Pulmonary Nodules in Lung Transplant Recipients

Pulmonary Nodules in Lung Transplant Recipients

Pulmonary Nodules in Lung Transplant Recipients* Etiology and Outcome Pyng Lee, MD; Omar A. Minai, MD, FCCP; Atul C. Mehta, MD, FCCP; Malcolm M. DeCam...

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Pulmonary Nodules in Lung Transplant Recipients* Etiology and Outcome Pyng Lee, MD; Omar A. Minai, MD, FCCP; Atul C. Mehta, MD, FCCP; Malcolm M. DeCamp, MD, FCCP; and Sudish Murthy, MD, FCCP; and the Cleveland Clinic Foundation Lung Transplant Program

Background: The pulmonary nodule (PN) poses a diagnostic and therapeutic challenge in the immunocompromised host. Common causes of PNs in lung transplant (LT) recipients include bacterial or fungal infections and posttransplant lymphoproliferative disorder (PTLD). However, experience in diagnosis and management of PNs is limited. Methods: Two hundred thirty-four LTs were performed between February 1990 and December 2000. Medical records of all patients with PNs were reviewed retrospectively. Data on presentation, radiographic features, diagnostic methods, therapy, and outcome were collected and analyzed. Results: Twenty-three patients had PNs after a follow-up of 20.1 ⴞ 20.1 months (mean ⴞ SD). The mean age was 45.5 ⴞ 14.4 years, with a male:female ratio of 17:6. Thirteen patients received single LT, 9 patients received bilateral LT, and 1 patient received heart-LT. Cough and dyspnea were the most common symptoms at presentation, and PNs were better detected by CT than chest radiography. Solitary PNs were due to bronchogenic carcinoma and PTLD, while multiple PNs were due to invasive pulmonary aspergillosis (IPA), cytomegalovirus pneumonitis, bronchiolitis obliterans, and metastatic carcinoma. Bronchoscopy with BAL and transbronchial lung biopsy was the usual method of diagnosis (n ⴝ 17, 74%), and our mortality rate was 70%. Conclusion: PNs are not uncommon in patients following LT. The majority were due to IPA and PTLD. Prophylaxis with itraconazole against Aspergillus, and acyclovir for Epstein-Barr virusnegative LT recipients, serial CT and surveillance bronchoscopy for early detection of Aspergillus infections, and rituximab therapy for PTLD could improve the outcome of these patients. (CHEST 2004; 125:165–172) Key words: Aspergillus; carcinoma; cytomegalovirus; lung transplant; posttransplant lymphoproliferative disorder; pulmonary nodule Abbreviations: BLT ⫽ bilateral lung transplant; BO ⫽ bronchiolitis obliterans; CF ⫽ cystic fibrosis; CMV ⫽ cytomegalovirus; CT-FNA ⫽ CT-guided fine-needle aspiration; CXR ⫽ chest radiography; EBV ⫽ Epstein-Barr virus; FB ⫽ fiberoptic bronchoscopy; IPA ⫽ invasive pulmonary aspergillosis; IPF ⫽ idiopathic pulmonary fibrosis; LT ⫽ lung transplant; OKT3 ⫽ murine monoclonal antibody; PN ⫽ pulmonary nodule; PTLD ⫽ posttransplant lymphoproliferative disorder; SLT ⫽ single lung transplant; TBBX ⫽ transbronchial lung biopsy; VATS ⫽ video-assisted thoracoscopic surgery

infiltrates are commonly encountered P ulmonary in lung transplant (LT) recipients, and are largely due to infection or rejection.1– 4 The pulmonary nodule (PN) in an immunocompromised patient poses a diagnostic and therapeutic challenge, as it *From the Department of Respiratory Medicine and Critical Care Medicine (Dr. Lee), Singapore General Hospital, Singapore; and the Departments of Pulmonary and Critical Care Medicine (Drs. Minai and Mehta) and Thoracic and Cardiovascular Surgery (Drs. DeCamp and Murthy), The Cleveland Clinic Foundation, Cleveland, OH. Manuscript received September 6, 2001; revision accepted July 1, 2003. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: [email protected]). www.chestjournal.org

