Gregor Warnecke

Hannover Medical School, Hanover, Lower Saxony, Germany

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Publications (145)477.74 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective A high proportion of lung transplantation recipients develops de novo donor specific anti-HLA antibodies (DSA) early after lung transplantation. We have recently shown that de novo DSA occurrence is associated with significantly increased mortality. Here, we wished to study the efficacy of a pre-emptive treatment protocol. Methods A retrospective observational study was conducted on all lung transplantations at Hanover Medical School between January 2009 and May 2013. Results Among the 500 transplanted patients, 86 patients (17%) developed early DSA. Of these, 56 (65%; group A) patients received therapeutic plasma exchange (tPE), 30 (35%; group B) patients did not. Among group A patients, 51 also received Rituximab. Between groups, there was no statistically significant difference in mortality, incidence of pulsed steroid therapies or biopsy-diagnosed rejections, incidence of bronchitis obliterans syndrome (BOS) or infections requiring hospitalization at 1 year and 3 years. Also, there were no statistically significant differences after matching 21 group A to 21 group B patients through propensity score analysis. Significantly more group A than group B patients cleared DSA at hospital discharge (32 group A [65%] vs 9 group B [34%] patients [p=0.01]). At last control (median 14, IQR 5-24, months after transplantation), 11 group A (22%) and 9 group B patients (33%) still showed DSA (p=0.28). Conclusions Preemptive treatment with tPE and Rituximab led to improved elimination of DSA early after lung transplantation (p=0.01). However, spontaneous elimination in untreated group B patients also occurred frequently. This treatment protocol was not associated with significantly improved outcome.
    The Journal of Heart and Lung Transplantation. 09/2014;
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    ABSTRACT: Airway stenosis represents the commonest airway complication following lung transplantation, affecting between 7% and 18% of patients. Existing treatment options offer limited efficacy and can cause additional patient morbidity. Paclitaxel-coated balloons (PCB) have proved effective in managing postinterventional coronary artery re-stenosis. In a first-in-man study, we evaluated similar PCBs in refractory nonanastomotic airway stenosis in 12 patients. Following a single application, luminal patency was maintained in 50% at 270 days. No significant peri-interventional or early postinterventional complications occurred. Given these encouraging initial findings, further studies appear warranted.
    American Journal of Transplantation 07/2014; · 6.19 Impact Factor
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    ABSTRACT: Background The impact of early donor specific anti-HLA antibodies (DSA) on patient and graft survival following lung transplantation remains controversial. This study aims to analyze risk factors for DSA that developed before initial hospital discharge after lung transplantation (early DSA) and to compare mid-term outcomes in patients with or without DSA. Methods Between 01/2009 and 08/2013, 546 patients underwent lung transplantation at our institution. One hundred (18%) patients developed early DSA (Group A), 446 (82%) patients (Group B) did not. Patient records were retrospectively reviewed. Results Retransplantation (OR=2.7; 95% confidence interval [CI] 1.1 to 6.5 p=0.03), preoperative HLA antibodies (OR=2.1; 95%CI 1.2-3.4 p=0.003) and primary graft dysfunction (PGD) score grade 2-3 at 48 hours (OR=2.6; 95%CI 1.5-4.6 p=0.001) were associated with early DSA development. Overall, 1 and 3-year survival in Group A and B patients was 79±4% vs. 88±2% and 57±8% vs. 74±3%, respectively (p=0.019). Eleven Group A (11%) and 32 Group B (7%) patients died prior to hospital discharge (p=0.34). Among patients surviving beyond discharge, 1 and 3-year survival in Group A and B patients was 89±4% vs. 95±1% and 65±8% vs. 80±3% in group A and B patients, respectively (p=0.04). Multivariate analysis identified early anti-HLA class II DSA (OR=1.9; 95% CI 1.0-3.4, p=0.04) as an independent risk factor for post-discharge mortality but not for in-hospital mortality. Conclusions Preoperative HLA antibodies, re-transplantation or postoperative PGD increase the risk of developing early DSA, which were independently associated with an increased risk for mortality.
