Sleep-disordered breathing before and after lung transplantation.

BACKGROUND: Sleep-disordered breathing (SDB) is common in patients with severe chronic respiratory failure, but there are no data describing the prevalence of SDB among patients listed for lung transplantation or the effect of transplantation on SDB. We sought to determine the prevalence and impact of SDB before and after lung transplantation. METHODS: We performed polysomnography (PSG) on 117 of 183 (64%) consecutive patients (64 males, 53 females) listed for lung transplantation between 1998 and 2001. SDB was defined as respiratory disturbance index (RDI) >or=10 or an awake oxygen saturation >90% and >or=10% of total sleep time (TST) with oxygen saturation (SaO2) or=10% of TST with SaO2 or=10. Eight of 32 had both >or=10% of TST with SaO2 or=10. Nine of 30 (30%) patients on oxygen and 1 of 7 on NIV had SDB. Post-transplant, SDB resolved in 6 of 11 patients with the condition, but 4 of 14 without previous SDB developed new SDB. SDB (treated or not) did not influence whether patients survived to transplant (p = 0.8), nor did a diagnosis of SBD prior to transplant influence post-transplant survival (p = 0.7). CONCLUSIONS: SDB is common before lung transplantation. Lung transplantation improves oxygenation, but new-onset SDB may occur after the procedure.

Severity of lymphocytic bronchiolitis predicts long-term outcome after lung transplantation.

RATIONALE: Severe and recurrent acute vascular rejection of the pulmonary allograft is an accepted major risk factor for obliterative bronchiolitis. OBJECTIVES: We assessed the role of lymphocytic bronchiolitis as a risk factor for bronchiolitis obliterans syndrome (BOS) and death after lung transplantation. METHODS: Retrospective analysis of 341 90-day survivors of lung transplant performed in 1995-2005 who underwent 1,770 transbronchial lung biopsy procedures. MEASUREMENTS AND MAIN RESULTS: Transbronchial biopsies showed grade B0 (normal) (n = 501), B1 (minimal) (n = 762), B2 (mild) (n = 176), B3 (moderate) (n = 70), B4 (severe) (n = 4) lymphocytic bronchiolitis, and Bx (no bronchiolar tissue) (n = 75). A total of 182 transbronchial biopsies were ungraded (8 inadequate, 142 cytomegalovirus, 32 other diagnoses). Lung transplant recipients were grouped by highest B grade before diagnosis of BOS: B0 (n = 12), B1 (n = 166), B2 (n = 89), and B3-B4 (n = 51). Twenty-three were unclassifiable. Cumulative incidence of BOS and death were dependent on highest B grade (Kaplan-Meier, P < 0.001, log-rank). Multivariable Cox proportional hazards analysis showed significant risks for BOS were highest B grade (relative risk [RR], 1.62; 95% confidence interval [CI], 1.31-2.00) (P < 0.001), longer ischemic time (RR, 1.00; CI, 1.00-1.00) (P < 0.05), and recent year of transplant (RR, 0.93; CI, 0.87-1.00) (P < 0.05), whereas risks for death were BOS as a time-dependent covariable (RR, 19.10; CI, 11.07-32.96) (P < 0.001) and highest B grade (RR, 1.36; CI, 1.07-1.72) (P < 0.05). Acute vascular rejection was not a significant risk factor in either model. CONCLUSIONS: Severity of lymphocytic bronchiolitis is associated with increased risk of BOS and death after lung transplantation independent of acute vascular rejection.

Cyclosporine C2 target levels and acute cellular rejection after lung transplantation.

