Denis Hadjiliadis

Clinical Impact of Community‐Acquired Respiratory Viruses on Bronchiolitis Obliterans After Lung Transplant

Community‐acquired viral respiratory tract infections (RTI) in lung transplant recipients may have a high rate of progression to pneumonia and can be a trigger for immunologically mediated detrimental effects on lung function. A cohort of 100 patients was enrolled from 2001 to 2003 in which 50 patients had clinically diagnosed viral RTI and 50 were asymptomatic. All patients had nasopharyngeal and throat swabs taken for respiratory virus antigen detection, culture and RT‐PCR. All patients had pulmonary function tests at regular intervals for 12 months. Rates of rejection, decline in forced expiratory volume (L) in 1 s (FEV‐1) and bacterial and fungal superinfection were compared at the 3‐month primary endpoint. In the 50 patients with RTI, a microbial etiology was identified in 33 of 50 (66%) and included rhinovirus (9), coronavirus (8), RSV (6), influenza A (5), parainfluenza (4) and human metapneumovirus (1). During the 3‐month primary endpoint, 8 of 50 (16%) RTI patients had acute rejection versus 0 of 50 non‐RTI patients (p = 0.006). The number of patients experiencing a 20% or more decline in FEV‐1 by 3 months was 9 of 50 (18%) RTI versus 0 of 50 non‐RTI (0%) (p = 0.003). In six of these nine patients, the decline in FEV‐1 was sustained over a 1‐year period consistent with bronchiolitis obliterans syndrome (BOS). Community‐acquired respiratory viruses may be associated with the development of acute rejection and BOS.

Gastroesophageal reflux disease in lung transplant recipients

Abstract: Background: Chronic allograft dysfunction after lung transplantation contributes to poor long‐term survival. A link between gastric aspiration and post‐transplant lung dysfunction has been suggested, but little is known about the significance of gastroesophageal reflux disease (GERD) after lung transplantation.

DEVELOPMENT OF AN ANTIBODY SPECIFIC TO MAJOR HISTOCOMPATIBILITY ANTIGENS DETECTABLE BY FLOW CYTOMETRY AFTER LUNG TRANSPLANT IS ASSOCIATED WITH BRONCHIOLITIS OBLITERANS SYNDROME

Background. Chronic allograft rejection manifested as bronchiolitis obliterans syndrome (BOS) is the leading cause of late death after lung transplantation. Although increasing evidence suggests an association between anti-human leukocyte antigens (HLA) antibodies and chronic rejection of kidney or heart allografts, the clinical significance of anti-HLA antibodies in lung recipients is less clear, especially in previously unsensitized recipients. The use of flow cytometry based panel reactive antibody (flow-PRA) provides a highly sensitive means to identify the development of de novo anti-HLA antibodies in lung recipients. Methods. Flow-PRA testing was used to analyze the pre- and posttransplant sera in stable BOS free lung recipients who survived at least 6 months. Patients without prior sensitization as defined by a negative pretransplant flow-PRA were analyzed posttransplant for the presence of anti-HLA antibodies by flow-PRA. A proportional hazards model was used to determine the impact of anti-HLA antibody on BOS risk. Results. Sera from 90 recipients at Duke University with negative pretransplant flow-PRA were tested by flow-PRA at various time points after transplant. Sera from 11% (10/90) of recipients were found to contain anti-HLA antibodies detectable by flow-PRA. Nine patients (90%) developed anti-HLA antibodies specific for donor antigens, and one patient developed anti-HLA class II antibodies, not specific to donor antigens. Among the nine patients with donor antigen specific antibodies, flow-PRA specificity analysis demonstrated eight were specific for class II antigens and one for class I antigens. In a multivariate model that controls for other BOS risk factors, a positive posttransplant flow-PRA was significantly associated with BOS grades 1,2, or 3 (hazard ratios [HR] 3.19; 95% confidence interval [CI]: 1.41–7.12, P =0.005) and BOS grade 2 or 3 (HR 4.08; 95% CI: 1.66–10.04, P =0.002). Four patients with de novo anti-HLA antibodies died during follow-up; all four had BOS. Among BOS patients, the presence of anti-HLA antibodies was associated with a significantly worse survival (P =0.05, log-rank test). Conclusions. Although uncommon, previously unsensitized lung transplant recipients can develop anti-HLA antibodies to donor class II antigens. The development of de novo anti-HLA antibodies significantly increases the risk for BOS, independent of other posttransplant events. Furthermore, de novo anti-HLA antibodies identify BOS patients with significantly worse survival. Additional studies are needed to determine if class II–directed anti-HLA antibodies contribute mechanistically to the chronic rejection process in lung recipients.

