Martin Carby

Early outcomes of bilateral sequential single lung transplantation after ex-vivo lung evaluation and reconditioning

BACKGROUND Ex vivo lung perfusion (EVLP) is a novel approach for extended evaluation and/or reconditioning of donor lungs not meeting standard International Society for Heart and Lung Transplantation criteria for transplantation. METHODS We retrospectively evaluated 13 consecutive EVLP runs between January 2009 and December 2010. Lungs rejected for routine transplantation were implanted to the EVLP circuit and reperfused using acellular supplemented Steen Solution (Vitrolife, Göteborg, Sweden) up to a target flow rate of 40% of the donors calculated flow at a cardiac index of 3.0 liters/min/m(2); target left atrial pressure < 5 mm Hg; and pulmonary artery pressure < 15 mm Hg. Mechanical ventilation was introduced after rewarming to 32°C: tidal volume, 6 to 8 ml/kg; respiratory rate, 7 to 8 breaths/min; duration of inspiration/expiration (I/E) ratio, 1:2; and positive end-expiratory pressure, 5 to 10 cm H(2)O. Hemodynamic and respiratory data monitoring with hourly clinical assessment were performed. Donor data, conversion rate to transplantation, and recipient outcome were analyzed. RESULTS Donor data (n = 13) were: age, 44.23 ± 8.33 years; female/male, 8:5; cause of death: intracranial hemorrhage, 11 (85%), stroke, 1 (7.5%), hypoxic brain injury, 1 (7.5%); smoking history, 9 (69%), 17.44 ± 8.92 pack-years; mechanical ventilation, 102.6 ± 91.92 hours; chest x-ray imaging: abnormal, 12 (92.5%); normal, 1 (7.5%). EVLP: mean 141 ± 28.83 minutes. Arterial partial pressure of oxygen/fraction of inspired oxygen 100% before termination of the circuit vs pre-retrieval value: 57.32 ± 9.1 vs 42.36 ± 14.13 kPa (p < 0.05). Six (46%) pairs of donor lungs were transplanted. Median follow-up was 297.5 days (range, 100-390 days), with 100% survival at 3 months. CONCLUSIONS EVLP may facilitate assessment and/or reconditioning of borderline lungs, with a conversion rate of 46 % and good short-term survival.

De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation

BACKGROUND Bronchiolitis obliterans syndrome (BOS) is the major cause of late graft failure after lung transplantation. The objective was to determine whether de novo donor human leukocyte antigen (HLA)-specific antibodies (DSA) are associated with the development of BOS or patient survival. Data were analyzed from 188 lung transplant recipients with a follow-up period up to 8 years. METHODS HLA antibody monitoring was performed at 3-month intervals post-transplant at routine outpatient clinic attendances and during the investigation of any acute deterioration. HLA antibody data were available for 148 patients; 66 (45%) had produced HLA antibodies after transplant, of which 38 (26%) were DSA and 28 (19%) non-donor-specific HLA antibodies. RESULTS De novo DSA was associated with development of BOS Stage 1 (BOS1; hazard ratio [HR] = 2.302, p = 0.0015), BOS2 (HR = 3.627, p < 0.0001) and BOS3 (HR = 5.736, p < 0.0001). De novo persistent DSA correlated strongly with shorter time to onset of BOS3 (HR = 6.506, p = 0.0001). There was a significant reduction in patient survival associated with de novo DSA (HR = 1.886, p = 0.047). In multivariable analyses, de novo DSA was an independent predictor for development of all stages of BOS as well as an independent predictor of poor patient survival. CONCLUSIONS De novo DSA is a major risk factor for progression to BOS and shorter patient survival. Treatments to remove antibodies or limit antibody-mediated damage could be considered when DSA are first detected. However, a randomized, controlled trial of treatment options would enable a clearer understanding of the benefits, if any, of antibody-removal therapies.