BACKGROUND: Acute pulmonary allograft rejection (AR) is the most important risk factor for bronchiolitis obliterans syndrome (BOS), which is associated with reduced quality of life and decreased survival after lung transplantation (LTx). Trough (C0) cyclosporine (CyA) levels have a poor correlation with area-under-the-curve (AUC) measurements of cyclosporine exposure compared with 2-hour post-dose (C2) levels, but there are no published guidelines for C2 levels after LTx. Hence, we assessed the utility of C2 target levels to prevent AR. METHODS: Fifty consecutive de novo LTx patients (bilateral, 44; single, 3; heart-lung, 3; cystic fibrosis, 20; non-cystic fibrosis, 30) managed with CyA were assigned target C2 levels as follows: >800 microg/liter within 48 hours; >1,200 microg/liter from Week 1 to Month 1; >1,000 microg/liter in Month 2; >800 microg/liter in Month 3; >700 in microg/liter in Months 3 to 6; and >600 microg/liter thereafter. Surveillance transbronchial biopsies (TBBxs) were performed at 3, 6, 9 and 12 weeks. An intention-to-treat analysis was performed and results compared with our historic controls managed by C0 monitoring. RESULTS: Fifteen of 50 (30%) LTx recipients developed AR on 23 of 171 TBBxs (Grade A2:A3 = 21:2) during follow-up (mean +/- SD) of 1,185 +/- 426 days (range, 16 to 1,790 days). Eighteen of 23 AR episodes occurred after sub-target C2 levels. The 30-day, 1-, 3- and 5-year actuarial survival rates were 98%, 94%, 82% and 77%, respectively. Thirteen of 48 (27%) evaluable LTx recipients developed BOS with 1-, 3- and 5-year freedom-from-BOS rates of 96%, 79% and 59%, respectively. Only 1 patient developed severe renal dysfunction. CONCLUSIONS: Achieving and maintaining target C2 levels after LTx is associated with reduced rates of AR and BOS, preservation of renal function, and excellent short-term survival rates when compared with historic controls.

Intravenous ribavirin is a safe and cost-effective treatment for respiratory syncytial virus infection after lung transplantation.

BACKGROUND: Community-acquired viral infections, such as respiratory syncytial virus (RSV), represent a risk factor for bronchiolitis obliterans syndrome (BOS), the major limiting factor for long-term survival after lung transplantation (LTx). RSV often presents with acute bronchiolitis and may be fatal in 10% to 20% of patients. Standard therapies for RSV include nebulized ribavirin with or without steroids, but are costly and inconvenient. We investigated the utility of intravenous (IV) ribavirin with steroids for the treatment of RSV infection after LTx. METHODS: RSV was identified in nasopharyngeal and throat swabs (NPS) using indirect fluorescent antibody (IFA) testing in 18 symptomatic patients, which was confirmed by viral culture in 14. Data were collected for the period between April 2002 and October 2004. The study included 10 men and 8 women, mean age 42 +/- 15 (range 18 to 63) years. Transplant procedures were 5 single LTx and 13 bilateral LTx. RSV diagnosis was made on Day 1,374 +/- 1,270 (range 61 to 4,598, median 935) post-operatively. Underlying diagnoses included cystic fibrosis (n = 9), emphysema (n = 7) and pulmonary fibrosis (n = 2). All 18 patients received intravenous (IV) ribavirin (33 mg/kg on Day 1 and 20 mg/kg/day thereafter in 3 divided doses) with oral prednisolone (1 mg/kg) until repeat NPS were negative for RSV on IFA. Median therapy was 8 days (6 to 15). RESULTS: The mortality rate was 0%. Mean FEV1 fell from 2.1 +/- 1.0 liter (0.7 to 3.7 liters) to 1.8 +/- 0.9 liter (0.5 to 3.6 liters) (p < 0.001), but recovered to 2.1 +/- 0.9 (0.7 to 3.7 liters) within 3 months and was maintained at follow-up of 521 +/- 328 days (141 to 1,023 days, median 302). Only 1 patient developed bronchiolitis obliterans syndrome (BOS). Complications included mild hemolytic anemia (blood hemoglobin fell from 122 +/- 22 [84 to 154] g/liter to 107 +/- 18 [75 to 138] g/liter, p = 0.02). Cost savings per 8-day course were $US15,913 when compared with nebulized therapy at 6 g/day (p < 0.001). CONCLUSIONS: This is the largest reported series of treated RSV cases after LTx and the first to show that therapy with IV ribavirin and oral corticosteroids is well tolerated and effective. Cost utility vs nebulized therapy has been established. Early diagnosis and management are essential to prevent airway epithelial injury and subsequent BOS.

Cyclosporine C2 monitoring improves renal dysfunction after lung transplantation.

