M.A. Malouf

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 Vincents 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.

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.

Use of Extracorporeal Membrane Oxygenation as a Bridge to Primary Lung Transplant: 3 Consecutive, Successful Cases and a Review of the Literature

Many transplant centers have considered extracorporeal membrane oxygenation (ECMO) to be a contraindication to lung transplantation, due to historically poor outcomes. However, recent advances in the technical aspects of ECMO have enabled patients to be supported with relative safety for several weeks until a donor lung becomes available. We present 3 young patients with acute (in 1 case, acute on chronic), severe respiratory failure that was refractory to conventional ventilation, who were placed on venovenous ECMO. In each case, a clinical decision was made that the patients respiratory failure was irreversible and they were successfully managed with urgent lung transplantation.

Anti-viral prophylaxis reduces the incidence of lymphoproliferative disease in lung transplant recipients

BACKGROUND Post-transplant lymphoproliferative disease (PTLD) is a serious, often fatal complication after solid organ transplantation. Primary Epstein-Barr virus (EBV) infection is the major risk factor for PTLD after lung transplantation, with 30% to 50% of EBV-naive patients who seroconvert and are diagnosed with PTLD. METHOD In this study, we analyzed the incidence of PTLD in lung and heart-lung transplant recipients before 1996 (historic group) and then compared the impact of long-term anti-viral prophylaxis on the development of PTLD in EBV-seronegative recipients from January 1996 to December 2000 (post-1996 group). Routine induction therapy was not given after 1995. Patients not surviving 30 days, 25 of 341 (7.3%), were excluded. RESULTS Historic group: PTLD developed in 7 of 167 (4.2%) patients, at a mean of 394 +/- 278 (95-885) days. The mortality was 87.5% at a mean follow-up of 186 +/- 207 (17-520) days after diagnosis. Post-1996 group: Eighteen of 149 (12.3%) patients were EBV seronegative at the time of transplantation, and of these 15 (83%) began receiving continuous anti-viral prophylaxis: acyclovir or valacyclovir or ganciclovir from January 1996. None of the EBV-seronegative recipients receiving continuous anti-viral prophylaxis were diagnosed with PTLD; however, 1 of 3 (33%) of the EBV-seronegative recipients who did not receive anti-viral prophylaxis were diagnosed with PTLD. In the EBV-seronegative recipients, no deaths had been caused by PTLD at a mean follow-up of 806 +/- 534 (39-1,084) days. In the post-1996 group, PTLD developed in 1 of 131 (0.76%) EBV-seropositive recipients. CONCLUSION Continuous, specific anti-viral prophylaxis in high-risk EBV-seronegative recipients significantly reduces the incidence of PTLD after lung transplantation in the absence of induction therapy.

Comparison of Low-Molecular-Weight Heparin, Administered Primarily at Home, with Unfractionated Heparin, Administered in Hospital, and Subcutaneous Heparin, Administered at Home for Deep-Vein Thrombosis

In this study, 294 patients with acute proximal DVT (deep venous thrombosis) were randomly assigned to receive intravenous standard heparin in the hospital (98 patients) or low-molecular-weight heparin (LMWH) (nadroparin 0.1 mL [equivalent to 100 AXa IU] per kg of body weight subcutaneously twice daily) administered primarily at home (outpatients) or alternatively in hospital (97 patients) or subcutaneous calcium heparin (SCHep) (99 patients, 0.5 mL bid) administered directly at home. The study design allowed outpatients taking LMWH heparin to go home immediately and hospitalized patients taking LMWH to be discharged early. Patients treated with standard heparin or LMWH received the oral anticoagulant starting on the second day, and heparin was discontinued when the therapeutic range (INR 2-3) had been reached. Anticoagulant treatment was maintained for 3 months. Patients treated with SCHep were injected twice daily for 3 months without oral anticoagulants. Patients were evaluated for inclusion and follow-up with color duplex scanning. Venography was not used. In case of suspected pulmonary embolism (PE) a ventilatory-perfusional lung scan was performed. Endpoints of the study were recurrent or extension of DVT, bleeding, the number of days spent in hospital, and costs of treatments. Of the 325 patients included, 294 completed the study. Dropouts totaled 31 (10.5%); six of the 325 included patients (1.8%) died from the related, neoplastic illness. Recurrence or extension of DVT was observed in 6.1% of patients in the LMWH group, in 6.2% in the standard heparin group, and in 7.1% in the SCHep group. Most recurrences (11/17) were in the first month in all groups. Bleedings were all minor, mostly during hospital stay. Hospital stay in patients treated with LMWH was 1.2 ± 1.4 days in comparison with 5.4 ± 1.2 in those treated with standard heparin. There was no hospital stay in the SCHep group. Average treatment costs in 3 months in the standard heparin group (US

