|Year : 2016 | Volume
| Issue : 3 | Page : 1198-1202
Combined prednisolone and pirfenidone in bleomycin-induced lung disease
Preyas J Vaidya1, HS Sandeepa2, Tejinder Singh3, SK Susheel Kumar4, Rajat Bhargava5, Gopal Ramakrishnan6, Prashant N Chhajed7
1 Institute of Pulmonology, Medical Research and Development; Lung Care and Sleep Center, Fortis Hospitals, Mumbai, Maharashtra, India
2 Institute of Pulmonology, Medical Research and Development, Mumbai, Maharashtra, India
3 Department of Medical Oncology, Fortis Hospitals, Mumbai, Maharashtra, India
4 Department of Radiology, Dr. Balabhai Nanavati Hospital, Mumbai, Maharashtra, India
5 Department of Radiology, Fortis Hospitals, Mumbai, Maharashtra, India
6 Department of Medical Oncology, Dr. Balabhai Nanavati Hospital, Mumbai, Maharashtra, India
7 Institute of Pulmonology, Medical Research and Development; Lung Care and Sleep Center, Fortis Hospitals; Department of Respiratory Medicine, Dr. Balabhai Nanavati Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||4-Jan-2017|
Prashant N Chhajed
Institute of Pulmonology, Medical Research and Development, A/405, Sangam, Corner of S V Road and Saibaba Road, Santacruz West, Mumbai - 400 054, Maharashtra
Source of Support: None, Conflict of Interest: None
Bleomycin is a cytostatic drug commonly employed in the treatment of Hodgkin's disease, seminomas, and choriocarcinoma. Bleomycin may induce a chronic pulmonary inflammation that may progress to fibrosis. So far, only corticosteroids have been used in the treatment of bleomycin-induced lung disease with variable results. Pirfenidone is an antifibrotic drug that has been approved for the treatment of idiopathic pulmonary fibrosis. We report two cases of bleomycin-induced lung disease treated successfully with pirfenidone and oral corticosteroids.
Keywords: Bleomycin lung toxicity, interstitial lung disease, n-acetylcysteine, pirfenidone, prednisolone
|How to cite this article:|
Vaidya PJ, Sandeepa H S, Singh T, Susheel Kumar S K, Bhargava R, Ramakrishnan G, Chhajed PN. Combined prednisolone and pirfenidone in bleomycin-induced lung disease. J Can Res Ther 2016;12:1198-202
|How to cite this URL:|
Vaidya PJ, Sandeepa H S, Singh T, Susheel Kumar S K, Bhargava R, Ramakrishnan G, Chhajed PN. Combined prednisolone and pirfenidone in bleomycin-induced lung disease. J Can Res Ther [serial online] 2016 [cited 2017 Mar 27];12:1198-202. Available from: http://www.cancerjournal.net/text.asp?2016/12/3/1198/197530
| > Introduction|| |
Bleomycin is a potent anticancer drug commonly employed in the treatment of Hodgkin's disease, seminomas, and choriocarcinoma. Bleomycin administration causes lung inflammation leading to a cytokine response. In a research setting, bleomycin is used to induce lung inflammation to examine the effect of antifibrotic agents in animals., Therefore, as a potential side effect bleomycin may induce a chronic pulmonary inflammation that may progress to fibrosis when used in its therapeutic role in humans.
Corticosteroids have been the mainstay of treatment in cases of bleomycin-induced lung disease. A few case reports have shown that addition of immunosuppressive agents like azathioprine improve the outcome. The antifibrotic role of pirfenidone has been examined in animal models by creating pulmonary inflammation using bleomycin. Pirfenidone has been recently approved for the treatment of idiopathic pulmonary fibrosis. The role of antifibroblast growth factor pirfenidone and antioxidants have been examined in animal models but has not been evaluated in bleomycin-induced lung disease in humans.,, We present two cases of bleomycin-induced lung disease successfully treated using a combination of pirfenidone and prednisolone.
