[Lung transplantation: current situation and developments]. / Lungentransplantation: aktueller Stand und Entwicklungen.

Lung transplantation is currently the gold standard treatment for end-stage lung diseases. Advances in the preservation of donor lungs, the surgical technique and immunosuppressive therapy have led to lung transplantation now being a routine procedure. Nevertheless, the shortage of donor organs, the acute and particularly chronic lung allograft dysfunction (CLAD) still represent major challenges even in experienced centers. Research in this area is still necessary to improve the long-term survival of lung recipients.

Persistence of de novo donor specific HLA-Antibodies after lung transplantation: a potential marker of decreased patient survival.

The impact of de novo donor-specific anti-HLA antibodies (DSA) on outcomes in lung transplantation is still a matter of debate. We hypothesize that differentiating DSA by persistent and transient appearance may offer an additional risk assessment. The clinical relevance of HLA-antibodies was investigated prospectively in 72 recipients with a median follow-up period of 21 months. The presence of HLA-antibodies was analysed by single antigen bead assay prior to and after (3 weeks, 3, 6, 12 and 18 months) transplantation. In 23 patients (32%) de novo DSA were detected. In 10 of these patients (44%) DSA persisted throughout the follow-up period whereas 13 of these patients (56%) had transient DSA. There was a trend towards lower one-year-survival in DSA positive compared to DSA negative patients (83% versus 94%; p=0.199). Remarkably, patients with persistent DSA had significantly reduced survival (one-year survival 60%) compared with both patients without DSA and those with transient DSA (p=0.005). Persistent DSA represented an independent prognostic factor for reduced overall survival in multivariate analysis (HR 8.3, 95% CI 1.8-37.0; p=0.006). Persistence of DSA during the first year after transplantation seems to be more harmful for lung allograft function than transiently detected DSA at an early stage. This article is protected by copyright. All rights reserved.

Posaconazole liquid vs tablet formulation in lung transplant recipients.

Posaconazole is an extended-spectrum triazole antifungal used in the treatment and prophylaxis of Aspergillus infections. It is available as oral suspension (POS-Liq) and delayed-release tablets (POS-Tab). The aim of this longitudinal, retrospective study was to compare the clinical effectiveness, toxicity and pharmacokinetics of POS-Liq vs POS-Tab in lung transplant recipients (LTx-recipients), who were treated with both formulations subsequently. Twenty-four consecutive LTx-recipients with 191 documented posaconazole trough levels (PTLs) for POS-Liq or POS-Tab were included. The administered daily doses were 300 mg for POS-Tab and 600 mg (prophylaxis) or 800 mg (therapy) for POS-Liq. Target PTLs were ≥700 ng/mL (prophylaxis) and ≥1250 ng/mL (therapy). The overall prophylactic and therapeutic response rates were 78% and 67%, respectively. No cases of hepatotoxicity or QT-prolongation were observed with either formulation. The achieved target PTLs were tripled under POS-Tab compared to POS-Liq with fewer risk factors for sub-therapeutic PTLs. Concomitant administration of POS-Tab significantly reduced the tacrolimus concentration-to-dose ratio (P = .001). We suggest the use of POS-Tab is appropriate for prophylaxis and therapy of Aspergillus infections in LTx-recipients, since POS-Tab displayed more reliable PTLs with no added adverse events. However, we recommend regular drug monitoring for POS-Liq and for therapy with POS-Tab and that immunosuppressant levels are monitored closely when the posaconazole formulation is switched.

Identification of a plasma miRNA biomarker signature for allergic asthma: A translational approach.

