Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation.

Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications.

Three-year results of an investigator-driven multicenter, international, randomized open-label de novo trial to prevent BOS after lung transplantation.

BACKGROUND: Chronic lung allograft dysfunction (CLAD), predominantly manifest as bronchiolitis obliterans syndrome (BOS), is the primary cause of morbidity and death after lung transplantation. We assessed the efficacy and safety of 2 de novo immunosuppression protocols to prevent BOS. METHODS: This was a multicenter, prospective, international, randomized (1:1) open-label superiority study of de novo enteric-coated mycophenolate sodium (MPS) vs delayed-onset everolimus (RAD), both arms in combination with cyclosporine (CsA) monitored by 2-hour post-dose (C2) levels, and corticosteroids. Target C2 levels were lower in the RAD group because RAD is known to potentiate CsA nephrotoxicity. Cytolytic induction therapy was not used. Patients were stratified at entry for cystic fibrosis. Confirmation of anastomotic healing was required for randomization. Primary efficacy was freedom from BOS Grade 1 on intention-to-treat (ITT) analysis. Secondary efficacy parameters were patient and graft survival and severity of rejection. Treatment failure was defined by graft loss, patient death, drug cessation, or need for other therapy. RESULTS: The 3-year freedom from BOS Grade 1 was 70% for MPS (n = 80) vs 71% for RAD (n = 84; p = 0.95 by log-rank) in ITT but was lower in the RAD arm of the per-protocol population (p = 0.03). The 3-year survival was 84% (MPS) vs 76% (RAD; p = 0.19 by log-rank). Thirteen patients switched from MPS vs 31 from RAD (p < 0.01). Days on MPS were greater than days on RAD (p < 0.01). Rejection events proven by biopsy specimen were more common on MPS (p = 0.02), as were leucopenia (p < 0.01), diarrhea (p < 0.01), and cytomegalovirus infection (p = 0.04). Venous thromboembolism was more frequent on RAD (p = 0.02). Creatinine at 3 years was 160 ± 112 µmol/1iter in MPS patients vs 152 ± 98 µmol/1iter in RAD patients (p = 0.67). CONCLUSIONS: This 3-year ITT analysis found no significant difference between arms but was underpowered to accept the null hypothesis that RAD and MPS have equivalent efficacy in preventing BOS or death after lung transplantation.

Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: results of a prospective, randomized international trial in lung transplantation.

BACKGROUND: Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation. In this study we assessed the efficacy and safety of two de novo immunosuppression protocols to prevent BOS. METHODS: Our study approach was a multicenter, prospective, randomized (1:1) open-label superiority investigation of de novo tacrolimus vs cyclosporine, with both study arms given mycophenolate mofetil and prednisolone after lung transplantation. Cytolytic induction therapy was not employed. Patients were stratified at entry for cystic fibrosis. Primary outcome was incidence of BOS 3 years after transplant (intention-to-treat analysis). Secondary outcomes were survival and incidence of acute rejection, infection and other adverse events. RESULTS: Group demographic data were well matched: 110 of 124 tacrolimus vs 74 of 125 cyclosporine patients were treated per protocol (p < 0.01 by chi-square test). Cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) vs 21.3% (cyclosporine) (cumulative incidence curves, p = 0.037 by Gray's test, pooled over strata). Univariate proportional sub-distribution hazards regression confirmed cyclosporine as a risk for BOS (HR 1.97, 95% CI 1.04 to 3.77, p = 0.039). Three-year cumulative incidence of acute rejection was 67.4% (tacrolimus) vs 74.9% (cyclosporine) (p = 0.118 by Gray's test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) vs 88.6% and 82.8% (cyclosporine) (p = 0.382 by log-rank test). Cumulative infection rates were similar (p = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (p = 0.09). CONCLUSIONS: Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of acute rejection. However, no survival advantage was detected.

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.

Sedative drug requirements during bronchoscopy are higher in cystic fibrosis after lung transplantation.