could be due to infectious (bacterial, viral, or fungal) or noninfectious (neoplasia or pulmonary infarction) causes, and experience with its diagnosis and therapy is limited. We report our experience in the etiology, diagnosis, treatment, and outcome of PNs in 23 patients over a decade of lung transplantation. Patients and Methods Between February 1990 and December 2000, 234 lung transplants were performed at our institution. Of these, 140 patients Correspondence to: Omar A. Minai, MD, FCCP, Staff Physician, Department of Pulmonary and Critical Care Medicine, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: [email protected] CHEST / 125 / 1 / JANUARY, 2004

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(60%) received single-LT (SLT), 89 patients (38%) received bilateral-LT (BLT), and 5 patients (2%) received heart-LT. The indications for lung transplantation included obstructive lung disease (emphysema or ␣1-antitrypsin deficiency) in 121 patients; suppurative lung disease (cystic fibrosis [CF] or bronchiectasis) in 42 patients; restrictive lung disease (idiopathic pulmonary fibrosis [IPF]) in 29 patients; pulmonary vascular disease (primary pulmonary hypertension or Eisenmenger syndrome) in 29 patients; and other causes of end-stage lung diseases (eosinophilic granuloma, sarcoidosis, lymphangioleiomyomatosis, pulmonary hemosiderosis, or bronchiolitis obliterans [BO]) in 13 patients. The medical records of all patients with PNs, defined as a spherical or oval intrapulmonary opacity measuring ⱕ 3 cm on chest radiography (CXR),5,6 identified through the transplant center and radiology databases were reviewed retrospectively. Data on PNs such as number, size, distribution, margin characteristics, cavitation, and calcification as well as patient demographics (recipient and donor), smoking history, indications for LT, type of LT, immunosuppressive regimens, symptoms, diagnostic methods, therapeutic modalities, and outcome were recorded. Immunosuppression and Prophylaxis All patients received initial immunosuppression according to protocol: (1) cyclosporin at 2 mg/kg/d IV perioperatively, then 8 to 12 mg/kg/d po titrated to achieve whole blood levels of 250 to 350 ␮g/mL; (2) methylprednisone 1 g IV intraoperatively prior to graft reperfusion, followed by 125 mg q8h for six doses postoperatively, followed by a standard prednisone oral taper; and (3) azathioprine at 2 mg/kg/d IV. These patients were subsequently maintained on a triple regimen of the following: (1) cyclosporin A or tacrolimus (po) titrated to whole blood levels of 250 to 350 ␮g/mL or 8 to 12 ng/mL, respectively; 2) prednisone, 0.25 mg/kg/d po over the first 6 to 9 months, then to 15 mg every other day after 1 year; and (3) azathioprine or mycophenolic acid (po) adjusted to maintain absolute lymphocyte count ⬎ 500 ⫻ 103/L. Rejection episodes were treated with methylprednisolone, 1g/d IV, for 3 days followed by a slow taper. There were four acute rejection episodes documented in our study, and all responded well to methylprednisolone. Every patient received prophylaxis against Pneumocystis carinii with trimethoprim-sulfamethoxazole double strength, one tablet (po) three times a week. Mismatched cytomegalovirus LT recipients received IV ganciclovir according to protocol: 5 mg/kg bid for 2 weeks, followed by 5 mg/kg three times weekly for 3 months. Hyperimmune globulin was used at 150 mg/kg within the first 48 h of transplantation, and then once a week at 2, 4, 6, and 8 weeks after transplant when the cytomegalovirus serology result was positive for the donor but negative for the recipient. Prophylaxis against Aspergillus infections with nebulized amphotericin and itraconazole 200 mg qd po was started as part of the protocol in 1998. Nebulized amphotericin twice daily was administered postoperatively and maintained until serum itraconazole was in the therapeutic range, and itraconazole was continued for 18 months. Follow-up Outpatient visits at 3 weeks and 6 weeks after LT and then every 1 to 3 months included CXR, pulmonary function tests, CBC count, metabolic panel, and drug levels. Fiberoptic bronchoscopy (FB) with BAL and transbronchial biopsy (TBBX) were performed at 3 weeks and 6 weeks, and then at 3, 6, 9, and 12 months after LT. CT of the chest consisting of sequential acquisition of 10-mm sections at 10-mm intervals from the lung apex to the diaphragm 166

