Richard D. Cornwell

Colon cancer in lung transplant recipients with CF: Increased risk and results of screening

OBJECTIVE To determine the incidence of colon cancer in lung transplant recipients with cystic fibrosis (CF) and review screening colonoscopic findings in other recipients with CF. METHODS A retrospective chart review was performed for all patients with CF transplanted at the University of Wisconsin Hospital and Clinics (January 1994 through December 2010). RESULTS Four of 70 transplant recipients with CF developed fatal colon carcinoma following transplantation, and the cancer was advanced in all 4 recipients (age 31, 44, 44, 64) at the time of diagnosis. In contrast, only one of 287 recipients transplanted for non-CF indications developed colon cancer. Of all recipients with CF who did not develop colon cancer, 20 recipients underwent screening colonoscopy at 1 to 12 years following transplantation. Seven (35%) of the screened transplant recipients (ages 36, 38, 40, 41, 43, 49, 51) had colonic polyps in locations ranging from cecum to sigmoid colon and up to 3 cm in diameter. CONCLUSIONS In contrast to non-CF recipients, patients with CF displayed a significant incidence of colon cancer (4 of 70 recipients; 5.7%) with onset ranging from 246 days to 9.3 years post-transplant, which may be due to a combination of their underlying genetic disorder plus intense, sustained immunosuppression following lung transplantation. Colonoscopic screening may identify patients with pre-malignant colonic lesions and prevent progression to colonic malignancy.

Redo lung transplantation for acute and chronic lung allograft failure: long-term follow-up in a single center

OBJECTIVE This study was undertaken to evaluate outcomes of redo lung transplantation (LT) for acute and chronic graft failure. METHODS Between 1988 and 2007, 388 LT procedures were performed on 369 patients. From those, 17 (4.6%) patients had redo LT once and 2 patients had redo LT twice. Patient survival and recurrence of bronchiolitis obliterans syndrome (BOS) after redo LT were reviewed. RESULTS The overall survival rates of the 17 redo LT recipients at 1, 2 and 5 years were 59+/-23%, 59+/-23% and 42+/-25%, respectively. For the chronic graft failure group (n=12), survival rates at 1, 2 and 5 years were 67+/-26%, 67+/-26% and 44+/-30%, respectively. These survival rates were significantly lower than the survival rates observed in our experience after primary LT (n=352, 1-, 2- and 5-year survival rates of 88+/-4%, 80+/-4% and 65+/-5%, respectively. For the acute graft failure group (n=5), the 1-year survival rate was 40%; two patients remain free from BOS. Two patients had a second redo LT, one died from multi-organ failure on postoperative day 86 and the other died from pulmonary aspergillosis on postoperative day 214. CONCLUSIONS Redo LT is a valid therapeutic option for selected patients with BOS and might be an option for highly selected patients with acute lung graft failure. Outcomes from a second redo LT are poor, and a second lung retransplantation must be used very cautiously, if at all.

Soluble HLA class I in epithelial lining fluid of lung transplants: associations with graft outcome.

We hypothesized that the small amounts of donor HLA-A and HLA-B proteins detected in the serum during organ allograft rejection are indicative of higher local releases within the graft itself. We determined the concentrations of total HLA class I (HLA-I) and, in selected cases, specific donor and host HLA-A and HLA-B proteins, in the epithelial lining fluid (ELF) sampled by bronchoalveolar lavage (BAL) of lung transplant recipients (n = 37) and of normal controls (n = 25). We found that 1) HLA-I proteins were enriched in the lung ELF relative to other proteins; 2) the concentration of HLA-I in the ELF of well-functioning transplants was similar to that in normal lungs; 3) HLA-I proteins and total proteins were elevated in the ELF of patients who developed chronic rejection or refractory acute rejection; 4) the concentration of HLA-I was correlated with the percentage of neutrophils but not with the percentage of lymphocytes in the ELF of transplanted lungs; and 5) only the percentage of lymphocytes was elevated in the ELF of transplant patients with active CMV infections. Total HLA-I from the ELF was found to contain a mixture of both donor- and recipient-type HLA-A and HLA-B proteins and the donor-type HLA-A2 was found to be highly enriched in the ELF relative to serum.

The impact of the lung allocation scoring system at the single national Veterans Affairs Hospital lung transplantation program