BACKGROUND: We noted that patients with cystic fibrosis tended to need higher doses of sedatives during bronchoscopy. We undertook this study to assess the sedative drug doses administered during bronchoscopy in lung transplant recipients and to assess if there is a change in the dosage requirements over time following lung transplantation. METHODS: In all, 773 transbronchial biopsy procedures performed via flexible bronchoscopy were analyzed in 140 consecutive lung transplant recipients. Conscious sedation was achieved with intermittent boluses of intravenous midazolam and fentanyl. Intravenous propofol boluses of 10 to 30 mg were administered when optimal sedation was not achieved with midazolam doses of 0.20 to 0.25 mg/kg and fentanyl 2 to 2.5 micrograms/kg. RESULTS: Mean doses of midazolam and fentanyl administered were 0.15+/-0.07 mg/kg (range 0.02 to 0.44 mg/kg) and 1.8+/-0.8 micrograms/kg (range 0.1 to 6.67 micrograms/kg) respectively. Midazolam and fentanyl doses administered to patients with cystic fibrosis were the highest compared to those with other disease types (P<0.0001). Examining the sedative doses administered over time following transplantation, there was a significant linear (P<0.001) and quadratic (P=0.0023) effect of time for midazolam and a significant linear (P=0.003) and a trend (P=0.08) for a quadratic effect for fentanyl. Propofol was effectively used in seven lung transplant recipients in whom adequate sedation could not be achieved with high doses of midazolam and fentanyl. CONCLUSIONS: There is an increase in sedative drug requirement with time for both midazolam and fentanyl after transplantation, which is significantly higher in patients with cystic fibrosis.

Chlamydia pneumoniae infection after lung transplantation.

BACKGROUND: Chlamydia pneumoniae is established as a common agent of acute respiratory tract infection and has been implicated in the pathogenesis of asthma and chronic obstructive pulmonary disease. Airway disease is a prominent cause of morbidity and mortality after lung transplantation. We investigated the role of C pneumoniae as a pulmonary pathogen after lung transplantation. METHODS: Eighty lung transplant recipients underwent 232 bronchoscopies with bronchoalveolar lavage with or without transbronchial lung biopsy during 1 year for surveillance of rejection and infection, or where clinically indicated. RESULTS: C pneumoniae was detected using nested polymerase chain reaction in 9 of 36 (25%) recipients studied within 30 days of lung transplantation, 3 of whom remained positive on repeat lavage and died from airway disease in the first year post-operatively. By comparison, all 27 recipients with negative lavage survived >1 year. Lavage was positive for C pneumoniae in 18 of 71 (25%) recipients studied >30 days after lung transplantation, 5 of whom had pneumonia and 8 of whom had bronchiolitis obliterans syndrome. Eleven also had acute pulmonary allograft rejection. CONCLUSIONS: Persistent infection with C pneumoniae (whether donor-derived, de novo or re-activated) appears deleterious to pulmonary allograft function and is associated with early mortality, rejection and bronchiolitis obliterans syndrome after lung transplantation. A trial of empiric antibiotic therapy for C pneumoniae may therefore be warranted in the attempt to prevent progressive inflammatory airway disease.

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.

Risk factors and management of bleeding associated with transbronchial lung biopsy in lung transplant recipients.

The aim of this study was to assess specific risk factors associated with bleeding during transbronchial biopsy (TBBx) in lung transplant recipients. Risk factors analyzed included gender, type of transplant, acute rejection, bronchiolitis obliterans syndrome (BOS) status, infections, number of biopsies obtained per procedures, serum creatinine level and post-operative day since transplantation. The bronchoscope was not wedged to obtain TBBx and associated bleeding was managed using the "back-and-forth" technique. The severity of bleeding is shown to be independent of any specific risk factor and the back-and-forth technique described herein can be safely employed in lung transplant recipients to manage bleeding associated with TBBx performed without wedging of the bronchoscope.