| > Cases|| |
A 55-year-old female having Hodgkin's lymphoma had completed her fifth cycle of chemotherapy which included bleomycin. She had no history of any pulmonary symptoms or disease. She was admitted with chief complaints of dyspnea on exertion, fatigue, and giddiness for 10 days. On examination, she had tachycardia, tachypnea, and oxygen saturation of 86% at rest on room air. On auscultation, she had fine crepitant rales distributed all over the chest. Complete hemogram was normal. Serum creatinine was 1.1 mg/dl, serum glutamic oxaloacetic transaminase was 13 IU, and serum glutamic pyruvic transaminase was 12 IU. Chest X-ray showed inhomogeneous infiltrates involving upper, mid, and lower lung zones bilaterally. High-resolution computed tomography (HRCT) of chest [Figure 1] showed the extensive areas of interlobar and intralobular interstitial septal thickening and patchy areas of ground glass attenuation bilaterally. Pulmonary function test revealed very severe restriction forced vital capacity (FVC) 30% of predicted (FVC = 0.9 L). Two-dimensional echocardiography revealed mild pulmonary arterial hypertension (pulmonary arterial systolic pressure 44 mm Hg) and left ventricular ejection fraction of 55%. Sputum cultures were negative. Serum lactate dehydrogenase levels were within normal limits. The patient did not agree for a lung biopsy. A diagnosis of bleomycin-induced lung disease was made on the clinical and radiological basis. The patient was given information about bleomycin lung disease and the current approach of management. The patient was also given information regarding the off-label use of pirfenidone and n-acetylcysteine in bleomycin-induced lung disease. The patient agreed for the administration of oral prednisolone 40 mg once daily, oral n-acetylcysteine 600 mg thrice daily and pirfenidone. Pirfenidone was started at the dose of 200 mg three times daily and increased up to 400 mg thrice daily after 3 weeks (best tolerated dose). Oral prednisolone was tapered gradually and omitted over 8 weeks. The patient showed remarkable improvement during follow-ups. Her repeat HRCT scan [Figure 2] showed remarkable regression in the interstitial involvement and resolution of the ground glass opacities. Follow-up lung functions showed a significant improvement in her FVC 74% of predicted (1.59 L). Her treatment with pirfenidone and n-acetylcysteine lasted for 6 months. At 1-year after stopping the treatment, the patient had a remarkable clinical benefit and was working full time.
|Figure 1: Pretreatment high-resolution computed tomography chest showing extensive areas of interlobar and intralobular interstitial septal thickening and patchy areas of ground glass attenuation bilaterally in lower lobes|
Click here to view
|Figure 2: Post-treatment high-resolution computed tomography chest showing remarkable improvement in interstitial septal thickening and ground glass opacities|
Click here to view
A 45-year-old male was diagnosed with classical Hodgkin's lymphoma and was started on adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy regime. After six cycles of chemotherapy regime containing bleomycin 10 IU/m 2, the patient started complaining of a cough and dyspnea modified Medical Research Council (mMRC) grade 2. An HRCT scan of the chest showed diffuse bilateral ground glass opacities and subpleural fibrotic shadows with interlobular interstitial septal thickening which most likely being bleomycin-induced pulmonary toxicity [Figure 3] and [Figure 4]. Spirometry revealed an FVC of 28% of predicted value. The patient was started on 1 mg/kg prednisolone and was discharged. The patient had further worsening of dyspnea to mMRC grade 4 with hypoxemia and was admitted for the same after 2 weeks of therapy. A repeat HRCT scan of the chest was done which revealed an increase in ground glass opacities and subpleural fibrotic shadows predominantly in the lower lobes [Figure 5] and [Figure 6]. Sputum cultures sent were negative. Serum lactate dehydrogenase levels were within normal limits. The patient was started on nasal oxygen, 2 mg/kg prednisolone, and pirfenidone 200 mg thrice a day and gradually escalated to 600 mg thrice a day and n-acetylcysteine 600 mg thrice a day. The patient was counseled about the off-label use of pirfenidone and had agreed for its administration. The patient stabilized over 10 days and was discharged off oxygen and on 1 mg/kg oral prednisolone, 1800 mg pirfenidone, and 1800 mg per day of n-acetylcysteine. The patient did not tolerate n-acetylcysteine due to gastric discomfort which got relieved on stopping the drug. On outpatient follow-up, pirfenidone was escalated to 2400 mg per day which was not well tolerated, and the dose was reduced back to 1800 mg per day as best tolerated dose. The patient gradually improved and prednisolone was tapered 10 mg every 4 weeks till a dose of 5 mg per day was reached. Therapy with pirfenidone and prednisone was totally continued for 6 months and patient had a remarkable clinical recovery. A lung function at this stage revealed normal diffusion and FVC of 88% of predicted. A follow-up HRCT scan of the chest revealed a remarkable resolution of ground glass opacities and resolution of interstitial septal thickening and fibrotic shadows [Figure 7] and [Figure 8]. The patient started working full time after 6 months of therapy.
