T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction.

Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-ß. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-ß-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD.

Aspergillus fumigatus in cystic fibrosis: An update on immune interactions and molecular diagnostics in allergic bronchopulmonary aspergillosis.

A wide spectrum of pathological conditions may result from the interaction of Aspergillus fumigatus and the immune system of its human host. Allergic bronchopulmonary aspergillosis is one of the most severe A. fumigatus-related diseases due to possible evolution toward pleuropulmonary fibrosis and respiratory failure. Allergic bronchopulmonary aspergillosis occurs almost exclusively in cystic fibrosis or asthmatic patients. An estimated 8%-10% of patients with cystic fibrosis experience this condition. The diagnosis of allergic bronchopulmonary aspergillosis relies on criteria first established in 1977. Progress in the understanding of host-pathogen interactions in A. fumigatus and patients with cystic fibrosis and the ongoing validation of novel laboratory tools concur to update and improve the diagnosis of allergic bronchopulmonary aspergillosis.

Aspergillus fumigatus components distinguish IgE but not IgG4 profiles between fungal sensitization and allergic broncho-pulmonary aspergillosis.

Aspergillus fumigatus is the causative agent of allergic broncho-pulmonary aspergillosis. Prompt and accurate diagnosis may be difficult to achieve with current clinical and laboratory scores, which do not include immune responses to recombinant A. fumigatus allergens. We measured specific immunoglobulin E and G4 directed to recombinant A. fumigatus allergens in 55 cystic fibrosis patients without allergic broncho-pulmonary aspergillosis but sensitized to A. fumigatus and in nine patients with allergic broncho-pulmonary aspergillosis (two with cystic fibrosis and seven with asthma). IgG4 responses to recombinant A. fumigatus allergens were detected in all patients, but neither prevalence nor levels were different between the two patient groups. On the other hand, both prevalence and levels of IgE responses to Asp f 3, Asp f 4, and Asp f 6 helped distinguish allergic broncho-pulmonary aspergillosis from A. fumigatus sensitization with good negative and positive predictive values.

HLA-G*01:04∼UTR3 Recipient Correlates With Lower Survival and Higher Frequency of Chronic Rejection After Lung Transplantation.

Lung transplantation (LTx) is a valid therapeutic option for selected patients with end-stage lung disease. Soluble HLA-G (sHLA-G) has been associated with increased graft survival and decreased rejection episodes in solid organ transplantation. HLA-G haplotypes named UTRs, defined by SNPs from both the 5'URR and 3'UTR, have been reported to reliably predict sHLA-G level. The aim of this retrospective study was to determine the impact of HLA-G alleles and UTR polymorphism from LTx recipients on anti-HLA allo-immunization risk, overall survival and chronic rejection (CLAD). HLA-G SNPs were genotyped in 124 recipients who underwent LTx from 1996 to 2010 in Marseille, 123 healthy individuals and 26 cystic fibrosis patients not requiring LTx. sHLA-G levels were measured for 38 LTx patients at D0, M3 and M12 and for 123 healthy donors. HLA-G*01:06∼UTR2 was associated with a worse evolution of cystic fibrosis (p = 0.005) but not of long-term survival post-LTx. HLA-G*01:04∼UTR3 haplotype was associated with lower levels of sHLA-G at D0 and M3 (p = 0.03), impaired long-term survival (p = 0.001), increased CLAD occurrence (p = 0.03) and the production of de novo donor-specific antibodies (DSA) at M3 (p = 0.01). This study is the first to show the deleterious association of different HLA-G alleles and UTRs in LTx.

Evaluation of the Aspergillus Western blot IgG kit for diagnosis of chronic aspergillosis.