Gastroesophageal Reflux in Bronchiolitis Obliterans Syndrome: A New Perspective

BACKGROUND Long-term survival after lung transplantation (LTx) is limited largely by bronchiolitis obliterans syndrome (BOS). Gastroesophageal reflux disease (GERD) is proposed as a risk factor for BOS development. This study investigates the relationship between BOS and GERD measured by esophageal impedance. METHODS After the initiation of routine screening for GERD, 59 LTx recipients underwent ambulatory esophageal impedance monitoring. Exposure to acid reflux and non-acid liquid reflux was recorded. Clinical outcomes were reviewed to analyze any effect of reflux on the time to development of BOS. RESULTS Thirty-seven (65%) had abnormal acid reflux and 16 (27%) had abnormal non-acid reflux. There was no relationship between acid reflux and BOS. The hazard ratio (HR) for development of BOS in the presence of abnormal non-acid reflux was 2.8 (p = 0.043). The HR for development of BOS increased to 3.6 (p = 0.022) when the number of acute rejection episodes was also taken into account. CONCLUSIONS GERD is prevalent in LTx recipients and may represent a modifiable risk factor for BOS. This study found non-acid reflux, measured by esophageal impedance to be associated with the development of BOS. Prospective studies are now required to investigate a causal association between GERD and the development of BOS and to establish the role of surgery for GERD in preventing progression to BOS. The methods used to identify GERD in future studies may be important.

The relationship between illness perceptions and panic in chronic obstructive pulmonary disease.

BACKGROUND Elevated levels of anxiety and panic are common in respiratory disease. To date the cognitive-behavioural model of panic has been utilised to help explain and manage panic in respiratory disease. This cross-sectional study investigated the relationship between illness perceptions and panic in chronic obstructive pulmonary disease (COPD) within a self-regulatory framework of adaptation to physical illness. METHODS Fifty-nine participants with COPD completed questionnaires measuring illness perceptions, anxiety and depression, frequency and severity of panic attacks and impact of disease on daily life and well-being. The percent forced expiratory volume in the first second (FEV(1)%) was used as an objective measure of lung function. RESULTS High levels of clinical anxiety and depression were reported (35% and 19% respectively). Sixty-three percent of participants reported experiencing a panic attack during the previous year and of these 51% during the previous month. Panic was unrelated to level of disease severity. Specific illness perceptions (beliefs relating to illness identity, timeline, consequences and emotional representations) were important in differentiating between panickers and non-panickers. CONCLUSIONS The results highlight the importance of assessing illness perceptions within the framework of the self-regulatory model to provide an additional theoretical perspective for investigating and managing panic in chronic respiratory disease.

Pre-transplant donor HLA-specific antibodies: characteristics causing detrimental effects on survival after lung transplantation.

BACKGROUND The impact of Luminex-detected HLA antibodies on outcomes after lung transplantation is unclear. Herein we have undertaken a retrospective study of pre-transplant sera from 425 lung transplants performed between 1991 and 2003. METHODS Pre-transplant sera, originally screened by complement-dependent cytotoxicity (CDC) assays, were retrospectively tested for the presence of HLA-specific antibodies using HLA-coated Luminex beads and C4d deposition on Luminex beads. The results were correlated with graft survival at 1 year. RESULTS Twenty-seven patients were retrospectively identified as having been transplanted against donor-specific HLA antibodies (DSA) and 36 patients against non-donor-specific HLA antibodies (NDSA). DSA-positive patients had 1-year survival of 51.9% compared with 77.8% for NDSA and 71.8% for antibody-negative patients (p = 0.029). One-year survival of patients with complement-fixing DSA was 12.5% compared with 62.5% for non-complement-fixing DSA, 75.8% for non-complement-fixing NDSA and 71.8% for antibody-negative patients (p < 0.0001). DSA-positive patients with mean fluorescence intensity (MFI) >5,000 had 1-year survival of 33.3% compared with 71.4% for MFI 2,000 to 5000 and 62.5% for MFI <2,000 (p = 0.0046). Multivariable analysis revealed DSA to be an independent predictor of poor patient survival within 1 year (p = 0.0010, hazard ratio [HR] = 3.569) as well as complement-fixing DSA (p < 0.0001, HR = 11.083) and DSA with MFI >5,000 (p = 0.0001, HR = 5.512). CONCLUSIONS Pre-formed DSA, particularly complement-fixing DSA, and high MFI are associated with poor survival within the first year after lung transplantation. Risk stratification according to complement fixation or MFI levels may allow for increased transplantation in sensitized patients.

