Malouf syndrome

The clinical significance of minimal acute rejection (grade A^sub 1^) 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 A^sub 1^ histology at a mean postoperative day of 229 ± 340. Sixty four of 255 surveillance A^sub 1^ lesions progressed to high-grade acute rejection by 3 months of follow-up, whereas 40 developed new lymphocytic bronchiolitis. Twenty-four A^sub 1^ biopsies were symptomatic, with only two cases progressing to high-grade rejection after steroid therapy. Seventy-eight of 184 patients experienced multiple (≥ 2) A^sub 1^ biopsies in the first 12 months after transplant. Bronchiolitis obliterans syndrome developed in 68% of patients with multiple A^sub 1^ lesions at a mean of 599 ± 435 days, compared with 43% of patients with one or less A^sub 1^ lesions at a mean of 819 ± 526 (p = 0.022). Eighteen patients experienced multiple A^sub 1^ 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 A^sub 1^ transbronchial lung biopsies, the conventional treatment of observation only is now challenged even in patients who are asymptomatic. Patients who experience multiple A^sub 1^ lesions develop an earlier onset of obliterative bronchiolitis and may warrant alternative immunosuppressive strategies.

Keywords: lung transplant; minimal rejection; obliterative bronchiolitis

The greatest impediment to the long-term survival of lung transplant recipients remains obliterative bronchiolitis, for which high-grade (≥ A^sub 2^) acute rejection (AR) is an established risk factor (1,2). Fiberoptic bronchoscopy with multiple transbronchial lung biopsies (TRBs) to obtain histologic specimens is the "gold standard" of evaluation of the pulmonary allograft (3, 4). Clinical reasons for performing diagnostic TBB are radiographic infiltrates, a 10% or more decline in FEV^sub 1^, or symptoms referable to the lower respiratory tract. The revised working formulation for the grading of AR proposed by the Lung Rejection Study Group in 1996 (5) is based exclusively on the presence of perivascular and interstitial mononuclear cell infiltrates. This classification system includes grade A^sub 0^ (no AR), A^sub 1^ (minimal), A^sub 2^ (mild), A^sub 3^ (moderate), and A^sub 4^ (severe) lesions. Histologically, grade A^sub 1^ is characterized by scattered infrequent perivascular mononuclear infiltrates in alvcolated lung parenchyma that are not obvious at low (X40) magnification. Clinically, high-grade AR refers to A^sub 2^ or more histology for which intravenous and/or oral pulse steroid therapy is regarded as optimum treatment irrespective of symptoms. Minimal AR in a patient who is asymptomatic on surveillance protocol is generally regarded as a benign histological entity (6-8). However, controversy exists regarding the requirement for oral steroids in the treatment of A^sub 1^ lesions in patients who are asymptomatic. Limited data suggest that minimal-grade TBBs, irrespective of symptoms, progress infrequently to high-grade rejection and are not associated with the subsequent development of obliterative bronchiolitis (9, 10). Nonetheless, these descriptions are based on small numbers of patients and are often retrospective in nature. Accordingly, we prospectively analyzed the occurrence and short-term prognosis of A^sub 1^ TBB seen on surveillance and diagnostic procedures in our lung transplant population. The outcome of patients who experienced multiple A^sub 1^ lesions in the first 12 months after transplant is described. Selected results from this study have been reported previously in the form of an abstract (11).

METHODS

This study was a prospective analysis of 1,159 TBBs in 184 subjects performed at St. Vincent's Hospital Sydney from January 1995 to December 2000, recorded on a computerized database. During this period, 197 patients underwent heart-lung or lung transplantation at our institution. Thirteen patients (6.6%) died less than 30 days after transplanttwo from anastomotic dehisccnce, three primary graft failure, and eight overwhelming infection. Therefore, the study population included 184 heart-lung and lung recipients who survived over 30 clays after transplant and had at least one bronchoscopic procedure performed according to a surveillance protocol at 3, 6, 9 weeks and at 3, 6, 12 months alter transplant. All patients who underwent surveillance bronchoscopies demonstrated stable gas exchange, spirometry, and chest radiographs. A diagnostic TBB was also performed in patients who are clinically symptomatic, for 10% or more decline in FEV^sub 1^, or to assess infiltrates seen on chest radiographs. Follow-up biopsies were performed routinely and were defined as a second biopsy within 45 days of an initial biopsy, which showed an acute allograft rejection grade of A^sub 2^ or more (12). The pretransplant diagnoses and type of transplant of study subjects are summarized in Table E1 of the online supplement.