OBJECTIVE The lung allocation score (LAS) has changed the distribution of donor lungs for transplantation. This study was undertaken to evaluate the impact of the LAS on a unique patient population undergoing lung transplantation (LTX) at the single national Veterans Affairs (VA) LT center. METHODS One hundred and ten consecutive VA patients underwent LTX between 1994 and 2007. Patients transplanted using the LAS (LAS, n=26) were compared to patients transplanted prior to introduction of the LAS (pre-LAS, n=84). RESULTS Waiting time decreased from 353.8+/-254.7 (pre-LAS) to 238.0+/-306.6 (LAS) days (p<0.01). Recipient diagnoses have changed with an increase in idiopathic pulmonary fibrosis [11% (9/84) pre-LAS vs 46% (12/26) LAS, p<0.01] and a decrease in emphysema [57% (48/84) pre-LAS vs 35% (9/26) LAS, p<0.01]. Mean LAS calculation was 33.1+/-2.9 for pre-LAS versus 41.9+/-9.8 for the LAS (p<0.01). Postoperative complications did not differ between the groups. Length of hospital stay decreased from 44.3+/-42.9 (pre-LAS) to 18.1+/-12.3 (LAS) days (p<0.01). Hospital mortality and 1-year survival did not differ between the pre-LAS and LAS groups (7% vs 8%; p=0.72 and 92% [95% confidence interval (CI) 86-98] vs 92% [CI 82-100]; p=0.23, respectively). CONCLUSIONS The LAS appears to be achieving its objectives by reducing waitlist time and altering the distribution of lung disease being transplanted on the basis of medical necessity in the U.S. VA population. In addition, the LAS does not appear to have adversely affected short-term post-transplant outcomes in our recipient cohort.

Soluble donor HLA class I and β2m-free heavy chain in serum of lung transplant recipients: steady-state levels and increases in patients with recurrent CMV infection, acute rejection episodes, and poor outcome

We determined the concentration of donor sHLA/beta(2)m and total beta(2)m-free heavy chain (HC) in the serum of lung transplant recipients with ELISA assays. While we were unable to detect specific donor beta(2)m-free HCs due to a lack of available antibodies, we could determine if events that led to an increase in the release of beta(2)m-free HC also led to an increase in the release of donor sHLA/beta(2)m, particularly the 36 kDa, proteolytically cleaved form. We found that lung transplants constituitively release donor sHLA/beta(2)m at ng/ml levels. The levels (both of donor sHLA/beta(2)m and total beta(2)m-free HC) were significantly increased in CMV-sero-negative recipients (but not in CMV-sero-positive recipients) at the onset of post-transplant CMV disease. Acute rejection episodes were also associated with an increased release of donor sHLA/beta(2)m, but not of beta(2)m-free HC. However, in patients with particularly poor outcome (i.e., graft loss within 1 year) there was a significant release of beta(2)m-free HC. Analysis of one such patient showed a predominance of 36 kDa forms of donor-sHLA/beta(2)m. Our data are consistent with the hypothesis that the metalloproteinase that cleaves beta(2)m-free HC is active during uncontrolled CMV infection and acute rejection. However, recall responses to CMV and controlled immune responses to donor may result in little or no activation of sHLA class I release.

Safety of and cellular response to segmental bronchoprovocation in allergic asthma.

Rationale Despite its incorporation into research studies, the safety aspects of segmental allergen bronchoprovocation and differences in cellular response among different allergens have received limited consideration. Methods We performed 87 segmental challenges in 77 allergic asthma subjects. Allergen dose was based on each subject’s response to whole lung allergen challenge. Bronchoalveolar lavage was performed at 0 and 48 hours. Safety indicators included spirometry, oxygen saturation, heart rate, and symptoms. Results Among subjects challenged with ragweed, cat dander, or house dust mite, there were no differences in safety indicators. Subjects demonstrated a modest oxygen desaturation and tachycardia during the procedure that returned to normal prior to discharge. We observed a modest reduction in forced vital capacity and forced expiratory volume in one second following bronchoscopy. The most common symptoms following the procedure were cough, sore throat and fatigue. Total bronchoalveolar lavage fluid cell numbers increased from 13±4 to 106±108×104 per milliliter and eosinophils increased from 1±2 to 44±20 percent, with no significant differences among the three allergens. Conclusions In mild allergic asthma, segmental allergen bronchoprovocation, using individualized doses of aeroallergens, was safe and yielded similar cellular responses.

Lung transplant for interstitial lung disease: outcomes before and after implementation of the united network for organ sharing lung allocation scoring system.

OBJECTIVES This study was undertaken to evaluate whether the adoption of the united network for organ sharing lung allocation score (LAS) was associated with significant changes in lung transplantation (LTX) outcomes for patients with interstitial lung disease (ILD) who underwent LTX at the University of Wisconsin Hospital and Clinics. METHODS Outcomes for 107 consecutive patients with various forms of ILD who underwent LTX between January 1993 and March 2009 were examined. Patients transplanted following the implementation of the LAS system (LAS, n = 56) were compared with those transplanted prior to LAS implementation (pre-LAS, n = 51) for whom LAS scores were calculated. RESULTS Patients with idiopathic pulmonary fibrosis (IPF) comprised the majority of patients with ILD. Recipients transplanted after the implementation of the LAS were significantly older (pre-LAS: 50.4 vs. LAS: 56.7 years, P < 0.01), required more supplemental oxygen (3 vs. 5 l/min, P < 0.01) and displayed lower cardiac index values (3.1 vs. 2.6 l/m(2), P < 0.01). The estimated LAS was significantly increased from 38.3 (pre-LAS) to 43.3 (LAS), P < 0.01. However, waiting time decreased from 266 to 78 days (P < 0.01). The rate of bilateral vs. single LTX was lower (35 vs. 16%, P = 0.02) for the post-LAS group. Cold ischaemic time was shorter in the post-LAS group (434 vs. 299 min, P < 0.01), and the length of hospital stay decreased from 24 to 11 days (P < 0.01). Hospital mortality (11 vs. 7%, P = 0.51) and post-transplant survival did not differ between the groups. CONCLUSIONS Post-transplant outcomes for patients with ILD or the subset of recipients with IPF were not adversely affected by the implementation of the LAS.

