Methotrexate and rheumatoid arthritis associated interstitial lung disease.

QUESTION ADDRESSED BY THE STUDY: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD. METHODS: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. RESULTS: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001). ANSWER TO THE QUESTION: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients.

Pneumocystis pneumonia after lung transplantation: A retrospective multicenter study.

BACKGROUND: Lung transplantation (LT) is an identified risk factor for Pneumocystis pneumonia (PCP). However, PCP management and outcomes remain poorly described in LT recipients and PCP incidence is rarely documented in this population. METHODS: PCP episodes that occurred in 9 French LT centers between January 2010 and October 2017 were included in this analysis. PCP was defined as compatible clinical and radiologic findings associated with fungal identification. RESULTS: Forty-seven PCP were included. The annual incidence rate of PCP was 2.7/1000 patients/year. Patients had a mean age of 53 ± 14 years. Median time from LT was 2.4 ± 3.0 years. Sixty-five percent of patients were not on prophylaxis at the time of PCP while all patients were receiving steroids at the time of PCP. Diagnosis was obtained by bronchoalveolar lavage in 91% (direct examination: 47%, PCR: 62%). The majority of patients were treated with trimethoprim-sulfamethoxazole (78%). Fifty-five percent of patients were hospitalized in ICU for organ failure (for which non-invasive ventilation was used for 21% and mechanical ventilation for 23%). Mortality rate was 15% at day 28 and reached 23% at day 90. Mortality was associated with decreased FEV1, everolimus treatment, Pseudomonas aeruginosa coinfection, fungal coinfection (especially Aspergillus sp.), mechanical ventilation and vasopressors. PCP primary prophylaxis, steroid modification during PCP and the number of immunosuppressive molecules were not associated with mortality. CONCLUSION: PCP is associated with a high mortality in LT. Our data suggest the need for a lifetime PCP prophylaxis in LT recipients. The benefit of adjuvant steroids remains unclear.

Long-term efficacy and safety of 2CdA (cladribine) in extra-pulmonary adult-onset Langerhans cell histiocytosis: analysis of 23 cases from the French Histiocytosis Group and systematic literature review.

Langerhans cell histiocytosis (LCH) is a rare protean disease that usually affects children. Few data are available for management of adult-onset cases. A complete picture of the efficacy and safety of 2CdA (2-chlorodeoxyadenosine, cladribine) is lacking. We report a retrospective multicentre study of 23 adult LCH (a-LCH) patients who received single-agent 2CdA and a systematic literature review. All had previously received systemic therapy (vinblastine, n = 19). Response to 2CdA was evaluable in 22 cases. Overall response rate (ORR) was 91%. Complete response (CR) occurred in 11 cases (50%). Nine patients (39%) developed grade 3-4 neutropenia and/or severe infection. A literature review yielded 48 additional cases. A pooled analysis confirmed our findings (ORR: 88%, CR: 49%). CRs were rare with cumulative dose <50 mg/m2 . Disease progression rates were 20% and 30% at two and five years, respectively. Partial response (PR) to 2CdA was predictive of disease progression. Among eight re-treated patients, five went into CR, two in PR, and one died. Single-agent 2CdA is effective in reactivated a-LCH, including at intermediate doses. Toxicity, significant but acceptable, warrants infectious prophylaxis. Complete responders may enter prolonged remission. Further studies are needed to determine 2CdA sequencing with other agents (vinblastine, cytarabine).

Pregnancy after lung and heart-lung transplantation: a French multicentre retrospective study of 39 pregnancies.

Pregnancy after lung and heart-lung transplantation remains rare. This French study deals with change in lung function after a pregnancy and the maternal and newborn outcomes. We retrospectively included 39 pregnancies in 35 women aged >20 years. Data on patients, course of pregnancies and newborns were collected from nine transplantation centres. Mean age at time of pregnancy was 28 years. Cystic fibrosis affected 71% of patients. Mean±sd time between transplantation and pregnancy was 63±44 months. 26 births occurred (67%) with a mean term of 36 weeks of amenorrhoea and a mean birthweight of 2409 g. Prematurity was observed in 11 cases (43%). Forced expiratory volume in 1 s was 83.9% of predicted before pregnancy and 77.3% of predicted 1 year after the end of pregnancy (p=0.04). 10 patients developed chronic lung allograft dysfunction after delivery. Nine patients died at a mean±sd time after transplantation of 8.2±7 years and a mean±sd time after pregnancy of 4.6±6.5 years. These data show that pregnancy remains feasible in lung and heart-lung transplant recipients, with more frequent maternal and newborn complications than in the general population. Survival in this cohort appears to be similar to the global survival observed in lung transplant recipients. Planned pregnancy and multidisciplinary follow-up are crucial.

