Macrophage Polarization Favors Epithelial Repair During Acute Respiratory Distress Syndrome.

OBJECTIVES: Alveolar macrophage polarization and role on alveolar repair during human acute respiratory distress syndrome remain unclear. This study aimed to determine during human acute respiratory distress syndrome: the alveolar macrophage polarization, the effect of alveolar environment on macrophage polarization, and the role of polarized macrophages on epithelial repair. DESIGN: Experimental ex vivo and in vitro investigations. SETTING: Four ICUs in three teaching hospitals. PATIENTS: Thirty-three patients with early moderate-to-severe acute respiratory distress syndrome were enrolled for assessment of the polarization of alveolar macrophages. INTERVENTIONS: Polarization of acute respiratory distress syndrome macrophages was studied by flow cytometry and quantitative polymerase chain reaction. Modulation of macrophage polarization was studied in vitro using phenotypic and functional readouts. Macrophage effect on repair was studied using alveolar epithelial cells in wound healing models. MEASUREMENTS AND MAIN RESULTS: Ex vivo, alveolar macrophages from early acute respiratory distress syndrome patients exhibited anti-inflammatory characteristics with high CD163 expression and interleukin-10 production. Accordingly, early acute respiratory distress syndrome-bronchoalveolar lavage fluid drives an acute respiratory distress syndrome-specific anti-inflammatory macrophage polarization in vitro, close to that induced by recombinant interleukin-10. Culture supernatants from macrophages polarized in vitro with acute respiratory distress syndrome-bronchoalveolar lavage fluid or interleukin-10 and ex vivo acute respiratory distress syndrome alveolar macrophages specifically promoted lung epithelial repair. Inhibition of the hepatocyte growth factor pathway in epithelial cells and hepatocyte growth factor production in macrophages both reversed this effect. Finally, hepatocyte growth factor and soluble form of CD163 concentrations expressed relatively to macrophage count were higher in bronchoalveolar lavage fluid from acute respiratory distress syndrome survivors. CONCLUSIONS: Early acute respiratory distress syndrome alveolar environment drives an anti-inflammatory macrophage polarization favoring epithelial repair through activation of the hepatocyte growth factor pathway. These results suggest that macrophage polarization may be an important step for epithelial repair and acute respiratory distress syndrome recovery.

High Emergency Lung Transplantation: dramatic decrease of waiting list death rate without relevant higher post-transplant mortality.

Many candidates for lung transplantation (LT) die on the waiting list, raising the question of graft availability and strategy for organ allocation. We report the experience of the new organ allocation program, "High Emergency Lung Transplantation" (HELT), since its implementation in our center in 2007. Retrospective analysis of 201 lung transplant patients, of whom 37 received HELT from 1st July 2007 to 31th May 2012. HELT candidates had a higher impairment grade on respiratory status and higher Lung Allocation Score (LAS). HELT patients had increased incidence of perioperative complications (e.g., perioperative bleeding) and extracorporeal circulatory assistance (75% vs. 36.6%, P = 0.0005). No significant difference was observed between HELT and non-HELT patients in mechanical ventilation duration (15.5 days vs. 11 days, P = 0.27), intensive care unit length of stay (15 days vs. 10 days, P = 0.22) or survival rate at 12 (81% vs. 80%), and 24 months post-LT (72.9% vs. 75.0%). Lastly, mortality on the waiting list was spectacularly reduced from 19% to 2% when compared to the non-HELT 2004-2007 group. Despite a more severe clinical status of patients on the waiting list, HELT provided similar results to conventional LT. These results were associated with a dramatic reduction in the mortality rate of patients on the waiting list.

Assessment of lung edema during ex-vivo lung perfusion by single transpulmonary thermodilution: A preliminary study in humans.

BACKGROUND: Single transpulmonary thermodilution (SD) with extravascular lung water index (EVLWI) could become a new tool to better assess lung graft edema during ex-vivo lung perfusion (EVLP). In this study we compare EVLWI with conventional methods to better select lungs during EVLP and to predict post-transplant primary graft dysfunction (PGD). METHODS: We measured EVLWI, arterial oxygen/fraction of inspired oxygen (P/F) ratio, and static lung compliance (SLC) during EVLP in an observational study. At the end of EVLP, grafts were accepted or rejected according to a standardized protocol blinded to EVLWI results. We compared the respective ability of EVLWI, P/F, and SLC to predict PGD. Mann-Whitney U-test, Fisher's exact test, and receiver-operating characteristic (ROC) curve data were used for analysis. p < 0.05 was considered statistically significant. RESULTS: Thirty-five lungs were evaluated by SD during EVLP. Three lungs were rejected for pulmonary edema. Thirty-two patients were transplanted, 8 patients developed Grade 2 or 3 PGD, and 24 patients developed Grade 0 or 1 PGD. In contrast to P/F ratio, SLC, and pulmonary artery pressure, EVLWI differed between these 2 populations (p < 0.001). The area under the ROC for EVLWI assessing Grade 2 or 3 PGD at the end of EVLP was 0.93. Donor lungs with EVLWI >7.5 ml/kg were more likely associated with a higher incidence of Grade 2 or 3 PGD at Day 3. CONCLUSIONS: Increased EVLWI during EVLP was associated with PGD in recipients.

