Isabelle Danner-Boucher

Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome

This study aims to describe the haemodynamic and survival characteristics of patients with pulmonary hypertension in the recently individualised syndrome of combined pulmonary fibrosis and emphysema. A retrospective multicentre study was conducted in 40 patients (38 males; age 68±9 yrs; 39 smokers) with combined pulmonary fibrosis and emphysema, and pulmonary hypertension at right heart catheterisation. Dyspnoea was functional class II in 15%, III in 55% and IV in 30%. 6-min walk distance was 244±126 m. Forced vital capacity was 86±18%, forced expiratory volume in 1 s 78±19%, and carbon monoxide diffusion transfer coefficient 28±16% of predicted. Room air arterial oxygen tension was 7.5±1.6 kPa (56±12 mmHg). Mean pulmonary artery pressure was 40±9 mmHg, cardiac index 2.5±0.7 L·min−1·m−2 and pulmonary vascular resistance 521±205 dyn·s·cm−5. 1-yr survival was 60%. Higher pulmonary vascular resistance, higher heart rate, lower cardiac index and lower carbon monoxide diffusion transfer were associated with shorter survival. Patients with combined pulmonary fibrosis and emphysema syndrome and pulmonary hypertension confirmed by right heart catheterisation have a dismal prognosis despite moderately altered lung volumes and flows and moderately severe haemodynamic parameters.

High prevalence of triazole resistance in Aspergillus fumigatus, especially mediated by TR/L98H, in a French cohort of patients with cystic fibrosis

OBJECTIVES Triazole resistance in Aspergillus fumigatus due to a single azole resistance mechanism (TR/L98H) is increasingly reported in European countries. Data from patients with cystic fibrosis (CF) are limited. Our study aimed to investigate the prevalence and molecular mechanisms of azole resistance in A. fumigatus in a cohort of patients with CF. METHODS Eighty-five A. fumigatus isolates from 50 CF patients, collected between January 2010 and April 2011, were retrospectively analysed for azole resistance using agar plates containing 4 mg/L itraconazole. MICs of itraconazole, voriconazole and posaconazole were determined according to EUCAST methodology for each isolate able to grow on this medium. Species identification was performed by sequencing of the β-tubulin gene. Sequencing analysis of the cyp51A gene and its promoter region was conducted. RESULTS Nine isolates (four patients, 8% prevalence) were able to grow on itraconazole-containing agar plates. Itraconazole resistance was confirmed by EUCAST methodology (MICs >2 mg/L). All isolates had mutations in the cyp51A gene at residues previously involved in azole resistance: L98H (n = 5), M220T (n = 4) and G54R (n = 1). One patient had three genetically distinct azole-resistant isolates identified during the study. The isolates with L98H that were recovered from three patients (6% prevalence) also had the 34 bp tandem repeat in the promoter region of cyp51A (TR/L98H) and displayed multiazole resistance. CONCLUSIONS We report an 8% prevalence of itraconazole resistance in CF patients in our centre, mostly driven by TR/L98H (6%). Our data confirm that TR/L98H occurs in France and can be highly prevalent in CF patients.

Disseminated Scedosporium/Pseudallescheria Infection after Double-Lung Transplantation in Patients with Cystic Fibrosis

ABSTRACT We report a case of disseminated Scedosporium/Pseudallescheria infection due to Pseudallescheria boydii sensu stricto after lung transplantation in a patient with cystic fibrosis. Dissemination occurred under voriconazole. Despite surgery and combination therapy with voriconazole, caspofungin, and terbinafine, the patient died 8 months after transplantation. Previously reported cases are reviewed.

One-year experience with high-emergency lung transplantation in France.

Background The continuing significant number of patients who die while on a waiting list for lung transplantation (LTx) has led several countries to modify their lung allocation rules in recent years. France has implemented high-emergency allocation rules to allow patients at imminent risk of death to undergo priority transplantation within several days. The aim of this study was to report on the early (2-year) experience of high-emergency LTx (HELTx) in France. Methods From July 1, 2007, to June 30, 2008, 186 patients underwent LTx in France in nine centers. Among them, 32 patients (17.2%) underwent HELTx (19 with cystic fibrosis, 7 pulmonary fibrosis, and 6 other diagnoses). The reasons for HELTx were risk of invasive mechanical ventilation (n=20), invasive mechanical ventilation (n=8), and extracorporeal membrane oxygenation (n=4). Results The median time between being placed on the HELTx waiting list and LTx was 3 days (interquartile range: 1–8 days). Survival rates in the HELTx group were 90.5%, 71%, 64.5%, 55%, and 51.5% at 1, 3, 6, 12, and 24 months, respectively, which were significantly lower than for 154 patients who underwent regular, nonurgent LTx during the study period (88.5%, 83%, 79%, 77%, and 71%, respectively). Conclusions Our data demonstrate that the new LTx allocation rules implemented in France since 2007 allow for rapid organ procurement for patients at imminent high risk of death. HELTx is feasible but yields poorer survival than elective LTx. Further studies are needed to assess implications of this organ allocation policy on the long run.

