Human leukocyte antigen mismatches predispose to the severity of bronchiolitis obliterans syndrome after lung transplantation

BACKGROUND: Obliterative bronchiolitis (OB) is the most important cause of long-term morbidity and mortality in lung transplant recipients, and probably results from alloimmune airway injury. Bronchiolitis obliterans syndrome (BOS), defined as a staged decline in pulmonary function, is the clinical correlate of OB. OBJECTIVE: Evaluation of the risk and severity of BOS on the basis of the incompatibility of donor and recipient human leukocyte antigen (HLA) molecules. DESIGN: Retrospective cohort study. SETTING: Large university hospital. PARTICIPANTS: Lung transplant recipients between January 1990 and January 2000. MEASUREMENTS: We determined the BOS stage using internationally promulgated guidelines with a minor modification on all recipients at their 4-year transplant anniversary. Recipients whose graft function had deteriorated or who died due to causes other than BOS were excluded from the study. HLA loci mismatches and other covariables, including recipient age, donor age, cytomegalovirus (CMV) mismatch, cold ischemic time, use of cardiopulmonary bypass, ventilatory days, episodes of acute rejection and CMV pneumonitis, mean trough cyclosporin A (CsA) level, episodes of subtherapeutic CsA levels, and histopathology of OB and diffuse alveolar damage were entered into the analysis of BOS predictors. RESULTS: Sixty-four patients met the inclusion and exclusion criteria of the study at the 4-year posttransplant time point. In univariate analyses, the number of combined HLA-A and HLA-B mismatches was strongly associated with the stage of BOS at 4 years (p = 0.002). This association remained significant after the inclusion of other potential risk factors for BOS in multiple linear regression models. Pretransplant and posttransplant proportional odds models confirmed that the increasing number of combined HLA-A and HLA-B mismatches increased the overall severity of BOS (adjusted odds ratio, 1.84 [p = 0.035] vs 1.69 [p = 0.067], respectively). A trend toward significance was seen with HLA-DR mismatching (p = 0.17). CONCLUSIONS: The degree of HLA class I mismatching between donors and recipients predisposes lung transplant recipients to the development and severity of BOS.     

Reproducibility of measurements of exhaled NO, and cell count and cytokine concentrations in induced sputum.

Sputum induction is a noninvasive, well-tolerated method for studying airway inflammation. When induction with hypertonic saline is repeated at short time-intervals (<24 h), the cell profile of sputum has not been reproducible. To determine the proper interval between sampling cell profiles and cytokine contents of sputum samples that had been induced 48 h apart, were compared. In addition, the inducible nitric oxide synthase (iNOS) expression of sputum cells was compared to the levels of exhaled nitric oxide (NO). Sputum induction and measurement of exhaled NO was performed in 31 healthy nonatopic volunteers. Cell differentials were counted. Concentrations of interleukin (IL)-4, IL-6, tumour necrosis factor (TNF)alpha, eosinophil cationic protein (ECP) were measured in sputum supernatant, and iNOS was determined. Reproducibility of cell counts was high (r=0.836 total cells, r=0.762 neutrophils, r=0.966 eosinophils, r=0.742 macrophages). IL-4 (r=0.398), IL-6 (r=0.566), TNFalpha (r=0.658) and ECP (r=0.501) were also less reproducible in healthy volunteers. Consistent with the low levels of NO in the exhaled air (18.5+/-2.6 ppb and 19.3+/-2.8 parts per billion (ppb) on the two study days, r=0.976, p=0.0000), expression of iNOS was not detected. In conclusion, in healthy subjects, induced sputum cell counts are reproducible. Even though the success rate in nonatopic populations is relatively low, sputum induction appears to be a valid method for detecting inflammatory changes within the airways, when being performed 48 h apart.     

Comparison between tracheal tubes for orotracheal fibreoptic intubation

We have compared impingement of the tracheal tube against the larynx using a standard preformed tube, warmed preformed tube or two flexible spiral-wound tracheal tubes with different tip designs, in 100 adult patients undergoing orotracheal fibreoptic intubation under general anaesthesia, in a prospective, randomized study. The rates of impingement were 20 of 30 with the standard tube, 12 of 30 with the warmed standard tube (P = 0.07) and eight of 20 with both spiral tubes. However, impingement with the spiral tubes took longer to overcome if a sharp tipped rather than an obtuse tipped tube was used. Manipulations after impaction led to oesophageal intubation in one patient, and in one patient fibreoptic intubation failed. We conclude that resistance to the tracheal tube occurred frequently when the spiral-wound tubes were used.      

Molecular characterization of gene regulatory networks in primary human tracheal and bronchial epithelial cells

Background

Robust methods to culture primary airway epithelial cells were developed several decades ago and these cells provide the model of choice to investigate many diseases of the human lung. However, the molecular signature of cells from different regions of the airway epithelium has not been well characterized.