Christopher M. Burton

Pulmonary Hypertension in End-stage Pulmonary Sarcoidosis: Therapeutic Effect of Sildenafil?

BACKGROUND The objectives of this study were to assess the frequency and severity of pulmonary hypertension (PH) and the effect of sildenafil treatment in patients with recalcitrant pulmonary sarcoidosis. METHODS This investigation was a single-center, retrospective study of all patients (n = 25) with end-stage pulmonary sarcoidosis referred for lung transplantation. Hemodynamic measurements were evaluated by right-side cardiac catheterization in 24 of 25 patients. Sildenafil treatment for patients with sarcoidosis-associated PH was introduced in April 2004. RESULTS The study group of 24 patients (16 men, 8 women) had a median age of 45 (range 35 to 58) years, and duration of sarcoidosis of 11 (range 2 to 38) years. Mean pulmonary arterial pressure (MPAP) was median 36 (range 18 to 73) mm Hg. PH (MPAP >25 mm Hg) was present in 19 of 24 patients (79%). Sildenafil was administered to 12 of 13 patients at a dose of 150 (range 75 to 225) mg/day for 4 (range 1 to 12) months. Sildenafil treatment was associated with reductions in MPAP of -8 mm Hg (CI -1 to -15 mm Hg), and PVR -4.9 Wood units (CI -7.2 to -2.6 Wood units). Cardiac output and cardiac index also increased during treatment (p = 0.01, respectively). There were no consistent changes in 6-minute walk distance. CONCLUSIONS Patients with severe pulmonary sarcoidosis have a high prevalence of PH. Sildenafil treatment was associated with significant improvements in hemodynamic parameters.

Acute cellular rejection is a risk factor for bronchiolitis obliterans syndrome independent of post-transplant baseline FEV1.

BACKGROUND Post-transplant baseline forced expiratory volume in 1 second (FEV(1)) constitutes a systematic bias in analyses of bronchiolitis obliterans syndrome (BOS). This retrospective study evaluates risk factors for BOS adjusting for the confounding of post-transplant baseline FEV(1). METHODS A multivariate survival and competing risk analysis of a large consecutive series of patients (n = 389) from a national center 1992 to 2004. Exclusion criteria were patients not surviving at least 3 months after transplantation (n = 39) and no available lung function measurements (n = 4). RESULTS The first maximum FEV(1) occurred at a median 183 days post-transplant. Freedom from BOS was 81%, 53%, 38% and 15%, and cumulative incidence of BOS was 18%, 43%, 57% and 77% at 1, 3, 5 and 10 years post-transplantation, respectively. Acute cellular rejection was independently associated with an increased cause-specific hazard of BOS (hazard ratio 1.4, confidence interval 1.1 to 1.8, p = 0.009). The absolute value of baseline FEV(1) was a significant confounder in all survival and competing risk analyses of BOS (p < 0.05). CONCLUSION Despite early diagnosis and prompt treatment, acute cellular rejection remains an independent risk factor for the development of BOS after adjusting for the confounding of post-transplant baseline FEV(1).

Minimal acute cellular rejection remains prevalent up to 2 years after lung transplantation: a retrospective analysis of 2697 transbronchial biopsies.

Background. Acute cellular rejection (ACR) is the most consistently reported risk factor for the development of bronchiolitis obliterans syndrome, an important cause of late mortality after lung transplantation. This retrospective study comprised all transbronchial biopsies (TBB) obtained during the first 2 years after transplantation in a consecutive cohort of 299 patients transplanted 1996–2006 (n=2697). Methods. TBB were aligned to the closest TBB surveillance schedule. Results. Patients completed a mean of 6±2 (median 8) TBB schedules. The proportion of patients demonstrating ACR (≥A2) decreased with increasing time from transplantation from 43% at 2 weeks to 27% at 6 months, and 13% and 4% at 1 and 2 years, respectively (trend test, P<0.0001). There was a significant trend between increased previous occurrence of ACR and increasing subsequent risk of A≥2 from 1, 3, and 12 months after transplantation (P<0.0001, P=0.0005, and P=0.001, respectively). Multivariate analyses identified interleukin-2-receptor induction with daclizumab versus antithymocyte globulin was independently associated with more frequent/severe ACR (P<0.0001). Conclusions. Minimal ACR remains prevalent up to 2 years after lung transplantation. Previous occurrence of ACR was associated with an increased risk of subsequent ACR.