Immunoprecipitin detection (IPD) is the current reference confirmatory technique for anti-Aspergillus antibody detection; however, the lack of standardization is a critical drawback of this assay. In this study, we evaluated the performance of the Aspergillus Western blot (Asp-WB) IgG kit (LDBio Diagnostics, Lyon, France), a recently commercialized immunoblot assay for the diagnosis of various clinical presentations of chronic aspergillosis. Three hundred eight serum samples from 158 patients with aspergillosis sensu lato (s.l.) were analyzed. More specifically, 267 serum samples were derived from patients with Aspergillus disease, including 89 cases of chronic pulmonary aspergillosis, 10 of aspergilloma, and 32 of allergic bronchopulmonary aspergillosis, while 41 samples were from patients with Aspergillus colonization, including 15 cystic fibrosis (CF) and 12 non-CF patients. For blood donor controls, the Asp-WB specificity was 94%, while the kit displayed a sensitivity for the aspergillosis s.l. diagnosis of 88.6%, with a diagnostic odds ratio (DOR) of 119 (95% confidence interval [CI], 57 to 251). The DOR values were 185.22 (95% CI,78.79 to 435.45) and 43.74 (95% CI, 15.65 to 122.20) for the diagnosis of Aspergillus disease and Aspergillus colonization, respectively. Among the patients, the sensitivities of the Asp-WB in the diagnosis of Aspergillus colonization were 100% and 41.7% in CF and non-CF patients, respectively. The Asp-WB yielded fewer false-negative results than did IPD. In conclusion, the Asp-WB kit performed well for the diagnosis of various clinical presentations of aspergillosis in nonimmunocompromised patients, with an enhanced standardization and a higher sensitivity than with IPD, which is the current reference method.

Donor to recipient age matching in lung transplantation: A European experience.

BACKGROUND: The age profile of organ donors and patients on lung transplantation (LT) waiting lists have changed over time. In Europe, the donor population has aged much more rapidly than the recipient population, making allocation decisions on lungs from older donors common. In this study we assessed the impact of donor and recipient age discrepancy on LT outcomes in the UK and France. METHODS: A retrospective analysis of all adult single or bilateral LT in France and the UK between 2010 and 2021. Recipients were stratified into 3 age author groups: young (≤30 years), middle-aged (30-60) and older (≥60). Their donors were also stratified into 2 groups <60, ≥60. Primary graft dysfunction (PGD) rates and recipient survival was compared between matched and mismatched donor and recipient age groups. Propensity matching was employed to minimize covariate imbalances and to improve the internal validity of our results. RESULTS: Our study cohort was 4,696 lung transplant recipients (LTRs). In young and older LTRs, there was no significant difference in 1 and 5-year post-transplant survival dependent on the age category of the donor. Young LTRs who received older donor grafts had a higher risk of severe grade 3 PGD. CONCLUSION: Our findings show that clinically usable organs from older donors can be utilized safely in LT, even for younger recipients. Further research is needed to assess if the higher rate of PGD3 associated with use of older donors has an effect on long-term outcomes.

[High anti-topoisomerase-1 autoantibodies levels are associated with the extension of skin fibrosis and vascular progression in patients with systemic sclerosis]. / Des taux élevés d'auto-anticorps anti-topo-isomérase-1 sont associés à l'extension de la fibrose cutanée et à la progression vasculaire chez les patients atteints de sclérodermie systémique.

