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Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 (POU2AF1), T-cell leukemia/lymphoma protein 1A (TCL1A), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test p

Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease, predisposing to an increased risk of infection. A complete picture of these infections is lacking., Research Question: Describe the characteristics and clinical outcomes of patients diagnosed with aPAP, and to identify risk factors associated with opportunistic infections., Methods: We conducted a retrospective cohort including all patients diagnosed with aPAP between 2008 and 2018 in France and Belgium. Data were collected using a standardised questionnaire including demographics, comorbidities, imaging features, outcomes and microbiological data., Results: We included 104 patients, 2/3 were men and median age at diagnosis was 45 years. With a median follow-up of 3.4 years (IQR 1.7-6.6 years), 60 patients (58%), developed at least one infection, including 23 (22%) with opportunistic infections. Nocardia spp was the main pathogen identified (n=10). Thirty-five (34%) patients were hospitalised due to infection. In univariate analysis, male gender was associated with opportunistic infections (p=0.04, OR=3.88; 95% CI (1.02 to 22.06)). Anti-granulocyte macrophage colony-stimulating factor antibody titre at diagnosis was significantly higher among patients who developed nocardiosis (1058 (316-1591) vs 580 (200-1190), p=0.01). Nine patients had died (9%), but only one death was related to infection., Interpretation: Patients with aPAP often presented with opportunistic infections, especially nocardiosis, which highlights the importance of systematic search for slow-growing bacteria in bronchoalveolar lavage or whole lung lavage., Competing Interests: Competing interests: The authors reported no conflict of interest related to this work. SMA reports having received consultancy for board membership, consultancy or speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis and Roche, GSK, BMS, Chiesi and Pfizer; and travel support from Boehringer Ingelheim. Other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Forced vital capacity (FVC) is routinely used to quantify the severity and identify the progression of idiopathic pulmonary fibrosis (IPF). Although less commonly used, lung transfer of carbon monoxide (TLCO) correlates better with the severity of IPF than does FVC., Methods: Aiming at studying how FVC behaves in relation to TLCO, we analysed cross-sectional data from 430 IPF patients, of which 221 had at least 2 assessments (performed 2.4 ± 1.9 years apart) available for longitudinal analyses. Thresholds for identifying "abnormal" FVC and TLCO values were the statistically-defined lower limits of normal (LLN). For patients with longitudinal data, mean annual absolute declines of FVC and TLCO were calculated., Results: The correlation between FVC and TLCO (%predicted) was weak (R 2 =0.21). FVC was "abnormal" (i.e.,

Background: There is growing evidence of gender-specific phenotypic differences among patients with idiopathic pulmonary fibrosis (IPF), which may affect patient outcomes., Objectives: We present the characteristics of patients with IPF at inclusion in the French Rare Disease Cohort - Interstitial Lung Disease (RaDiCo-ILD) with the aim of characterizing gender-specific phenotypic differences., Methods: Patients with IPF who were enrolled in the national, multicentre RaDiCo-ILD cohort were included. Demographic characteristics, comorbidities, health-related quality of life (HRQoL) scores, pulmonary function, chest imaging, and IPF treatment were collected at inclusion and described by gender., Results: The cohort included 724 patients with IPF (54% of RaDiCo-ILD cohort), of whom 82.9% were male. The proportion of male and female patients with a prior history of smoking was 75.0% and 26.8%, respectively. Emphysema was present in 17.0% (95% confidence interval [CI]: 10.0, 24.0) of men and 5.4% (95% CI: 1.2, 9.6) of women. At inclusion, females had poorer HRQoL than males based on St. George's Respiratory Questionnaire scores (48.5 [95% CI: 43.9, 53.0] and 41.5 [39.4, 43.6], respectively). The mean forced vital capacity per cent predicted was 77.7% (95% CI: 76.2, 79.3) and 87.4% (83.4, 91.4) for males and females, respectively. Honeycombing on high-resolution computed tomography (HRCT) was present in 70.8% (95% CI: 61.0, 80.6) of males and 45.8% (95% CI: 35.1, 56.5) of females., Conclusions: This analysis of patients with IPF at inclusion in the RaDiCo-ILD cohort provides evidence that comorbid emphysema, lung volume reduction, and honeycombing on HRCT are more common characteristics of males than females., (© 2021 S. Karger AG, Basel.)