BACKGROUND: Cyclosporine (CyA) toxicity is a potential cause of renal dysfunction, which occurs in 38% of lung transplant (LTx) recipients within 5 years. Reducing CyA to "sub-therapeutic" trough (C0) levels increases the risk of rejection. The 2-hour post-dose concentration (C2) is favored as the best single-point surrogate measure of CyA area under the curve (AUC), which reflects drug exposure. In this investigation we assess the effect of conversion to CyA C2 monitoring on renal dysfunction after LTx. METHODS: Fifteen patients (M:F = 12:3), aged 47 +/- 14 years (range 28 to 62), 3.5 +/- 2.7 (0.2 to 9.0) years post-LTx, with C0 in the therapeutic range (maintenance 100 to 200 microg/liters) (Behring/EMIT immunoassay) and abnormal renal function, were converted from C0 monitoring to C2 monitoring with dose reductions targeting C2 levels of 300 to 600 microg/liter over a 12-month period. RESULTS: CyA dose was reduced from 6.4 +/- 7.3 (1.2 to 27.9) to 3.1 +/- 2.7 (0.8 to 9.0) mg/kg/day (p = 0.04), with a reduction in C2 levels from 799 +/- 341 (299 to 1,466) to 390 +/- 148 (195 to 675) microg/liter (p < 0.001). Improvements in serum creatinine (0.20 +/- 0.07 [0.12 to 0.35] vs 0.16 +/- 0.04 [0.11 to 0.22] mmol/liter [p = 0.005]) were maintained during the study follow-up period of 1 year. Only 1 patient developed acute rejection and group mean forced expiratory volume in 1 second (FEV(1)) remained stable (2.4 +/- 1.0 [1.1 to 4.0] vs 2.4 +/- 1.2 [1.1 to 4.6] liters). CONCLUSIONS: C2 monitoring is a practical method of improving renal dysfunction that allows safe dose reductions of CyA when formal AUC monitoring is not feasible. Extended use of this strategy is associated with long-term benefits.

Enhanced clinical utility of de novo cyclosporine C2 monitoring after lung transplantation.

BACKGROUND: The 2-hour post-cyclosporine (CyA) dose concentration (C2) is favored as the best single-point correlate of CyA area-under-the-concentration curve. CyA nephrotoxicity is a prominent cause of renal dysfunction that affects 38% of lung transplant (LTx) recipients at 5 years. METHODS: We assessed the utility of de novo C2 monitoring after LTx by comparing 2 sequential groups of 18 bilateral LTx recipients followed with traditional de novo trough CyA (C0) monitoring and de novo C2 monitoring, respectively. Target C0 levels were 450 microg/liter and 250 microg/liter at 1 week and 3 months (3/12). Target C2 levels were 1,200 microg/liter and 800 microg/liter. Groups were matched for anthropometrics and diagnoses. Baseline serum creatinine (Cr) was lower in the C0 group than in the C2 group (65 +/- 17 vs 81 +/- 21 micromol/liter, p = 0.02). RESULTS: At 3 months, survival for both groups was 100%, but the C0 group had a greater increase in Cr from baseline (90 +/- 54% vs 33 +/- 23%, p < 0.001) despite similar CyA dosage (6.6 +/- 3.8 vs 6.5 +/- 2.9 mg/kg/day, p = 0.94). There was no difference in forced expiratory volume in 1 second (% predicted) (71 +/- 16 vs 69 +/- 14, p = 0.68), mean acute vascular rejection score per patient (2.61 +/- 2.12 vs 1.44 +/- 1.72, p = 0.079), mean bronchial rejection score per patient (3.72 +/- 1.81 vs 2.83 +/- 1.58, p = 0.126) or rate of infection (1.85 vs 1.79 events per 100 patient-days). CONCLUSIONS: De novo C2 monitoring, which reduces both the risk of CyA toxicity and the risk of sub-therapeutic dosing, is a safe and effective technique for short-term preservation of renal function after LTx.

Association of minimal rejection in lung transplant recipients with obliterative bronchiolitis.