BACKGROUND: Anti-centromere antibodies, anti-topoisomerase-1 antibodies (ATA), and anti-RNA-polymerase III antibodies are three Systemic Sclerosis (SSc)-specific autoantibodies. Their detection is helpful in determining the prognosis. We aimed to evaluate whether ATA levels were associated with disease severity at diagnosis or disease progression during follow-up in ATA positive patients. METHODS: We conducted a single-centre French retrospective observational study, between 2014 and 2021. ATA positive patients fulfilling the ACR/EULAR 2013 classification criteria for SSc with a minimal follow-up of 1 year and 2 ATA dosages were included. SSc patients with high IgG ATA levels at baseline (>240IU/mL) were compared with SSc patients with low levels (≤240IU/mL), at inclusion and at 1 and 3 years. A variation of at least 30 % of ATA levels was considered significant. RESULTS: Fifty-nine SSc patients were included and analysed. There was a predominance of women and of patients with diffuse interstitial lung disease. Patients with high ATA levels exhibited a higher skin sclerosis assessed by the modified Rodnan skin score (P=0.0480). They had a lower carbon monoxide transfer coefficient (P=0.0457), a lower forced vital capacity (FVC) (P=0.0427) and more frequently had a FVC under 80 %, when compared to patients with low ATA levels (P=0.0423). Initial high ATA levels were associated with vascular progression at one year (21.95 % vs. 0 %; P=0.0495). CONCLUSION: ATA levels are associated with skin sclerosis and vascular progression in SSc. Beyond the detection of ATA, quantifying this autoantibody might be of interest in predicting disease severity and prognosis in SSc.

Outcomes of lung transplantation for pleuroparenchymal fibroelastosis: A French multicentric retrospective study.

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) has no currently available specific treatment. Benefits of lung transplantation (LT) for PPFE are poorly documented. METHODS: We conducted a nation-wide multicentric retrospective study in patients who underwent lung or heart-lung transplantation for chronic end-stage lung disease secondary to PPFE between 2012 and 2022 in France. RESULTS: Thirty-one patients were included. At transplantation, median age was 48 years [IQR 35-55]. About 64.5% were women. Twenty-one (67.7%) had idiopathic PFFE. Sixteen (52%) had bilateral LT, 10 (32%) had single LT, 4 (13%) had lobar transplantation and one (3%) had heart-lung transplantation. Operative mortality was 3.2%. Early mortality (<90 days or during the first hospitalization) was 32%. Eleven patients (35.5%) underwent reoperation for hemostasis. Eight (30.8%) experienced bronchial complications. Mechanical ventilation time was 10 days [IQR 2-55]. Length of stay in intensive care unit and hospital were 34 [IQR 18-73] and 64 [IQR 36-103] days, respectively. Median survival was 21 months. Post-transplant survival rates after 1, 2, and 5 years were 57.9%, 42.6% and 38.3% respectively. Low albuminemia (p = 0.046), FVC (p = 0.021), FEV1 (p = 0.009) and high emergency lung transplantation (p = 0.04) were associated with increased early mortality. Oversized graft tended to be correlated to a higher mortality (p = 0.07). CONCLUSION: LT for PPFE is associated with high post-operative morbi-mortality rates. Patients requiring high emergency lung transplantation with advanced disease, malnutrition, or critical clinical status experienced worse outcomes. GOV IDENTIFIER: NCT05044390.

Evaluation of colistin susceptibility in multidrug-resistant clinical isolates from cystic fibrosis, France.

The emergence of multidrug-resistant (MDR) bacteria in cystic fibrosis (CF) patients has led to the use of colistin drug and the emergence of colistin-resistant Gram-negative bacteria. The aim of this study was to compare the disk diffusion and Etest methods for colistin susceptibility testing on MDR bacteria associated with CF from Marseille, France. Forty-nine MDR clinical isolates (27 Stenotrophomonas maltophilia, 22 Achromobacter xylosoxidans) were used in this study. Disk diffusion and Etest assays were used to assess the reliability of these two techniques. For S. maltophilia, 25 out of 27 isolates had low minimum inhibitory concentrations (MICs, 0.125-0.75 mg/L), whereas two isolates displayed high MICs (32 mg/L). Similarly, 19 out of 22 A. xylosoxidans isolates had low MICs (0.75-3.0 mg/L), whereas three isolates had high MICs (32-256 mg/L). The diameters of zone inhibition with a 50-µg colistin disk displayed a good correlation with the MICs obtained by the Etest. Susceptible and resistant strains were eventually separated using a disk diffusion assay at a cut-off of ≤ 12 mm for a 50-µg disk. Colistin displayed excellent activity against S. maltophilia and A. xylosoxidans and the disk diffusion assay could be confidently used to determine the susceptibility to colistin for MDR Gram-negative bacteria in the context of CF.