Randomised double-blind, placebo-controlled trial of coenzyme Q, therapy in class II and III systolic heart failure.

BACKGROUND: Coenzyme Q10 (CoQ10) supplementation has been reported to improve symptoms of heart failure and quality of life, and to reduce hospitalisation. Most prior trials have been open-label and in some, only 50% of patients took angiotensin converting enzyme inhibitors (ACEI). AIM: To determine the effects of CoQ10 in patients with a New York Heart Association (NYHA) Class II or III heart failure due to ischaemic or dilated cardiomyopathy who have been treated with ACEI but not beta-blockers. METHODS: Thirty-nine patients in NYHA Class II or III heart failure were randomised in ad ouble-blind, placebo-controlled study with 150 mg/day of oral CoQ10 or placebo. RESULTS: Thirty-five patients completed the trial. After 3 months of therapy, the NYHA class in the CoQ10 group (n = 17) showed a significant improvement of 0.5 class compared with the placebo (n = 18) (P = 0.01). Specific Activities Scale class showed a significant (P = 0.004) improvement in the CoQ10 group, but no change in the placebo group. The C-min walk-test distance showed a significant (P = 0.047) increase in the CoQ10 group with no change in the placebo group (between-group difference P = 0.29). For the Naughton exercise test times the difference in increase in exercise time approached significance in favour of the CoQ10 group (P = 0.056). There was a correlation between the increase in exercise time and the increase in serum CoQ10 level (P = 0.024). There was a threefold increase in the CoQ10 level in the treated group (0.7 +/- 0.4 to 2.1+/- 0.3 microg/mL), but no change in the placebo group. CONCLUSIONS: This pilot study accords with published data suggesting that CoQ10 therapy improves cardiac functional status in patients with moderately severe dilated cardiomyopathy receiving maximal non beta-blocker therapy. Future multicentre studies with larger numbers are indicated.

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.

Management of acute hypoxemia during flexible bronchoscopy with insertion of a nasopharyngeal tube in lung transplant recipients.

STUDY OBJECTIVES: To assess the utility of nasopharyngeal tube insertion in the management of hypoxemia during flexible bronchoscopy (FB) in lung transplant recipients, and to determine the incidence and risk factors of upper-airway obstruction (UAO) leading to significant hypoxemia during FB. SETTING: Heart-lung transplant unit of a university hospital. PATIENTS AND METHODS: Ninety-six lung transplant recipients (47 men and 49 women; mean +/- SD age, 41.4 +/- 13.1 years) underwent 714 FB procedures from January 1997 to May 2000. INTERVENTION: A fall in oxygen saturation (< or = 90%) in patients receiving 6 L/min of oxygen via nasal prongs was treated with insertion of a nasopharyngeal tube, continued oxygen supplementation, and withdrawal of the bronchoscope to the trachea. If oxygen desaturation persisted at < 90% despite additional oxygen administration via a 7F catheter placed either just above the larynx or in the proximal trachea, the bronchoscope was withdrawn, reversal of sedation was administered, and bag and mask ventilation was instituted until satisfactory spontaneous ventilation was achieved. RESULTS: Forty-six patients (47.9%) were treated with nasopharyngeal tube insertion on 102 occasions at a mean duration of 168 +/- 178 days after lung transplantation. In 90 of 102 procedures (88.2%), significant hypoxemia due to UAO was successfully treated with nasopharyngeal tube insertion. The mean oxygen saturation after nasopharyngeal tube insertion was 97 +/- 3%. Male gender, increase in body mass index after lung transplantation, and presence of obstructive sleep apnea were significant factors associated with the need for nasopharyngeal tube insertion during FB in lung transplant recipients. CONCLUSIONS: Significant oxygen desaturation during FB in lung transplant recipients is mainly due to UAO. Insertion of a nasopharyngeal tube is a novel and a highly effective approach to the management of acute hypoxemia during FB.