The Effect of Reflux and Bile Acid Aspiration on the Lung Allograft and Its Surfactant and Innate Immunity Molecules SP-A and SP-D

Gastro‐esophageal reflux and related pulmonary bile acid aspiration were prospectively investigated as possible contributors to postlung transplant bronchiolitis obliterans syndrome (BOS). We also studied the impact of aspiration on pulmonary surfactant collectin proteins SP‐A and SP‐D and on surfactant phospholipids—all important components of innate immunity in the lung. Proximal and distal esophageal 24‐h pH testing and broncho‐alveolar lavage fluid (BALF) bile acid assays were performed prospectively at 3‐month posttransplant in 50 patients. BALF was also assayed for SP‐A, SP‐D and phospholipids expressed as ratio to total lipids: phosphatidylcholine; dipalmitoylphosphatidylcholine; phosphatidylglycerol (PG); phosphatidylinositol; sphingomyelin (SM) and lysophosphatidylcholine. Actuarial freedom from BOS was assessed.

The effect of recipient's age on lung transplant outcome.

Selection criteria for organ transplantation have evolved over time. Age has been revisited periodically. We studied the outcome of lung transplant adjusted by age in a single center transplant population. We matched the 42 lung graft recipients older than 60 years transplanted by July 1999 to younger controls by lung disease, transplant era within 2 years, type of transplant and gender. The female to male ratios were 17/25 among the older cohort (median age 61.6 years), and 15/27 (median age 51.9 years) among the matched younger. Survival analysis demonstrated a significant difference: at 1 year, 60% versus 86%, and at 5 years, 37% versus 57%, for older and younger, respectively, p = 0.005. Excess annual mortality, calculated with the declining exponential approximation to life expectancy (DEALE), showed an older/younger ratio of 1.9. Eleven deaths occurred within 6 months among the older patients, 10 due to infection. After 6 months, there were 20 more deaths, 6 due to malignancy, 5 to Bronchiolitis Obliterans Syndrome (BOS), 3 to infection and 6 to other causes. Among the younger there were 6 deaths within 6 months and 12 more thereafter; among the latter, 8 were due to BOS.

Laparoscopic antireflux surgery in the lung transplant population

Background: Lung transplantation has emerged as a viable therapeutic option for patients with a variety of end-stage pulmonary diseases. As immediate posttransplant surgical outcomes have improved, the greatest limitation of lung transplantation remains chronic allograft dysfunction. Gastroesophageal reflux disease (GERD) with resultant aspiration has been implicated as a potential contributing factor in allograft dysfunction. GERD is prevalent in end-stage lung disease patients, and it is even more common in patients after transplantation. We report here on the safety of laparoscopic fundoplication surgery for the treatment of GERD in lung transplant patients. Methods: Eighteen of the 298 lung transplants performed at Duke University Medical Center underwent antireflux surgery for documented severe GERD. The safety and benefit of laparoscopic fundoplications in this population was evaluated. Results: The antireflux surgeries included 13 laparoscopic Nissen fundoplications, four laparoscopic Toupets, and one open Nissen (converted secondary to extensive adhesions). Two of the 18 patients reported recurrence of symptoms (11%), and two others reported minor GI complaints postoperatively (nausea, bloating). There were no deaths from the antireflux surgery. After fundoplication surgery, 12 of the 18 patients showed measured improvement in pulmonary function (67%). Conclusions: GERD occurs commonly in the posttransplant lung population. Laparoscopic fundoplication surgery, when indicated, can be done safely with minimal morbidity and mortality. In addition to the resolution of reflux symptoms, improvement in pulmonary function may be seen in this population after fundoplication. Lung transplant patients with severe GERD should be strongly considered for antireflux surgery.