Blood CD9+ B cell, a biomarker of bronchiolitis obliterans syndrome after lung transplantation.

Bronchiolitis obliterans syndrome is the main limitation for long-term survival after lung transplantation. Some specific B cell populations are associated with long-term graft acceptance. We aimed to monitor the B cell profile during early development of bronchiolitis obliterans syndrome after lung transplantation. The B cell longitudinal profile was analyzed in peripheral blood mononuclear cells from patients with bronchiolitis obliterans syndrome and patients who remained stable over 3 years of follow-up. CD24hi CD38hi transitional B cells were increased in stable patients only, and reached a peak 24 months after transplantation, whereas they remained unchanged in patients who developed a bronchiolitis obliterans syndrome. These CD24hi CD38hi transitional B cells specifically secrete IL-10 and express CD9. Thus, patients with a total CD9+ B cell frequency below 6.6% displayed significantly higher incidence of bronchiolitis obliterans syndrome (AUC = 0.836, PPV = 0.75, NPV = 1). These data are the first to associate IL-10-secreting CD24hi CD38hi transitional B cells expressing CD9 with better allograft outcome in lung transplant recipients. CD9-expressing B cells appear as a contributor to a favorable environment essential for the maintenance of long-term stable graft function and as a new predictive biomarker of bronchiolitis obliterans syndrome-free survival.

Automated Volumetric Quantification of Emphysema Severity by Using Ultrashort Echo Time MRI: Validation in Participants with Chronic Obstructive Pulmonary Disease.

Background The validity of three-dimensional (3D) ultrashort echo time (UTE) MRI for the assessment of emphysema in patients with chronic obstructive pulmonary disease (COPD) at high spatial resolution is, to the knowledge of the authors, unknown. Purpose To assess whether noncontrast agent-enhanced 3D UTE MRI at submillimeter spatial resolution can be used to determine the extent of emphysema by using both qualitative visual scoring and fully automated volumetric quantification. Materials and Methods Twenty-eight participants with COPD and 10 control participants (mean age, 70 years ± 7 [standard deviation] and 64 years ± 4, respectively) were prospectively enrolled between 2015 and 2017. Participants underwent pulmonary function testing, CT, and MRI. CT was used as the reference standard. Qualitative scoring of emphysema extent was performed by two readers. Fully automated quantification of percentage of low-attenuation volume by using a threshold of -950 HU (%LAV-950HU) at CT and percentage of low-signal-intensity volume by using an adaptive threshold of 0.20 (%LSV0.20) at MRI were the respective emphysema indexes. Comparison of means was performed by using Student t test, correlation was determined by using Pearson test, agreement was found by using weighted κ index, and reproducibility was determined by using intraclass correlation coefficient. Diagnostic performance was assessed by calculating the area under the receiver operating characteristics curve (AUC). Results With qualitative scoring, agreement between UTE MRI and CT was good (weighted κ, 0.79; 95% confidence interval: 0.71, 0.83). With automated volumetric quantification, %LSV0.20 was significantly correlated with %LAV-950HU in participants with COPD (r, -0.80; P < .001) and correlated with forced expiratory volume in 1 second percentage predicted (r, -0.55; P = .002). %LSV0.20 was significantly higher in participants with COPD than in control participants (P < .001). The diagnostic performance and reproducibility of %LSV0.20 were good (AUC, 1.00 [95% confidence interval: 0.88, 1.00], and intraclass correlation coefficient, > 0.99, respectively). Conclusion A fully automated method with three-dimensional ultrashort echo time MRI reproducibly quantified the volumetric extent of emphysema in participants with chronic obstructive pulmonary disease. © RSNA, 2019 Online supplemental material is available for this article.

Quantitative CT assessment of bronchial and vascular alterations in severe precapillary pulmonary hypertension.

