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Progression of Idiopathic Pulmonary Fibrosis in Native Lungs After Single Lung Transplantation* FREE TO VIEW

Momen M. Wahidi, MD; James Ravenel, MD; Scott M. Palmer, MD, MHS, FCCP; H. Page McAdams, MD
Author and Funding Information

Affiliations: *From the Department of Internal Medicine (Drs. Wahidi and Palmer), Division of Pulmonary and Critical Care, and the Department of Radiology (Drs. Ravenel and McAdams), Duke University Medical Center, Durham, NC.,  Now at the Medical University of South Carolina, Columbia, SC.

Correspondence to: Momen M. Wahidi, MD, Division of Pulmonary and Critical Care, Duke University Medical Center, Box 3221, Durham, NC 27710; e-mail: wahid001@mc.duke.edu



Chest. 2002;121(6):2072-2076. doi:10.1378/chest.121.6.2072
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This retrospective, single-center study was conducted to assess the response of native idiopathic pulmonary fibrosis (IPF) lungs to a potent cyclosporine-based immunosuppressive regimen in single-lung transplantation recipients. The study included IPF patients who had undergone single-lung transplantation and had chest CT scans before and after transplantation. Five patients underwent single-lung transplantation for IPF between April 1992 and January 2001, and met entry criteria. All patients were placed on an immunosuppressive regimen consisting of prednisone, azathioprine, and cyclosporine. In two of the five patients, ground glass attenuation in the native IPF lung improved post-transplantation. However, fibrotic changes progressed in all five patients. In patients with advanced IPF, a potent cyclosporine-based immunosuppressive regimen is not likely to have an effect on the progression of the disease.

Figures in this Article

Idiopathic pulmonary fibrosis (IPF) is an incurable disease with a 5-year survival rate of 30 to 50% from the time of diagnosis.1To date, there are no sufficient data to support a favorable effect of any treatment on the progressive course of IPF. Corticosteroids have become the conventional treatment despite their limited efficacy.2It is estimated that 15 to 30% of patients with IPF improve while receiving corticosteroids.35 Azathioprine has been used as a second-line therapeutic agent in IPF patients with poor responses or intolerance to corticosteroids. In one study, Raghu et al6randomized patients to prednisone and azathioprine or to prednisone and placebo, and found a trend toward an improved survival rate in the combined-treatment group. Several case reports710 have documented an encouraging response to cyclosporine in IPF patients.

Lung transplantation patients are placed on a potent immunosuppressive regimen to prevent the rejection of the donor lung. Our objective was to assess the response of native IPF lungs to this potent immunosuppressive regimen, which most commonly consists of prednisone, azathioprine, and cyclosporine, in single-lung transplantation recipients. The response to treatment was assessed with chest CT scans as an indicator of disease activity that correlates well with clinical and functional measures.

We searched the Duke University Medical Center lung transplantation database for all single-lung transplantation recipients between April 1992 and January 2001. Patients were included in the study if they had a histologic diagnosis of usual interstitial pneumonitis on explanted lung tissue and had undergone chest CT scans before and after transplantation.

We excluded patients who had post-transplantation chest CT scans performed < 6 months from the date of lung transplantation or had radiographic findings that were suggestive of superimposed disease in the native lung, such as edema or infection. The medical records of patients were reviewed to determine their immunosuppressive regimen, and the reason for and timing of the post-transplantation chest CT scan.

Lung window images from the chest CT scans, both conventional and high-resolution CT (HRCT) scans, were scored by two thoracic radiologists by consensus review. Because not all pretransplantation and post-transplantation CT studies contained HRCT images, the analysis was based either on conventional 7-mm thick sections or on a combination of 7-mm conventional images and 1-mm HRCT images. The reviewers were aware of the diagnosis of IPF. Pretransplantation examinations were evaluated without knowledge of which lung was to be explanted. Post-transplantation examinations were randomized and evaluated without knowledge of the findings from the pretransplantation chest CT scan, the findings from other post-transplantation chest CT scans, or the time of the CT scan after transplantation. Individual lobes were scored for ground glass attenuation and fibrosis using a system previously described by Gay et al.11 Ground glass attenuation was scored as follows: 0, no ground glass opacity; 1, < 5% of the lobe had ground glass opacity; 2, 5 to 25% of the lobe had ground glass opacity; 3, 26 to 50% of the lobe had ground glass opacity; 4, 51 to 75% of the lobe had ground glass opacity; and 5, 76 to 100% of the lobe had ground glass opacity. Fibrosis was similarly scored as follows: 0, no fibrosis; 1, septal thickening without honeycombing; 2, honeycombing and septal thickening involving up to 25% of the lobe; 3, honeycombing and septal thickening involving 26 to 50% of the lobe; 4, honeycombing and septal thickening involving 51 to 75% of the lobe; and 5, honeycombing and septal thickening involving 76 to 100% of the lobe.