Background: In idiopathic pulmonary fibrosis (IPF), some physiological parameters measured during a 6-min walk test (6-MWT) impart reliable prognostic information. Sit-to-stand tests (STSTs) are field exercise tests that are easier to implement than the 6-MWT in daily practice., Objectives: The aims of the study were to test the reproducibility and compare 2 STSTs (the 1-min STST [1-STST] and the semi-paced 3-min chair rise test [3-CRT]) in IPF, and to determine if selected physiological parameters (speed of displacement and changes in pulse oxygen saturation [SpO2]) are interchangeable between the STSTs and the 6-MWT., Methods: Thirty-three patients with stable IPF were studied in 3 French expert centers. To test reproducibility, intra-class correlations (ICCs) of parameters measured during tests performed 7-14 days apart were calculated. To test interchangeability, the agreement and correlation of physiological responses measured during STSTs and during 6-MWT were studied., Results: Vertical displacements and changes in SpO2 during both STSTs were reproducible, with ICCs ranging from 0.78 [0.63-0.87] to 0.95 [0.92-0.97]. Vertical displacements during 1-STST and 3-CRT were correlated with 6-MWT distance (correlation coefficients (r) of 0.72 and 0.77, respectively; p < 0.001). Similarly, correlations were found between changes in SpO2 measured during the 2 STSTs and the 6-MWT, with coefficients ranging from 0.73 to 0.91 (p < 0.001). Distance walked and SpO2 during 6-MWT were well estimated from vertical displacement and SpO2 during the 2 STSTs, respectively., Conclusion: The correlations found between the 2 STSTs and the 6-MWT suggest that STSTs may be of interest to assess displacement and exercise-induced changes in SpO2 in IPF patients., (© 2021 S. Karger AG, Basel.)

Background: There are chronic forms of hypersensitivity pneumonitis (cHP) that can progress to pulmonary fibrosis. There is no recommended treatment for patients whose respiratory condition continues to deteriorate in spite of antigen avoidance. Whether rituximab may be beneficial to patients with cHP is unknown. The aim of this study was to describe the course of 20 patients with cHP under rituximab therapy., Methods: This retrospective study was conducted from November 2018 to July 2019 in 7 French university hospitals. Forced Vital Capacity (FVC) was measured 6 months before rituximab therapy onset (M - 6), at rituximab onset (M0), and 6 months later (M+6)., Results: FVC decreased significantly in the 6 months preceding the introduction of rituximab (65% [44; 112%] at M - 6 versus 59% [39; 102%] at M0; p = 0.0001), but it did not differ significantly from that at 6 months after the introduction of rituximab (61% [38; 99%]). The decline in FVC between M0 and M+6 (-3% [-15; +19%]) was significantly less than between M - 6 and M0 (-8% [-21; 0%]) (p = 0.0002). Between M0 (37% [16; 73%]) and M + 6 (45% [15; 70%]), the median DLCO remained stable (p = 0.12). DLCO improved at M+6 in 5 of the 8 patients (63%) for whom a DLCO value was available at M+6 improved their DLCO., Conclusion: Rituximab seems well tolerated, and may lead to stabilization or improvement of lung function in some patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Bronchial diseases are characterised by the weak efficiency of mucus transport through the lower airways, leading in some cases to the muco-obstruction of bronchi. It has been hypothesised that this loss of clearance results from alterations in the mucus rheology, which are reflected in sputum samples collected from patients, making sputum rheology a possible biophysical marker of these diseases and their evolution. However, previous rheological studies have focused on quasi-static viscoelastic (linear storage and loss moduli) properties only, which are not representative of the mucus mobilisation within the respiratory tract. In this paper, we extend this approach further, by analysing both quasi-static and some dynamic (flow point) properties, to assess their usability and relative performance in characterising several chronic bronchial diseases (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) and distinguishing them from healthy subjects. We demonstrate that pathologies influence substantially the linear and flow properties. Linear moduli are weakly condition-specific and even though the corresponding ranges overlap, distinct levels can be identified. This directly relates to the specific mucus structure in each case. In contrast, the flow point is found to strongly increase in muco-obstructive diseases, which may reflect the complete failure of mucociliary clearance causing episodic obstructions. These results suggest that the analysis of quasi-static and dynamic regimes in sputum rheology is in fact useful as these regimes provide complementary markers of chronic bronchial diseases.

