizziness (63 [18%] vs 35 [10%]) than did those in the placebo group. Fewer overall deaths (19 [6%] vs 29 [8%]) and fewer deaths related to idiopathic pulmonary fibrosis (12 [3%] vs 25 [7%]) occurred in the pirfenidone 2403 mg/day groups than in the placebo groups. INTERPRETATION The data show pirfenidone has a favourable benefit risk profile and represents an appropriate treatment option for patients with idiopathic pulmonary fibrosis. FUNDING InterMune.

Combined pulmonary fibrosis and emphysema: A distinct underrecognised entity

The syndrome resulting from combined pulmonary fibrosis and emphysema has not been comprehensively described. The current authors conducted a retrospective study of 61 patients with both emphysema of the upper zones and diffuse parenchymal lung disease with fibrosis of the lower zones of the lungs on chest computed tomography. Patients (all smokers) included 60 males and one female, with a mean age of 65 yrs. Dyspnoea on exertion was present in all patients. Basal crackles were found in 87% and finger clubbing in 43%. Pulmonary function tests were as follows (mean±sd): total lung capacity 88%±17, forced vital capacity (FVC) 88%±18, forced expiratory volume in one second (FEV1) 80%±21 (% predicted), FEV1/FVC 69%±13, carbon monoxide diffusion capacity of the lung 37%±16 (% predicted), carbon monoxide transfer coefficient 46%±19. Pulmonary hypertension was present in 47% of patients at diagnosis, and 55% during follow-up. Patients were followed for a mean of 2.1±2.8 yrs from diagnosis. Survival was 87.5% at 2 yrs and 54.6% at 5 yrs, with a median of 6.1 yrs. The presence of pulmonary hypertension at diagnosis was a critical determinant of prognosis. The authors hereby individualise the computer tomography-defined syndrome of combined pulmonary fibrosis and emphysema characterised by subnormal spirometry, severe impairment of gas exchange, high prevalence of pulmonary hypertension, and poor survival.

The immune paradox of sarcoidosis and regulatory T cells

Sarcoidosis is characterized by extensive local inflammation (granuloma, cytokine secretion) associated with anergy (poor response to antigens in vitro and in vivo). We postulated that this paradoxical situation would correspond to a disequilibrium between effector and regulatory T lymphocytes (T reg cells). We show that CD4+CD25brightFoxP3+ cells accumulate at the periphery of sarcoid granulomas, in bronchoalveolar lavage fluid, and in peripheral blood of patients with active disease. These cells exhibited powerful antiproliferative activity, yet did not completely inhibit TNF-α production. Sarcoidosis is therefore associated with a global T reg cell subset amplification whose activity would be insufficient to control local inflammation. At the same time, peripheral T reg cells exert powerful antiproliferative activity that may account for the state of anergy. Altogether, these findings advance our conceptual understanding of immune regulation in a way that resolves the immune paradox of sarcoidosis and permit us to envisage a profound clinical impact of T reg cell manipulation on immunity.

Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis

Background: Pulmonary hypertension (PH) is a rare complication of sarcoidosis, although it is not uncommon in advanced disease. Methods: A retrospective series of 22 sarcoidosis patients (16 men) of mean (SD) age 46 (13) years with PH was divided into two groups depending on the absence (stage 0: n = 2, stage II: n = 4, stage III: n = 1) or presence (n = 15) of radiographic pulmonary fibrosis at the time of PH diagnosis. Results: In both groups PH was moderate to severe and there was no response to acute vasodilator challenge. In non-fibrotic cases no other cause of PH was found, suggesting a specific sarcoidosis vasculopathy, although no histological specimens were available. In cases with fibrosis there was no correlation between haemodynamics and lung volumes or arterial oxygen tensions, suggesting other mechanisms for PH in addition to pulmonary destruction and hypoxaemia. These included extrinsic arterial compression by lymphadenopathies in three cases and histologically proven pulmonary veno-occlusive disease in the five patients who underwent lung transplantation. Ten patients received high doses of oral prednisone for PH (stage 0: n  =  1, stage II: n  =  4 and stage IV: n  =  5); three patients without pulmonary fibrosis experienced a sustained haemodynamic response. Survival of the overall population was poor (59% at 5 years). Mortality was associated with NYHA functional class IV but not with haemodynamic parameters or with lung function. Conclusion: Two very different phenotypes of sarcoidosis combined with PH are observed depending on the presence or absence of pulmonary fibrosis. PH is a severe complication of sarcoidosis.