Pulmonary scedosporium infection following lung transplantation

2,760) were considered to be 100%; in comparison costs in the LMWH group was 28% of the standard heparin and 8% in the SCHep group. This study indicated that LMWH and SCHep can be used safely and effectively to treat patients with proximal DVT at home at a lower cost.

An investigator-driven study of everolimus in surgical lung biopsy confirmed idiopathic pulmonary fibrosis

Abstract: Infectious complications are frequent following lung transplantation. Tracheobronchial aspergillosis is the predominant fungal infection in these patients. Infections with Scedosporium apiospermium (Pseudoallescheria boydii) and Scedosporium prolificans (Scedosporium inflatum) have mainly been described in bone marrow transplant recipients and only occasionally in solid organ transplant recipients. We analysed risk factors, the clinical course and outcome of seven lung transplant recipients who developed pulmonary scedosporium infection. Scedosporium apiospermium was documented in bronchoalveolar lavage (BAL) of all seven and Scedosporium prolificans in the BAL of four of these patients. Scedosporium was detected 9–58 months after transplantation. Five of the seven patients had been treated for several months with itraconazole because of previous detection of aspergillus in BAL. All seven patients with scedosporium infection showed airway problems, including early ischemic airway stenosis in one and bronchiolitis obliterans syndrome in the other six patients. Combined treatment with itraconazole and fluconazole was not able to eradicate scedosporium. Four of the seven patients died with advanced bronchiolitis obliterans 3–35 months after the diagnosis of pulmonary scedosporium infection. Three patients are currently alive 3, 6 and 7 years after transplantation, showing persistent scedosporium infection. In conclusion, pulmonary scedosporium infection was seen in lung transplant recipients with structurally abnormal airways and under long‐term therapy with itraconazole. Eradication of scedosporium proved difficult, but under combined treatment with itraconazole and fluconazole this opportunistic infection did not disseminate.

Ultraflex stents for the management of airway complications in lung transplant recipients.

Background and objective:  We evaluated the efficacy and safety of everolimus, a macrocyclic proliferation signal inhibitor with anti‐fibroproliferative activity to prevent disease progression or death in patients with IPF, a progressive, fatal disease with no known effective therapy.

Achilles tendon disease in lung transplant recipients: association with ciprofloxacin

Objective:  We present our experience with the use of the Ultraflex (nitinol) stents in the management of airway complications in lung transplant (LT) recipients.

Exhaled breath condensate (EBC) biomarkers in pulmonary fibrosis

Achilles tendonitis or rupture are uncommon complications following the use of fluoroquinolones, with a reported incidence in the general population of 0.4%. The aims of the current study were to determine the incidence of Achilles tendon disease (ATD) in lung transplant recipients (LTR) and to identify risk factors. Questionnaires were sent to 150 LTR of whom 101 responded (67%). Twenty-two LTR (21.8%) experienced ATD (tendonitis 16, rupture six). The mean age of LTR who developed ATD was 52.9±6.1 yrs (range: 19–63.5 yrs). Only the use of ciprofloxacin was significantly associated with ATD (p<0.05). Age, sex, underlying disease necessitating transplantation, serum creatinine and cyclosporine levels were not associated with ATD. The association between ciprofloxacin and ATD was not dose related. Of the 72 LTR who had received ciprofloxacin, 20 (28%) developed ATD (tendonitis 15, rupture five). In patients receiving ciprofloxacin, there was no association between the mean cumulative dose of prednisolone and ATD. Tendon rupture occurred with a lower ciprofloxacin dosage than tendonitis and the mean recovery duration was significantly longer. To conclude, lung transplant recipients receiving ciprofloxacin are at significant risk of developing Achilles tendon disease. The association between ciprofloxacin and Achilles tendon disease appears to be idiosyncratic rather than dose-related.