    The Journal of Heart and Lung Transplantation 06/2014; · 5.11 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2014; 33(4):S17–S18. · 5.11 Impact Factor
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    ABSTRACT: Background Infection and rejection represent major complications following lung transplantation and are often associated with pulmonary infiltrates. The differential diagnosis of these infiltrates depends on their timing after transplantation. The aim of this study was to characterize lung transplant recipients (LTR) presenting with new pulmonary infiltrates.MethodsA retrospective analysis of all LTR and heart–lung transplant recipients attending outpatient follow-up at our institution between September 1, 2006 and October 14, 2011 was performed. All patients presenting with new pulmonary infiltrates on chest x-ray who underwent bronchoscopy were included.ResultsA total of 913 patients accounted for 13,156 attendances, with 3,912 bronchoscopies being performed. Seventy-eight patients (9%) exhibited new pulmonary infiltrates and proceeded to bronchoscopy. Infiltrates occurred at a median 15 (interquartile range [IQR] 5–39) months after transplantation. Forty-eight patients (62%) were male, and median patient age was 47 (IQR 29–57) years. Subsequent investigation revealed pneumonia to be the underlying cause in 63 patients (81%). In the remaining patients, chronic lung allograft dysfunction (CLAD) was responsible in 6 (8%), acute rejection in 5 (6%), and toxic pneumonitis in 4 (5%) patients. Overall 1-year survival in LTR presenting with new infiltrates was 97%, compared with 96% for all LTR attending our Outpatient Department.Conclusions New pulmonary infiltrates occurring after the first month in LTR are most likely due to infection. Through prompt diagnosis and treatment, early mortality appears unaffected. Late mortality remains attributable to CLAD.
    Transplant Infectious Disease 04/2014; · 1.98 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2014; 33(4):S17. · 5.11 Impact Factor
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    ABSTRACT: Primary graft dysfunction (PGD) is the most important cause of early morbidity and mortality in lung transplantation (LTX) with an incidence of 8% to 20%. We hypothesized that application of C1-esterase-inhibitor (C1-INH) in LTX-recipients showing early signs of severe PGD would attenuate the condition. Starting as of May 2010, all recipients showing a PaO2/FiO2 ratio of less than 100 as early sign of PGD at first measurement in the OR were immediately treated with C1-INH. Postoperative courses of C1-INH-treated recipients were compared with a subgroup of recipients that developed severe PGD (PGD3-group) within 72 hours after LTX but did not receive C1-INH. Additionally, a third group consisting of all remaining recipients was assembled. A total of 275 LTX were performed between May 2010 and September 2012 at our center. Among these, 24 patients (8.7%) revealed a first PaO2/FiO2 ratio less than 100 and were treated with C1-INH (C1-INH-group). The PGD3-group consisted of 14 patients; the control cohort consisted of 237 patients. PGD scores were significantly higher in the C1-INH-group and PGD3-group as compared with the control group at all times postoperatively. ICU stay was longest in the PGD3 cohort and prolonged in C1-INH patients compared with the control group (29 [2-70] vs. 9 [2-83] vs. 3 [1-166] days, P=0.002). One-year survival in the PGD3-cohort was 71.4%, the C1-INH-treated-group had a one-year-survival of 82.5%, the control group had the best outcome (95%) (P=0.001). Treatment of PGD with C1-INH led to acceptable outcome. Although survival in the C1-INH treated patients was lower than in the remaining collective, it was as good or better, compared with the PGD3 group and as what is internationally regarded as reasonable after LTX.