was performed if a PN was detected by a radiologist or transplant physician on CXR followed by FB, BAL, and TBBX of PNs. CT-guided fine-needle aspiration (CT-FNA) and video-assisted thoracoscopic surgery (VATS) were complementary procedures if FB failed to achieve diagnosis. All patients detected with PNs underwent CT imaging and FB during the course of their illness. Definitions For the purposes of our study, Aspergillus infection was categorized as follows: (1) airway colonization if bronchial specimens were positive for Aspergillus without clinical signs of illness; (2) isolated tracheobronchitis if endobronchial specimens were positive without invasive disease; (3) aspergilloma on finding a mycetoma on CXR or CT with positive culture results; and (4) invasive pulmonary aspergillosis (IPA) if nodules, infiltrates, or cavities were observed on radiographs with positive culture results and/or histologic evidence of tissue invasion. Posttransplant lymphoproliferative disorder (PTLD) was diagnosed on review of histology, immunohistochemistry, flow cytometry, gene rearrangement, and EBV studies.7 Diagnoses of cytomegalovirus (CMV) pneumonitis, BO, and neoplasia were based on characteristic features of biopsy specimens. Statistical analysis of the data with ␹2 and Fisher exact tests was performed; p ⱕ 0.05 was considered significant.

Results Patient Demographics Twenty-three of 234 LT recipients (10%) acquired PNs after a mean follow-up of 20.1 ⫾ 20.1 months (mean ⫾ SD) [range, 2 to 61 months]. The mean age was 45.5 ⫾ 14.4 years (range, 20 to 64 years), with a male:female ratio of 17:6. Thirteen patients were SLT recipients due to emphysema (n ⫽ 9), ␣1antitrypsin deficiency (n ⫽ 1), and IPF (n ⫽ 3). Nine patients were BLT recipients due to CF (n ⫽ 7) and bronchiectasis (n ⫽ 2), and one patient underwent heart-LT for sarcoidosis and cardiomyopathy. Of these, 14 patients (61%) had a history of smoking. Etiology, Clinical, and Radiologic Findings, and Diagnostic Methods The etiology of PNs in our LT recipients could be classified into three main groups: PTLD (n ⫽ 9), IPA (n ⫽ 8), and other causes (n ⫽ 6), such as CMV pneumonitis (n ⫽ 2), non-small cell carcinoma of the native lung (n ⫽ 2), metastatic renal cell carcinoma (n ⫽ 1), and BO (n ⫽ 1). Time to development of PTLD, IPA, and neoplasia following LT were 9.0 ⫾ 15.4 months (range, 2 to 50 months), 35.0 ⫾ 21.3 months (range, 5 to 61 months), and 22.5 ⫾ 21.99 months (range, 7 to 38 months), respectively (Tables 1–3). The majority of the patients reported dyspnea (n ⫽ 21, 91%) and cough (n ⫽ 19, 83%), while fever (n ⫽ 8, 35%) and weight loss (n ⫽ 9, 39%) were more often observed in those with infection and Clinical Investigations

Table 1—Demographics of LT Recipients With PNs due to Aspergillus (n ⴝ 8)* Patient No./Age, yr/ Sex/Reason for LT

Location/Lobe

Solitary nodules 1/38/M/IPF 2/55/M/COPD Multiple nodules 3/32/M/CF 4/47/F/COPD 5/58/F/COPD 6/22/M/CF 7/25/M/CF 8/53/M/␣1-antitrypsin deficiency