[Computed tomography lung density and small vessel quantification in pulmonary hypertension associated with progressive fibrosing interstitial lung disease (PF-ILD)]. / Densité pulmonaire et quantification vasculaire tomodensitométrique dans l'hypertension pulmonaire associée aux pneumopathies interstitielles diffuses fibrosantes.

INTRODUCTION: The main objective of this work was to investigate a possible link between lung density, small pulmonary vessels, and pulmonary hypertension (PH) in patients with progressive fibrosing interstitial lung disease (PF-ILD). METHODS: The study focused on patients with PF-ILD, all of whom underwent right cardiac catheterization and chest computed tomography prior to lung transplantation. Computed tomography scans were analyzed quantitatively for density and pulmonary vascularity. The relationship between computed tomography features and PH was investigated. RESULTS: Fifty-one patients with usual interstitial pneumonia (UIP) damage on lung explant were included. mPAP was positively correlated with lung mass (r=0.36, P=0.03) and lung volume (r=0.43, P=0.007). Patients with severe PH had more voxels lower than -856 Hounsfield Units (HU) (+16%, P=0.02), fewer voxels greater than -700 HU (-20%, P=0.03), and a higher lung volume (+1.57L, P=0.007) compared to patients without PH. No correlation was found between vascularization and HTP. CONCLUSIONS: Patients with PF-ILD and severe PH have lower lung density than patients with moderate or without PH.

[Updated indications and contraindications in 2022 for lung transplantation in France]. / Transplantation pulmonaire en France : actualisation des indications et contre-indications en 2022.

Lung transplantation (LTx) is the last-resort treatment for end-stage respiratory insufficiency, whatever its origin, and represents a steadily expanding field of endeavor. Major developments have been impelled over the years by painstaking efforts at LTx centers to improve donor and recipient selection, and multifaceted attempts have been made to meet the challenges raised by surgical management, perioperative care, and long-term medical complications. The number of procedures has increased, leading to improved post-LTx prognosis. One consequence of these multiple developments has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. With these considerations in mind, the Francophone Pulmonology Society (Société de Pneumology de Langue Française [SPLF]) has set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force has examined the most recent literature and evaluated the risk factors that continue to limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

[French practical guidelines for the diagnosis and management of IPF - 2021 update, full version]. / Recommandations pratiques pour le diagnostic et la prise en charge de la fibrose pulmonaire idiopathique ­ Actualisation 2021. Version intégrale.

BACKGROUND: Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated. METHODS: Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients' association. The method was developed according to rules entitled "Good clinical practice" in the overall framework of the "Guidelines for clinical practice" of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale. RESULTS: After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION: These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis.

[French practical guidelines for the diagnosis and management of IPF - 2021 update, short version]. / Recommandations pratiques pour le diagnostic et la prise en charge de la fibrose pulmonaire idiopathique ­ Actualisation 2021. Version courte.

BACKGROUND: Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated. METHODS: Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients' association. The method was developed according to rules entitled "Good clinical practice" in the overall framework of the "Guidelines for clinical practice" of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale. RESULTS: After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION: These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis.

Non-classic cystic fibrosis associated with D1152H CFTR mutation.