    Transplantation 02/2014; · 3.78 Impact Factor
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    ABSTRACT: Purpose INSPIRE Trial is an international, FDA pivotal trial to assess the clinical efficacy and safety of OCS™ device to preserve, recruit and assess the donor lungs for transplantation as compared to current cold storage technique. Methods and Materials INSPIRE is a prospective, international, multi-center, randomized controlled trial comparing preservation of donor lungs using OCS-Lung perfusion device (Treatment Group) to Cold flush and storage (Control Group). A total of 264 primary lung transplant recipients will be randomized into the trial. Donor Inclusion Criteria: age <65, normal gas exchange at time of final acceptance of donor lung, and no active primary pulmonary disease. Recipient Inclusion Criteria: age ≥ 18 years old; registered male or female primary double lung transplant candidate; & signed written informed consent for the trial. Donor Exclusion Criteria: positive serology; presence of moderate to severe traumatic lung injury; & presence of confirmed active pneumonia. Recipient Exclusion Criteria: prior solid organ or bone marrow transplant; single lung recipient; chronic use of renal dialysis or diagnosed of chronic renal dysfunction; and multi-organ transplant recipient. Results Primary study endpoint is a composite of patient and graft survival at day 30 post transplantation, and incidence of ISHLT Primary Graft Dysfunction (PGD) Grade 3 at 72 hours post-transplantation. Secondary Endpoints: Incidence of ISHLT Primary Graft Dysfunction Grade 3 at 72 hours post-transplantation; Incidence of ISHLT Primary Graft Dysfunction Grade 2 or 3 at 72 hours post-transplantation; Patient survival at day 30; Graft survival at day 30. Other Endpoints: PGD score at T0, T24, and T48 hours; duration of invasive mechanical ventilation; length of post transplant ICU stay; length of post-transplant hospital stay; & additional hospital admission post initial discharge. Conclusions To-date 60 patients were transplanted in the trial. We will report the interim results at the late breaking clinical trial session at ISHLT 2013.
    The Thoracic and Cardiovascular Surgeon 02/2014; 32(4):S16. · 0.93 Impact Factor
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    ABSTRACT: Accurate immunosuppression is of critical importance in preventing rejection, while avoiding toxicity following lung transplantation. The mainstay immunosuppressants are calcineurin inhibitors, which require regular monitoring due to interactions with other medications and diet. Adherence to immunosuppression and patient knowledge is vital and can be improved through patient education. Education using tablet-computers was investigated. To compare tablet-PC education and conventional education in improving immunosuppression trough levels in target range 6 months after a single education. Secondary parameters were ratio of immunosuppression level measurements divided by per protocol recommended measurements, time and patient satisfaction regarding education. Single-centre, open labelled randomised controlled trial. Patients >6 months after lung-transplantation with <50% of calcineurin inhibitor trough levels in target range. Tablet-pc education versus personal, nurse-led education. Calcineurin inhibitor levels in target range 6 months after education, level variability, interval adherence, knowledge and adherence was studied. As outcome parameter, renal function was measured and adverse events registered. Sixty-four patients were 1:1 randomised for either intervention. Levels of immunosuppression 6 months after education were equal (tablet-PC 58% vs. conventional 48%, p = 0.27), both groups improved in achieving a CNI trough level within target range by either education method (delta tablet-PC 29% vs. conventional 20%). In all patients, level variability decreased (-20.4%), whereas interval adherence remained unchanged. Knowledge about immunosuppression improved by 7% and compliance tests demonstrated universal improvements with no significant difference between groups. Education is a simple, effective tool in improving adherence to immunosuppression. Tablet-PC education was non-inferior to conventional education. ClinicalTrials.gov NCT01398488 http://clinicaltrials.gov/ct2/show/NCT01398488?term=gottlieb+tablet+pc+education&rank=1.
    PLoS ONE 01/2014; 9(3):e90828. · 3.53 Impact Factor
  • Heart Lung &amp Circulation 01/2014; · 1.25 Impact Factor
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    ABSTRACT: To prospectively evaluate quantitative airway wall measurements of thin-section CT for the diagnosis of Bronchiolitis Obliterans Syndrome (BOS) following lung transplantation. In 141 CT examinations, bronchial wall thickness (WT), the wall area percentage (WA%) calculated as the ratio of the bronchial wall area and the total area (sum of bronchial wall area and bronchial lumen area) and the difference of the WT on inspiration and expiration (WTdiff) were automatically measured in different bronchial generations. The measurements were correlated with the lung function parameters. WT and WA% in CT examinations of patients with (n = 25) and without (n = 116) BOS, were compared using the unpaired t-test and univariate analysis of variance, while also considering the differing lung volumes. Measurements could be performed in 2,978 bronchial generations. WT, WA%, and WTdiff did not correlate with the lung function parameters (r<0.5). The WA% on inspiration was significantly greater in patients with BOS than in patients without BOS, even when considering the dependency of the lung volume on the measurements. WT on inspiration and expiration and WA% on expiration did not show significant differences between the groups. WA% on inspiration was significantly greater in patients with than in those without BOS. However, WA% measurements were significantly dependent on lung volume and showed a high variability, thus not allowing the sole use of bronchial wall measurements to differentiate patients with from those without BOS.