RML/native LLL/LT RUL/RLL/LUL/LLL/LT RUL/RLL/LUL/LLL (Bilateral) RUL/RML/RLL/LLL (Bilateral) RUL/RLL/LLL/LT RUL/RML/RLL/LUL/LLL/LT RML/RLL/LUL/LLL (Bilateral)

Size, cm

Onset After LT, mo

Diagnostic Procedures

Therapy

Outcome

3.0 2.0

61 51

FB/BAL/TBBX FB/BAL/TBBX

Amphotericin Amphotericin

Death Death

2 to 2.5 1.5 to 2.0 1 to 2.0 1 to 2.0 2.5 to 3.0 2.5 to 3.0

46 24 47 5 17 9

FB/BAL/TBBX FB/BAL/TBBX FB/BAL/TBBX FB/BAL/TBBX FB/BAL/TBBX FB/BAL/TBBX

Amphotericin Amphotericin Amphotericin Amphotericin Amphotericin Amphotericin

Death Death Death Death Death Death

*M ⫽ male; F ⫽ female; RML ⫽ right middle lobe; LLL ⫽ left lower lobe; LUL ⫽ left upper lobe; RUL ⫽ right upper lobe; RLL ⫽ right lower lobe.

were neoplastic: PTLD (n ⫽ 8), bronchogenic carcinoma (n ⫽ 2), and metastatic carcinoma (n ⫽ 1). Cavitary PNs detected on CT in six patients (26%) were due to IPA (Fig 2), and none were calcified. FB with BAL and TBBX was the method of diagnosis in 17 patients (73%), while CT-FNA (n ⫽ 2, 9%), VATS (n ⫽ 2, 9%), and biopsy of an extrapulmonary site (n ⫽ 2, 9%) were complementary procedures in the diagnostic workup of our patients. All cases of IPA were diagnosed via FB/ TBBX.

malignancy. Although most PNs were detected initially by CXR, CT scan was better at defining number, distribution, size, margin, cavitation, and calcification. More than 70% of PNs involved the transplanted lungs, while those due to bronchogenic carcinoma affected the native lungs more commonly. Seven patients (30%) presented with solitary PNs, and they were due to PTLD (n ⫽ 3) [Fig 1], bronchogenic carcinoma (n ⫽ 2), and IPA (n ⫽ 2). Sixteen patients (70%) had multiple nodules, which were consequent to IPA (n ⫽ 6), PTLD (n ⫽ 6) [Fig 2], CMV pneumonitis (n ⫽ 2), BO (n ⫽ 1), and metastatic carcinoma (n ⫽ 1). When correlated with histology, PNs with CT description of smooth margins (n ⫽ 10) were nonneoplastic: IPA (n ⫽ 7), CMV pneumonitis (n ⫽ 2), and BO (n ⫽ 1). PNs with irregular margins (n ⫽ 13)

Response to Therapy and Outcome Overall mortality in our study population was 70%, and it was due to IPA (n ⫽ 8), PTLD (n ⫽ 4), neoplasia (n ⫽ 3), and CMV pneumonitis (n ⫽ 1). Of the eight patients with PNs due to IPA, five

Table 2—Demographics of LT Recipients With PNs due to PTLD (n ⴝ 9)* Patient No./Age, yr/ Sex/Reason for LT

Size, cm

Onset After LT, mo

LLL/LT (colon)

2.5

50

2/34/M/CF

RML/LT (stomach)

1.5

15

Biopsy of colonic mass (polyclonal) FB/TBBX (polyclonal)

3/58/M/IPF

RUL/LT

1.0

3

FB/EBBX (monoclonal)

1 to 2.0 1 to 2.0

4 4

1 1 1 1

2 4 4 5

CT-FNA (monoclonal) Biopsy of gastric and colonic masses (monoclonal) VATS biopsy (monoclonal) FB/TBBX (monoclonal) FB/TBBX (monoclonal) FB/EBBX (monoclonal)

Solitary nodules 1/53/F/COPD

Multiple nodules 4/51/M/COPD 5/32/F/bronchiectasis 6/60/M/IPF 7/20/M/CF 8/62/M/bronchiectasis 9/23/F/CF

