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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Although transbronchial lung biopsy (TBBx) is widely acknowledged as the "gold standard" for diagnosis of acute rejection, controversy exists regarding the need to perform follow-up procedures. Over a 5-yr period, we performed 1,142 TBBx of which 173 were follow-up TBBx in 99 patients with pulmonary allograft rejection greater than or equal to International Society for Heart and
Lung Transplantation (ISHLT) grade A2 on initial TBBx. Rejection
on the previous 173 TBBx was associated with lymphocytic bronchiolitis/bronchitis (LBB) 
ISHLT grade B2 in 82 patients and with
cytomegalovirus (CMV) pneumonitis in 16 patients. Persistent rejection ( A2) was observed in 45 of 173 (26%) follow-up TBBx.
Persistent B grade rejection ( B2) was present in 28 patients
whereas new B grade rejection developed in 11 patients with A2
grade rejection. Rejection B2 was significantly (p < 0.05) associated with rejection A2. Fifteen follow-up TBBx showed new B
grade rejection without signs of A2 rejection. A new diagnosis of
CMV pneumonitis was made in 33 of 173 (19%). CMV pneumonitis occurred in 35 follow-up TBBx, four associated with A2 rejection and eight with B2 rejection. The overall incidence of bronchiolitis obliterans syndrome (BOS) in both groups was similar.
Patients with persistent rejection on follow-up TBBx developed
BOS at a median of 1.3 yr and median of 2.0 yr (p = not significant
[NS]) posttransplantation. The practice of follow-up TBBx after rejection within 2 yr posttransplant is clinically useful as it provides
valuable diagnostic information.
Keywords: lung transplantation; rejection; transbronchial lung biopsy
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Bronchiolitis obliterans is the major limiting factor in the long-term survival of lung transplant recipients (1). Chronic rejection is thought to be the major cause of bronchiolitis and is significantly associated with the number and severity of acute rejection episodes (4). Transbronchial lung biopsy (TBBx) was introduced to diagnose rejection and remains the "gold standard" for the diagnosis of acute rejection (8). Diagnostic TBBx is performed in patients with respiratory symptoms, a decrease in lung function, or changes on chest radiograph. TBBx has also been employed as a surveillance procedure, performed for the early detection of asymptomatic rejection and as a follow-up procedure to evaluate the response to treatment, although the latter remains controversial (11). Cytomegalovirus (CMV) pneumonitis and persistent rejection are adverse events that may occur after a treated rejection episode. The aims of this study were to analyze the diagnostic value of follow-up TBBx performed in lung transplant recipients after a histologically proven rejection episode, and to assess the clinical outcome of patients with or without persistent rejection.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Between 1995 and 1999, we performed 1,142 TBBx in our heart-lung and lung transplant patient population, which consisted of 303 patients. All TBBx were performed in theater under neurolept anesthesia. After bronchoalveolar lavage, three to six biopsies were taken from both the lower and middle lobe of the right lung or from the lower lobe and lingula of the left lung. TBBx were graded according to the standardized nomenclature described by the Lung Rejection Study Group (9, 10). Acute rejection diagnosis was based on the existence of perivascular and interstitial mononuclear infiltrates. The working formulation of acute rejection grading criteria described by the Lung Rejection Study Group is as follows: A0 = no significant abnormality; A1 = minimal rejection; A2 = mild rejection; A3 = moderate rejection; and A4 = severe rejection. Lymphocytic bronchitis/bronchiolitis (LBB) is divided into five grades for classification: B0 = no airway inflammation; B1 = minimal airway inflammation; B2 = mild airway inflammation; B3 = moderate airway inflammation; B4 = severe airway inflammation; and Bx = ungradable due to no evaluable bronchial tissue. CMV pneumonitis was defined as inclusion bodies in TBBx associated with inflammatory infiltrates. Anti-CMV staining was performed using early immediate antigen detection. All biopsy results were determined by the same pathologist.
TBBx were routinely performed at 3, 6, 9 wk and at 3, 6, 12 mo
posttransplant. Further diagnostic TBBx were performed at any time
for any decline in FEV1 10%, radiographic infiltrates, or respiratory symptoms. Follow-up TBBx were performed in all patients with
evidence of acute rejection A2 on the initial biopsy. An initial TBBx
was defined as the first TBBx that showed pulmonary allograft rejection ( grade A2). A follow-up TBBx was defined as a second biopsy
performed within 45 d of the initial biopsy.
Of the 1,142 TBBx, there were 173 follow-up biopsies in 99 patients. Of these, 53 were bilateral lung, 32 were single-lung, and 14 were heart-lung transplants. There were 56 females and 43 males. The
underlying diseases were emphysema (n = 41) (including 
1-antitrypsin deficiency), cystic fibrosis (n = 27), cryptogenic fibrosing alveolitis (n = 11), Eisenmenger's syndrome (n = 7), primary pulmonary
hypertension (n = 6), bronchiectasis (n = 5), and pulmonary Langerhans cell histiocytosis (n = 2). The mean patient age was 40.2 yr with a
standard deviation of 13.1 yr (range 12.6 to 57.8).