BACKGROUND: Asthma is a heterogeneous chronic disease with different phenotypes and treatment responses. Thus, there is a high clinical need for molecular disease biomarkers to aid in differentiating these distinct phenotypes. As MicroRNAs (miRNAs), that regulate gene expression at the post-transcriptional level, are altered in experimental and human asthma, circulating miRNAs are attractive candidates for the identification of novel biomarkers. This study aimed to identify plasmatic miRNA-based biomarkers of asthma, through a translational approach. METHODS: We prescreened miRNAs in plasma samples from two different murine models of experimental asthma (ovalbumin and house dust mite); miRNAs deregulated in both models were further tested in a human training cohort of 20 asthma patients and 9 healthy controls. Candidate miRNAs were then validated in a second, independent group of 26 asthma patients and 12 healthy controls. RESULTS: Ten miRNA ratios consisting of 13 miRNAs were differentially regulated in both murine models. Measuring these miRNAs in the training cohort identified a biomarker signature consisting of five miRNA ratios (7 miRNAs). This signature showed a good sensitivity and specificity in the test cohort with an area under the receiver operating characteristic curve (AUC) of 0.92. Correlation of miRNA ratios with clinical characteristics further revealed associations with FVC % predicted, and oral corticosteroid or antileukotriene use. CONCLUSION: Distinct plasma miRNAs are differentially regulated both in murine and in human allergic asthma and were associated with clinical characteristics of patients. Thus, we suggest that miRNA levels in plasma might have future potential to subphenotype patients with asthma.

Bronchiolitis obliterans syndrome due to donor-specific HLA-antibodies.

Chronic lung allograft dysfunction (CLAD) is a limiting factor for long-term survival in lung transplant recipients. Donor-specific human leukocyte antigen (HLA)-antibodies (DSA) have been suggested as potential risk factors for CLAD. However, their impact on clinical outcome following lung transplantation remains controversial. We performed a single-center study of 120 lung transplant recipients transplanted between 2006 and 2011. Patient sera were investigated before and after transplantation. The sera were screened by means of Luminex(®) technology (Luminex Inc., Austin, TX, USA) for IgG-HLA-class I and class II antibodies (ab). Using single antigen beads, DSA were identified and correlated retrospectively with clinical parameters. After transplantation 39 out of 120 patients (32.5%) were positive for HLA-ab. The incidence of de novo DSA formation was 27 of 120 patients (22.5%). Eleven of 27 (41%) of de novo DSA-positive patients developed BOS compared to 13 of 93 (14%) DSA-negative patients (p = 0.002). Furthermore, the generation of de novo DSA was independently associated with the development of BOS in multivariable analysis [hazard ration (HR) 2.5, 95% confidence interval (CI) 1.0-6.08; p = 0.046). Our results indicate that de novo DSA are associated with the development of BOS after lung transplantation. Monitoring of HLA-ab after transplantation is useful for identifying high-risk patients and offers an opportunity for early therapeutic intervention.

Acute phase proteins do not account for unmeasured anions in critical illness.

BACKGROUND: The increasingly recognized prognostic impact of the strong ion gap in critical illness is in contrast to its largely unknown chemical nature. Experimental and clinical evidence suggest that acute phase proteins might account for elevation of the strong ion gap. The hypothesis of this investigation was that acute phase proteins account for strong ion gap in critically ill patients. MATERIALS AND METHODS: The charges of the two acute phase proteins C-reactive protein and fibrinogen were estimated by a computer model. Additionally, 142 patients admitted to a medical intensive care unit of a university hospital were studied prospectively during a six month period. Serial daily observations were recorded and classified according to the systemic inflammatory state. The acute phase proteins C-reactive protein and fibrinogen were measured and the strong ion gap was calculated from the measured acid-base variables. RESULTS: The approximated mean charges of C-reactive protein and fibrinogen at a pH of 7.4 are -4.0 and -13.6 per molecule, respectively. Therefore, their negative charge is too small to explain the elevated strong ion gap even during a substantial increase of C-reactive protein and fibrinogen due to an acute-phase reaction. Moreover, C-reactive protein did not correlate with the strong ion gap when partialized for creatinine (R = 0.02, P = 0.567). Fibrinogen did not correlate with the strong ion gap. Creatinine correlated with the strong ion gap (R = 0.42, P < 0.001). Neither systemic inflammatory state nor increasing C-reactive protein levels were associated with an increasing strong ion gap. CONCLUSION: Acute phase proteins do not account for an elevated strong ion gap in critically ill patients.