Systematic Analysis of Blood Cell Transcriptome in End-Stage Chronic Respiratory Diseases

Background End-stage chronic respiratory diseases (CRD) have systemic consequences, such as weight loss and susceptibility to infection. However the mechanisms of such dysfunctions are as yet poorly explained. We hypothesized that the genes putatively involved in these mechanisms would emerge from a systematic analysis of blood mRNA profiles from pre-transplant patients with cystic fibrosis (CF), pulmonary hypertension (PAH), and chronic obstructive pulmonary disease (COPD). Methods Whole blood was first collected from 13 patients with PAH, 23 patients with CF, and 28 Healthy Controls (HC). Microarray results were validated by quantitative PCR on a second and independent group (7PAH, 9CF, and 11HC). Twelve pre-transplant COPD patients were added to validate the common signature shared by patients with CRD for all causes. To further clarify a role for hypoxia in the candidate gene dysregulation, peripheral blood mononuclear cells from HC were analysed for their mRNA profile under hypoxia. Results Unsupervised hierarchical clustering allowed the identification of 3 gene signatures related to CRD. One was common to CF and PAH, another specific to CF, and the final one was specific to PAH. With the common signature, we validated T-Cell Factor 7 (TCF-7) and Interleukin 7 Receptor (IL-7R), two genes related to T lymphocyte activation, as being under-expressed. We showed a strong impact of the hypoxia on modulation of TCF-7 and IL-7R expression in PBMCs from HC under hypoxia or PBMCs from CRD. In addition, we identified and validated genes upregulated in PAH or CF, including Lectin Galactoside-binding Soluble 3 and Toll Like Receptor 4, respectively. Conclusions Systematic analysis of blood cell transcriptome in CRD patients identified common and specific signatures relevant to the systemic pathologies. TCF-7 and IL-7R were downregulated whatever the cause of CRD and this could play a role in the higher susceptibility to infection of these patients.

Phaeohyphomycosis due to Alternaria infectoria: a single-center experience with utility of PCR for diagnosis and species identification

The term phaeohyphomycosis refers to a rare group of fungal infections characterized by the presence of dark-walled hyphae or yeast-like cells in affected tissues. Herein, we report on the clinical and epidemiological characteristics of six cases of phaeohyphomycosis due to Alternaria spp. that occurred in our hospital over a 30-month period (from January 2008 to June 2010). Interestingly, whereas histopathological examinations were positive and fungal cultures yielded molds in all cases, mycological identification using conventional phenotypic methods was never possible despite prolonged incubation of the isolates. Identification of Alternaria infectoria species complex was obtained for each isolate by amplification and sequencing of the internal transcribed spacer of the ribosomal DNA (ITS rDNA). All patients had favourable outcomes following the introduction of azole-based antifungal therapy. This case series describes the clinical course of these six patients and highlights the utility of molecular identification to help in the identification of the etiologic agent when classical mycological methods have failed.

Prevalence of the reversed halo sign in neutropenic patients compared with non-neutropenic patients: Data from a single-centre study involving 27 patients with pulmonary mucormycosis (2003-2016)

Pulmonary mucormycosis (PM) is a life‐threatening infection and the diagnosis can be challenging. The objective was to retrospectively explore the value of the RHS in our cohort of 27 patients with mucormycosis and its relation to neutropenia. This was a retrospective study including all patients with a diagnosis of probable or proven invasive PM according to the 2008 EORTC/MSG criteria between September 2003 to April 2016. Fishers exact test and Mann‐Whitney test, with a P‐value statistically significant under .05 (P<.05), were used to compare neutropenic and non‐neutropenic groups. 27 patients were eligible. The RHS could be identified in 78% of cases in the neutropenic group, and was less common in the non‐neutropenic group (31%) (P<.05). Reticulations inside ground‐glass opacity in case of RHS were present in 13 out of 15 patients (87%). Mucorales DNA detection by PCR on serum provided, a median time to the first PCR‐positive sample of 3 days (−33 to +60 days) before diagnosis was confirmed. Six patients had IPA co‐infection. In conclusion, RHS is more frequent in case of PM in neutropenic patients compare to non‐neutropenic patients. Its presence in immunocompromised patients should be sufficient to promptly start Mucorales‐active antifungal treatment, while its absence especially in non‐neutropenic cases should not be sufficient to exclude the diagnosis.