European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare lung disease, which occurs sporadically or in association with the genetic disease tuberous sclerosis complex (TSC) 1, 2. Sporadic LAM affects ∼1 in 400,000 adult females; in TSC, LAM occurs in 30–40% of adult females 3, 4 and exceptionally in males and children 5, 6. Patients with LAM usually develop progressive dyspnoea and recurrent pneumothorax, chylous collections and occasional haemoptysis 1. Extra pulmonary lymphadenopathy and cystic masses of the axial lymphatics termed lymphangioleiomyomas can result in abdominal and pelvic lymphatic obstruction 7. LAM is often associated with angiomyolipoma in the kidneys 8, and an increased frequency of meningioma 9. LAM varies in clinical features and rate of progression: this together with an absence of clear prognostic factors results in patients being given conflicting information about prognosis. Diagnosis is made by tissue biopsy (generally from the lung but occasionally from lymph nodes or lymphangioleiomyomas) and/or a combination of history and high-resolution computed tomography scanning (HRCT). Pathological diagnosis relies on characteristic LAM cell morphology and positive immunoreactivity to smooth muscle actin and HMB-45 antibodies. Increasingly HRCT is used to diagnose LAM without resorting to lung biopsy; however a number of conditions with multiple pulmonary cysts can mimic LAM. As LAM is rare, there have been no controlled trials of its management. Supportive treatment includes management of airflow obstruction and hypoxaemia with bronchodilators and oxygen respectively, specific treatment for surgical or pleural complications including pneumo- and chylothorax, and interventional treatment of renal lesions 10, 11. As LAM is a disease of females and is thought to be accelerated by oestrogen, oophorectomy, tamoxifen, progesterone and gonadotropin-releasing hormone (GnRH) analogues have been used without evidence that they are effective. The recent finding of abnormalities in the TSC1/2 genes resulting …

Pulmonary lymphangioleiomyomatosis. A study of 69 patients. Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires (GERM"O"P).

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disorder of unknown cause characterized by peribronchial, perivascular, and perilymphatic proliferation of abnormal smooth muscle cells leading to cystic lesions. The hypothesis of hormonal dependence and the effectiveness of hormonal therapy have not yet been demonstrated conclusively, and the prevalence of extrathoracic manifestations and the survival of patients with LAM are somewhat contradictory. A multicentric retrospective study was conducted in an attempt to describe better the initial features, the diagnostic procedures, the associated lesions, and, above all, the management and course of LAM in a large homogeneous series of 69 stringently selected patients, with a majority of cases diagnosed since 1990. The aim of the study, based on a review of the literature, also was to provide a comprehensive view of this uncommon disease. The clinical features were in keeping with previous studies, but we found that exertional dyspnea and pneumothorax were the most common features, and chylous involvement was less frequent. LAM was diagnosed after menopause in about 10% of cases. The onset of LAM occurred during pregnancy in 20% of cases, and a clear exacerbation of LAM was observed in 14% of cases during pregnancy. Pulmonary LAM was diagnosed on lung histopathology in 83% of cases, but renal angiomyolipoma, observed in 32% of our patients, may be a useful diagnostic criterion when associated with typical multiple cysts on chest CT scan or with chylous effusion. Chest CT scan was more informative than chest X-ray (normal in 9% of cases), and may be indicated in spontaneous pneumothorax or renal angiomyolipoma in women of childbearing age. About 40% of the patients had a normal initial spirometry, while an obstructive ventilatory defect (44%), a restrictive ventilatory defect (23%), was observed in other patients. Initial diffusing capacity for carbon monoxide was frequently decreased (82%). Hormonal therapy was administered in 57 patients, but a clear > or = 15% improvement of FEV1 was observed in only 4 evaluable patients, treated with tamoxifen and progestogens (n = 2), progestogen (n = 1), and oophorectomy (n = 1). Probably 1 of the most urgent needs for clinical research in LAM is to test the currently available hormonal treatments in the context of international multicenter prospective controlled studies. Pleurodesis was performed in 40 patients. Lung transplantation was performed in 13 patients, 7.8 +/- 5.2 years after onset of LAM, in whom the mean FEV1 was 0.57 +/- 0.15 L. After a follow-up of 2.3 +/- 2.2 years, 9 patients were alive. Mean follow-up from onset of disease to either death or closing date was 8.2 +/- 6.3 years. Overall survival was better than usually reported in LAM, and Kaplan-Meier plot showed survival probabilities of 91% after 5 years, 79% after 10 years, and 71% after 15 years of disease duration.