After each lobe was scored individually, an average score for all lobes was obtained. Scores for both lungs were derived, but only those of the native lungs were used for further analysis. In addition, each lobe was scored for the percentage involvement by both ground glass attenuation and fibrosis. An average score then was then generated for all lobes.

Our search revealed 18 patients with IPF who underwent single-lung transplantation between April 1992 and January 2001. Of these, five patients fulfilled our selection criteria. In the remaining 13 patients, 12 were excluded for lack of post-transplantation chest CT scans, and 1 was excluded for a diagnosis of pulmonary fibrosis that was associated with rheumatoid arthritis.

All five selected patients underwent lung transplantation operation and standard postoperative management, as described in detail elsewhere,12 and were placed on an immunosuppressive regimen consisting of prednisone, azathioprine, and cyclosporine. None of these patients received induction immunosuppression with an antithymocyte agent. Prednisone was initially dosed at 20 mg/d and was reduced by 5 mg every 3 months to a maintenance dose of 5 mg/d in the absence of any lung allograft rejection. Cyclosporine dosages were adjusted to achieve a serum level of 250 to 300 ng/mL in the first 6 months post-transplantation and 200 to 250 ng/mL in subsequent months. Azathioprine was dosed at 1 to 2 mg/kg/d, and the dose was adjusted based on each patient’s WBC count. Reasons for obtaining post-transplantation chest CT scans included detection of bronchiolitis obliterans in three patients, and further delineation of nodule(s) seen in the transplanted lung on chest radiographs in two patients.

Prior to lung transplantation, two of five patients had ground glass attenuation on chest CT scans with an average score of 3. In both of these cases, the ground glass score decreased following transplantation. However, there was an increase in the fibrosis scores during the same period for both patients (Table 1) . Figure 1 illustrates these changes in patient 5. In the remaining three patients, ground glass attenuation was not present pretransplantation but developed post-transplantation in two of the patients. The fibrosis score remained unchanged in one patient (maximal score pretransplantation), improved transiently and later progressed in one patient, and progressed in three patients (Table 1). The average degree of involvement by both ground glass attenuation and fibrosis in the native lung increased post-transplantation in three patients, did not change in one patient (100% involvement pretransplantation), and decreased slightly in one patient (Table 2 ).

IPF poses a significant therapeutic challenge with its poor response and progressive course. As a result, physicians are relentlessly looking for novel therapeutic agents. Corticosteroids are considered the mainstay of treatment. Many immunosuppressive agents have been tried with limited benefit as therapy, including azathioprine, cyclophosphamide, methotrexate, and chlorambucil. Similarly, antifibrotic agents, such as colchicine, D-penicillamine, and interferon-β, had disappointing effects on the course of IPF. One report13has shown a promising response in nine patients with IPF who were treated with interferon-γ, and a large, multicenter, randomized clinical trial is currently underway. Cyclosporine suppresses the function of the T lymphocytes, which may play a role in the pathogenesis of IPF.14

In a study by Alton et al, seven patients were treated with cyclosporine following a poor response to prednisolone and cyclophosphamide. Patients had an initial clinical and physiological improvement; however, the improvement was not sustained. Fukazawa et al8 reported complete resolution of IPF in an 11-year-old girl after the use of cyclosporine; however, her diagnosis was not well-confirmed. Two reports of improvement of IPF native lungs after transplantation exist, one in a patient with IPF7 and the other in patients with desquamative interstitial pneumonia.10

We chose chest CT scans as an indicator of disease activity since other clinical and physiologic parameters are confounded by the contribution of the transplanted non-IPF lung. Chest CT scans have been demonstrated in multiple studies1518 to be a valid and objective measure of disease severity in interstitial lung disease and IPF.