Fiberoptic bronchoscopy was performed in the operating theater under topical lignocaine anesthesia and intravenous sedation. After bronchoalveolar lavage, 10-12 TBBs were obtained from both the lower and middle lobes of the right lung or lower and lingula lobes of the left lung. The diagnosis of AR was based on the presence of pcrivascular and interstitial mononuclear infiltrates. TBBs were graded for AR according to the standardized nomenclature described by the Lung Rejection Study Group (4, 5). Airway inflammation was divided into five grades for classification, including grade B^sub 0^ (no airway inflammation), grade B^sub 1^ (minimal), grade B^sub 2^ (mild), grade B^sub 5^ (moderate), and grade B^sub 4^ (severe airway inflammation). Lymphocytic bronchiolitis was defined as grade B^sub 2^ or more inflammation. Cytomegalovirus pneumonitis on TBB was defined by the presence of typical inclusion bodies associated with inflammatory infiltrates. Immunoperoxidase staining used the early immediate antigen method. Histologic specimens were reported by the same histopathologist throughout the evaluation period.

All patients received initial immunosuppressive therapy of oral cyclosporin A targeting blood trough levels of 300-350 μg/L, azathioprine 2-3 mg/kg, and prednisolone 1 mg/kg daily in two divided doses. Oral steroids were subsequently tapered by 5 mg second daily to a maintenance dose of 0.25 mg/kg/day. AR was treated with intravenous methylprednisolone 15 mg/kg/day for 3 days and generally followed with an oral steroid taper commencing at 1 mg/kg. Patients were changed to tacrolimus (0.15 mg/kg) for recurrent (more than two episodes) or persistent rejection on follow-up biopsy, after receiving a second course of methylprednisolone. Minimal ARs (grade A^sub 1^) in patients who are asymptomatic were not routinely treated and constituted the surveillance group. Patients who were symptomatic with A^sub 1^ TBB received oral prednisolone commencing at 1 mg/kg, tapering by 5 mg every second day thereafter and formed the diagnostic group. All A^sub 1^ TBBs were followed for 3 months according to surveillance and diagnostic protocols to assess progression to high-grade AR and/or lymphocytic bronchiolitis. Biopsies showing normal lung parenchyma (grade A^sub 0^) were used for a comparison of outcome and constituted the control group. Given the natural tendency for rejection to peak in incidence during the lirst 3 months after transplant, the mean postoperative day to occurrence for both groups was compared. Patients with multiple A^sub 1^ lesions were defined as those with at least two TBBs depicting this finding in the first 12 months after transplant. The subgroup that did not experience or progress to high-grade rejection after transplant formed the multiple, non-high-grade group. Bronchiolitis obliterans syndrome (BOS) was defined according to the recommendations of the International Society for Heart and Lung Transplantation (13).

Statistical analysis was performed using computer-assisted software (SPSS, version 11.0; SPSS Inc., Chicago, IL). Continuous variables are presented as mean ± SD, and differences were compared by way of Student's t test. Categoric variables were compared using the chi-square test. Freedom from BOS and survival for each group have been compared using Kaplan-Meier analysis and Mantel-Cox log-rank test. We considered p of less than 0.05 as statistically significant.

RESULTS

One thousand one hundred fifty-nine TBBs were performed in 184 patients (93 males and 91 females) of mean age of 39.4 ± 13.3 years (range 12-62). Six hundred eighty-four (59%) bronchoscopic examinations were performed during the first 6 months after transplantation, 267 (23%) between 7 and 9 months, and 104 (9%) each between 10 and 12 months and beyond 1 year. Eight hundred thirty-seven (72.2%) TBBs were performed as surveillance and 322 (27.8%) for a clinical indication. Histologic features of highgrade AR, lymphocytic bronchiolitis, or infection were found in 18.9% of surveillance and 86.4% of procedures with clinical indications. Two hundred seventy nine of 1,159 TBBs (24%) in 128 (69%) study participants confirmed A^sub 1^ histology at a mean of 229 ± 340 days (range 11-2045) after transplant. Twentyfour (9%) A^sub 1^ biopsies were associated with clinical symptoms, whereas the remaining 255 (91%) A^sub 1^ lesions were detected on surveillance procedures. Five hundred eighty-five biopsies (50.5%) showed no AR with normal lung parenchyma (International Society for Heart and Lung Transplantation grade A^sub 0^).

