Air travel and incidence of pneumothorax in lymphangioleiomyomatosis.

BACKGROUND: Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease of women characterized by multiple lung cysts leading to respiratory insufficiency and frequent pneumothorax (PT). Air travel (AT) could increase the risk of PT in LAM through rupture of subpleural cysts induced by atmospheric pressure changes in aircraft cabin. To determine whether AT increases the risk of PT in LAM, we performed a retrospective survey of members of European LAM patient associations. A flight-related PT was defined as occurring ≤30 days after AT. RESULTS: 145 women reported 207 PT. In 128 patients with available data, the annual incidence of PT was 8% since the first symptoms of LAM and 5% since LAM diagnosis, compared to 0.006% in the general female population. Following surgical or chemical pleurodesis, the probability of remaining free of PT recurrence was respectively 82, 68, and 59% after 1, 5 and 10 years, as compared to only 55, 46 and 39% without pleurodesis (p = 0.026). 70 patients with available data performed 178 AT. 6 flight-related PT occurred in 5 patients. PT incidence since first symptoms of LAM was significantly higher ≤30 days after AT as compared to non-flight periods (22 versus 6%, risk ratio 3.58, confidence interval 1.40-7.45). CONCLUSIONS: The incidence of PT in LAM is about 1000 times higher than in the general female population, and is further increased threefold after AT. Chemical or surgical pleurodesis partly reduces the risk of PT recurrence in LAM.

Clinical phenotypes and survival of pre-capillary pulmonary hypertension in systemic sclerosis.

Pre-capillary pulmonary hypertension (PH) in systemic sclerosis (SSc) is a heterogeneous condition with an overall bad prognosis. The objective of this study was to identify and characterize homogeneous phenotypes by a cluster analysis in SSc patients with PH. Patients were identified from two prospective cohorts from the US and France. Clinical, pulmonary function, high-resolution chest tomography, hemodynamic and survival data were extracted. We performed cluster analysis using the k-means method and compared survival between clusters using Cox regression analysis. Cluster analysis of 200 patients identified four homogenous phenotypes. Cluster C1 included patients with mild to moderate risk pulmonary arterial hypertension (PAH) with limited or no interstitial lung disease (ILD) and low DLCO with a 3-year survival of 81.5% (95% CI: 71.4-88.2). C2 had pre-capillary PH due to extensive ILD and worse 3-year survival compared to C1 (adjusted hazard ratio [HR] 3.14; 95% CI 1.66-5.94; p = 0.0004). C3 had severe PAH and a trend towards worse survival (HR 2.53; 95% CI 0.99-6.49; p = 0.052). Cluster C4 and C1 were similar with no difference in survival (HR 0.65; 95% CI 0.19-2.27, p = 0.507) but with a higher DLCO in C4. PH in SSc can be characterized into distinct clusters that differ in prognosis.

A 12-week combination of clarithromycin and prednisone compared to a 24-week prednisone alone treatment in cryptogenic and radiation-induced organizing pneumonia.

Background: Some data suggest that anti-inflammatory macrolides may be effective to treat organizing pneumonia (OP) and prevent relapses, but no formal comparison with prednisone alone is available. To explore this issue, we retrospectively compared the efficacy of a 12-week combined regimen of clarithromycin and prednisone with a 24-week prednisone alone regimen in OP. Methods: A standard 12-week regimen of combined clarithromycin and prednisone was designed for the treatment of cryptogenic or radiation-induced OP, aiming at reducing the cumulated prednisone dose and the relapse rate. Its use was left to the discretion of the treating physicians, members of the Groupe d'Etudes et de Recherche sur les Maladies Orphelines Pulmonaires. Data were compared to a historical control group treated with a standard 24-week prednisone alone regimen. Results: 16 patients were treated with combined therapy and 21 with prednisone alone. Complete radiological remission was achieved in 63% of the combined therapy group and 81% of the prednisone alone group (p=0.38). Symptomatic relapses occurred in 81% of the combined therapy group, and 52% of the prednisone alone group (p=0.14). No side effect of clarithromycin was reported. Conclusions: In patients with cryptogenic or radiation-induced OP, a 12-week regimen of clarithromycin and prednisone showed no benefit on remission rate and relapse rate as compared to a 24-week prednisone only regimen. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 230-238).