BACKGROUND: Little is known about in vivo alterations at bronchial and vascular levels in severe pulmonary hypertension (PH) of different etiologies. We aimed to compare quantitative computed tomography (CT) data from the following three groups of severe precapillary PH patients: COPD, idiopathic pulmonary arterial hypertension (iPAH), and chronic thromboembolic PH (CTEPH). PATIENTS AND METHODS: This study was approved by the institutional review board. Severe PH patients (mean pulmonary arterial pressure [mPAP] ≥35 mmHg) with COPD, iPAH, or CTEPH (n=24, 16, or 16, respectively) were included retrospectively between January 2008 and January 2017. Univariate analysis of mPAP was performed in each severe PH group. Bronchial wall thickness (WT) and percentage of cross sectional area of pulmonary vessels less than 5 mm2 normalized by lung area (%CSA<5) were measured and compared using CT, and then combined to arterial partial pressure of oxygen (PaO2) to generate a "paw score" compared within the three groups using Kruskal-Wallis and its sensitivity using Fisher's exact test. RESULTS: WT was higher and %CSA<5 was lower in the COPD group compared to iPAH and CTEPH groups. Mosaic pattern was higher in CTEPH group than in others. In severe PH patients secondary to COPD, mPAP was positively correlated to %CSA<5. By contrast, in severe iPAH, this correlation was negative, or not correlated in severe CTEPH groups. In the COPD group, "paw score" showed higher sensitivity than in the other two groups. CONCLUSION: Unlike in severe iPAH and CTEPH, severe PH with COPD can be predicted by "paw score" reflecting bronchial and vascular morphological differential alterations.

Widening the landscape of heritable pulmonary hypertension mutations in paediatric and adult cases.

BACKGROUND: Heritable forms of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH) diverge by lung histopathological lesions, clinical and para-clinical presentation, their responsible genes, and mode of transmission. Since the identification of the BMPR2 gene in families affected by PAH, mutations in several other genes have been discovered for both forms. The mutation landscape in these new genes is not yet well known. METHODS: We set up a next-generation sequencing-based targeted sequencing gene panel allowing known genes for PAH and PVOD/PCH to be analysed simultaneously. Genetic analysis was prospectively performed on 263 PAH and PVOD/PCH patients (adult and paediatric cases). RESULTS: Pathogenic mutations were identified in 19.5% of sporadic PAH patients (n=180), 54.5% of familial PAH patients and 13.3% of PVOD/PCH patients. BMPR2 was the most frequently mutated gene, followed by TBX4 in both paediatric and adult PAH. BMP9 mutations were identified in 1.2% of adult PAH cases. EIF2AK4 biallelic mutations were restricted to PVOD/PCH. A truncating mutation and a predicted loss-of-function variant were also identified in BMP10 in two severely affected sporadic PAH female patients. CONCLUSION: Our results confirm that mutations are found in genes beyond BMPR2 in heritable PAH, emphasise the role of TBX4 and BMP9, and designate BMP10 as a new PAH gene.

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.

BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

Overcoming non-specific binding to measure the active concentration and kinetics of serum anti-HLA antibodies by surface plasmon resonance.

Human leukocyte antigen (HLA) donor-specific antibodies are key serum biomarkers for assessing the outcome of transplanted patients. Measuring their active concentration, i.e. the fraction that really interacts with donor HLA, and their affinity could help deciphering their pathogenicity. Surface plasmon resonance (SPR) is recognized as the gold-standard for measuring binding kinetics but also active concentrations, without calibration curves. SPR-based biosensors often suffer from non-specific binding (NSB) occurring with the sensor chip surface and the immobilized targets, especially for complex media such as human serum. In this work we show that several serum treatments such as dialysis or IgG purification reduce NSB but insufficiently for SPR applications. We then demonstrate that the NSB contribution to the SPR signal can be eliminated to determine precisely and reliably the active concentration and the affinity of anti-HLA antibodies from patients' sera. This was achieved even at concentrations close to the limit of quantification of the method, in the 0.5-1 nM range. The robustness of the assay was demonstrated by using a wide range of artificially generated NSB and by varying the density of the targets captured onto the surface. The assay is of general interest and can be used with molecules generating strong NSB, as far as a non-cognate target structurally close to the target can be captured on the same flow cell, in a different binding cycle. Compared with current fluorescence-based methods that are semi-quantitative, we expect this SPR-based assay to help better understanding anti-HLA antibodies pathogenicity and improving organ recipients' management.

High circulating CD4+CD25hiFOXP3+ T-cell sub-population early after lung transplantation is associated with development of bronchiolitis obliterans syndrome.