Severe pulmonary hypertension leading to heart–lung transplantation and revealing breast cancer

To the Editors: Pulmonary tumour embolism is considered to be a rare cause of pulmonary hypertension. The incidence, studied in autopsy series, varies from 3 to 26% of patients with solid tumour [1]. It occurs most frequently in breast, stomach, lung, liver, prostate and pancreas adenocarcinoma [1]. The literature shows a male predominance and an average age of 52.4 yrs [2]. The signs are those of any pulmonary hypertension, occurring either during the history of a known neoplasia or as the first manifestation of malignancy. Pre-mortem diagnosis is difficult to confirm and definitive diagnosis is usually made on an autopsy study. Several studies have reported pulmonary wedge aspiration cytology performed during a right heart catheterisation as a useful pre-mortem diagnostic tool [3]. Treatment consists of treating the neoplasia. Specific treatment for pulmonary hypertension has not been evaluated. Most frequently, evolution leads to refractory right cardiac failure and death [4]. In rare cases improvement has been reported after chemotherapy [5] or endarterectomy [6]. Two mechanisms can be involved in the development of pulmonary hypertension in tumour pulmonary embolism: the first one is by mechanical occlusion of the small pulmonary arteries by multiple neoplastic microemboli, the second one is through development of pulmonary tumour thrombotic microangiopathy (PTTM) as a result of …

Total lung capacity size matching in fibrosis lung transplantation

Single (S) or bilateral (B) lung transplantation (LT) is offered for end stage, life-threatening pulmonary fibrosis (PF). Currently, no strong recommendation helps transplantation teams for choosing optimal total lung capacity (TLC) for size matching. We conducted a retrospective analysis of all LT performed in PF patients from 1988 to 2015 in Nantes University hospital, France, in order to study donor vs. recipient TLC. We defined transplanted BLT-TLC as follows: theoretic donor TLC minus lung volume surgical reduction, divided by theoretic recipient TLC. Transplanted SLT-TLC was similarly calculated, taking into account measured TLC of the remaining lung. 24 patients (46 ± 9 years, 10 SLT and 14 BLT) were included. Survival after transplantation for BLT, SLT and both was respectively 35.7%, 50% and 41.7% at 1 year, 21.5%, 10% and 16.7% at 5 years, with a median survival of 347 days for BLT and 272 days for SLT (p=0.38). Mean transplanted TLC was higher in BLT (86.4 ± 20.2% pred.) than in SLT (65.1 ± 7.2% pred.) (p = 0.007) and higher than recipient TLC measured / theoretic in BLT (54 ± 22%) and SLT (48 ± 10%) (p=0.038). Average lung volume reduction was 12.3% in BLT and was performed in 35.7% of BLT and 20% of SLT. When classifying patients according to different thresholds of transplanted TLC percentage (70% or 80% pred.), no mortality difference was observed in SLT, BLT or both groups. Taking into account surgical lung volume reduction, we report a lower transplanted TLC in BLT and SLT than the one suggested by Barnard et al. (Barnard J.B, J Heart Tranplant 2013;32:849-860). The best TLC size matching appears to be somewhere between measured and theoretic TLC recipient but has to be further explored.

WS03.6 Pregnancies after lung transplantation: A retrospective multicenter French study about 39 pregnancies

Objectives Pregnancy after lung transplantation remains rare. This French study deals with maternal and newborn outcomes and change in lung function after a pregnancy. Methods We retrospectively included 39 pregnancies in 35 lung transplant recipients over more than 20 years. Data about patients, course of pregnancies and newborns were collected from nine of the eleven French transplantation centers. Results Mean age at time of pregnancy was 28±5years. Cystic fibrosis affected 71% of our patients. Mean time between transplantation and pregnancy was 63±44 months. Twenty six births occurred (67%) with a mean term of 36±5 weeks gestation and a mean birth weight of 2409±921 g. Prematurity was observed in 11 cases (43%). Forced expiratory volume in one second was measured at 83.9% pred. before pregnancy and at 77.3% pred. 12 months later (p = 0.04). Ten patients developed chronic lung allograft dysfunction, 22.5±14.6 months after delivery. Up to now, nine patients died with a mean time after transplantation of 8.2±7 years and a mean time after pregnancy of 4.6±6.5 years. Conclusion Pregnancy in lung transplant recipients is possible. Maternal and newborn complications are more frequent than in general population. Survival in this cohort appears to be similar to global survival observed in lung transplant recipients. Planned pregnancy and multidisciplinary follow-up are crucial.