BACKGROUND: Limited knowledge exists on phenotypes associated with the D1152H cystic fibrosis transmembrane conductance regulator (CFTR) mutation. METHODS: Subjects with a D1152H allele in trans with another CFTR mutation were identified using the French Cystic Fibrosis Registry. Phenotypic characteristics were compared with those of pancreatic insufficient (PI) and pancreatic sufficient (PS) cystic fibrosis (CF) subjects in the Registry (CF cohort). RESULTS: Forty-two subjects with D1152H alleles were identified. Features leading to diagnosis included chronic sinopulmonary disease (n = 25), congenital absence of the vas deferens (n = 11), systematic neonatal screening (n = 4), and genetic counseling (n = 2). Median age at diagnosis was 33 [interquartile range (IQR, 24-41)] years in D1152H subjects. Median sweat chloride concentrations were 43.5 (39-63) mmol/l in D1152H subjects and were markedly lower than in PI and PS CF subjects (p < 0.05). Bronchiectasis was present in 67% of D1152H subjects, but Pseudomonas aeruginosa colonization and pancreatic insufficiency were present in <30% of subjects. Estimated rates of decline in forced expiratory volume in 1 s (FEV(1)) were lower in D1152H subjects vs PI CF subjects (p < 0.05). None of the D1152H subjects identified since 1999 had died or required lung transplantation. CONCLUSIONS: When present in trans with a CF-causing mutation, D1152H causes significant pulmonary disease, but all subjects had prolonged survival.

Characteristics of Systemic Sclerosis patients with positive anti-Th/To antibodies: About 6 patients and literature review.

Among the antibodies described in Systemic Sclerosis (SSc), anti-Th/To antibodies (anti-Th/To) are rare and have been poorly studied. Thus, little is known about the profile of anti-Th/To positive patients. From our local Biobank (Marseille, France), we retrospectively selected data for 6 patients positive for anti-Th/To with an Immunodot assay. All of them suffered from SSc, sharing clinical and biological common features such as a limited cutaneous form of SSc, a decreased lung diffusing capacity and a speckled nuclear nucleolar immunofluorescence pattern of antinuclear antibodies screening on HEp-2 cells. In order to further characterize patients positive for anti-Th/To, we performed a thorough literature review. From 402 studied patients positive for anti-Th/To, we confirmed that these antibodies are associated with the limited cutaneous form of the disease (88% of the patients), and with an SSc related-pulmonary involvement (50%). The review analysis pointed out the rarity of the anti-Th/To with an estimated mean frequency of 3.4% of all SSc patients worldwide, their usual exclusivity with respect to the specific antibodies of scleroderma, and their high specificity (around 98%) for the diagnosis of SSc.

Lung function in Birt-Hogg-Dubé syndrome: a retrospective analysis of 96 patients.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD. RESULTS: Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased < 80%pred in 33% of cases. When adjusted for age, gender, smoking and history of pleurodesis, lung function parameters did not significantly decline over a follow-up period of 6 years. CONCLUSIONS: Cystic lung disease in BHD does not affect respiratory function at baseline except for slightly increased RV and reduced DLco. No significant deterioration of lung function occurs in BHD over a follow-up period of 6 years.

[Abdominal cystic tumor revealing lymphangioleiomyomatosis]. / Tumeurs kystiques rétropéritonéales compliquées révélatrices d'une lymphangioléiomyomatose.

We report the case of a 39 year-old woman with many years of intermittent abdominal pain who was found to have cystic masses evocative of cystic lymphangioma involving the posterior mediastinal and retroperitoneum. Worsening abdominal pain led to a recommendation for laparoscopic unroofing and decompression of the cysts. During the postoperative period, hemorrhagic shock required reintervention with excision of the tumoral mass. Pathologic examination revealed lymphangioleiomyomatosis (LAM). On the 15th postoperative day, the patient developed a chylopneumothorax which required prolonged chest tube drainage. The presence of multiple polycystic lesions in the pulmonary parenchyma supported the diagnosis of diffuse LAM with primary extrapulmonary presentation. This diagnosis should be considered preoperatively since it modifies the treatment: a complete excision of the cystic lesions seems to be necessary in order to prevent bleeding and lymphatic extravasation.

Respiratory impairment in Niemann-Pick B disease: Two case reports and review for the pulmonologist.