Cough determinants in patients with neuromuscular disease.

Neuromuscular disease leads to cough impairment. Cough augmentation can be achieved by mechanical insufflation (MI) or manually assisted coughing (MAC). Many studies have compared these two methods, but few have evaluated them in combination. In 155 neuromuscular patients, we assessed determinants of peak cough flow (PCF) using stepwise correlation. Maximal inspiratory capacity contributed 44% of the variance (p<0.001), expiratory reserve volume 13%, and maximal expiratory pressure 2%. Thus, augmenting inspiration seems crucial. However, parameters dependent on expiratory muscles independently influence PCF. We measured vital capacity and PCF in 10 neuromuscular patients during cough augmentation by MI, MAC, or both. MI or MAC significantly improved VC and PCF (p<0.01) as compared to the basal condition and VC and PCF were higher during MI plus MAC than during MAC or MI alone (p<0.01). In conclusion, combining MAC and MI is useful for improving cough in neuromuscular patients.

Lung transplantation from initially rejected donors after ex vivo lung reconditioning: the French experience.

OBJECTIVES: Only 15% of brain death donors are considered suitable for lung transplantation (LTx). The normothermic ex vivo lung perfusion technique is used to potentially increase the availability of high-risk lung donors. We report our experience of LTx with initially rejected donors after ex vivo lung reconditioning (EVLR). METHODS: From April 2011 to May 2013, we performed EVLR for 32 pairs of donor lungs deemed unsuitable for transplantation and rejected by the 11 French lung transplant teams. After EVLR, lungs with acceptable function were transplanted. During the same period, 81 double-lung transplantations (DLTx) were used as controls. RESULTS: During EVLR, 31 of 32 donor lungs recovered physiological function with a median PO2/FiO2 ratio increasing from 274 (range 162-404) mmHg to 511 (378-668) mmHg at the end of EVLR (P < 0.0001). Thirty-one DLTx were performed. The incidence of primary graft dysfunction 72 h after LTx was 9.5% in the EVLR group and 8.5% in the control group (P = 1). The median time of extubation, intensive care unit and hospital lengths of stay were 1, 9 and 37 days in the EVLR group and 1 (P = 0.17), 6 (P = 0.06) and 28 days (P = 0.09) in the control group, respectively. Thirty-day mortality rates were 3.3% (n = 1) in the EVLR group and 3.7% (n = 3) in the control group (P = 0.69). One-year survival rates were 93% in the EVLR group and 91% in the control group. CONCLUSIONS: EVLR is a reliable and repeatable technique that offers a significant increase of available donors. The results of LTx with EVLR lungs are similar to those obtained with conventional donors.

Severe pulmonary arterial hypertension as initial manifestation of intravascular lymphoma: case report.

Intravascular lymphoma (IVL) is a rare and usually fatal disease that belongs to the class of high-grade malignant lymphomas and which is characterized by proliferation of neoplastic lymphoid cells exclusively within the lumina of small blood vessels. Its polymorphic and nonspecific clinical manifestations make antemortem diagnosis very difficult. We report herein a case of IVL revealed by fatal, precapillary, pulmonary arterial hypertension and associated with long-lasting fever. Extensive investigation of the usual causes of pulmonary arterial hypertension was negative. The diagnosis of intravascular lymphoma was made on postmortem analysis, revealing diffuse and sometimes complete obliterations of the lumina of small blood vessels by large B-cell lymphoma, including pulmonary capillaries. Thus, we propose that IVL must be added to the spectrum of etiologies of subacute pulmonary arterial hypertension, notably in the context of associated fever, both entities requiring emergency diagnosis. For this purpose, blood collected via pulmonary capillary-wedge aspiration for cytologic examination may be associated with right-sided heart catheterization when this latter procedure is suitable.