In our study, chest CT findings of fibrosis, such as thickening in the interlobular septa, honeycombing, and traction bronchiectasis, continued to worsen in all five single-lung transplantation patients receiving a cyclosporine-based immunosuppressive regimen. Similarly, the average percentage of involvement in the native lungs by ground glass attenuation and fibrosis was unchanged or increased in all patients except one. The latter patient had an improvement in his ground glass score and a worsening in his fibrosis score. The decrease in the average percentage of involvement in the native lung of this patient can be explained by the higher degree of improvement in ground glass relative to the worsening in fibrosis. Two of five patients had improvement in their ground glass scores; however, their fibrosis continued to progress. Ground glass attenuation seen on an HRCT scan has been shown in prior studies to correlate with areas of inflammation on surgical lung biopsy specimens taken from IPF patients.19

Our findings are in concert with previous research demonstrating that IPF patients with a preponderance of ground glass attenuation seen on HRCT scans and/or inflammation seen on surgical lung biopsy specimens have a greater likelihood of responding to immunosuppressive treatment.11 Unfortunately, most IPF patients present at later stages of their disease with advanced fibrotic changes and minimal ground glass attenuation seen on HRCT scans.

Our study is limited by its retrospective nature and by the small number of patients. Furthermore, it is unknown what effect, if any, the presence of the donor lung might have had on the progression of native lung disease. Another limitation is the lack of HRCT studies for all patients. While this may have limited our ability to detect subtle ground glass attenuation, it is unlikely that it affected our ability to detect significant change in findings of fibrosis, including septal thickening, honeycombing, and traction bronchiectasis. This is particularly true in view of the advanced stage of pulmonary fibrosis found in this patient population.

In summary, our study demonstrated no effect of a potent cyclosporine-based immunosuppressive regimen on the progressive fibrosis associated with IPF. Large randomized, double-blinded, placebo-controlled studies are better suited to answer a question of efficacy of a therapeutic agent. However, this may not be appropriate in the case of cyclosporine, due to its apparent lack of effect on the progression of IPF in these patients, its cost, and its poor drug interaction and safety profiles. Further studies in IPF patients investigating the use of novel antifibrotic agents such as interferon-γ, thus, seem warranted and preferred over comparative trials involving cyclosporine or azathioprine.

Abbreviations: HRCT = high-resolution CT; IPF = idiopathic pulmonary fibrosis

Table Graphic Jump Location
Table 1. Ground Glass and Fibrosis Scores in Native IPF Lungs Following Single-Lung Transplantation*
* 

GG = ground glass score; FS = fibrosis score.

Figure Jump LinkFigure 1. Chest CT images made before single-lung transplantation in a patient with IPF (patient 5). A chest CT scan (1-mm collimation, lung window) obtained 1 year prior to the patient undergoing transplantation shows peripheral irregular linear opacities, honeycombing, and architectural distortion, findings that are typical of IPF. Note the ground glass opacity in the left upper and lower lobes.Grahic Jump Location
Figure Jump LinkFigure 2. A chest CT scan (1-mm collimation, lung window) obtained 2 years after the patient underwent unilateral right lung transplantation shows progressive fibrosis in the native left lung. Note the resolution of the ground glass opacity.Grahic Jump Location
Table Graphic Jump Location
Table 2. Average Percentage Involvement of Native Lungs by Ground Glass Attenuation and Fibrosis
. American Thoracic Society. European Respiratory Society. (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment; international consensus statement.Am J Respir Crit Care Med161,646-664. [PubMed]
 
Mapel, MW, Samet, JM, Coultas, DB Corticosteroids and the treatment of idiopathic pulmonary fibrosis: past, present, and future.Chest1996;110,1058-1067. [PubMed] [CrossRef]
 
Rudd, RM, Haslam, PL, Turner-Warwick, M Cryptogenic fibrosing alveolitis: relationships of pulmonary physiology and bronchoalveolar lavage to response to treatment and prognosis.Am Rev Respir Dis1981;124,1-8. [PubMed]
 