|Figure 3: High-resolution computed tomography scan shows patchy ground glass opacities with very few reticular markings suggesting interstitial pneumonitis|
Click here to view
|Figure 4: High-resolution computed tomography scan highlighting interstitial pneumonitis in the lower lobes|
Click here to view
|Figure 5: Intervening follow-up high-resolution computed tomography. Image at the same level shows a marked increase in ground glass opacities and reticular markings. Findings suggest interstitial pneumonitis with fibrosis|
Click here to view
|Figure 6: Intervening follow-up high-resolution computed tomography at lower lobe level shows predominant basal and reticular distribution of opacities and reticular markings|
Click here to view
|Figure 7: Final follow-up high-resolution computed tomography scan shows significant resolution of the ground glass opacities and reticular markings in the upper lobes with few residual fibrotic subpleural opacities|
Click here to view
|Figure 8: Final follow-up high-resolution computed tomography shows a significant resolution of the ground glass opacities and reticular markings with few residual fibrotic subpleural opacities in the lower lobes|
Click here to view
| > Discussion|| |
Bleomycin is an antibiotic agent with antitumor activity isolated from the fungus Streptomyces verticullaris. It forms an important part of the chemotherapy regimens of several tumor types such as germ cell tumors, lymphomas, Kaposi's sarcoma, cervical cancer, and squamous cell carcinomas of head and neck. Bleomycin causes tumor cell death by induction of free radicals. Bleomycin is deactivated in the body by the enzyme bleomycin hydrolase, which is found predominantly in the liver, spleen, bone marrow, and intestine. Hence, the major toxic effects of bleomycin are seen in the skin and lungs which lack in the enzyme bleomycin hydrolase. The pulmonary toxicity consists of interstitial pneumonitis or fibrosis. The mortality of patients with bleomycin-induced pneumonitis has been reported to be approximately 3% of all patients treated with bleomycin. The outcomes are worse in patients with lymphoma who manifest bleomycin-induced pneumonitis. Both the patients reported in the current study had remarkable lung injury which was attributed to the use of bleomycin.
The pulmonary toxicities of bleomycin have been studied extensively in animal models than in humans. Endothelial and epithelial injuries leading to edema are noted in the most common form of bleomycin-induced lung injury in animals. The endothelial injury leads to an influx of inflammatory cells, namely macrophages, lymphocytes, and neutrophils followed by fibroblasts leading to pulmonary fibrosis., One of the important sources of the cytokines involved in bleomycin-induced pneumonitis is the macrophage.In vitro, bleomycin activates human alveolar macrophages that subsequently produce cytokines such as tumor necrosis factor (TNF-alpha) and interleukin (IL)-1b. The free radicals that damage the endothelial damage are produced by bleomycin directly after oxidation of the bleomycin-Fe (II) complex and by activated polymorph nuclear leukocytes. The continued expression of TNF-alpha and IL-1 may ultimately predispose to the production of transforming growth factor-β (TGF-β), with the promotion of dysregulated collagen production and fibrosis. Following the administration of bleomycin to animals, TGF-β has been shown in several cell types in the lungs including macrophages, fibroblasts, endothelial cells, and eosinophils. Bleomycin is also used in research settings to induce pulmonary fibrosis type of reaction in the lungs. Some studies have evaluated the role of pirfenidone in animal models where lung inflammation was induced using bleomycin.,, These properties form the hypothesis and rationale to use pirfenidone in bleomycin-induced lung disease.
Bleomycin-induced pneumonitis often starts gradually during treatment, but the development of bleomycin-induced pneumonitis up to 6 months after discontinuation of bleomycin therapy has also been reported. On CT scans, bleomycin-induced changes may appear earlier than on chest radiographs. Often the CT scan chest reveals linear and subpleural nodular lesions in the lung bases. As the disease progresses, architectural distortion, bronchiectasis, and fibrotic changes may occur. In the current study, the CT scan findings comprised bilateral ground glass opacities and interlobular and interlobar septal thickening with interstitial fibrosis predominantly in the lower lobes. Until now, corticosteroids have been the mainstay of treatment. Short-term improvement occurs in 50–70% of glucocorticoid-treated patients, but symptoms may relapse once therapy is tapered. The second patient in the study had worsening of symptoms and radiological findings on systemic corticosteroids. There are no controlled studies of glucocorticoids or other immunosuppressive drugs for the treatment of bleomycin-induced pneumonitis in the literature to our knowledge.