Acid sphingomyelinase deficiency (ASMD), also called Niemann-Pick disease, is a storage disorder with pulmonary involvement but few respiratory symptoms in adults. However, the disease may evolve towards clinically relevant respiratory symptoms with referral to the pulmonologist for management and care. Based on two case reports illustrating respiratory impairment, the aim of this work was to review clinical features, diagnosis, respiratory prognostic and therapeutics for the pulmonologist. Overall, storage disorder should be suspected in the presence of hepatosplenomegaly and interstitial lung disease. Concomitant thrombopenia or hyperlipidemia should also draw attention. Following recent consensus guidelines, diagnosis is based on enzyme assay for ASM activity in blood, with subsequent gene sequencing once the biochemical diagnosis has been confirmed. Disease is slowly progressive and the main causes of death are respiratory and liver failure. Presence of emphysema lesions or worsening of respiratory symptoms should call for the intensification of treatment. Though enzyme replacement therapy is a promising way of development, lung transplantation might be considered for these patients in the absence of contraindication.

CTLA-4-mediated regulatory phenotype of T-cells in tolerant lung recipients.

Obliterative bronchiolitis (OB) is the major cause of long-term lung allograft loss resulting from an unclear immune process occurring in the absence of the donor's immune cells. The present authors hypothesised that interactions of autologous dendritic cells (DCs) with T-cells could differ in OB patients compared with healthy lung transplant recipients (LTRs). Monocyte-derived DCs from 14 OB and 35 non-OB LTRs were cultured with autologous T-cells. T-regulatory (T(reg)) cells, co-receptors, cytokine production, DC phenotype and indoleamine 2,3-dioxygenase (IDO) expression were assessed by flow cytometry. Experiments were repeated in the presence of Pseudomonas aeruginosa or anti-co-receptor antibodies. DCs from non-OB LTR upregulated T(reg) cells, cytotoxic T-lymphocyte antigen (CTLA)-4 and interleukin (IL)-10. By contrast CD28 and inducible T-cell co-stimulator were downregulated concomitantly to IL-13 and IL-4. Compared to OB, non-OB DCs displayed an immature phenotype with lower CD80 and CD83 and higher IDO levels of expression. Stimulation by P. aeruginosa did not abolish the tolerogenic effects of DCs on non-OB T-cells. Finally, decreased T(reg) cells and IL-10 production were detected when adding anti-CTLA-4 antibodies in non-OB LTR. The present study demonstrates that dendritic cells from nonobliterative bronchiolitis lung transplant recipients induce a tolerant T-cell phenotype which is dependent on cytotoxic T-lymphocyte antigen-4 engagement.

[When should patients be referred by the physician to the lung transplant team? Patient selection, indications, timing of referral and preparation for lung transplantation]. / Quand le pneumologue doit-il envisager la greffe pulmonaire pour un de ses patients adulte? Indications, critères de sélection, préparation à la greffe.

INTRODUCTION: Lung transplantation (LT) is accepted as a therapeutic option in a wide range of end stage lung diseases, with evidence supporting survival and quality of life benefits in transplant recipients. Appropriate patients who have good chance of survival with transplantation should be identified carefully. STATE OF THE ART: Four diagnoses account for approximately 80% of transplant recipients: chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis and alpha-1-antitrypsin deficiency emphysema. The aim of this review is to discuss the selection process of potential candidates and to assist physicians in referring these patients to a transplant team. The decision to refer patients for transplantation is difficult and depends on several parameters such as the results of transplantation, the referring physician's view of survival prospects with actual medical therapy according to the pathology, and also the patient's physical, nutritional and psychological status. The timing of listing patients remains a difficult decision which is imposed by both defined criteria and uncertain events such as the rapid worsening of the lung disease and the likely waiting time. PERSPECTIVES: The optimal modalities for pre-surgical rehabilitation programs and their postoperative impact should be evaluated. CONCLUSIONS: Careful selection of potential candidates for lung transplantation at the most appropriate time should lead to an improvement of survival of such patients.