Revisiting the systemic vasculitis in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): A study of 157 patients by the Groupe d'Etudes et de Recherche sur les Maladies Orphelines Pulmonaires and the European Respiratory Society Taskforce on eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

OBJECTIVE: To guide nosology and classification of patients with eosinophilic granulomatosis with polyangiitis (EGPA) based on phenotype and presence or absence of ANCA. METHODS: Organ manifestations and ANCA status were retrospectively analyzed based on the presence or not of predefined definite vasculitis features or surrogates of vasculitis in patients asthma, eosinophilia, and at least one systemic organ manifestation attributable to systemic disease. RESULTS: The study population included 157 patients (mean age 49.4±14.1), with a follow-up of 7.4±6.4years. Patients with ANCA (31%) more frequently had weight loss, myalgias, arthralgias, biopsy-proven vasculitis, glomerulonephritis on biopsy, hematuria, leukocytoclastic capillaritis and/or eosinophilic infiltration of arterial wall on biopsy, and other renal disease. A total of 41% of patients had definite vasculitis manifestations (37%) or strong surrogates of vasculitis (4%), of whom only 53% had ANCA. Mononeuritis multiplex was associated with systemic vasculitis (p=0.005) and with the presence of ANCA (p<0.001). Overall, 59% of patients had polyangiitis as defined by definite vasculitis, strong surrogate of vasculitis, mononeuritis multiplex, and/or ANCA with at least one systemic manifestation other than ENT or respiratory. Patients with polyangiitis had more systemic manifestations including arthralgias (p=0.02) and renal disease (p=0.024), had higher peripheral eosinophilia (p=0.027), and a trend towards less myocarditis (p=0.057). Using predefined criteria of vasculitis and surrogates of vasculitis, ANCA alone were found to be insufficient to categorise patients with vasculitis features. CONCLUSION: We suggest a revised nomenclature and definition for EGPA and a new proposed entity referred to as hypereosinophilic asthma with systemic (non vasculitic) manifestations.

Primary cardiac lymphoma: diagnosis, treatment and outcome in a modern series.

Primary cardiac lymphoma (PCL) represents a rare subset of extranodal lymphomas for which the primary lesion arises from the heart and/or the pericardium. Fundamental characteristics of PCL remain uncertain, regarding optimal diagnosis strategy, pathological features, treatments, as well as prognostic factors. This is a single-institution retrospective study of patients with histologically proven lymphoma, presenting with exclusive or predominant myocardial invasion at time of diagnosis. Thirteen patients were included, all of whom had symptoms related to cardiac tumour location with chronic chest pain in six (46%), dyspnea in seven (54%) and arythmia in three (23%). Sub-acute and acute congestive heart failure were noticed in respectively nine (70%) and one (9%). PCL was identified at transthoracic echocardiography and computed tomography scan in 80 and 100% of patients, respectively. Most frequent location was the right atrium in 10 (77%) patients. Pericardial effusion was identified in 10 (77%). Pathological diagnosis-diffuse large B-cell lymphoma in 12 cases and Burkitt in 1 case-was made on cardiac surgical biopsies in 9 cases and by intravascular procedure in 2 cases. All patients received first-line chemotherapy, with a complete response rate of 62%. Recurrences occurred in 55% of patients, mostly at extracardiac extranodal sites. Our data confirm that PCL harbours specific clinical and anatomical features. The aggressiveness of PCL mainly results from the possible onset of acute cardiac events. Further molecular characterization may help to further individualize PCL among diffuse and intrathoracic lymphomas. Copyright © 2016 John Wiley & Sons, Ltd.