    PLoS ONE 01/2014; 9(4):e93783. · 3.53 Impact Factor
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    ABSTRACT: Bronchoscopy represents an important diagnostic and therapeutic tool in the management of lung transplant (LTx) recipients. Outpatient bronchoscopy reduces health costs and may improve quality of life amongst these patients. This retrospective study assessed the safety and efficacy of outpatient bronchoscopy including trans-bronchial biopsy.
    Transplantation research. 01/2014; 3:11.
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    ABSTRACT: There is a need to expand knowledge on cardio-pulmonary pathophysiology of bronchiolitis obliterans syndrome (BOS) following lung transplantation (LTx). The purpose of this study was to assess MRI-derived biventricular cardiac mass and function parameters as well as flow hemodynamics in patients with and without BOS after LTx. Using 1.5T cardiac MRI, measurements of myocardial structure and function as well as measurements of flow in the main pulmonary artery and ascending aorta were performed in 56 lung transplant patients. The patients were dichotomized into two gender matched groups of comparable age range: one with BOS (BOS stages 1-3) and one without BOS (BOS 0/0p). Significantly lower biventricular cardiac mass, right and left ventricular end-diastolic volume, biventricular stroke volume, flow hemodynamics and significant higher heart rate but preserved cardiac output were observed in patients with BOS 1-3 compared to the BOS 0/0p group (p<0.05). In a stepwise logistic regression analysis global cardiac mass (p = 0.046) and days after LTx (p = 0.0001) remained independent parameters to predict BOS. In a second model an indicator for the physical fitness level - walking number of stairs - was added to the logistic regression model. In this second model, time after LTx (p = 0.005) and physical fitness (p = 0.01) remained independent predictors for BOS. The observed changes in biventricular cardiac mass and function as well as changes in hemodynamic flow parameters in the pulmonary trunk and ascending aorta are likely attributed to the physical fitness level of patients after lung transplantation, which in turn is strongly related to lung function.
    PLoS ONE 01/2014; 9(12):e114001. · 3.53 Impact Factor
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    ABSTRACT: The long-term success of human lung transplantation is limited by the development of bronchiolitis obliterans syndrome. Acute rejection episodes and infections are important risk factors and seem to play major pathogenic roles. We established a relevant experimental model that mimics important aspects of human bronchiolitis obliterans syndrome. The Fischer 344-to-Lewis rat strain combination was used for orthotopic left lung transplantation. Isogeneic transplantations were performed in the Lewis rat. Recipients were treated with ciclosporin for 10 days. Lipopolysaccharide or vehicle was instilled into the airways 28 days after transplantation. Grafts were monitored by computed tomography, and recipients were euthanized on Days 28-90. The messenger RNA expression of selected chemokines and their receptors was measured on Days 28, 29, 33, 40 after transplantation. Graft histopathology on Day 90 was compared with lungs from patients who underwent re-transplantation due to end-stage allograft dysfunction. Lung allografts treated with ciclosporin and vehicle only sporadically displayed tissue remodeling. In contrast, lipopolysaccharide treatment induced severe inflammation. In the long-term, severe vascular remodeling, lung fibrosis, and fibroproliferative remodeling of airways were found that closely resemble the histopathologic changes in grafts from human patients with bronchiolitis obliterans syndrome. Chronic damage was virtually absent from pulmonary isografts and native right lungs. Chemokine (C-C motif) ligand 5 and chemokine (C-X-C motif) ligand 9-11, and their receptors, were over-expressed in allografts. Our experimental model mirrors key aspects of human bronchiolitis obliterans syndrome. It will be useful to elucidate its pathogenesis and to develop therapeutic approaches improving the long-term outcome of human lung transplantation.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 09/2013; · 3.54 Impact Factor