Restless Legs Syndrome Following Lung Transplantation Prevalence and Relationship With Tacrolimus Exposure

Context: Complications following lung transplantation are common and significantly reduce quality of life, and increase morbidity and mortality. Increasing evidence suggests sleep disorders are prevalent following lung transplantation, but factors associated with their development are not known. Objectives: We sought to evaluate the prevalence of restless legs syndrome (RLS) in a lung transplant population and determine if a relationship exists between RLS and exposure to immunosuppressant medications. Design, Setting, and Participants: Subjects were recruited through the University of Wisconsin Hospital and Clinics Lung Transplant Clinic (N = 125). Participants (N = 81) completed sleep questionnaires, including the four RLS diagnostic criteria, insomnia severity index, and Sheehan disability scale. Cumulative tacrolimus exposure was determined in 62 subjects by calculating an area under the curve (AUC) to assess for a relationship with restless legs syndrome. Results: Prevalence of RLS was 35 percent. Cumulative mean ± SEM tacrolimus exposure was similar in patients with RLS versus those without RLS (17446±1855 ng days/mL vs. 15303 ± 1643 ng days/mL, respectively; p = 0.42). Insomnia severity index scores (12.5 ± 1.0 vs 6.8 ± 0.7, p < 0.0001) and Sheehan disability scores (7.8 ± 1.3 vs 3.6 ± 0.6, p = 0.003) were significantly higher in those with vs those without RLS symptoms, respectively. Conclusions: Our data confirms increased prevalence of RLS following lung transplantation reported by previous studies. RLS symptoms were not related to estimated tacrolimus exposure. Predictors of RLS following lung transplantation need to be further investigated to better identify and control RLS symptoms and reduce associated insomnia and disability.

Extended lung preservation with UW solution does not adversely affect graft outcome.

INTRODUCTION: In orthotopic lung transplantation (OLT) in humans, 6 hours is generally regarded as the extent of total ischemic time. At UW, our practice has been to use organs that have sustained greater than 6 hours of cold ischemic time for transplantation. Standard preservation techniques include 1mg of PGE prior to cross clamp, infusion of 4L UW solution (4C), and retrograde pulmonary vein flushing of 1000cc UW solution per lung. METHODS: From October 1988 to March 1999, 122 consecutive OLT’s were retrospectively analyzed for preservation time (PT, cross clamp to pulmonary re-perfusion) and outcome (time to poor function). Poor function was defined as time to BOS1 (.20% decrease in FEV1 from post-op baseline) or graft loss. Recipients were divided into two groups; Group 1 PT,8hrs (n580), Group 2 PT.8hrs (n542). Groups were further sub divided by donor age; a ,22yrs, b 23-37yrs, c .38yrs. Bilateral OLT recipients PT were time to second lung re-perfusion. Inter group significance (p,0.05) was determined using chi-square and life table analysis. RESULTS: There were no significant differences between the two groups in terms of recipient age, recipient sex, donor age, and donor sex. Group 1 had significantly more COPD patients (p50.011), whereas Group 2 had significantly more bilateral transplant recipients (p50.0018). There were no significant differences between the two groups in terms of outcome (p50.139). When sub groups were examined for outcome vs. donor age, no significant difference was noticed: Group 1a vs 2a (p50.2953), Group 1b vs 2b (p50.6426) and Group 1c vs 2c (p50.3922). CONCLUSIONS: Preservation times in human orthotopic lung transplantation can be extended beyond 8 hours using UW solution without significantly compromising recipient outcomes.

Short- and long-term results after lung volume reduction surgery.

Lung volume reduction surgery (LVRS) is a palliative surgical procedure for patients with severe emphysema. Resection of nonfunctional emphysematous lung tissue has been reported to relieve breathlessness and to improve quality of life for many patients by improving lung elastic recoil, respiratory muscle function, and ventilation-perfusion matching. However, the risks and benefits of LVRS remain controversial, as mainly short-term data are available for carefully selected groups of LVRS patients and no prospective, randomized trials for LVRS with pulmonary rehabilitation versus optimal medical therapy plus pulmonary rehabilitation have been reported. Bilateral staple resection for LVRS appears to be superior to use of a laser or unilateral approach in the short term, but relatively little data exist on long-term outcomes. Additional clinical investigation is required to determine whether LVRS should be a widely accepted therapy for severe emphysema.