Prevalence and characteristics of TERT and TERC mutations in suspected genetic pulmonary fibrosis.

Telomerase reverse transcriptase (TERT) or telomerase RNA (TERC) gene mutation is a major monogenic cause of pulmonary fibrosis. Sequencing of TERT/TERC genes is proposed to patients with familial pulmonary fibrosis. Little is known about the possible predictors of this mutation and its impact on prognosis.We retrospectively analysed all the genetic diagnoses made between 2007-2014 in patients with pulmonary fibrosis. We evaluated the prevalence of TERT/TERC disease-associated variant (DAV), factors associated with a DAV, and the impact of the DAV on survival.237 patients with pulmonary fibrosis (153 with familial pulmonary fibrosis, 84 with telomere syndrome features without familial pulmonary fibrosis) were tested for TERT/TERC DAV. DAV was diagnosed in 40 patients (16.8%), including five with non-idiopathic interstitial pneumonia. Prevalence of TERT/TERC DAV did not significantly differ between patients with familial pulmonary fibrosis or with only telomere syndrome features (18.2% versus 16.4%). Young age, red blood cell macrocytosis, and low platelet count were associated with the presence of DAV; the probability of DAV was increased for patients 40-60 years. Transplant-free survival was lower with than without TERT/TERC DAV (4.2 versus 7.2 years; p=0.046).TERT/TERC DAV were associated with specific clinical and biological features and reduced transplant-free survival.

Respiratory manifestations of eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

The respiratory manifestations of eosinophilic granulomatosis with polyangiitis (EGPA) have not been studied in detail.In this retrospective multicentre study, EGPA was defined by asthma, eosinophilia and at least one new onset extra-bronchopulmonary organ manifestation of disease.The study population included 157 patients (mean±sd age 49.4±14.1 years), with a mean±sd blood eosinophil count of 7.4±6.4×109 L-1 at diagnosis. There was a mean±sd of 11.8±18.2 years from the onset of asthma to the diagnosis of EGPA, of 1.4±8.4 years from the first onset of peripheral eosinophilia to the diagnosis of EGPA, and of 7.4±6.4 years from EGPA diagnosis to the final visit. Despite inhaled and oral corticosteroid treatment, the severity of asthma increased 3-6 months before the onset of the systemic manifestations. Asthma was severe in 57%, 48%, and 56% of patients at diagnosis, at 3 years, and at the final visit, respectively. Persistent airflow obstruction was present in 38%, 30%, and 46% at diagnosis, at 3 years, and at the final visit, respectively.In EGPA, asthma is severe, antedates systemic manifestations by a mean of 12 years, and progresses to long-term persistent airflow obstruction despite corticosteroids in a large proportion of patients, which affects long-term management and morbidity.

Severe Prolonged Cough as Presenting Manifestation of FIP1L1-PDGFRA+ Chronic Eosinophilic Leukaemia: A Widely Ignored Association.

Chronic eosinophilic leukaemia associated with the FIP1L1-PDGFRA fusion gene (F/P+ CEL) is a rare cause of marked persistent hypereosinophilia, arising almost exclusively in male patients. Clinical presentations are heterogeneous with a higher incidence of eosinophil-mediated cardiomyopathy than in other hypereosinophilic syndrome variants. Features of chronic myeloproliferative disease are often present, including splenomegaly and elevated serum vitamin B12 levels. The diagnosis is made by fluorescence in situ hybridization (FISH) showing the deletion of the CHIC2 locus and/or RT-PCR showing the FIP1L1-PDGFRA fusion transcript. Treatment with imatinib mesylate, a tyrosine kinase inhibitor, results in rapid and complete resolution of hypereosinophilia and associated symptoms, except for those related to sub-endocardial fibrosis that may be irreversible. We report the case of a male patient in whom isolated intractable cough remained the only clinical manifestation of F/P+ CEL for 4 years. Furthermore, eosinophil autofluorescence, an as yet unreported artefact in this setting, precluded the detection of the CHIC2 deletion and further delayed diagnosis, underlining that both FISH and RT-PCR should be performed when this disease is suspected.