Location/Lobe

RUL/RML RLL/LT RUL/RLL/LLL/LT (stomach, colon) RUL/RML/RLL/LT RUL/RML/RLL/LLL/LT RLL/LT RMSB/LT

to to to to

2.0 2.0 2.0 2.0

Diagnostic Procedures

Therapy

Outcome

None

Death

Ganciclovir, rituximab, interferon-␣2b Ganciclovir, interferon-␣2b, laser

Death

Ganciclovir Ganciclovir, rituximab

Death Death

Ganciclovir, Ganciclovir, Ganciclovir, Ganciclovir, EC/BB

Alive Alive Alive Alive

rituximab rituximab rituximab rituximab,

Alive

*RMSB ⫽ right mainstem bronchus; EBBX ⫽ endobronchial biopsy; EC ⫽ electrocautery; BB ⫽ balloon bronchoplasty. See Table 1 for expansion of other abbreviations. www.chestjournal.org

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Table 3—Demographics of LT Recipients With PNs due to Other Causes (n ⴝ 6)* Patient No./Age, yr/ Sex/Reason for LT

Location/Lobe

Size, cm

Onset After LT, mo

Solitary nodules 1/64/M/COPD

RML/native

3.0

7

2/55/M/COPD

RML/native

2.0

38

1 to 2.0

14 12

5/51/M/COPD

RUL/RML/RLL/LUL/LLL 1 to 2.0 (bilateral) RUL/LUL/LLL (bilateral) 1 to 2.0

6/37/F/CF

RUL/RML/LUL/LT

27

Multiple nodules 3/54/M/sarcoidosis 4/62/M/COPD

RUL/RML/RLL/LT

1.0

3

Diagnostic Procedures/ Cause

Therapy

Outcome

VATS/NSCLC (stage 3B plus CRF) CT-FNA NSCLC (stage 2 plus BO)

Palliation

Death

Palliative radiotherapy

Death

FB/TBBX/metastatic renal cell cancer (stage 4) FB/BAL/TBBX/CMV pneumonitis FB/BAL/TBBX/CMV pneumonitis FB/TBBX/BO

Palliative radiotherapy

Death

Ganciclovir, foscarnet, Death hyperimmune globulin Ganciclovir, foscarnet, Alive hyperimmune globulin Methotrexate Alive

*CRF ⫽ chronic renal failure; NSCLC ⫽ non-small cell lung cancer. See Table 1 for expansion of other abbreviations.

patients were SLT recipients for emphysema and IPF, and three patients were BLT recipients for CF. Two of these patients had previous CMV pneumonitis. Despite early diagnosis of all IPA by FB/TBBX and prompt treatment with IV amphotericin, mortality was 100%. It is noteworthy that six of eight patients (75%) acquired IPA prior to the implementation of prophylaxis against Aspergillus with nebulized amphotericin and itraconazole per protocol. Mortality from neoplasia was also 100% due to stage of disease at presentation (stage 3B and 4) and associated comorbidity (chronic renal failure and chronic BO) [Table 3]. Nine LT recipients were found to have PTLD following biopsy of PNs by FB, CT-FNA, VATS, and biopsy of extrathoracic sites (Table 2). Eighty-nine percent of our patients were EBV negative at pre-

Figure 1. CT scan of the lung showing a single nodule in the right lower lobe. Pathology was consistent with PTLD of the lung. 168

transplant evaluation and donor EBV status was unknown, as EBV matching of donor and recipient was not performed at our institution. Seven patients acquired early (⬍ 1 year after LT) monoclonal PTLD, and two patients acquired late (⬎ 1 year after LT) polyclonal PTLD that also involved the colon and stomach. Mortality was 44%, which was independent of age, gender, smoking, comorbidity, or previous CMV infection. Management included a reduction of immunosuppression, ganciclovir (IV), and interferon-␣2b. Six patients received rituximab, an anti-CD20 Ig, as adjunctive therapy; and a good response, defined as resolution of PNs (Fig 3), was observed in four patients whose disease remained in remission during the study period. Two patients with endobronchial involvement (Fig 4) also received endoscopic treatment with laser or electrocautery and balloon bronchoplasty.