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    ABSTRACT: Paraquat is a highly toxic herbicide, which not only leads to acute organ damage, but also to pulmonary fibrosis. There are only anecdotal reports of rescue lung transplantation, as paraquat is stored and only slowly released from different tissues. Bridging the time to complete depletion of paraquat from the body could render this exceptional therapy strategy possible, but not much is known on the time interval after which transplantation can safely be performed. We report on a case of accidental paraquat poisoning in a 23 years old Caucasian man, who developed respiratory failure due to pulmonary fibrosis. The patient was listed for high urgency lung transplantion, and extracorporeal membrane oxygenation was implemented to bridge the time to transplantation. The patient died 32 days after paraquat ingestion, before a suitable donor organ was found. In postmortem tissue specimen, no paraquat was detectable anymore. This case report indicates that complete elimination of paraquat after oral ingestion of a lethal dose is achievable. The determined time frame for this complete elimination might be relevant for patients, in which lung transplantation is considered.
    BMC pharmacology & toxicology. 09/2013; 14(1):45.
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    ABSTRACT: Despite the scarcity of donor lungs, most potential donor organs are not offered by organ procurement organizations or are turned down by transplant centers because no suitable recipient is found according to regular allocation. Although extended criteria donors (ECDs) have recently been considered by many programs, the lung utilization rate remains <30% in most countries. The allocation policy of Eurotransplant for donor lungs that have been turned down for donor-related medical reasons by 3 centers is to attempt a rescue offer, for which centers choose the recipients themselves. At Hannover Medical School we systematically divert these organs to more stable recipients to avoid adverse transplant outcomes. We follow up on these transplants and compare them with those following regular allocation. This study is an analysis of all organ offers and corresponding recipients at our center during the period from January 2010 to August 2011. A total of 183 lung transplantations were performed, 111 regular donor lung offers were accepted for their intended recipient, whereas a total of 72 rescue lung offers, including all extended criteria donors, were accepted for recipients selected by our center. Donor characteristics differed between the 2 groups accordingly. Median age of ECD organ donors was significantly higher than that of regular donors (46.0 [IQR 21] vs 40.0 [IQR 22] years, p = 0.02). Donor mechanical ventilation time did not differ (3.5 ± 4.8 vs 3.0 ± 4.0 days, p = 0.33, not statistically significant [NS]). Donor oxygenation ratio (PaO2:FIO2) at time of organ offer was significantly lower (398.3 ± 110.3 vs 423.0 ± 97.6 mm Hg, p = 0.02). Recipients of rescue allocation organs were older than regularly selected recipients (53.7 ± 11.7 vs 46.7 ± 15.4 years, p = 0.0003), needed a shorter time for mechanical ventilation post-operatively (19.5 ± 306.6 vs 68.5 ± 718.8 hours, p = 0.02), and had shorter hospital stays (24.0 ± 23.4 vs 47.0 ± 43.4 days, p > 0.0001). Intensive care stay length did not differ significantly (2.0 ± 14.5 vs 5.0 ± 23.7 days, p = 0.21 [NS]). Post-operative survival up to 27 months after transplantation was not worse in recipients receiving rescue allocation when compared with standard allocation lung offers (81.62% vs 80.76%, p = 0.89 [NS]). The pre-operative status of the 2 recipient cohorts differed considerably, as indicated by the standard allocation group consisting of 65.8% "high-urgency" (HU)-listed patients, whereas the rescue offers were used for only 11.1% of HU-listed recipients, reflecting our center's policy. Rescue allocation donor lungs can be used safely for transplantation and therefore salvaged for the donor pool. The data support our policy of accepting marginal donor lungs for stable recipients. This practice leads to very good overall survival.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 08/2013; · 3.54 Impact Factor