BACKGROUND: Chronic bronchiolitis obliterans syndrome (BOS) remains a major limitation for long-term survival after lung transplantation. The immune mechanisms involved and predictive biomarkers have yet to be identified. The purpose of this study was to determine whether peripheral blood T-lymphocyte profile could predict BOS in lung transplant recipients. METHODS: An in-depth profiling of CD4+ and CD8+ T cells was prospectively performed on blood cells from stable (STA) and BOS patients with a longitudinal follow-up. Samples were analyzed at 1 and 6 months after transplantation, at the time of BOS diagnosis, and at an intermediate time-point at 6 to 12 months before BOS diagnosis. RESULTS: Although no significant difference was found for T-cell compartments at BOS diagnosis or several months beforehand, we identified an increase in the CD4+CD25hiFoxP3+ T-cell sub-population in BOS patients at 1 and 6 months after transplantation (3.39 ± 0.40% vs 1.67 ± 0.22% in STA, p < 0.001). A CD4+CD25hiFoxP3+ T-cell threshold of 2.4% discriminated BOS and stable patients at 1 month post-transplantation. This was validated on a second set of patients at 6 months post-transplantation. Patients with a proportion of CD4+CD25hiFoxP3+ T cells up to 2.4% in the 6 months after transplantation had a 2-fold higher risk of developing BOS. CONCLUSIONS: This study is the first to report an increased proportion of circulating CD4+CD25hiFoxP3+ T cells early post-transplantation in lung recipients who proceed to develop BOS within 3 years, which supports its use as a BOS predictive biomarker.

Donor Club Cell Secretory Protein G38A Polymorphism Is Associated With a Decreased Risk of Primary Graft Dysfunction in the French Cohort in Lung Transplantation.

BACKGROUND: Club Cell Secretory Protein (CCSP) G38A polymorphism has recently been involved in lung epithelial susceptibility to external injuries. Lung transplantation (LT) is currently limited by ischemia-reperfusion injury leading to primary graft dysfunction (PGD). We thus hypothesized that donor CCSP G38A polymorphism might impact the risk of PGD after LT. METHODS: We focused on LT included in the French multicentric Cohort in Lung Transplantation (COLT), performed between January 2009 and December 2014, and associated with preoperative blood samples from the donor and the recipient. Characteristics of the donors, recipients, procedures, early and late outcomes were prospectively recorded in COLT. The CCSP serum concentration and CCSP gene G38A polymorphism were retrospectively determined in a blind manner. Their association with grade 3 PGD was studied in univariate and multivariate analysis. RESULTS: The study group included 104 LT donors and recipients, 84 with grade 0 to 2 PGD and 20 with grade 3 PGD. Preoperative CCSP serum concentration was significantly higher in the donors (median, 22.54 ng/mL; interquartile range, 9.6-43.9) than in the recipients (median, 7.03 ng/mL; interquartile range, 0.89-19.2; P < 0.001) but none impacted the risk of grade 3 PGD (P = 0.93 and P = 0.69, respectively). Donor CCSP G38A polymorphism was associated with a decreased risk of grade 3 PGD in univariate (AG + AA 3/21 = 14.2% vs GG 10/26 = 38.4%, P = 0.044) and multivariate analysis (odds ratio associated with AG + AA, 0.22; 95% confidence interval, 0.041-0.88; P = 0.045), but recipient CCSP G38A polymorphism was not. CONCLUSIONS: Donor CCSP G38A polymorphism is associated with a decreased risk of severe PGD after LT in the COLT study. These findings should be confirmed in the frame of a prospective study.

Management and long-term outcomes of sarcoidosis-associated pulmonary hypertension.

Studies reporting the effects of modern strategies with pulmonary arterial hypertension (PAH)-targeted therapies in sarcoidosis-associated pulmonary hypertension (S-APH) are limited.Clinical and haemodynamic data from newly diagnosed patients with severe S-APH (mean pulmonary artery pressure (mPAP) >35 mmHg or mPAP 25-35 mmHg with cardiac index <2.5 L·min-1·m-2) were collected from the French Pulmonary Hypertension Registry between 2004 and 2015.Data from 126 patients with severe S-APH were analysed (mean±sd age 57.5±11.6 years, 74% radiological stage IV). 97 patients (77%) received PAH-targeted therapy and immunosuppressive therapy was initiated or escalated in 33 patients at the time of pulmonary hypertension diagnosis. Four months after PAH-targeted therapy initiation, mean±sd pulmonary vascular resistance decreased from 9.7±4.4 to 6.9±3.0 Wood units (p<0.001), without significant improvement in exercise capacity. Among the 11 patients treated only with immunosuppressive therapy, a haemodynamic improvement was observed in four patients, including two with compressive lymph nodes. After a median follow-up of 28 months, 39 patients needed PAH-targeted therapy escalation, nine underwent lung transplantation and 42 had died. Survival at 1, 3 and 5 years was 93%, 74% and 55%, respectively.PAH-targeted therapy improved short-term pulmonary haemodynamics in severe S-APH without change in exercise capacity. Immunosuppressive therapy improved haemodynamics in selected patients. Pulmonary hypertension in sarcoidosis remains associated with a poor prognosis.