Many Faces of Bronchiolitis and Organizing Pneumonia.

As the bronchioles have a strategic position between the airways and the alveolar structures, they are at a site where disorders of many origins may develop, including infections, inflammatory and/or fibrosing processes of immune, occupational, environmental, tumoral, and iatrogenic origin, which may result in predominant bronchiolitis and/or organizing pneumonia. This etiologic variety results in many distinct entities and syndromes, common or rare, with new or renewed faces such as bronchiolocentric interstitial pneumonia or organizing pneumonia primed by radiation to the breast.

Risk of Direct Oral Anticoagulant Bioaccumulation in Patients with Pulmonary Hypertension.

BACKGROUND: Patients treated for pulmonary arterial hypertension (PAH) frequently receive vitamin K antagonists (VKAs) for PAH or validated indications (such as atrial fibrillation or venous thromboembolism). In these latter indications, VKAs are challenged by direct oral anticoagulants (DOAs). Decreased dosage of DOAs has been proposed in patients at risk of bioaccumulation. OBJECTIVES: We aimed to evaluate the frequency of bioaccumulation risks in patients treated with PAH-targeted therapy, particularly regarding the presence of validated indications. METHODS: We conducted a retrospective study in three different PAH referral centers. All patients receiving PAH-targeted therapy were classified according to demographics, prescription and indications of VKAs, and the presence of major bioaccumulation risk factors (renal failure, low body weight, strong P-glycoprotein or cytochrome P3A4 inhibitors). RESULTS: Two hundred and thirty-nine of the 366 patients included received VKAs, 94 for validated indications. At least one major risk factor was found in 231 (63.1%) of the whole study population, and in 54 (57.4%) of the patients anticoagulated for a validated indication. No specific patient phenotype could be individualized. CONCLUSIONS: About 1 in 2 patients treated with PAH therapy has at least one of the three major risk factors for DOA bioaccumulation. DOAs in the PH setting could be associated with bioaccumulation and should be individualized, mainly in patients with confirmed indication.

Connective tissue diseases, multimorbidity and the ageing lung.

Connective tissue diseases encompass a wide range of heterogeneous disorders characterised by immune-mediated chronic inflammation often leading to tissue damage, collagen deposition and possible loss of function of the target organ. Lung involvement is a common complication of connective tissue diseases. Depending on the underlying disease, various thoracic compartments can be involved but interstitial lung disease is a major contributor to morbidity and mortality. Interstitial lung disease, pulmonary hypertension or both are found most commonly in systemic sclerosis. In the elderly, the prevalence of connective tissue diseases continues to rise due to both longer life expectancy and more effective and better-tolerated treatments. In the geriatric population, connective tissue diseases are almost invariably accompanied by age-related comorbidities, and disease- and treatment-related complications, which contribute to the significant morbidity and mortality associated with these conditions, and complicate treatment decision-making. Connective tissue diseases in the elderly represent a growing concern for healthcare providers and an increasing burden of global health resources worldwide. A better understanding of the mechanisms involved in the regulation of the immune functions in the elderly and evidence-based guidelines specifically designed for this patient population are instrumental to improving the management of connective tissue diseases in elderly patients.

A prospective study of the 6†min walk test as a surrogate marker for haemodynamics in two independent cohorts of treatment-naïve systemic sclerosis-associated pulmonary arterial hypertension.