Forty-one (14.7%) initial A^sub 1^ lesions had an associated lymphocytic bronchiolitis, with 32 detected on surveillance and 9 on diagnostic TBB. In 13 (4.6%) A^sub 1^ TBBs, insufficient bronchiolar airway epithelium was present to permit accurate B grade classification. In the surveillance group, persistent lymphocytic bronchiolitis was found in 17 cases at 3 months follow-up, including 15 with B^sub 2^ and 2 with B^sub 3^ histology. Figure 1 summarizes the occurrence and outcome of A^sub 1^ TBBs. Sixty-four (25.1%) surveillance A^sub 1^ cases progressed to high-grade AR, including 51 with A^sub 2^ and 13 with A^sub 3^ histology. New lymphocytic bronchiolitis developed in 40 (15.7%) TBBs, although it coexisted with high-grade rejection in 16 cases. Therefore, the overall progression of surveillance TBB A^sub 1^ to either high-grade AR and/or new lymphocytic bronchiolitis was 34.5% (n = 88) at 3 months. Table 1 displays an outcome comparison between the surveillance group and the control group of biopsies with A^sub 0^ histology. The mean postoperative day to occurrence and the percentage with initial lymphocytic bronchiolitis were similar across both groups. However, surveillance A^sub 1^ TBBs were more likely to have progressed to new lymphocytic bronchiolitis and high-grade AR during follow-up (chi-square analysis, p

In the diagnostic A^sub 1^ group, only two cases (8.3%) progressed to high-grade AR at 3 months of follow-up after an oral pulse of steroids. No cases of cytomegalovirus pneumonitis developed during this time as a consequence of augmented immunosuppression. Progression to AR was significantly reduced (p

Seventy-eight of 184 patients (42%) experienced multiple (two or more) A^sub 1^ TBBs in the first 12 months after transplant. Thirty-seven of 78 patients (46%) had these depicted in consecutive procedures. Patient survival and time to mean (50%) freedom from BOS were analyzed comparing patients with multiple A^sub 1^ lesions ("multiple" group) and those with one ore less A^sub 1^ TBB ("single" group) during the evaluation period. The multiple group consisted of 78 patients with a mean follow-up of 1,054 ± 565 days (range 215-2,229) and the single group, 106 patients with a mean follow-up of 1,232 ± 537 days (range 266-2,261). The average number of AR (A^sub 2^ or more) episodes per patient in the multiple group during the follow-up period was 1.74 versus 1.0 in the single group (t test, p = 0.001). BOS developed in 68% of patients with multiple A^sub 1^ TBB at a mean of 599 ± 435 days compared wilh 43% of patients with one A^sub 1^ lesion or less at a mean of 819 ± 526. The freedom from BOS of the two groups up to 6 years after transplantation is depicted in Figure 2A and confirms a statistically significant development of BOS in the multiple A^sub 1^ group (time to mean freedom from BOS: logrank, p = 0.022). There were 38 (48.7%) postoperative deaths in the multiple group and 52 (49.1%) in the single group during follow-up. However, the survival of each group on log-rank Mantel-Cox Kaplan Mcier analysis as depicted in Figure 2B, was not significantly different despite the difference in BOS (p = 0.9956).

We postulated that the differences in the multiple and single groups was the higher rate of progression to high-grade AR in those patients that experience multiple A^sub 1^ TBBs. Therefore, we analyzed that group of patients who experienced multiple A^sub 1^ TBBs but who did not go on to develop biopsy-confirmed rejection of grade A^sub 2^ or more after transplant. Eighteen patients belonged to this category ("multiple non-high-grade" group) with a mean follow-up of 1,048 ± 549 days. Figure 3A depicts the freedom from BOS of patients with multiple A^sub 1^ TBBs with no high-grade AR compared wilh those with one A^sub 1^ or less (single group) and shows a significant difference (time to mean freedom from BOS: log-rank, p = 0.020). BOS developed in 56% of patients at a mean of 456 ± 245 days in the multiple non-high-grade group compared with 43% of patients in the single group at 819 ± 526 days. Eight (44.4%) patients died during follow-up in the multiple non-high-grade group compared with 52 (49.1 %) in the single group. There was no significant difference in patient survival, as shown in Figure 3B (Mantel-Cox, p = 0.43).