Introduction: In 2015, the International Society for Heart and Lung Transplantation (ISHLT) published a consensus document for the selection of lung transplant candidates. In the absence of recent French recommendations, this guideline is useful in order to send lung transplant candidates to the transplantation centers and to list them for lung transplantation at the right time., Background: The main indications for lung transplantation in adults are COPD and emphysema, idiopathic pulmonary fibrosis and interstitial diseases, cystic fibrosis and pulmonary arterial hypertension (PAH). The specific indications for each underlying disease as well as the general contraindications have been reviewed in 2015 by the ISHLT. For cystic fibrosis, the main factors are forced expiratory volume in one second, 6-MWD, PAH and clinical deterioration characterized by increased frequency of exacerbations; for emphysema progressive disease, the BODE score, hypercapnia and FEV1; for PAH progressive disease or the need of specific intravenous therapy and NYHA classification. Finally, the diagnosis of fibrosing interstitial lung disease is usually a sufficient indication for lung transplantation assessment., Outlook and Conclusion: These new recommendations, close to French practices, help clinicians to find the right time for referral of patients to transplantation centers. This is crucial for the prognosis of lung transplantation., (Copyright © 2019 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Cryptococcal meningitis is a critical illness affecting 0.2% to 5% solid-organ transplant recipients with a 40% to 50% mortality. We report the case of a 48-year-old lung transplant recipient, who, 15 months after a right lung graft, kept parakeets and developed meningitis due to Cryptococcus neoformans. Immunosuppressive treatment was based on a quadruple sequential immunosuppressive therapy that included induction therapy with thymoglobulin, followed by corticosteroids, calcineurin inhibitors, and mycophenolate mofetil. Antifungal susceptibility testing of Cryptococcus neoformans showed resistance to flucytosine and intermediate sensitivity to fluconazole. Initial treatment adhered to international guidelines; however, the patient could not tolerate an effective double-antifungal therapy during the first 2 months of treatment. Despite this delayed treatment for an aggressive infection in an immunocompromised patient, the patient survived without relapse and received maintenance treatment with fluconazole during the course of 3 years. Administration of calcineurin inhibitors as immunosuppressive treatment may partly explain this outcome, as this therapeutic class is known to protect from severe forms of cryptococcal meningitis.

Background: After lung transplantation (LT), immunoglobulin (Ig) G plasma concentrations<6 g/L are common and correlate with an increased risk of chronic lung allograft dysfunction (CLAD) and a poorer survival., Methods: We conducted an open substitution intervention with nonspecific intravenous Ig (IVIg), in all patients with IgG plasma less than 6 g/L post-LT in 54 of 84 consecutive recipients since 1998 who survived more than 3 months. Pre-LT and post-LT events were retrospectively analyzed., Results: Both substituted and nonsubstituted groups demonstrated similar donor or recipient characteristics and events over a median follow-up of 2.8 years (Q1-Q3, 1.4-5.7], except for initial diagnosis with more chronic obstructive pulmonary disease patients and less cases of pulmonary arterial hypertension in NS group. Intravenous Ig substitution started 3.5 months (0.5-9.4) after transplantation and lasted 4.5 months after (1.0-17.7), mean cumulative dose was 52.8±47.7 g. In multivariate Cox regression model, hypogammaglobulinemic patients who were substituted with IVIg had actually a 5-year survival (hazard ratio, 0.63; 95% confidence interval, 0.26-1.49; P=0.29) and CLAD-free 5-year survival (hazard ratio, 0.51; 95% confidence interval, 0.15-1.67; P=0.27) really close to nonhypogammaglobulinemic and nonsubstituted patients. Complementary analysis using propensity score and time-dependent analysis showed that survival and CLAD-free survival were not different in both groups., Conclusion: Intravenous Ig post-LT achieved similar survival and CLAD-free survival in recipients with hypogammaglobulinemia as compared to those with normal IgG plasmatic rate. A randomized control trial is required to confirm benefic effects of IVIg and disentangle mechanisms, including protection from infections, acute cellular and humoral rejections in patients with hypogammaglobulinemia after LT.