Prognostic value of serum carcinoembryonic antigen levels in patients who undergo lung transplantation

BACKGROUND Potential candidates for lung transplantation undergo a rigorous evaluation before transplant. Serum carcinoembryonic antigen (CEA) levels are used as a screening tool for occult malignancy in many lung transplant centers. We reviewed the pre-transplant CEA levels in lung transplant recipients in our institution to determine their prognostic significance. MATERIALS AND METHODS We performed a retrospective database review of the first 200 patients that had undergone lung or heart-lung transplant at our institution (dates were 1/20/92-7/25/98). Data extracted included CEA levels (in ng/ml) at the time of lung transplant evaluation, demographic data, and survival. Patients had one of the following diagnoses: alpha-1-anti-trypsin deficiency, cystic fibrosis, chronic obstructive pulmonary disease, Eisenmengers syndrome, idiopathic pulmonary fibrosis, primary pulmonary hypertension, sarcoidosis, or other. RESULTS After excluding re-transplants, CEA results were available for 174 of 193 (90.2%) patients. CEA levels were elevated in 85 patients (48.9%) with a mean value of 3.15 +/- 2.55 (normal < 2.5). Solid organ cancers developed in 6 patients, at a median follow-up of 27.5 months after transplant. Their mean pre-transplant CEA level was similar to the rest of the group (3.52 +/- 2.05). Pre-transplant CEA levels did not predict post-transplant survival. Patients with idiopathic pulmonary fibrosis had the highest pre-transplant CEA levels, whereas patients with primary pulmonary hypertension and Eisenmengers syndrome had the lowest (5.36 +/- 4.59, 0.83 +/- 0.56, and 1.43 +/- 0.81, respectively; p = 0.0001). CONCLUSIONS CEA levels are high in patients with end-stage lung disease, especially IPF. Their levels appear to be a marker of the underlying disease and do not predict the post-transplant survival or development of malignancy.

Anti-reflux surgery improves pulmonary function in lung transplant patients

months posttransplant, 23 (40%) had a positive BAL culture for Pseudomonas. In Kaplan-Meier analysis, early colonization with Pseudomonas is associated with decreased survival (p 0.027, by log-rank test), and a fourfold increase risk of death (hazard ratio 4.09, 95% CI 1.05,15.8, by Cox proportional hazards test). Other predictors of survival were donor age 30 yr. old (p 0.04), and more than 2 episodes of acute rejection (p 0.003). Conclusion: Early colonization or infection with Pseudomonas aeruginosa in CF lung transplant recipients is associated with significantly worse long-term survival. Additional research is needed to define the risk factors for early posttransplant infection, mechanisms of colonization in the donor lungs, and independent contribution of colonization to late death through multivariate analyses.

High Dose Intravenous Methylprednisone in the Treatment of Severe Acute Respiratory Syndrome

The case of a 72-year-old woman with probable severe acute respiratory syndrome is reported. While on treatment with ribavirin and antibiotics (for community-acquired pneumonia), the patient continued to have progressive clinical deterioration and chest radiographic evidence of respiratory deterioration. Pulse dose intravenous corticosteroids were used in an unsuccessful attempt to treat the inflammatory component of this respiratory illness.

Lung transplantation in recipients with previous lung volume reduction surgery

of 100%, Sp of 45% and a PPV and NPV of 52 and 100% respectively . If we then assumed that patients had to have at least 2 measurements (3 to 6 weeks apart) of eNO 15ppb during the 3 months preceding the diagnosi s of BOS, only 4/11 CRnegative patients fulfilled that criterium, resulting in an improvement of Sp (80%) and PPV(73%), however, with some loss of S (92%) and NPV (94%), due to one false negative result. In Conclusion: the accuracy of eNO measurements for the diagnosis of chronic rejection after lung transplantation is high, when patients have 2 values of eNO 15ppb with 3-6 weeks in between the measurement.