Gregor Zimmermann

Prognostic Value of Bronchoalveolar Lavage Neutrophilia in Stable Lung Transplant Recipients

BACKGROUND Bronchoalveolar lavage (BAL) neutrophilia may identify patients prone to develop bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). This study assessed the predictive value of BAL neutrophilia in stable recipients. METHODS Evaluated were 63 consecutive recipients 3 to 12 months after LTx demonstrating no acute rejection (AR) and lymphocytic bronchitis (LB; B < or = 1 without infection; BOS, 0). Recipients were subdivided into never-BOS (follow-up > or = 12 months) and ever-BOS groups (i.e., BOS development > or = 1 after bronchoscopy). RESULTS The groups were statistically indistinguishable for demographic data and preceding AR and LB episodes. Onset of BOS was at a median of 232 days (range, 87-962) after bronchoscopy. The ever-BOS group (16 patients) demonstrated a significantly higher percentage of neutrophils compared with the never-BOS group (47 patients) at the time of bronchoscopy (33.6% +/- 2.1% vs 9.9% +/- 1.1%, p < 0.05). By Cox regression analysis, a BAL neutrophil percentage of > or = 20% remained a significant predictor for BOS > or = 1 (hazard ratio, 3.57; 95% confidence interval, 1.71-8.40, p < 0.05) distinct from known potential BOS predictor variables. The positive and negative predictive value of BAL neutrophilia of > or = 20% for future BOS was 0.72 and 0.93, respectively (p < 0.05). CONCLUSION BAL neutrophilia in stable recipients is of predictive value to identify recipients at risk for BOS. These data warrant prospective confirmation and further studies to evaluate the benefit of preemptive therapy for potential BOS patients.

Potential functional and survival benefit of double over single lung transplantation for selected patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a frequent indication for lung transplantation (LTX) with pulmonary hypertension (PH) negatively affecting outcome. The optimal procedure type remains a debated topic. The aim of this study was to evaluate the impact of pretransplant PH in IPF patients. Single LTX (SLTX, n = 46) was the standard procedure type. Double LTX (DLTX, n = 30) was only performed in cases of relevant PH or additional suppurative lung disease. There was no significant difference for pretransplant clinical parameters. Preoperative mean pulmonary arterial pressure was significantly higher in DLTX recipients (22.7 ± 0.8 mmHg vs. 35.9 ± 1.8 mmHg, P < 0.001). After transplantation, 6‐min‐walk distance and BEST‐FEV1 were significantly higher for DLTX patients (6‐MWD: 410 ± 25 m vs. 498 ± 23 m, P = 0.02; BEST‐FEV1: 71.2 ± 3.0 (% pred) vs. 86.2 ± 4.2 (% pred), P = 0.004). Double LTX recipients demonstrated a significantly better 1‐year‐, overall‐ and Bronchiolitis obliterans Syndrome (BOS)‐free survival (P < 0.05). Cox regression analysis confirmed SLTX to be a significant predictor for death and BOS. Single LTX offers acceptable survival rates for IPF patients. Double LTX provides a significant benefit in selected recipients. Our data warrant further trials of SLTX versus DLTX stratifying for potential confounders including PH.

Anti-inflammatory effects of antibacterials on human Bronchial epithelial cells.

BackgroundHuman Bronchial epithelial cells (hu-BEC) have been claimed to play a significant role in the pathogenesis of chronic inflammatory airway diseases like COPD. In this context IL-8 and GM-CSF have been shown to be key cytokines. Some antibiotics which are routinely used to treat lower respiratory tract infections have been shown to exert additional immunomodulatory or anti-inflammatory effects. We investigated whether these effects can also be detected in hu-BEC.MethodsHu-BEC obtained from patients undergoing lung resections were transferred to air-liquid-interface (ALI) culture. These cultures were incubated with cefuroxime (CXM, 10-62.5 mg/l), azithromycin (AZM, 0.1-1.5 mg/l), levofloxacin (LVX, 1-8 mg/l) and moxifloxacin (MXF, 1-16 mg/l). The spontaneous and TNF-α (10 ng/ml) induced expression and release of IL-8 and GM-CSF were measured using PCR and ELISA in the absence or presence of these antibiotics.ResultsThe spontaneous IL-8 and GM-CSF release was significantly reduced with MXF (8 mg/l) by 37 ± 20% and 45 ± 31%, respectively (both p < 0.01). IL-8 release in TNF-α stimulated hu-BEC decreased by 16 ± 8% (p < 0.05) with AZM (1.5 mg/l). With MXF a concentration dependent decrease of IL-8 release was noted up to 39 ± 7% (p < 0.05). GM-CSF release from TNF-α stimulated hu-BEC was maximally decreased by 35 ± 24% (p < 0.01) with MXF (4 mg/l).ConclusionUsing ALI cultures of hu-BEC we observed differential effects of antibiotics on spontaneous and TNF-α induced cytokine release. Our data suggest that MXF and AZM, beyond bactericidal effects, may attenuate the inflammatory process mediated by hu-BEC.