Chronic rejection of a lung transplant is characterized by a profile of specific autoantibodies

Obliterative bronchiolitis (OB) continues to be the major limitation to long‐term survival after lung transplantation. The specific aetiology and pathogenesis of OB are not well understood. To explore the role of autoreactivity in OB, we spotted 751 different self molecules onto glass slides, and used these antigen microarrays to profile 48 human serum samples for immunoglobulin G (IgG) and IgM autoantibodies; 27 patients showed no or mild bronchiolitis obliterans syndrome (BOS; a clinical correlate of OB) and 15 patients showed medium to severe BOS. We now report that these BOS grades could be differentiated by a profile of autoantibodies binding to 28 proteins or their peptides. The informative autoantibody profile included down‐regulation as well as up‐regulation of both IgM and IgG specific reactivities. This profile was evaluated for robustness using a panel of six independent test patients. Analysis of the functions of the 28 informative self antigens showed that eight of them are connected in an interaction network involved in apoptosis and protein metabolism. Thus, a profile of autoantibodies may reflect pathological processes in the lung allograft, suggesting a role for autoimmunity in chronic rejection leading to OB.

Interstitial inflammatory lesions of the pulmonary allograft: a retrospective analysis of 2697 transbronchial biopsies.

Background. Parenchymal and bronchial inflammatory and fibrotic lesions other than acute cellular rejection (ACR) and lymphocytic bronchiolitis are prevalent; however, the context in which they appear is unknown, and often no specific treatment is instigated. Objectives. To describe the prevalence, incidence and possible associations between commonly identified inflammatory and fibrotic lesions in the pulmonary allograft. Methods. Retrospective chart review of all transbronchial biopsies performed within the first 2 years of 299 lung-transplanted patients in the period 1996 to 2006. Results. A total of 2697 biopsies were evaluated corresponding to a mean of 6±2 (median 8) completed schedules per patient. Diffuse alveolar damage (DAD) was the second most common histological finding within the first 2 weeks after transplantation. The peak prevalence of bronchiolitis obliterans organizing pneumonia (BOOP) and interstitial pneumonitis occurred at 4 to 6 weeks, and 6 to 12 weeks, respectively. There was a steady increase in the cumulative proportion of patients with fibrosis and bronchiolitis obliterans, at each successive scheduled surveillance time point beyond 3 months posttransplantation. The strongest histological correlations were between ACR and lymphocytic bronchiolitis (OR 5.1, P<0.0001) or interstitial fibrosis (OR 3.2, P<0.0001). Patients with interstitial pneumonitis and pulmonary hemosiderosis were also more likely to demonstrate the finding of interstitial fibrosis (OR 3.0 and 3.7, P<0.0001, respectively). Acute cellular rejection was not associated with DAD, and patients with lymphocytic bronchiolitis were not more likely to demonstrate features of organizing pneumonia (DAD or BOOP). Conclusions. Histologic findings of ACR, lymphocytic bronchiolitis, BOOP, and interstitial pneumonitis were directly associated with the development of interstitial fibrosis and bronchiolitis obliterans.

Common variable immune deficiency and lung transplantation

We report on a male patient with bronchiectasis secondary to common variable immune deficiency (CVID) receiving lung transplantation. The patient had been diagnosed with CVID many y prior to right-sided single lung transplantation and was receiving appropriate immunoglobulin substitution therapy. He received antithymocyte globulin induction and maintenance triple therapy with cyclosporine, azathioprine and prednisolone. The early post-operative course was complicated by the development of severe acute cellular rejection and organizing pneumonia. Despite immunoglobulin replacement and antifungal prophylaxis and treatment, Aspergillus fumigatus was repeatedly cultured from bronchoalveolar lavage fluid, 18 months after transplantation. The patient died following a protracted period of repeated hospital admissions, 46 months after transplantation. A review of the literature suggests that many CVID patients appear to have had a complicated post-operative course after lung- and other solid-organ transplantation, and highlights the need for the establishment of international registries for transplanted patients with uncommon conditions.

Cytomegalovirus infection in lung transplant patients: the role of prophylaxis and recipient-donor serotype matching.