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    European Journal of Intensive Care Medicine 08/2013; · 5.17 Impact Factor
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    ABSTRACT: Topical in situ cooling of the donor lungs is a prerequisite for procurement of non-heart-beating donor lungs and may be of interest for living related lung donation. Twenty-four single lung transplants were performed in 4 groups of Landrace pigs (6 per group). Control LPD, control Celsior and topical cooling in situ, followed by LPD (exLPD) or Celsior (exCel) ex situ flush, were employed. All lungs were perfused antegrade with 1 liter of solution at 4°C. Lungs were stored immersed in preservation solution for 24 hours at 4°C. After transplantation of the left lung, the right recipient bronchus and pulmonary artery were clamped. Four of 6 animals each in the LPD and Celsior groups and all 6 animals in both the exLPD and the exCel groups survived the 7-hour reperfusion. The mean oxygenation index was favorably preserved in the exCel group at 7 hours after reperfusion (417 ± 81) over all other groups (LPD 341 ± 133, Celsior 387 ± 86, exLPD 327 ± 76; p < 0.0001). Pulmonary vascular resistance showed significantly lower values in the Celsior and exCel groups (LPD 1,310 ± 620, Celsior 584 ± 194, exLPD 1,035 ± 361, exCel 650 ± 116 dyn/s/cm(5) at 7 hours after reperfusion; p < 0.0001). Consistently, the wet-to-dry lung weight ratio also indicated beneficial graft protection in the exCel group (LPD 8.1 ± 0.8, Celsior 8.4 ± 0.8, exLPD 7.5 ± 1.0, exCel 3.1 ± 0.9; p < 0.0001). Initial topical cooling followed by backtable perfusion is a sufficient technique for pulmonary graft preservation providing excellent post-transplant function. Celsior subsequent to in-situ topical cooling revealed the most beneficial results in this setting. This combined technique could advance non-heart-beating, living related lung lobe donation and, potentially, regular heart-beating lung donation.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 08/2013; 32(8):832-8. · 3.54 Impact Factor
  • European Respiratory Journal 08/2013; 42(2):542-4. · 6.36 Impact Factor
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    ABSTRACT: Different types of endothelial cells (EC) fulfill distinct tasks depending on their microenvironment. ECs are therefore difficult to genetically manipulate ex vivo for functional studies or gene therapy. We assessed lentiviral vectors (LVs) targeted to the EC surface marker CD105 for in vivo gene delivery. The mouse CD105-specific vector, mCD105-LV, transduced only CD105-positive cells in primary liver cell cultures. Upon systemic injection, strong reporter gene expression was detected in liver where mCD105-LV specifically transduced liver sinusoidal ECs (LSECs), but not Kupffer cells which were mainly transduced by non-targeted LVs. Tumor ECs were specifically targeted upon intratumoral vector injection. Delivery of the erythropoietin gene with mCD105-LV resulted in substantially increased erythropoietin and hematocrit levels. The human CD105-specific vector (huCD105-LV) transduced exclusively human LSECs in mice transplanted with human liver ECs. Interestingly, when applied at higher dose and in absence of target cells in the liver, huCD105-LV transduced ECs of a human artery transplanted into the descending mouse aorta. The data demonstrate for the first time targeted gene delivery to specialized endothelial cells upon systemic vector administration. This strategy offers novel options to better understand the physiological functions of endothelial cells and to treat genetic diseases such as those affecting blood factors.
    Blood 07/2013; · 9.78 Impact Factor

Publication Stats

784 Citations
477.74 Total Impact Points

Institutions

  • 2000–2014
    • Hannover Medical School
      • • Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG)
      • • Department of Cardiology and Angiology
      Hanover, Lower Saxony, Germany
  • 2013
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 2007–2010
    • Oxford University Hospitals NHS Trust
      • Nuffield Department of Surgery
      Oxford, England, United Kingdom
  • 2003
    • Klinikum Braunschweig
      Brunswyck, Lower Saxony, Germany