Stack, HR, Choo-Kang, YFJ, Heard, BE The prognosis of cryptogenic fibrosing alveolitis.Thorax1972;27,535-542. [PubMed]
 
Turner-Warwick, M, Burrows, B, Johnson, A Cryptogenic fibrosing alveolitis: response to corticosteroid treatment and its effect on survival.Thorax1980;35,593-599. [PubMed]
 
Raghu, G, Depaso, WJ, Cain, K, et al Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial.Am Rev Respir Dis1991;144,291-296. [PubMed]
 
Lok, SS, Smith, E, Doran, HM, et al Idiopathic pulmonary fibrosis and cyclosporine: a lesson from single-lung transplantation.Chest1998;114,1478-1481. [PubMed]
 
Fukazawa, M, Kawano, M, Hisano, S, et al Efficacy of cycolsporin A for idiopathic pulmonary fibrosis.Eur J Pediatr1990;149,441-442. [PubMed]
 
Alton, EW, Johnson, M, Turner-Warwick, M Advanced cryptogenic fibrosing alveolitis: preliminary report on treatment with cyclosporin A.Respir Med1989;83,277-279. [PubMed]
 
Hodges, TN, Schwarz, MI, Zamora, MR Improvement of the native lung following single lung transplant in patients with desquamative interstitial pneumonitis [abstract]. Am J Respir Crit Care Med. 1997;;155 ,.:A741
 
Gay, SE, Kazerooni, EA, Toews, GB, et al Idiopathic pulmonary fibrosis: predicting response to therapy and survival.Am J Respir Crit Care Med1998;157,1063-1072. [PubMed]
 
Lau, CL, Palmer, SM, D’Amico, TA, et al Lung transplantation at Duke University Medical Center.Clin Transpl1998;,327-340
 
Ziesche, R, Hofbauer, E, Wittman, K, et al A preliminary study of long-term treatment with interferon gamma-1b and low dose prednisolone in patients with idiopathic pulmonary fibrosis.N Engl J Med1999;341,1264-1269. [PubMed]
 
Nagai, S, Fujimura, N, Hirata, T, et al Differentiation between idiopathic pulmonary fibrosis and interstitial pneumonia associated with collagen vascular diseases by comparison of the ratio of OKT4+ and OKT8+ cells in BALF T lymphocytes.Eur J Respir Dis1985;67,1-9. [PubMed]
 
Nishimura, K, Kitaichi, M, Izumi, T, et al Usual interstitial pneumonia: histologic correlation with high-resolution CT.Radiology1992;182,337-342. [PubMed]
 
Terriff, BA, Kwan, SY, Chan-Yeung, MM, et al Fibrosing alveolitis: chest radiography and CT as predictors of clinical and functional impairment at follow-up in 26 patients.Radiology1992;184,445-449. [PubMed]
 
Müller, NL, Staples, CA, Miller, RR, et al Disease activity in idiopathic pulmonary fibrosis: CT and pathological correlation.Radiology1987;165,731-734. [PubMed]
 
Staples, CA, Müller, NL, Vedal, S, et al Usual interstitial pneumonia: correlation of CT with clinical, functional, and radiologic findings.Radiology1987;162,377-381. [PubMed]
 
Remy-Jardin, M, Giraud, F, Remy, J, et al Importance of ground glass attenuation in chronic diffuse infiltrative lung disease: pathologic-CT correlation.Radiology1993;189,693-698. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Chest CT images made before single-lung transplantation in a patient with IPF (patient 5). A chest CT scan (1-mm collimation, lung window) obtained 1 year prior to the patient undergoing transplantation shows peripheral irregular linear opacities, honeycombing, and architectural distortion, findings that are typical of IPF. Note the ground glass opacity in the left upper and lower lobes.Grahic Jump Location
Figure Jump LinkFigure 2. A chest CT scan (1-mm collimation, lung window) obtained 2 years after the patient underwent unilateral right lung transplantation shows progressive fibrosis in the native left lung. Note the resolution of the ground glass opacity.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Ground Glass and Fibrosis Scores in Native IPF Lungs Following Single-Lung Transplantation*
* 

GG = ground glass score; FS = fibrosis score.