Development of a Multivariate Prediction Model for Early-Onset Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome in Lung Transplantation.

BACKGROUND: Chronic lung allograft dysfunction and its main phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), are major causes of mortality after lung transplantation (LT). RAS and early-onset BOS, developing within 3 years after LT, are associated with particularly inferior clinical outcomes. Prediction models for early-onset BOS and RAS have not been previously described. METHODS: LT recipients of the French and Swiss transplant cohorts were eligible for inclusion in the SysCLAD cohort if they were alive with at least 2 years of follow-up but less than 3 years, or if they died or were retransplanted at any time less than 3 years. These patients were assessed for early-onset BOS, RAS, or stable allograft function by an adjudication committee. Baseline characteristics, data on surgery, immunosuppression, and year-1 follow-up were collected. Prediction models for BOS and RAS were developed using multivariate logistic regression and multivariate multinomial analysis. RESULTS: Among patients fulfilling the eligibility criteria, we identified 149 stable, 51 BOS, and 30 RAS subjects. The best prediction model for early-onset BOS and RAS included the underlying diagnosis, induction treatment, immunosuppression, and year-1 class II donor-specific antibodies (DSAs). Within this model, class II DSAs were associated with BOS and RAS, whereas pre-LT diagnoses of interstitial lung disease and chronic obstructive pulmonary disease were associated with RAS. CONCLUSION: Although these findings need further validation, results indicate that specific baseline and year-1 parameters may serve as predictors of BOS or RAS by 3 years post-LT. Their identification may allow intervention or guide risk stratification, aiming for an individualized patient management approach.

Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis.

Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53-6.12; p=9.45×10-4). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10-2).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.

Chronic effects of air pollution on lung function after lung transplantation in the Systems prediction of Chronic Lung Allograft Dysfunction (SysCLAD) study.

An irreversible loss in lung function limits the long-term success in lung transplantation. We evaluated the role of chronic exposure to ambient air pollution on lung function levels in lung transplant recipients (LTRs).The lung function of 520 LTRs from the Cohort in Lung Transplantation (COLT) study was measured every 6 months. The levels of air pollutants (nitrogen dioxide (NO2), particulate matter with an aerodynamic cut-off diameter of x µm (PMx) and ozone (O3)) at the patients' home address were averaged in the 12 months before each spirometry test. The effects of air pollutants on forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) in % predicted were estimated using mixed linear regressions. We assessed the effect modification of macrolide antibiotics in this relationship.Increased 12-month levels of pollutants were associated with lower levels of FVC % pred (-2.56%, 95% CI -3.86--1.25 for 5 µg·m-3 of PM10; -0.75%, 95% CI -1.38--0.12 for 2 µg·m-3 of PM2.5 and -2.58%, 95% CI -4.63--0.53 for 10 µg·m-3 of NO2). In patients not taking macrolides, the deleterious association between PM and FVC tended to be stronger and PM10 was associated with lower FEV1Our study suggests a deleterious effect of chronic exposure to air pollutants on lung function levels in LTRs, which might be modified with macrolides.

Nitrogen monoxide and carbon monoxide transfer interpretation: state of the art.

Just a few clinicians routinely measure the subcomponents of the lung diffusing capacity for Carbone monoxide (DLCO ). This is because the measurement of membrane and blood conductances for CO (DmCO and DbCO  = Î¸CO  × Vc , respectively) by the classic Roughton and Forster method is complicated and time consuming. In addition, it mistakenly assumes a close relationship between alveolar oxygen partial pressure (PAO2 ) and mean intracapillary oxygen partial pressure (PcapO2 ) which is the true determinant of specific conductance of haemoglobin for CO (θCO ). Besides that, the critical multistep oxygenation method along with different linear equations relating 1/θCO to PcapO2 gave highly scattered DmCO and Vc values. The Dm and Vc can also be derived from a simultaneous measurement of DLNO and DLCO with the blood resistance for NO assumed to be negligible. However, recent in vitro and in vivo experiments point towards a finite value of θNO (about 4·5 mlNO  × mlblood-1  × min-1  × mmHg-1 ). Putting together the arguments and our clinical data allows us to report here the state of the art in partitioning the CO diffusing capacity into its constitutive components, with the goal to encourage further studies examining the sensitivity of DmCO and Vc to alterations observed in parenchymal diseases.