After transplant all patients received triple immunosuppressive therapy with oral cyclosporine targeting trough whole blood levels of 200 to 500 µg/L, azathioprine (1 to 3 mg/kg), and prednisolone (0.2 to 0.5 mg/kg). Patients transplanted before 1995 received additional induction therapy with antilymphocyte globulin (ALG) for 1 to 7 d. Acute rejection was treated with methylprednisolone 12.5 mg/kg/d intravenously for 3 d and an oral taper 1 mg/kg/d reducing by 5 mg every second day to 0.2 mg/kg/d. Recurrent or persistent rejection was treated with a second course of corticosteroids administered intravenously as described plus a switch from cyclosporine to tacrolimus (0.01 to 0.03 mg/kg). CMV-seronegative patients transplanted with a graft from a positive CMV donor received antiviral prophylaxis intravenously with ganciclovir for a total of 10 wk. CMV pneumonitis was treated with ganciclovir (5 mg/kg intravenously, twice a day) for 14 d followed by 10 mg/kg/d 3 times a week for the next 14 d.
Bronchiolitis obliterans syndrome (BOS) was defined according to the recommendations of an International Society for Heart and Lung Transplantation (ISHLT) Lung Rejection Study Group (19).
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Initial TBBx
A total of 173 follow-up TBBx were performed in 99 patients
who had shown an acute rejection episode A2 on their initial TBBx. The majority of patients had one episode of rejection leading to a follow-up TBBx, whereas 28 patients had
two, 12 three, and five patients more than three follow-up
TBBx. In one patient with repeated rejection and CMV pneumonitis there were a total of 11 follow-up TBBx. The severity
of rejection in the initial TBBx is shown in Figure 1. There was
one TBBx (1%) with grade A4 rejection, 45 (26%) with grade
A3 rejection, and the remaining 127 (73%) were grade A2.
Mild to severe grade A rejection on initial TBBx was associated with mild to moderate grade B rejection in 47% of cases,
consisting of 15 TBBx with B3 and 67 with B2. Most previous TBBx (68%) showing rejection A2 were carried out within
the first 3 mo after transplantation. The percentage of patients
with moderate (A3) or severe (A4) rejection on initial TBBx
was similar within different time periods after transplantation.
CMV pneumonitis occurred concurrently with rejection in 16 patients (9%).
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Transbronchial Follow-up Biopsies
Persistent vascular rejection grade ( A2) was found in 45 of
173 (26%) follow-up TBBx (Figure 1). There were 6 (3%) follow-up TBBx with grade A3 rejection. As shown in Figure 2,
the percentage of follow-up TBBx with rejection A2 compared with the total number of follow-up TBBx performed
was similar within each time period as long as 2 yr posttransplantation. There have only been four follow-up TBBx done
beyond 2 yr, none of which showed persistent vascular rejection. CMV pneumonitis was found in 34 follow-up TBBx
(20%) and combined with A grade rejection in four patients. More than 80% of follow-up TBBx showing CMV pneumonitis were performed within the first 3 mo after transplantation.
Figure 3 displays the different subgroups of follow-up TBBx
in regard to rejection A2, B2, and CMV pneumonitis. Rejection A2 was found in 26 of 45 follow-up TBBx (58%)
whereas in 15 of 45 (33%), rejection A2 was found concurrently with rejection B2. CMV pneumonitis without vascular rejection was observed in 22 follow-up TBBx and combined with LBB ( B2) in another eight patients. B grade
rejection without signs of grade A rejection or CMV was
present in 9% of follow-up TBBx (15 of 173). A total of 83 (48%) of all follow-up TBBx showed neither rejection nor
CMV on histology.
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LBB
As described previously, LBB ( B2) was present in 82 (47%)
of initial TBBx. After treatment of rejection, LBB persisted in 28 of 82 (34%) follow-up TBBx (Figure 4). Persistent rejection A2 was present more frequently if LBB rejection also
persisted in the follow-up TBBx compared with follow-up
TBBx without rejection B2, although this did not reach significance (38% versus 15%; p = 0.06, Fisher exact test). In
contrast, there was no difference in the incidence of CMV on
follow-up TBBx with or without persistent B grade rejection
(18% versus 15%). After treatment, rejection B2 resolved
completely and there were no signs of rejection A2 or CMV
in 45% (37 of 82) on follow-up TBBx. New LBB was observed in 11 patients on follow-up TBBx. Rejection B2 was associated with rejection A2 in six and CMV pneumonitis in three
of these cases. Another patient showed grade B3 rejection on
the follow-up TBBx but there was no evaluable bronchiolar
tissue on initial TBBx (A3Bx). In this instance, it could not be
determined if LBB was new or ongoing. The total number of
LBB in follow-up TBBx was therefore 40 (23%) (Figure 5).