Table Graphic Jump Location
Table 2. Average Percentage Involvement of Native Lungs by Ground Glass Attenuation and Fibrosis

References

. American Thoracic Society. European Respiratory Society. (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment; international consensus statement.Am J Respir Crit Care Med161,646-664. [PubMed]
 
Mapel, MW, Samet, JM, Coultas, DB Corticosteroids and the treatment of idiopathic pulmonary fibrosis: past, present, and future.Chest1996;110,1058-1067. [PubMed] [CrossRef]
 
Rudd, RM, Haslam, PL, Turner-Warwick, M Cryptogenic fibrosing alveolitis: relationships of pulmonary physiology and bronchoalveolar lavage to response to treatment and prognosis.Am Rev Respir Dis1981;124,1-8. [PubMed]
 
Stack, HR, Choo-Kang, YFJ, Heard, BE The prognosis of cryptogenic fibrosing alveolitis.Thorax1972;27,535-542. [PubMed]
 
Turner-Warwick, M, Burrows, B, Johnson, A Cryptogenic fibrosing alveolitis: response to corticosteroid treatment and its effect on survival.Thorax1980;35,593-599. [PubMed]
 
Raghu, G, Depaso, WJ, Cain, K, et al Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial.Am Rev Respir Dis1991;144,291-296. [PubMed]
 
Lok, SS, Smith, E, Doran, HM, et al Idiopathic pulmonary fibrosis and cyclosporine: a lesson from single-lung transplantation.Chest1998;114,1478-1481. [PubMed]
 
Fukazawa, M, Kawano, M, Hisano, S, et al Efficacy of cycolsporin A for idiopathic pulmonary fibrosis.Eur J Pediatr1990;149,441-442. [PubMed]
 
Alton, EW, Johnson, M, Turner-Warwick, M Advanced cryptogenic fibrosing alveolitis: preliminary report on treatment with cyclosporin A.Respir Med1989;83,277-279. [PubMed]
 
Hodges, TN, Schwarz, MI, Zamora, MR Improvement of the native lung following single lung transplant in patients with desquamative interstitial pneumonitis [abstract]. Am J Respir Crit Care Med. 1997;;155 ,.:A741
 
Gay, SE, Kazerooni, EA, Toews, GB, et al Idiopathic pulmonary fibrosis: predicting response to therapy and survival.Am J Respir Crit Care Med1998;157,1063-1072. [PubMed]
 
Lau, CL, Palmer, SM, D’Amico, TA, et al Lung transplantation at Duke University Medical Center.Clin Transpl1998;,327-340
 
Ziesche, R, Hofbauer, E, Wittman, K, et al A preliminary study of long-term treatment with interferon gamma-1b and low dose prednisolone in patients with idiopathic pulmonary fibrosis.N Engl J Med1999;341,1264-1269. [PubMed]
 
Nagai, S, Fujimura, N, Hirata, T, et al Differentiation between idiopathic pulmonary fibrosis and interstitial pneumonia associated with collagen vascular diseases by comparison of the ratio of OKT4+ and OKT8+ cells in BALF T lymphocytes.Eur J Respir Dis1985;67,1-9. [PubMed]
 
Nishimura, K, Kitaichi, M, Izumi, T, et al Usual interstitial pneumonia: histologic correlation with high-resolution CT.Radiology1992;182,337-342. [PubMed]
 
Terriff, BA, Kwan, SY, Chan-Yeung, MM, et al Fibrosing alveolitis: chest radiography and CT as predictors of clinical and functional impairment at follow-up in 26 patients.Radiology1992;184,445-449. [PubMed]
 
Müller, NL, Staples, CA, Miller, RR, et al Disease activity in idiopathic pulmonary fibrosis: CT and pathological correlation.Radiology1987;165,731-734. [PubMed]
 
Staples, CA, Müller, NL, Vedal, S, et al Usual interstitial pneumonia: correlation of CT with clinical, functional, and radiologic findings.Radiology1987;162,377-381. [PubMed]
 
Remy-Jardin, M, Giraud, F, Remy, J, et al Importance of ground glass attenuation in chronic diffuse infiltrative lung disease: pathologic-CT correlation.Radiology1993;189,693-698. [PubMed]
 
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