Lungs from donation after circulatory death donors: an alternative source to brain-dead donors? Midterm results at a single institution

OBJECTIVES Donor organ shortage remains to be the major limitation in lung transplantation, and donation after circulatory death (DCD) might represent one way to alleviate this problem. DCD was introduced to our institution in 2007 and has been a part of our clinical routine since then. Here, we present the mid-term results of lung transplantation from DCD in a single institution and compare the outcomes with the lung recipient cohort receiving lungs from donation after brain death (DBD). METHODS Since initiation of the DCD programme in March 2007, of the 157 lung transplantations performed, 26 (16.5%) were retrieved from DCD donors, with 25 double- and 1 single-lung transplants being performed. Results were compared with standard DBD transplantations. Analyses included, amongst others, donor characteristics, survival, prevalence of primary graft dysfunction, acute rejection, lung function tests during follow-up, onset of bronchiolitis obliterans syndrome (BOS) as well as duration of mechanical ventilation, hospital and intensive care unit length of stay. RESULTS While there was no significant difference between lung function, BOS and survival between the two groups, lungs from DCD donors had a higher PaO(2) (median; interquartile range) 498.3 (451.5; 525) vs. DBD 442.5 (371.25; 502) kPa before retrieval (P = 0.009). There was also a longer total ischaemic time in the DCD vs. DBD group: 320 min (298.75; 393.25) vs. 285.5 min (240; 373) (P = 0.025). All other parameters were comparable. CONCLUSIONS Medium-term results after lung transplantation with organs procured after circulatory death are comparable with those obtained after standard lung transplantation. Therefore, DCD could be used to significantly increase the donor pool.

Management of an ABO-Incompatible Lung Transplant

A 24‐year‐old woman with cystic fibrosis underwent bilateral sequential lung transplantation and unintentionally received an ABO incompatible graft (blood type A1 graft into a type O recipient). The recipient had a high titer of IgG anti‐A antibody (256 by the indirect antiglobulin test). Emergency treatment included antibody removal by plasmapheresis and additional immunosuppression with mycophenolate, rabbit antithymocyte globulin and polyspecific intravenous immunoglobulin. Subsequently, immunoadsorption and the anti‐CD20 antibody rituximab were used to remove anti‐A antibody and inhibit its resynthesis. Early graft function was good; one episode of rejection at Day 46 responded promptly to treatment with methylprednisolone. Subsequently, graft function continued to improve and anti‐A antibody titers remained low. No infectious or other complications were encountered. The treatment regimen that we adopted may prove useful in other cases of unplanned ABO‐incompatible organ transplants. The successful outcome suggests that planned ABO‐incompatible lung transplants may be possible.

Anti-reflux surgery for lung transplant recipients in the presence of impedance-detected duodenogastroesophageal reflux and bronchiolitis obliterans syndrome: A study of efficacy and safety

BACKGROUND The aim of this study was to determine the safety of anti-reflux surgery for lung transplant recipients and assess its effect on lung function. METHODS We retrospectively collected and analyzed data from all lung transplant recipients who underwent anti-reflux surgery at St Marys Hospital London from July 2005 to May 2012. The indications for surgery were histologic evidence of gastroesophageal reflux aspiration on bronchoscopy biopsy specimens or a positive impedance study with symptomatic reflux or a consistent decline/fluctuating forced expiratory volume in 1 second (FEV(1)). We studied the difference in mean FEV(1) and rate of change of FEV(1), before and after fundoplication. The safety of anti-reflux surgery was determined by post-operative morbidity and mortality and compared with predicted figures, using a risk prediction model based on the P-POSSUM (Portsmouth Modification of the Physiological and Operative Severity Score for Enumeration of Mortality and Morbidity) assessment. RESULTS Forty patients underwent laparoscopic Nissen fundoplication. Overall, mean FEV(1) declined from 2119 ± 890 to 1967 ± 1027 ml (p = 0.027), and mean rate of change in FEV(1) improved from -2.42 ± 4.40 to -0.41 ± 1.77 ml/day (p = 0.007). Patients referred for fundoplication based on histologic evidence of reflux (n = 9) showed an improvement in rate of change of FEV(1) from -3.39 ± 6.00 to -0.17 ± 1.50 ml/day (p = 0.057), and those with positive impedance study and consistent decline in FEV(1) (n = 13) showed a significant improvement from -3.62 ± 3.35 to -0.74 ± 2.33 ml (p = 0.021). Actual and predicted morbidity was 2.5% and 31%, respectively. Actual and predicted 30-day mortality was 0% and 1.9%, respectively. CONCLUSIONS Anti-reflux surgery is safe for lung transplant recipients and results in an improvement in the rate of change in FEV(1) despite a decline in mean FEV(1) post-operatively.