Is sirolimus a therapeutic option for patients with progressive pulmonary lymphangioleiomyomatosis

BackgroundLymphangioleiomyomatosis (LAM) is a rare lung disease characterised by progressive airflow obstruction. No effective medical treatment is available but therapy with sirolimus has shown some promise. The aim of this observational study was to evaluate sirolimus in progressive LAM.MethodsSirolimus (trough level 5 - 10 ng/ml) was administered to ten female patients (42.4 ± 11.9 years) with documented progression. Serial pulmonary function tests and six-minute-walk-distance (6-MWD) assessments were performed.ResultsThe mean loss of FEV1 was -2.30 ± 0.52 ml/day before therapy and a significant mean gain of FEV1 of 1.19 ± 0.26 ml/day was detected during treatment (p = 0.001). Mean FEV1 and FVC at baseline were 1.12 ± 0.15 l (36.1 ± 4.5%pred.) and 2.47 ± 0.25 l (69.2 ± 6.5%pred.), respectively. At three and six months during follow-up a significant increase of FEV1 and FVC was demonstrated (3 months ΔFEV1: 220 ± 82 ml, p = 0.024; 6 months ΔFEV1: 345 ± 58 ml, p = 0.001); (3 months ΔFVC: 360 ± 141 ml, p = 0.031; 6 months ΔFVC: 488 ± 138 ml, p = 0.006). Sirolimus was discontinued in 3 patients because of serious recurrent lower respiratory tract infection or sirolimus-induced pneumonitis. No deaths and no pneumothoraces occurred during therapy.ConclusionsOur data suggest that sirolimus might be considered as a therapeutic option in rapidly declining LAM patients. However, sirolimus administration may be associated with severe respiratory adverse events requiring treatment cessation in some patients. Moreover, discontinuation of sirolimus is mandatory prior to lung transplantation.

Effect of inpatient rehabilitation on quality of life and exercise capacity in long-term lung transplant survivors: a prospective, randomized study.

BACKGROUND The purpose of this study was to examine the effect of an inpatient rehabilitation program on health-related quality of life (HRQOL) and exercise capacity (EC) in long-term (>1 year after lung transplantation) survivors (LTSs) in comparison to a control group (CG). METHODS Sixty LTSs, 4.5 ± 3.2 years after lung transplantation (LTx), were randomly assigned to two equally sized groups that were stratified for gender and underlying disease. Thirty LTSs (age 49 ± 13 years, 13 male and 17 females, 19 double LTxs, 7 BOS Stage ≥ 1) attended an inpatient rehabilitation program (intervention group, IG) for 23 ± 5 days. The CG (age 50 ± 12 years, 13 males and 17 females, 20 double LTxs, 2 BOS Stage ≥ 1) received medical standard therapy (physiotherapy). Patients were evaluated by cardiopulmonary exercise testing, 6-minute walk test (6MWT), SF-36, SGRQ and the Quality of Life Profile for Chronic Diseases questionnaire before and after (18 ± 3 days) the program. RESULTS The groups were statistically indistinguishable in terms of clinical data. Each treatment group significantly improved their sub-maximal EC (6MWT: IG, 493 ± 90 m vs 538 ± 90 m, p < 0.001; CG, 490 ± 88 m vs 514 ± 89 m, p < 0.001) and maximal EC (VO(2peak): IG, 17.0 vs 18.5 ml/min/kg, p = 0.039; CG, 18.0 vs 19.5 ml/min/kg, p = 0.005), without reaching statistical significance between the groups. In both study groups, patients HRQOL tended to improve. Significant correlations were found between EC parameters and HRQOL scales. CONCLUSIONS Our data suggest that structured physical training may improve exercise tolerance in LTS. Our study results did not demonstrate a significant benefit of an inpatient over an outpatient exercise program.