The clinical significance of minimal acute rejection (grade A1) in lung transplant recipients is unknown. We prospectively analyzed 1,159 transbronchial lung biopsies in 184 patients. Two hundred seventy-nine biopsies in 128 participants confirmed A1 histology at a mean postoperative day of 229 +/- 340. Sixty four of 255 surveillance A1 lesions progressed to high-grade acute rejection by 3 months of follow-up, whereas 40 developed new lymphocytic bronchiolitis. Twenty-four A1 biopsies were symptomatic, with only two cases progressing to high-grade rejection after steroid therapy. Seventy-eight of 184 patients experienced multiple (> or = 2) A1 biopsies in the first 12 months after transplant. Bronchiolitis obliterans syndrome developed in 68% of patients with multiple A1 lesions at a mean of 599 +/- 435 days, compared with 43% of patients with one or less A1 lesions at a mean of 819 +/- 526 (p = 0.022). Eighteen patients experienced multiple A1 biopsies after transplant in the absence of high-grade rejection episodes yet also developed earlier obliterative bronchiolitis (456 +/- 245 days, p = 0.020). We conclude that for A1 transbronchial lung biopsies, the conventional treatment of observation only is now challenged even in patients who are asymptomatic. Patients who experience multiple A1 lesions develop an earlier onset of obliterative bronchiolitis and may warrant alternative immunosuppressive strategies.

Treated cytomegalovirus pneumonia is not associated with bronchiolitis obliterans syndrome.

The association of cytomegalovirus (CMV) infection with the development of bronchiolitis obliterans syndrome (BOS) is unclear. We studied 341 lung transplant recipients to assess whether histopathologically diagnosed CMV pneumonia treated with ganciclovir was a risk factor for development of BOS and patient survival. We also analyzed the relationship between CMV donor/recipient serologic status and BOS plus the temporal association between acute rejection and CMV pneumonia. Freedom from BOS for patients with (n = 151) and without (n = 190) CMV pneumonia was 83 and 90% (1 year), 52 and 56% (3 years), and 29 and 38% (5 years), respectively (p = 0.2660). Cumulative survival of patients with and without CMV pneumonia was 90 and 93% (1 year), 70 and 74% (3 years), and 58 and 63% (5 years), respectively (p = 0.1811). There were no significant differences in either development of BOS or patient survival with any combination of donor/recipient serostatus for CMV. Acute rejection occurred in the month preceding CMV pneumonia in 62 of 193 (32%) cases. Histopathologically confirmed CMV pneumonia treated with ganciclovir is not a risk factor for BOS or patient survival, nor is any particular CMV serologic donor/recipient group. CMV pneumonia often follows acute rejection, perhaps as a result of augmented immunosuppression.

Prospective analysis of 1,235 transbronchial lung biopsies in lung transplant recipients.

OBJECTIVE: Fiber-optic bronchoscopy with multiple transbronchial lung biopsies (TBB) is the gold standard of evaluation of the pulmonary allograft post-lung transplantation (LT). However, controversy exists regarding the need for surveillance procedures and number of biopsy specimens required for satisfactory yield. The potential morbidity in obtaining multiple TBB specimens remains poorly described. We report the largest series of TBB in LT recipients to date, highlighting the occurrence of acute rejection and infection for surveillance and diagnostic procedures. The safety of TBB is analyzed and a biopsy schedule proposed. METHODS: Prospective analysis of 1,235 TBB in 230 LT recipients performed at St Vincent's Hospital from January 1995 to June 2000. RESULTS: Eight hundred thirty-six (67.7%) TBB were performed as surveillance and 399 (32.3%) for a clinical indication. No significant acute rejection (AR) or infection was disclosed in 53.3% of procedures. The Lung Rejection Study Group requirement of at least five pieces of evaluable lung parenchyma was achieved in 98.2% of procedures. The average number of evaluable fragments per procedure was 6.4, whereas only 3 TBB (0.24%) contained no lung parenchyma and 44 (3.6%) no bronchial wall. Histologic features of AR, lymphocytic bronchiolitis or infection were found in 18.9% of surveillance and 86.4% of clinical TBBs. The yield of surveillance procedures between 4 and 12 months was just 1.1% for cytomegalovirus and 6.1% for AR. The overall complication rate was 6.35% with no deaths recorded. CONCLUSION: Taking 10 to 12 TBB specimens has a high diagnostic yield and rarely fails to provide adequate tissue. The role of surveillance procedures post-lung transplantation remains controversial.