Unilateral extrapulmonary airway bypass in advanced emphysema.

BACKGROUND Gas trapping in emphysema results in resting and dynamic hyperinflation. We tested the hypothesis that a direct connection between the lung parenchyma and the atmosphere could increase expiratory flow and thereby potentially improve dyspnea through the relief of gas trapping. METHODS Ex vivo we studied 7 emphysematous lungs and 3 fibrotic lungs (as controls) and measured expiratory flow before and after airway bypass insertion during a forced maneuver in an artificial thorax. Pilot studies were conducted in vivo in 6 patients with advanced emphysema using a size 9 endotracheal tube as a bypass surgically placed through the chest wall into the upper lobe. RESULTS In the ex vivo emphysematous lungs the volume expelled during a forced expiratory maneuver increased from 169 to 235 mL (p < 0.05). In the in vivo group 4 patients retained the bypass tube for 3 months or more; total lung capacity was reduced, and the forced expiratory volume in 1 second increased by 23% (mean percent predicted at baseline versus 3 months, 24.4% versus 29.5%). CONCLUSIONS An extrapulmonary airway bypass increases expiratory flow in emphysema. This may be a useful approach in hyperinflated patients with homogeneous emphysema.

A new and clinically relevant murine model of solid-organ transplant aspergillosis

SUMMARY Invasive fungal infections (IFIs) are a major cause of death in organ transplant patients. The murine hydrocortisone-mediated immunosuppression model of pulmonary aspergillosis is commonly used to characterise IFIs in these patients. However, this model does not take into account the effects of calcineurin inhibitors on transplant immunity to IFIs or the fungal calcineurin pathway, which is required for both virulence and antifungal drug resistance. To address these two issues, a new and clinically relevant transplant immunosuppression model of tacrolimus (FK506) and hydrocortisone-associated pulmonary aspergillosis was developed. We first characterised IFIs in 406 patients with a lung transplant. This showed that all of the patients with pulmonary aspergillosis were immunosuppressed with calcineurin inhibitors and steroids. Murine pharmacokinetic studies demonstrated that an ideal dose of 1 mg/kg/day of FK506 intraperitoneally produced blood trough levels in the human therapeutic range (5–12 ng/ml). There was increased mortality from pulmonary aspergillosis in a transplant-relevant immunosuppression model using both FK506 and hydrocortisone as compared with immunosuppression using hydrocortisone only. Lung histopathology showed neutrophil invasion and tracheobronchitis that was associated with reduced lung tumour necrosis factor-α (TNFα), JE (homologue of human MCP-1) and KC (homologue of human IL-8) at 24 hours, but increased lung TNFα, JE and KC at 48 hours when fungal burden was high. Furthermore, FK506 directly impaired fungal killing in alveolar macrophages in vitro, with FK506-mediated inhibition of the radial growth of Aspergillus fumigatus in vitro occurring at the low concentration of 5 ng/ml. Taken together, these findings show that the immunosuppressive activity of FK506 outweighs its antifungal activity in vivo. These observations demonstrate that FK506 impairs innate immune responses and leads to an incremental increase in susceptibility to IFIs when it is combined with steroids. This new and clinically relevant mouse model of invasive aspergillosis is a valuable addition to the further study of both fungal immunity and antifungal therapy in organ transplantation.