OBJECTIVES: Despite the wide use of the 6 min walk distance (6MWD), no study has ever assessed its validity as a surrogate marker for haemodynamics and predictor of outcome in isolated pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH). We designed this work to address this issue. METHODS: Treatment-naïve patients with SSc-PAH were prospectively included from two sources: the French PAH Network (a prospective epidemiological cohort) (n=83) and randomised clinical trials submitted for drug approval (Food and Drug Administration) (n=332). Correlations between absolute values of the 6MWD and haemodynamics at baseline, as well as between variations of 6MWD and haemodynamics during follow-up, were studied in both populations. RESULTS: In the French cohort, baseline cardiac output (CO) (R(2)=0.19, p=0.001) and New York Heart Association class (R(2)=0.10, p<0.001) were significantly and independently correlated with baseline 6MWD in multivariate analysis. A significant, independent, but weaker, correlation with CO was also found in the Food and Drug Administration sample (R(2)=0.04, p<0.001). During follow-up, there was no association between the changes in 6MWD and haemodynamic parameters in patients under PAH-specific treatments. CONCLUSIONS: In SSc-PAH, CO independently correlates with 6MWD at baseline, but accounts for a small amount of the variance of 6MWD in both study samples. This suggests that other non-haemodynamic factors could have an impact on the walk distance. Moreover, variations of 6MWD do not reflect changes in haemodynamics among treated patients. Our results suggest that 6MWD is not an accurate surrogate marker for haemodynamic severity, nor an appropriate outcome measure to assess changes in haemodynamics during follow-up in treated SSc-PAH.

Tracheobronchial Stenoses in Granulomatosis With Polyangiitis (Wegener's): A Report on 26 Cases.

Tracheobronchial stenoses (TBSs) are potentially severe manifestations of granulomatosis with polyangiitis (Wegener's) (GPA) that usually respond poorly to corticosteroids and immunosuppressive agents. We describe 26 GPA patients with ≥1 tracheal (mainly subglottic, SGS) and/or bronchial stenosis(ses) (BS(s)).Sixteen patients had solitary SGS and 10 had ≥1 BS(s). The male/female sex ratio was 9:17, and the median age at GPA diagnosis was 32 years (3:13 and 28 years, respectively, for SGS patients). Antineutrophil cytoplasm antibodies were proteinase 3-positive in 65.5% of the patients (50% of those with SGS).Despite conventional GPA therapy, 62% patients experienced ≥1 stenosis relapse(s) (81% of SGS patients, for a total of 1-8 relapses per patient). None of the several systemic or endoscopic treatments prevented future relapses. Cyclophosphamide induction therapy was effective in 4/6 patients with BS(s) and in 1 patient with SGS among the 7 treated. After many relapses, rituximab achieved remission in 3/4 SGS patients. Endoscopic treatments (dilation, laser, corticosteroid injection, etc.) had only transient efficacy. Other GPA manifestations relapsed independently of TBSs. One SGS patient died of acute respiratory distress syndrome.Our findings confirmed that TBSs are severe GPA manifestations that evolve independently of other organ involvements and do not respond to conventional systemic regimens. As previously described, our population was younger and comprised more females than usual GPA patients, especially those with SGS.The small number of patients and the wide variety of local and systemic treatments prevent us from drawing definitive conclusions about the contribution of each procedure. However, cyclophosphamide seemed to effectively treat BSs, but not SGS, and rituximab may be of interest for SGS management.

Inflammatory bowel diseases in anti-neutrophil cytoplasmic antibody-associated vasculitides: 11 retrospective cases from the French Vasculitis Study Group.