DISCUSSION

This study represents the largest prospective series of A^sub 1^ TBB in lung transplant recipients reported in the medical literature. Baz and colleagues (10) in 1996 from the Duke University Medical Center reported on 226 TBB in 43 transplant patients, of which 31 were A^sub 1^ lesions. Only two (6%) progressed to A^sub 2^ or more rejection within 3 months of follow-up. The surveillance and diagnostic biopsy protocol during the first 12 months after transplant described in this series were similar to that incorporated into our study. In addition, 7 to 10 biopsies were obtained per TBB procedure. In a Stanford University study (6), surveillance TBB evidence of A^sub 1^ or A^sub 2^ rejection progressed histologically in follow-up biopsy in 24% (6 of 25) of lung transplant recipients. Furthermore, only two of these patients (8% of all nontrcated patients) developed clinical symptoms consistent with AR. In our study, 279 A^sub 1^ TBB occurred in 1,159 procedures, with 9% associated with clinical symptoms. Approximately onethird of 255 surveillance A^sub 1^ lesions progressed to high-grade AR and/or new lymphocytic bronchiolitis at 3 months. In contrast, the natural progression of TBB depicting normal lung parenchyma (International Society for Heart and Lung Transplantation grade A^sub 0^) to high-grade AR or lymphocytic bronchiolitis during similar follow-up was only 14.2%. Therefore, we conclude that minimal AR in a patient who is asymptomatic on surveillance protocol is not necessarily a benign histologie entity and is a marker of increased risk for progression to higher grades of AR. Although we are not advocating routine steroid therapy for surveillance A^sub 1^ lesions, careful clinical assessment is strongly recommended to guide treatment.

Our institution's preference is to obtain 10-12 TBBs to exclude rejection or opportunistic infection confidently. In a previous publication, we have shown that the ratio of numbers of TBBs obtained at bronchoscopy to the final number of evaluable fragments at histology is approximately two to one (14). The Lung Rejection Study Group requires at least five pieces of alveolated lung parenchyma for specimen adequacy (5). Scott and colleagues (15) in 1991 provided data to assist in the determination of the true sensitivity and specificity of TBB. In a 12-month, single-operator study of 54 heart-lung transplant recipients who underwent 219 TBBs with 6-56 samples per procedure (mean 17.3), a sensitivity of 94% and a specificity of 90% were obtained for the diagnosis of AR. It was computed that 18 samples per procedure were required to have a 95% confidence of finding rejection. This recommendation is tempered by the practical reality in obtaining so many samples and fails to consider the volume of tissue obtained at bronchoscopy. Although our biopsy policy probably enhanced the sensitivity in A^sub 1^ diagnosis, this is likely a true reflection of prevalence in our transplant population. In addition, aggressive biopsy protocols probably reduce the incidence of a false-negative biopsy to an acceptable level. It is unlikely that doubling the number of recommended biopsies would have a corresponding affect on the prevalence of A^sub 1^ lesions as over 50% of TBBs show normal lung parenchyma.

Controversy exists regarding the requirement for oral steroids in the treatment of A^sub 1^ lesions in patients who are symptomatic. In our series, steroid treatment substantially reduced the progression to higher grades of rejection during follow-up. In addition, no new cases of lymphocytic bronchiolitis or cytomegalovirus infection occurred, and only two lesions depicting significant B grade inflammation persisted at 3 months. Therefore, for patients with a decline in pulmonary graft function, radiologic infiltrates, or symptoms referable to the respiratory tract, an oral pulse of prednisolone or equivalent is indicated for treatment of isolated A^sub 1^ TBB.