Blood Gene Expression Predicts Bronchiolitis Obliterans Syndrome.

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 < 0.01) and are not associated with time posttransplantation. This is the first published large-scale gene expression analysis of blood after lung transplantation. The three-gene blood signature could provide clinicians with new tools to improve follow-up and adapt treatment of patients likely to develop BOS.

Lung intragraft donor-specific antibodies as a risk factor for graft loss.

BACKGROUND: The effect of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) on graft survival is recognized in lung transplantation, but not all serum DSAs appear to be harmful. We wondered whether in situ DSA detection from graft biopsy specimens could help in identifying lung transplant recipients (LTRs) at higher risk for graft loss. METHODS: Class I and II HLA antibody single-antigen flow bead assays were performed in 53 LTRs to identify immunoglobulin G DSA in biopsy specimen eluates and in sera and to evaluate C1q binding ability of DSA in sera. Intragraft DSAs (gDSAs) were correlated with serum DSAs (sDSAs), clinical and histologic data, and graft survival. RESULTS: Twenty-eight (52.8%) LTRs had sDSAs, 12 (22.6%) had C1q-positive sDSAs, and 11 (20.8%) had gDSAs. Fifty sDSAs were found, among which 15 (30%) were C1q-positive and 14 (28%) were found in biopsy specimen eluates. One DSA was detected in the biopsy specimen only. Serum mean fluorescence intensity and biopsy fragment size were higher for sDSAs detected in biopsy specimens (p = 0.003 and p = 0.02, respectively). One-year post-biopsy graft survival was lower for LTRs with gDSAs (p = 0.008 by log-rank test). Presence of gDSA at the time of biopsy constituted a risk factor for graft loss in univariate (odds ratio, 6.67; 95% confidence interval [CI] 1.51-29.47; p = 0.008; hazard risk, 3.44; 95% CI, 1.47-8.01, p = 0.005) and multivariate (odds ratio, 5.85; 95% CI, 1.23-27.68; p = 0.03; hazard risk, 4.51; 95% CI, 1.83-11.13; p = 0001) analyses using logistic regression and a Cox proportional hazard model, respectively. CONCLUSIONS: In lung transplantation, gDSA appears to be a valuable biomarker to identify pathogenic DSA and LTRs with a higher risk for graft loss.

CT evaluation of small pulmonary vessels area in patients with COPD with severe pulmonary hypertension.

RATIONALE: Severe pulmonary hypertension (PH) is very uncommon in COPD, and a distinct phenotype has been hypothesised. We aimed to evaluate whether CT can help to recognise this condition non-invasively by measuring small pulmonary vessels. MATERIAL AND METHODS: Patients with COPD who underwent pulmonary function tests, unenhanced CT of the chest and right heart catheterisation (RHC) during a period of stability were included in the study. From 105 included patients, 20 patients with COPD with severe PH (mean pulmonary arterial pressure, mPAP>35 mm Hg) were compared with 20 FEV1-matched and age-matched patients with COPD with mild or without PH (mPAP<35 mm Hg). The percentage of total cross-sectional area of vessels less than 5 mm(2) normalised by lung area (%CSA<5) and 5-10 mm(2) (%CSA5-10), the mean number of cross-sectioned vessels (CSNs) and bronchial wall thickness (WT) were measured on CT examination and compared between groups. Paw scores combining PaO2 measurement and CT parameters best correlated with mPAP were compared by receiver operating characteristic analysis to predict severe PH in COPD. RESULTS: Patients with severe PH COPD had higher %CSA and CSN values than those of patients with COPD without severe PH. Using multiple regression analysis, %CSA<5 and WT were the best predictors of mPAP in patients with and without severe PH, respectively. A score combining %CSA<5, PaO2 and WT best predicted severe PH in patients with COPD. CONCLUSIONS: CT measurements of small vessels support a distinct vessel-related phenotype in patients with COPD with severe PH, and combined with WT and PaO2 parameters in the paw score, which may offer a non-invasive tool to select patients for RHC.