Figure 2. CT scan of the lung showing a single cavitary nodule in the left upper lobe in a patient with multiple nodules. Pathology and culture results were consistent with IPA of the lung. Clinical Investigations

Figure 3. CT scan of the lung showing a single nodule in the left lower lobe in a patient with multiple nodules. Pathology was consistent with PTLD of the lung (left). PTLD resolved after rituximab therapy with complete resolution of the nodules (right).

Discussion In the immunocompetent host, PNs are primarily due to bronchogenic or metastatic carcinoma.8 In the immunocompromised host, however, PNs can arise from a variety of causes, of which infections and PTLD are more common.3,4,9 End et al3 reported that PTLD, Aspergillus, and bacterial infections such as Pseudomonas and Staphylococcus were important causes for PNs detected in eight LT recipients after a median follow-up of 48.5 weeks. Schulman et al4 showed that in the 15 of 159 LT recipients who acquired PNs after 11 months of follow-up, Aspergillus and mycobacterial infections, as well as PTLD, accounted for 80% of PNs. There were also reports of nodular opacities following FB and TBBX due to focal hematomas,10 multiple rib fractures that mimicked PNs,11 and rare causes such as pulmonary tuberculosis,12 CMV pneumonitis,13 BO organizing pneumonia,14 and recurrent sarcoidosis.15 To date, our study of 23 LT recipients with PNs represents the largest series. Our study, like other series,3,4 shows that IPA and PTLD are the most common causes of PNs in LT recipients. Other causes include CMV pneumonitis, bronchogenic carcinoma, metastatic renal cell carcinoma, and BO. All of our patients were symptomatic at presentation, and CXR was able to detect PNs. CT was better at describing nodule distribution, number, size, and presence of cavitation. CT definition of the PN www.chestjournal.org

margin was helpful in our diagnostic workup, as nodules with smooth margins were more likely nonneoplastic than those with irregular margins.16 All cavitary PNs detected on CT, in our study, were due to IPA.17 Our data support the significant mortality associated with IPA in solid-organ transplantation reported by Schulman et al,4 Armstrong,18 Tritz and Woods,19 and Iwen et al,20 although Mehrad et al21 showed a lower mortality. Literature on lung transplantation reveals that Aspergillus affects the transplanted lung predominantly with airway colonization occurring in 10%, tracheobronchitis in 15%, and IPA in 8%.22 The lung graft is particularly at risk, as Aspergillus is a ubiquitous airborne organism that can be inhaled directly into the respiratory tract. Natural antimicrobial defense mechanisms, already impaired in the lung allograft, are further accentuated by immunosuppressive therapy,23 increasing its susceptibility to colonization, tissue invasion, and possibly dissemination. In SLT recipients, the clinically silent colonization of Aspergillus in the native lung may also serve as a nidus for subsequent infection.24,25 As serologic tests have not been shown to be of value in transplant patients,26 early diagnosis of IPA should be achieved using FB with BAL and TBBX or CT-FNA.27,28 Of the eight patients with PNs due to Aspergillus, six patients acquired Aspergillus beyond their first year after transplant. Four of these patients had one CHEST / 125 / 1 / JANUARY, 2004

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Figure 4. Bronchoscopic image of endobronchial tree at the level of the carina showing PTLD involving the right mainstem bronchus with near-total occlusion. The patient was treated with electrocautery and balloon bronchoplasty with excellent airway patency.