Introduction: Lung transplantation has experienced an increasing expansion with a significant improvement in results with the passage of time. Evaluation of these results consists of several domains: survival, function, quality of life and cost-effectiveness., Background: The success of lung transplantation is confirmed by a median survival that currently exceeds 5 years. Cystic fibrosis is the disease associated with the best results with, in France, a survival of 76% at 1 year, 56% at 5 years and 47% at 10 years and a median survival of 8 years. According to French data the 5-year survival is 46% for PAHT, 42% for COPD and 36% for pulmonary fibrosis. Studies have shown a survival benefit for cystic fibrosis and interstitial lung disease but definitive conclusions cannot be drawn for patients with COPD. Lung transplantation brings similar benefits in terms of quality of life and cost-effectiveness., Viewpoints: New statistical methods would allow a better estimate in terms of years of survival and quality of life to be made for each candidate on an individual basis., Conclusions: Lung transplantation improves survival and quality of life compared to medical treatment, at an acceptable cost. These outcomes should be assessed at both an individual and social level to justify the resources involved., (Copyright © 2010 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Objective: We investigated SF and serum proteomic fingerprints of patients suffering from RA, OA and other miscellaneous inflammatory arthritides (MIAs) in order to identify RA-specific biomarkers., Methods: SF profiles of 65 patients and serum profiles of 31 patients were studied by surface-enhanced laser desorption and ionization-time-of-flight-mass spectrometry technology. The most discriminating RA biomarkers were identified by matrix-assisted laser desorption ionization-time of flight and their overexpression was confirmed by western blotting and ELISA., Results: Three biomarkers of 10 839, 10 445 and 13 338 Da, characterized as S100A8, S100A12 and S100A9 proteins, were the most up-regulated proteins in RA SF. Their expression was about 10-fold higher in RA SF vs OA SF. S100A8 exhibited a sensitivity of 82% and a specificity of 69% in discriminating RA from other MIAs, whereas S100A12 displayed a sensitivity of 79% and a specificity of 64%. Three peptides of 3351, 3423 and 3465 Da, corresponding to the alpha-defensins-1, -2 and -3, were also shown to differentiate RA from other MIAs with weaker sensitivity and specificity. Levels of S100A12, S100A8 and S100A9 were statistically correlated with the neutrophil count in MIA SF but not in the SF of RA patients. S100A8, S100A9, S100A12 and alpha-defensin expression in serum was not different in the three populations., Conclusion: The most enhanced proteins in RA SF, the S100A8, S100A9 and S00A12 proteins, distinguished RA from MIA with high accuracy. Possible implication of resident cells in this increase may play a role in RA physiopathology.

Background: Lymphangioleiomyomatosis (LAM) is a rare disease, leading in some cases to end-stage respiratory failure. Lung transplantation (LT) represents a therapeutic option in advanced pulmonary LAM., Methods: We conducted a retrospective multicenter study of 44 patients who underwent LT for LAM at 9 centers in France between 1988 and 2006., Results: All patients were women with a mean age of 41+/-10 years at LT. There were 34 single-lung transplants and 11 bilateral transplants (one retransplantation). Prior clinical events related to LAM were present in 75% of the patients and previous thoracic surgical procedures were noted in 86.6% of cases. At the latest preoperative evaluation, 30 patients had an obstructive pattern (mean forced expiratory volume in 1 second: 26%+/-14% of predicted) and 15 had a combined restrictive and obstructive pattern, with a mean KCO=27%+/-8.8% of predicted, PaO2=52.8+/-10.4 and PaCO2=42.6+/-9.8 mm Hg. Intraoperative cardiopulmonary bypass was required in 13 cases. The length of mechanical ventilation was 7.5+/-12.8 days. The median duration of follow-up was 37 months. The 1, 2, 5, and 10 years survival rates were 79.6%, 74.4%, 64.7%, and 52.4%, respectively. Extensive pleural adhesions were found in 21 patients leading to severe intraoperative hemorrhage. Postoperative LAM-related complications were pneumothorax in the native lung in five patients, chylothorax in six, bronchial dehiscence or stenosis in seven. There were two cases of recurrence of LAM., Conclusion: Despite a high morbidity mainly caused by previous surgical interventions and disease-related complications, LT is a satisfactory therapeutic option for end-stage respiratory failure in LAM.