Limited data exist regarding the association between minimal grade lesions and the subsequent development of obliterative bronchiolitis. Schulman and colleagues (16) from Columbia University in 2001 published a univariate analysis of risk factors for obliterative bronchiolitis and reported no association with episodes of grade A^sub 1^ rejection. Similarly, Clelland and colleagues (9) have suggested that the prognosis of asymptomatic low-grade rejection (International Society for Heart and Lung Transplantation grade A^sub 1-2^) in heart-lung transplant recipients is favorable, with a low incidence of airway submucosal fibrosis on repeat TBBs at 12 months. However, to our knowledge, we are the first group to analyze the prognostic significance of multiple episodes of minimal rejection occurring in the first 12 months after transplant. Grade A^sub 1^ histology is a relatively common finding as outlined in our series. Approximately two-fifths of patients experienced multiple A^sub 1^ TBB in their first year after transplant, and these were each asymptomatic in 92% of recipients. This group of patients was statistically more likely to develop BOS and to develop it earlier during follow-up compared with those patients that experience only one or no episodes of A^sub 1^ histology. Nonetheless, percentage survival was not significantly altered between these groups. One plausible explanation is that the median lag time from diagnosis of BOS is sufficiently long to confound this short-term analysis of survival. The influence of preceding A^sub 1^ TBB on the natural history of BOS remains unknown. Furthermore, early diagnosis and the use of antifibroproliferative agents may be affecting survival in BOS (17). Although the role of surveillance TBB after lung transplantation remains controversial and requires analysis by a randomized controlled trial (14, 18-21), the finding of multiple episodes of A^sub 1^ TBB in clinically well patients may still warrant early consideration of augmented or changed immunosuppression.

AR is an established risk factor for the development of BOS, and therefore, it has been proposed that early detection is of paramount importance (1, 2, 22). The occurrence of biopsy proven high-grade AR in the multiple A^sub 1^ group was significantly higher than in the group with one or less A^sub 1^ TBB. This finding is consistent with the moderate risk of progression of minimal lesions to high-grade AR. Eighteen of 184 study participants comprised a subgroup with multiple A^sub 1^ TBB but no biopsyproven rejection grade A^sub 2^ or more in the first 12 months after transplant. Even in this group, patients showed earlier onset of BOS compared with the single group, and this was statistically significant (p = 0.020). Seventeen of the 18 patients had A^sub 1^ lesions, which were all detected on surveillance protocols. Although grade A^sub 1^ rejection on surveillance TBB may not demand routine oral steroid treatment, patients with multiple lesions in the absence of high-grade rejection remain at significant risk for the development of BOS. Augmented immunosuppression or a change to a more antifibroproliferative regimen may also be warranted in this subgroup of patients to prevent the devastating consequences of oblitcrative bronchiolitis.

In conclusion, grade A^sub 1^ TBBs are a relatively common finding in surveillance and diagnostic biopsy protocols in lung transplant recipients. These lesions in patients who are asymptomatic are not necessarily benign and have a moderate risk of progression to high-grade AR or lymphocytic bronchiolitis. Careful clinical assessment is mandatory, although the conventional wisdom of treatment with observation only is now challenged. Biopsy schedules may need to be altered in patients with A^sub 1^ TBB to incorporate a routine follow-up procedure to assess for progression to higher grade rejection. The continued use of pulsed oral prednisone therapy for the treatment of A^sub 1^ TBB on diagnostic procedures appears justified in light of the low risk of subsequent progression. Patients who experience multiple A^sub 1^ lesions in the first 12 months after transplant, irrespective of high-grade rejection episodes or symptoms, develop earlier onset oblitcrative bronchiolitis, and may warrant augmented immunosuppression.

Conflict of Interest Statement: P.M.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.L.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.N.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; M.L.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.P.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.R.G. has served in an unpaid capacity on the Steering Committee of an international multicenter trial of CellCept sponsored by Roche and received support to attend conferences to discuss this trial.

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Peter M. Hopkins, Christina L. Aboyoun, Prashant N. Chhajed, Monique A. Malouf, Marshall L. Plit, Stephen P. Rainer, and Allan R. Glanville

The Lung Transplant Unit, St. Vincent's Hospital, Sydney, Australia

(Received in original form February 5, 2003; accepted in final form August 3, 2004)

Correspondence and requests for reprints should be addressed to Peter M. Hopkins, M.B.B.S., F.R.A.C.P., Queensland Heart-Lung Transplant Unit, The Prince Charles Hospital, Department of Thoracic Medicine, Rode Road, Chermside, Brisbane, Queensland, Australia 4032. E-mail: peterwakatipu@hotmail.com

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Am J Respir Crit Care Med Vol 170. pp 1022-1026, 2004

Originally Published in Press as DOI: 10.1164/rccm.200302-165OC on August 5, 2004

Internet address: www.atsjournals.org

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