Usefulness of Exhaled Nitric Oxide to Guide Risk Stratification for Bronchiolitis Obliterans Syndrome After Lung Transplantation

The aim of this study was to assess fractional exhaled nitric oxide (FeNO) for the early diagnosis of bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTX). 611 FeNO measurements in 166 consecutive patients were classified depending on BOS stage at the time of assessment and course during minimum follow‐up of 3 months: (1) stable non‐BOS, (2) unstable non‐BOS, (3) stable BOS and (4) unstable BOS. Unstable course was defined as new onset of BOS≥1 or progression of BOS. FeNO before unstable course was significantly increased in comparison to their stable counterparts (non‐BOS: 28.9 ± 1.2 ppb, n = 40 vs. 16.4 ± 0.8 ppb, n = 131 and BOS: 32.5 ± 1.3 ppb, n = 35 vs. 15.3 ± 0.8 ppb, n = 26; p = 0.01 each). Average time from FeNO reading to onset of deterioration was 117 ± 9 days in non‐BOS and 136 ± 9 days in BOS patients. The positive and negative predictive value of FeNO >20 ppb for BOS was 69.0% and 96.9%, respectively. Serial measurements demonstrated significantly lower mean individual variation in stable recipients as compared to stable patients switching to unstable course (3.2 ± 0.3 ppb vs. 12.7 ± 1.4 ppb, p = 0.02). In particular, the excellent negative predictive value of persistently low FeNO readings for future BOS make FeNO assessments a useful tool for continuous risk stratification after LTX.

Haemodynamic changes in pulmonary hypertension in patients with interstitial lung disease treated with PDE‐5 inhibitors

Interstitial lung diseases (ILD) are often associated with pulmonary hypertension (PH). This study aimed to evaluate the therapeutic benefit of phosphodiesterase‐5 (PDE‐5) inhibitors in pulmonary hypertension secondary to ILD.

Tacrolimus and mycophenolate mofetil as first line immunosuppression after lung transplantation

The optimal maintenance therapy after lung transplantation remains to be established. The aim of this study was to analyse the impact of tacrolimus and mycophenolate mofetil (MMF) as first line immunosuppression on long‐term survival and Bronchiolitis Obliterans Syndrome (BOS). From January 1996 through December 2006, all 155 recipients receiving tacrolimus and MMF as maintenance immunosuppression were included in this study. Tacrolimus and MMF was discontinued in 36 patients (23.2%). The overall survival rates were 91.6% at 6 months, 86.4% at 1 year, 74.9% at 3 years, 60.3% at 5 years and 32.4% at 10 years. The overall freedom from acute rejection was 74.6%, 63.2% and 59.4% at 1, 3, and 5 years respectively. The overall BOS‐free survival was 95.6% at 1 year, 88.4% at 3 years, 69.5% at 5 years and 30.5% at 10 years. The development of BOS ≥ 1 was associated with a significantly increased risk of death and reduced long‐term survival. The combination of tacrolimus and MMF offers safe and reliable maintenance immunosuppression after lung transplantation. However, substantial improvements of long‐term survival and freedom from BOS might only be achieved by a change in organ allocation policies and patient management beyond differential immunosuppressive protocols.

The Munich-LTX-Score: predictor for survival after lung transplantation.

Huppmann P, Neurohr C, Leuschner S, Leuchte H, Baumgartner R, Zimmermann G, Meis T, von Wulffen W, Überfuhr P, Hatz R, Frey L, Behr J for the Munich Lung Transplant Group (MLTG). The Munich‐LTX‐Score: predictor for survival after lung transplantation. 
Clin Transplant 2012: 26: 173–183. 
© 2011 John Wiley & Sons A/S.

Suspected pulmonary embolism in patients with pulmonary fibrosis: Discordance between ventilation/perfusion SPECT and CT pulmonary angiography

Pulmonary embolism (PE) is a common differential diagnosis in patients with pulmonary fibrosis presenting with a clinical deterioration. Both ventilation/perfusion (V/Q)‐single photon emission computed tomography (SPECT) and computed tomographic pulmonary angiography (CTPA) are routinely used to detect PE. However, the value of V/Q‐SPECT and CTPA in this scenario has not been studied so far. We aimed to investigate the concordance of V/Q‐SPECT and CTPA in patients with pulmonary fibrosis and suspicion of pulmonary embolism.