episode, one patient had two episodes, and one patient had three episodes of acute rejection during their first year after transplant, who were treated with a steroid pulse. None of them had episodes of acute rejection within 1 month of the development of Aspergillus. Three of these patients carried a diagnosis of BO syndrome and were being treated with methotrexate, in addition to the standard immunosuppressive medications, when they acquired Aspergillus. None had received lymphocyte immune globulin, murine monoclonal antibody (OKT3), or photopheresis within 6 months prior to diagnosis of Aspergillus infection. Only one of these patients had two episodes of CMV infection requiring treatment. As IPA is a potentially fatal complication of immunosuppression, strategies aimed at prevention, early diagnosis, and treatment are of particular interest. Several studies demonstrate a reduction in the incidence of IPA following administration of aerosolized amphotericin29 or itraconazole, 400 mg/d,30 as part of the prophylactic regimen.31 Our study results lend further support to this observation, as six of eight patients acquired IPA prior to Aspergillus prophylaxis. Early diagnosis of IPA lies not only in the 170

identification of patients at risk such as previous CMV infection32 but, also, in the early recognition of patients with Aspergillus airway colonization33 or Aspergillus tracheobronchitis34 by regular surveillance mycologic cultures. The cornerstone of treatment of acute, semiinvasive, and IPA is medical with IV amphotericin or oral itraconazole alone or in combination therapy.35 The role of surgery in LT, although a well-established treatment for localized pulmonary aspergillosis in the immunocompetent host, remains undefined. At our institution, we have successfully managed a LT recipient who had refractory IPA of the native lung with pneumonectomy.36 Our mortality from PTLD was comparable with those reported by Armitage et al,37 Walker et al,38 and Aris et al.39 Five of seven patients with early onset (ⱕ 1 year after LT) PTLD responded to treatment, while two patients with late-onset (⬎ 1 year after LT) disseminated PTLD did not (Table 2). Our findings were similar to Armitage et al,37 who reported a higher incidence of disease dissemination and increased mortality among transplant recipients with late-onset PTLD compared with those with early onset PTLD. Although cyclosporin and OKT3 have been implicated in the pathogenesis of PTLD,40,41 the majority of our patients, except patient 2 who was treated with tacrolimus and photopheresis for chronic rejection of the lung allograft, were receiving cyclosporin at the time of diagnosis, and the two rejection episodes showed good response to methylprednisone (IV) without the need for OKT3. Our experience with rituximab in four of six patients appears promising, and it should be considered in the treatment armamentarium of PTLD following reports of its efficacy.42– 44 Other therapeutic modalities include ganciclovir or acyclovir, interferon-␣2b, surgical resection and limited field irradiation for localized lesions, and chemotherapy for refractory disease. Levine et al45 reported a lower incidence and mortality from PTLD, and postulated that prolonged acyclovir therapy could prevent the development of PTLD. Future trials addressing the beneficial effects of life-long prophylaxis with acyclovir for EBV-negative LT recipients aimed at reducing the incidence of PTLD are warranted.46

Conclusion The PN poses a diagnostic challenge in LT recipients because its cause is different from that in immunocompetent patients. PNs in LT are largely due to infections, PTLD, and malignancy. Although CXR is a useful screening tool, CT is better at defining PN characteristics, and serial CT should be Clinical Investigations

included in the diagnostic algorithm especially if IPA, PTLD, or malignancy is suspected. CT together with FB, BAL and TBBX, CT-FNA, or VATS biopsy of PNs ensures early diagnosis and treatment to improve outcome. Although our study demonstrated 100% mortality from IPA despite aggressive therapy with amphotericin, it is noteworthy that six of our eight patients did not receive prophylaxis against Aspergillus. Thus, we are of the opinion that an aggressive approach aimed at prevention, early detection, and treatment of Aspergillus infection is important to improve its outcome. This would include prophylaxis with nebulized amphotericin and itraconazole, serial CT, regular surveillance bronchoscopy with mycologic cultures, and prompt treatment of tracheobronchitis. With PTLD, we recommend a multimodality approach, including reduction in immunosuppressive therapy, acyclovir or ganciclovir, interferon-␣2b, rituximab, local therapy for localized lesions, and chemotherapy for refractory disease. Life-long prophylaxis with acyclovir as a preventive measure against PTLD should be considered for EBV-negative LT recipients.

13

14

15

16 17

18 19

20

21 22

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