Cytomegalovirus (CMV) remains an important cause of morbidity and mortality in lung transplant recipients. We investigated the incidence of CMV infection in relation to CMV prophylaxis, and recipient-donor CMV serotype, in a cohort of 250 consecutive lung transplant recipients. All patients received 3 months CMV prophylaxis with acyclovir (n = 67) or gancyclovir (n = 183). Recipient-donor CMV serotype matching was performed in patients receiving acyclovir: R + /D+(n = 38), R + /D−(n = 10), R − /D+(n = 1), R − /D−(n = 16), unknown (n = 2). Recipient-donor CMV serotype matching was not performed in patients receiving gancyclovir: R + /D+(n = 71), R + /D−(n = 42), R − /D+(n = 38), R − /D−(n = 31), unknown (n = 1). The overall incidence of CMV infection was 51% (n = 34) in the acyclovir group, and 42% (n = 77) in the gancyclovir group (p = 0.14). During the first 9 months after transplantation, the rate of CMV infection was higher in the acyclovir group (42%) compared with the gancyclovir group (30%) (p = 0.005). Multivariate analysis demonstrated the incidence of CMV infection during the first 9 months was higher for acyclovir prophylaxis (p<0.001) and R − /D+ serostatus (p<0.001) and lower with R − /D− serostatus (p = 0.02). In conclusion, gancyclovir significantly delays the onset of first CMV infection among lung transplant patients. CMV surveillance and choice of prophylaxis may be modified according to donor-recipient CMV serotype.

Integrative analysis correlates donor transcripts to recipient autoantibodies in primary graft dysfunction after lung transplantation.

Up to one in four lung‐transplanted patients develop pulmonary infiltrates and impaired oxygenation within the first days after lung transplantation. Known as primary graft dysfunction (PGD), this condition increases mortality significantly. Complex interactions between donor lung and recipient immune system are the suspected cause. We took an integrative, systems‐level approach by first exploring whether the recipient’s immune response to PGD includes the development of long‐lasting autoreactivity. We next explored whether proteins displaying such differential autoreactivity also display differential gene expression in donor lungs that later develop PGD compared with those that did not. We evaluated 39 patients from whom autoantibody profiles were already available for PGD based on chest radiographs and oxygenation data. An additional nine patients were evaluated for PGD based on their medical records and set aside for validation. From two recent donor lung gene expression studies, we reanalysed and paired gene profiles with autoantibody profiles. Primary graft dysfunction can be distinguished by a profile of differentially reactive autoantibodies binding to 17 proteins. Functional analysis showed that 12 of these proteins are part of a protein–protein interaction network (P = 3 × 10−6) involved in proliferative processes. A nearest centroid classifier assigned correct PGD grades to eight out of the nine patients in the validation cohort (P = 0·048). We observed significant positive correlation (r = 0·63, P = 0·011) between differences in IgM reactivity and differences in gene expression levels. This connection between donor lung gene expression and long‐lasting recipient IgM autoantibodies towards a specific set of proteins suggests a mechanism for the development of autoimmunity in PGD.

The effect of baseline lung function on the determination of time to bronchiolitis obliterans syndrome

Long term survival after lung transplantation depends on the development and severity of bronchiolitis obliterans syndrome (BOS). The objective of this study was to identify the relationship between baseline FEV1 and transplant procedure type, on the development and progression of BOS grade 0p to 3. All patients receiving a cadaveric lung transplant 1992-2004 were included in the study (n = 389). Exclusion criteria were patients surviving <3 months (n = 39) and missing spirometry measurements (n = 4). There were significant differences between the transplant procedures, heart-lung (HLTx), double-lung (DLTx), and single-lung (SLTx), with respect to recipient age, BMI, and indication for transplantation. Baseline FEV1 for HLTx (median 2.9L, quartiles 2.3–4.3L) and DLTx recipients (median 2.9L, quartiles 2.4–3.7L) were significantly larger than for patients undergoing SLTx procedures (median 1.6L, quartiles 1.3–1.9L), p<0.0001, respectively. Survival analyses demonstrated a significant association between baseline FEV1 per litre and the development of BOS: grade 0p (HR: 0.59, CI: 0.51–0.68, p<0.0001); grade 1 (HR: 0.60, CI: 0.51–0.70. p<0.0001); grade 2 (HR: 0.62, CI 0.52–0.74, p<0.0001); and grade 3 (HR: 0.73, CI 0.60–0.89, p = 0.002). There was a significant log-log linear relationship between baseline FEV1 and time to the development of BOS grades 0p to 3 in all patients developing the respective BOS grade (p<0.0001, respectively). Baseline lung function is an important confounder and should be considered in future risk factor evaluations for the development and progression to BOS.