Sergio Harari

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 …

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point http://ow.ly/p0RDL

Walking distance on 6-MWT is a prognostic factor in idiopathic pulmonary fibrosis

BACKGROUND AND AIM OF THE WORK Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality rates and a median survival of 2-3 years from time of diagnosis. The prognosis for any individual patient, however, is variable. To elucidate the clinical significance of 6-min walking test (6-MWT) in patients with IPF, we sought to assess the relationship between distance walked and desaturation during this test and pulmonary function tests (PFTs). We also evaluate the prognostic value of 6-MWT in comparison with PFTs at baseline and during follow-up. METHODS The clinical data of 44 patients with IPF were retrospectively analysed. Twenty-nine patients had an additional evaluation after 12 month of follow-up. RESULTS Distance walked in 6 min was independently related to mortality by multivariate analysis. Patients walking less then 212 m had a significantly lower survival than those walking farther, assessed by Kaplan-Meier survival curves (log-rank test, p<0.036). During a mean follow-up period of 19.8 months (range 3.2-46.4), 11 patients died of causes related to disease. Changes in meters walked at 12 months evaluation were also predictive of survival (p=0.05). CONCLUSIONS These results confirm that in IPF distance walked in 6 min is independent associated with mortality.

Cellular interactions in the pathogenesis of interstitial lung diseases

Interstitial lung disease (ILD) encompasses a large and diverse group of pathological conditions that share similar clinical, radiological and pathological manifestations, despite potentially having quite different aetiologies and comorbidities. Idiopathic pulmonary fibrosis (IPF) represents probably the most aggressive form of ILD and systemic sclerosis is a multiorgan fibrotic disease frequently associated with ILD. Although the aetiology of these disorders remains unknown, in this review we analyse the pathogenic mechanisms by cell of interest (fibroblast, fibrocyte, myofibroblast, endothelial and alveolar epithelial cells and immune competent cells). New insights into the complex cellular contributions and interactions will be provided, comparing the role of cell subsets in the pathogenesis of IPF and systemic sclerosis. Distinct cell populations contribute to the complex pathogenesis of IPF and systemic sclerosis-associated ILD http://ow.ly/AjFaz

Pleural and pulmonary involvement in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a rare complex autoimmune disease with a multisystem involvement. The clinical manifestations of this disease include an erythematous rash, oral ulcers, polyarthralgia, nonerosive arthritis, polyserositis, hematologic, renal, neurologic, pulmonary and cardiac abnormalties. The involvement of the respiratory system is frequent. Pleuro-pulmonary manifestations are present in almost half of the patients during the disease course and may be the presenting symptoms in 4-5% of patients with SLE. Complications directly associated to the disease include pleuritis with or without pleural effusion, alveolitis, interstitial lung disease, lupus pneumonitis, pulmonary hemorrhage, pulmonary arterial hypertension, and pulmonary thromboembolic disease. Complications due to secondary causes include pleuro-pulmonary manifestations of cardiac and renal failure, atelectasis due to diaphragmatic dysfunction, opportunistic pneumonia, and drug toxicity. The prevalence, clinical presentation, prognosis and response to treatment vary, depending on the pattern of involvement. As with other connective tissue diseases, early and specific therapeutic intervention may be indicated for many of these pleuro-pulmonary manifestations.

Lymphangioleiomyomatosis: what do we know and what are we looking for?

Lymphangioleiomyomatosis (LAM) is a rare disease characterised by proliferation of abnormal smooth muscle-like cells (LAM cells) leading to progressive cystic destruction of the lung, lymphatic abnormalities and abdominal tumours. It affects predominantly females and can occur sporadically or in patients with tuberous sclerosis complex. This review describes the recent progress in our understanding of the molecular pathogenesis of the disease and LAM cell biology. It also summarises current therapeutic approaches and the most promising areas of research for future therapeutic strategies.

Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients

This retrospective, multicentre study evaluated patients with lymphangioleiomyomatosis (LAM) and pre-capillary pulmonary hypertension (PH) by right heart catheterisation. It was conducted in 20 females with a mean±sd age of 49±12 yrs and a mean±sd time interval between LAM and PH diagnoses of 9.2±9.8 yrs. All, except for one patient, were receiving supplemental oxygen. 6-min walking distance was mean±sd 340±84 m. Haemodynamic characteristics were: mean pulmonary artery pressure (PAP) 32±6 mmHg, cardiac index 3.5±1.1 L·min−1·m−2 and pulmonary vascular resistance (PVR) 376±184 dyn·s·cm−5. Mean PAP was >35 mmHg in only 20% of cases. The forced expiratory volume in 1 s was 42±25%, carbon monoxide transfer factor was 29±13%, and arterial oxygen tension (Pa,O2) was 7.4±1.3 kPa in room air. Mean PAP and PVR did not correlate with Pa,O2. In six patients who received oral pulmonary arterial hypertension (PAH) therapy, the PAP decreased from 33±9 mmHg to 24±10 mmHg and the PVR decreased from 481±188 dyn·s·cm−5 to 280±79 dyn·s·cm−5. The overall probability of survival was 94% at 2 yrs. Pre-capillary PH of mild haemodynamic severity may occur in patients with LAM, even with mild pulmonary function impairment. PAH therapy might improve the haemodynamics in PH associated with LAM.

Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study

Lymphangioleiomyomatosis is a rare, progressive cystic lung disorder characterised by dysregulated activation of mammalian target of rapamycin (mTOR) signalling. This was a phase IIa, multicentre, open-label study of the mTOR inhibitor everolimus (2.5 mg·day−1 escalated to 10 mg·day−1) in 24 women with lymphangioleiomyomatosis. Primary endpoints were safety, pharmacokinetics and serum vascular endothelial growth factor-D (VEGF-D) levels; secondary endpoints were measures of lung function. Following 26 weeks of everolimus treatment, forced vital capacity exhibited stability, while forced expiration volume in 1 s improved from baseline, with mean changes (95% confidence interval) of 10 mL (−111–132) and 114 mL (11–217), respectively; 6-min walk distance improved by 47 m. Median VEGF-D and collagen IV levels decreased from baseline, from 1730 pg·mL−1 to 934.5 pg·mL−1, and 103 ng·mL−1 to 80.5 ng·mL−1, respectively. Adverse events were mostly grade 1−2; mouth ulceration, headache, nausea, stomatitis and fatigue were common. Serious adverse events suspected to be treatment related included peripheral oedema, pneumonia, cardiac failure and Pneumocystis jirovecii infection. Everolimus blood levels increased dose proportionally. In this study, everolimus improved some measures of lung function and exercise capacity and reduced serum VEGF-D and collagen IV. Side effects were generally consistent with known toxicities of mTOR inhibitors, although some were severe. Everolimus improved some lung function measures and reduced serum biomarkers in patients with LAM http://ow.ly/MkQQK

Pulmonary hypertension in patients with chronic myeloproliferative disorders

Pulmonary hypertension (PH) is a major complication of several haematological disorders. Chronic myeloproliferative diseases (CMPDs) associated with pulmonary hypertension have been included in group five of the clinical classification for pulmonary hypertension, corresponding to pulmonary hypertension for which the aetiology is unclear and/or multifactorial. The aim of this review is to discuss the epidemiology, pathogenic mechanism and treatment approaches of the more common forms of pulmonary hypertension in the context of CMPDs: chronic thromboembolic pulmonary hypertension, precapillary pulmonary hypertension and drug-induced PH. Epidemiology, pathogenic mechanism and treatment approach of PH in patients with chronic myeloproliferative diseases http://ow.ly/Q1QX4

Efficacy of pirfenidone for idiopathic pulmonary fibrosis: An Italian real life study

BACKGROUND In this retrospective Italian study, which involved all major national interstitial lung diseases centers, we evaluated the effect of pirfenidone on disease progression in patients with IPF. METHODS We retrospectively studied 128 patients diagnosed with mild, moderate or severe IPF, and the decline in lung function monitored during the one-year treatment with pirfenidone was compared with the decline measured during the one-year pre-treatment period. RESULTS At baseline (first pirfenidone prescription), the mean percentage forced vital capacity (FVC) was 75% (35-143%) of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted. Forty-eight patients (37.5%) had mild disease (GAP index stage I), 64 patients (50%) had moderate IPF (stage II), and 8 patients (6.3%) had severe disease (stage III). In the whole population, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355) in comparison to the pre-treatment period. Stratification of patients into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%) revealed that attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. Stratification of patients according to GAP index at baseline (stage I vs. II/III) also revealed that attenuation of decline in lung function was more pronounced in patients with more severe disease. CONCLUSIONS In this national experience, pirfenidone reduced the rate of annual FVC decline (p = 0.065). Since pirfenidone provided significant treatment benefit for patients with moderate-severe disease, our results suggest that the drug may also be effective in patients with more advanced disease.