LBB was significantly associated with rejection A2 (chi-square p < 0.05). In contrast, CMV pneumonitis was neither
significantly associated with rejection A2 nor with rejection B2. Overall 48% of all follow-up TBBx showed no signs of
perivascular rejection, LBB, or CMV pneumonitis.
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Transbronchial Follow-up Biopsies and Clinical Outcome
Patient survival and freedom from BOS were analyzed comparing patients with persistent rejection A2 (Group 1) and
those with no signs of rejection, LBB, or CMV pneumonitis
(Group 2) on follow-up TBBx. Group 1 consisted of 32 patients with a mean follow-up of 1,054 ± 565 (215 to 2,229) d
and Group 2, 38 patients with a mean follow-up of 1,232 ± 537 (266 to 2,261) d. There were nine deaths in both Group 1 (28%) and Group 2 (24%). There was no significant difference in patient survival between Groups 1 and 2 (Figure 6)
(Mantel-Cox; p = 0.45). Overall, 47% of patients in Group 1 developed BOS at a median of 1.3 yr compared with 53% of
patients in group 2 with a median of 2.0 yr posttransplantation. This time difference in the development of BOS was not
statistically significant by Mann-Whitney U test (p = 0.22).
The freedom from BOS of the two groups up to 4 yr posttransplant is shown in Figure 7.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The overall diagnostic yield on follow-up TBBx was 52%,
which included rejection A2, CMV infection, and lymphocytic bronchiolitis. Lymphocytic bronchiolitis was significantly
associated with perivascular rejection. CMV pneumonitis occurred in 20% of follow-up TBBx. In a smaller series of 25 patients with follow-up TBBx, Trulock and colleagues (11)
found a slightly higher result of 28% CMV pneumonitis cases.
Overall patient survival with and without persistent rejection
in follow-up TBBx was similar, 72% versus 76%, respectively; however, patients with persistent rejection on follow-up TBBx showed earlier onset of BOS compared with patients whose
rejection had resolved.
TBBx remains the "gold standard" and is a widely accepted
practice for the diagnosis of rejection in lung transplant recipients (4). Baz and colleagues (14) suggested that surveillance TBBx could be abandoned in patients who are free from
acute rejection or CMV pneumonitis 4 mo after transplantation. Only 21% of our patients remained free from rejection or
CMV infection within the first year of transplantation in this
study. Trulock and colleagues (11) reported that in 60% of 25 patients follow-up TBBx yielded either CMV pneumonitis or
rejection, including minimal A1 rejection. A large study by Sibley and colleagues (12) analyzed a total of 105 follow-up TBBx.
Grade A2 was found in 28% of patients. In this patient series, a considerable number of these rejection episodes resolved without antirejection treatment. A recent study by
Gaspert and colleagues (18) revealed grade A2 rejection and
CMV infection in 14% out of a total of 59 follow-up TBBx.
To our knowledge, this study contains the largest series of follow-up TBBx analyzed. The incidence of persistent rejection was similar to the study conducted by Sibley and colleagues. We also found that the percentage of follow-up TBBx with rejection remained the same throughout a 2-yr period posttransplantation. CMV was rarely found on TBBx later than 3 mo after transplantation, perhaps reflecting higher maintenance immunosuppression in the early postoperative period. Thus, follow-up TBBx performed for the detection of CMV pneumonitis can only be recommended within the first few postoperative months. In contrast, the diagnostic yield for the detection of rejection was independent of time after transplant.
LBB ( B2) was associated with 47% of initial TBBx A2
rejection. In the follow-up TBBx, rejection B2 resolved in
two-thirds of the patients. However, 11 patients developed
new B grade rejection in follow-up TBBx. In almost all of
these cases, B grade rejection was associated with vascular rejection or CMV. Overall there was a significant association of
LBB ( B2) with persistent A grade rejection. These findings
are in accordance with the study results of Husain and colleagues (7) showing that LBB rejection in the absence of infection is a manifestation of acute vascular rejection and a risk
factor for development of BOS. This was previously suggested
by Yousem and colleagues (5).
We found a similar survival in patients with persistent rejection on follow-up TBBx compared with those showing resolved rejection and no CMV. These results are similar to those recently reported by Swanson and colleagues (17). The high incidence of persistent rejection documented on follow-up TBBx shows that acute rejection is commonly refractory to corticosteroid therapy.
In conclusion, the practice of follow-up TBBx after biopsy-proven rejection posttransplant is clinically useful as it provides valuable diagnostic information for patient management.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Christina L. Aboyoun, Cardiopulmonary Transplant Unit, St. Vincent's Hospital, de Lacy 14, Victoria Street, Darlinghurst NSW, 2010 Australia. E-mail: caboyoun{at}stvincents.com.au
(Received in original form November 30, 2000 and in revised form March 27, 2001).
Acknowledgments:
Supported by the Australian Lung Transplant Research Trust, Sydney, Australia.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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