Ascertainment of Individual Risk of Mortality for Patients with Idiopathic Pulmonary Fibrosis

RATIONALE Several predictors of mortality in patients with idiopathic pulmonary fibrosis have been described; however, there is a need for a practical and accurate method of quantifying the prognosis of individual patients. OBJECTIVES Develop a practical mortality risk scoring system for patients with idiopathic pulmonary fibrosis. METHODS We used a Cox proportional hazards model and data from two clinical trials (n = 1,099) to identify independent predictors of 1-year mortality among patients with idiopathic pulmonary fibrosis. From the comprehensive model, an abbreviated clinical model comprised of only those predictors that are readily and reliably ascertained by clinicians was derived. Beta coefficients for each predictor were then used to develop a practical mortality risk scoring system. MEASUREMENTS AND MAIN RESULTS Independent predictors of mortality included age, respiratory hospitalization, percent predicted FVC, 24-week change in FVC, percent predicted carbon monoxide diffusing capacity, 24-week change in percent predicted carbon monoxide diffusing capacity, and 24-week change in health-related quality of life. An abbreviated clinical model comprising only four predictors (age, respiratory hospitalization, percent predicted FVC, and 24-wk change in FVC), and the corresponding risk scoring system produced estimates of 1-year mortality risk consistent with observed data (9.9% vs. 9.7%; C statistic = 0.75; 95% confidence interval, 0.71–0.79). CONCLUSIONS The prognosis for patients with idiopathic pulmonary fibrosis may be accurately determined using four readily ascertainable predictors. Our simplified scoring system may be a valuable tool for determining prognosis and guiding clinical management. Additional research is needed to validate the applicability and accuracy of the scoring system.

Six-minute-walk test in idiopathic pulmonary fibrosis: test validation and minimal clinically important difference.

RATIONALE The 6-minute-walk test (6MWT) is a practical and clinically meaningful measure of exercise tolerance with favorable performance characteristics in various cardiac and pulmonary diseases. Performance characteristics in patients with idiopathic pulmonary fibrosis (IPF) have not been systematically evaluated. OBJECTIVES To assess the reliability, validity, and responsiveness of the 6MWT and estimate the minimal clinically important difference (MCID) in patients with IPF. METHODS The study population included all subjects completing a 6MWT in a clinical trial evaluating interferon gamma-1b (n = 822). Six-minute walk distance (6MWD) and other parameters were measured at baseline and at 24-week intervals using a standardized protocol. Parametric and distribution-independent correlation coefficients were used to assess the strength of the relationships between 6MWD and measures of pulmonary function, dyspnea, and health-related quality of life. Both distribution-based and anchor-based methods were used to estimate the MCID. MEASUREMENTS AND MAIN RESULTS Comparison of two proximal measures of 6MWD (mean interval, 24 d) demonstrated good reliability (coefficient = 0.83; P < 0.001). 6MWD was weakly correlated with measures of physiologic function and health-related quality of life; however, values were consistently and significantly lower for patients with the poorest functional status, suggesting good construct validity. Importantly, change in 6MWD was highly predictive of mortality; a 24-week decline of greater than 50 m was associated with a fourfold increase in risk of death at 1 year (hazard ratio, 4.27; 95% confidence interval, 2.57- 7.10; P < 0.001). The estimated MCID was 24-45 m. CONCLUSIONS The 6MWT is a reliable, valid, and responsive measure of disease status and a valid endpoint for clinical trials in IPF.

Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference.

RATIONALE Forced vital capacity (FVC) is an established measure of pulmonary function in idiopathic pulmonary fibrosis (IPF). Evidence regarding its measurement properties and minimal clinically important difference (MCID) in this population is limited. OBJECTIVES To assess the reliability, validity, and responsiveness of FVC and estimate the MCID in patients with IPF. METHODS The study population included all 1,156 randomized patients in two clinical trials of IFN-γ1b. FVC and other measures of functional status were measured at screening or baseline and 24-week intervals thereafter. Reliability was assessed based on two proximal measures of FVC, validity was assessed based on correlations between FVC and other measures of functional status, and responsiveness was assessed based on the relationship between 24-week changes in FVC and other measures of functional status. Distribution-based and anchor-based methods were used to estimate the MCID. MEASUREMENTS AND MAIN RESULTS Correlation of percent-predicted FVC between measurements (mean interval, 18 d) was high (r = 0.93; P < 0.001). Correlations between FVC and other parameters were generally weak, with the strongest observed correlation between FVC and carbon monoxide diffusing capacity (r = 0.38; P < 0.001). Correlations between change in FVC and changes in other parameters were slightly stronger (range, r = 0.16-0.37; P < 0.001). Importantly, 1-year risk of death was more than twofold higher (P < 0.001) in patients with a 24-week decline in FVC between 5% and 10%. The estimated MCID was 2-6%. CONCLUSIONS FVC is a reliable, valid, and responsive measure of clinical status in patients with IPF, and a decline of 2-6%, although small, represents a clinically important difference.