OBJECTIVE: Coexistence of ANCA-associated vasculitis (AAV) and IBD is a rare condition that is rarely described in the literature. The aim of the study was to describe the main characteristics of patients presenting with both IBD and AAV. METHODS: A retrospective study of AAV patients in the French Vasculitis Study Group cohort who also had a diagnosis of IBD was conducted. We reviewed the medical records and outcomes of these patients. RESULTS: We identified 11 patients with AAV and IBD. Four patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss) also had ulcerative colitis and seven patients with granulomatosis with polyangiitis (GPA) had Crohn's disease. No Crohn's disease was observed in eosinophilic GPA and no ulcerative colitis in GPA. IBD started before AAV manifestations in six cases, simultaneously in two cases and after AAV manifestations in three cases. CONCLUSION: Coexistence of IBD and AAV is a rare condition. The therapeutic management of these patients includes corticosteroids in all cases and immunosuppressive drugs in some patients. Coexistence of IBD and AAV might be explained by common underlying inflammatory responses and cytokine profiles polarized towards either Th1 or Th2. Finally, in the presence of digestive manifestations in the context of AAV, the hypothesis of IBD should be assessed.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) Consensus Task Force recommendations for evaluation and management.

OBJECTIVE: To develop disease-specific recommendations for the diagnosis and management of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (EGPA). METHODS: The EGPA Consensus Task Force experts comprised 8 pulmonologists, 6 internists, 4 rheumatologists, 3 nephrologists, 1 pathologist and 1 allergist from 5 European countries and the USA. Using a modified Delphi process, a list of 40 questions was elaborated by 2 members and sent to all participants prior to the meeting. Concurrently, an extensive literature search was undertaken with publications assigned with a level of evidence according to accepted criteria. Drafts of the recommendations were circulated for review to all members until final consensus was reached. RESULTS: Twenty-two recommendations concerning the diagnosis, initial evaluation, treatment and monitoring of EGPA patients were established. The relevant published information on EGPA, antineutrophil-cytoplasm antibody-associated vasculitides, hypereosinophilic syndromes and eosinophilic asthma supporting these recommendations was also reviewed. DISCUSSION: These recommendations aim to give physicians tools for effective and individual management of EGPA patients, and to provide guidance for further targeted research.

Usual interstitial pneumonia end-stage features from explants with radiologic and pathological correlations.

Idiopathic pulmonary fibrosis (IPF) is the most frequent and severe idiopathic interstitial pneumonia, with typical high-resolution computed tomography (HRCT) features and histologic pattern of usual interstitial pneumonia (UIP); its main differential diagnosis is fibrotic nonspecific interstitial pneumonia (F-NSIP). Usual interstitial pneumonia was mainly described from lung biopsies, and little is known on explants. Twenty-two UIP/IPF explants were analyzed histologically and compared with previous open lung biopsies (OLBs; n = 11) and HRCT (n = 19), when available. Temporospatial heterogeneity and subpleural and paraseptal fibrosis were similarly found in UIP/IPF explants and OLB (91%-95%). Fibroblastic foci were found in 82% of OLBs and 100% of explants, with a higher mean score in explants (P = .023). Honeycombing was present in 64% of OLBs and 95% of explants, with a higher mean score in explants (P = .005). Almost 60% of UIP/IPF explants showed NSIP areas and 41% peribronchiolar fibrosis; inflammation, bronchiolar metaplasia, and vascular changes were more frequent in UIP/IPF explants; and Desquamative Interstitial Pneumonia (DIP)-like areas were not common (18%-27%). Numerous large airspace enlargements with fibrosis were frequent in UIP/IPF explants (59%). On HRCT, honeycombing was observed in 95% of the cases and ground-glass opacities in 53%, correlating with NSIP areas or acute exacerbation at histology. Six patients had combined IPF and emphysema. Lesions were more severe in UIP/IPF explants, reflecting the worsening of the disease. Usual interstitial pneumonia/IPF explants more frequently presented with confounding lesions such as NSIP areas, peribronchiolar fibrosis, and airspace enlargements with fibrosis sometimes associated with emphysema.

Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis.

Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genes TERT (reverse transcriptase) and TERC (RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF without TERT and TERC mutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygous RTEL1 mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this, RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygous RTEL1 mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus, RTEL1 enlarges the number of telomere-associated genes implicated in FPF.