Pirfenidone is a novel antifibrotic drug that has been demonstrated to have both preventive and therapeutic effects on bleomycin-induced pulmonary fibrosis in animals. The antifibrotic effect of pirfenidone appears to be mediated by its inhibitory effect on TGF-β expression, TGF-β-induced expression of collagen, and proliferation of various types of cells, including fibroblasts. Pirfenidone exerts both anti-inflammatory activity and antioxidant activity., Inomata et al. reported that pirfenidone decreases fibrocyte pool size in bleomycin-treated mice lungs through attenuation of both chemokine (CC motif) ligand-2 (CCL2) and CCL12 production. Moreover, a study comparing antifibrotic effects of prednisolone and pirfenidone in bleomycin-induced lung toxicity in mice reported the successful suppression of pulmonary fibrosis by pirfenidone.
Antioxidant-sensitive mechanism of n-acetylcysteine might be involved in the inhibition of IL-8 secretion by bleomycin-stimulated bronchial epithelial cells and that might be useful for the treatment of bleomycin-induced lung injury. N-acetylcysteine reduces the primary inflammatory events, thus preventing cellular damage and the subsequent development of pulmonary fibrosis in the bleomycin rat model.
In the current study, after discontinuation of bleomycin, pirfenidone was used initially along with corticosteroids and n-acetylcysteine and then was continued with n-acetylcysteine for a period of 6 months in one case. In the other case, n-acetylcysteine had to be discontinued after a week due to gastric intolerance which was relieved after its discontinuation. A recent study has shown that there is no benefit of n-acetylcysteine in the treatment of idiopathic pulmonary fibrosis., There were no side effects reported by the patient on the best-tolerated dose and the liver functions were normal during the treatment period. Therapy was discontinued after 6 months once the improvement in lung functions and radiology were documented. The optimal dose of pirfenidone in the current study was extrapolated from the recommendations about its use in idiopathic pulmonary fibrosis.,, In the current study, the best-tolerated dose for pirfenidone was 1800 mg per day. An important aspect in the treatment of bleomycin-induced pneumonitis is to start the treatment before fibrosis sets in. The improved outcomes in our cases may be attributed to starting pirfenidone at the outset with prednisolone.
| > Conclusion|| |
The novel antifibrotic agent pirfenidone in combination with prednisolone might be considered as a therapeutic option in bleomycin-induced lung disease. Further studies on the use of pirfenidone in bleomycin-induced lung disease will help in additionally clarifying its role in the combined treatment of this disease.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Adamson IY, Bowden DH. The pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Am J Pathol 1974;77:185-97.
Iyer SN, Wild JS, Schiedt MJ, Hyde DM, Margolin SB, Giri SN. Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. J Lab Clin Med 1995;125:779-85.
Peng R, Sridhar S, Tyagi G, Phillips JE, Garrido R, Harris P, et al.
Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: A model for “active” disease. PLoS One 2013;8:e59348.
Maher J, Daly PA. Severe bleomycin lung toxicity: Reversal with high dose corticosteroids. Thorax 1993;48:92-4.
Ratner M. Landmark approvals in idiopathic pulmonary fibrosis. Nat Biotechnol 2014;32:1069-70.
Kate A, Sandeepa H, Kumar SS, Kamat N, Gopal R, Chhajed P. Bleomycin induced lung disease treated with pirfenidone:First report. Am J Respir Crit Care Med 2012;185:A5907.
Tanaka K, Azuma A, Miyazaki Y, Sato K, Mizushima T. Effects of lecithinized superoxide dismutase and/or pirfenidone against bleomycin-induced pulmonary fibrosis. Chest 2012;142:1011-9.
Serrano-Mollar A, Closa D, Prats N, Blesa S, Martinez-Losa M, Cortijo J, et al. In vivo
antioxidant treatment protects against bleomycin-induced lung damage in rats. Br J Pharmacol 2003;138:1037-48.
Sleijfer S. Bleomycin-induced pneumonitis. Chest 2001;120:617-24.
Martin WG, Ristow KM, Habermann TM, Colgan JP, Witzig TE, Ansell SM. Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's lymphoma. J Clin Oncol 2005;23:7614-20.
Scheule RK, Perkins RC, Hamilton R, Holian A. Bleomycin stimulation of cytokine secretion by the human alveolar macrophage. Am J Physiol 1992;262 (4 Pt 1):L386-91.
Bartram U, Speer CP. The role of transforming growth factor beta in lung development and disease. Chest 2004;125:754-65.
Zhang K, Flanders KC, Phan SH. Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis. Am J Pathol 1995;147:352-61.
Oku H, Shimizu T, Kawabata T, Nagira M, Hikita I, Ueyama A, et al.
Antifibrotic action of pirfenidone and prednisolone: Different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol 2008;590:400-8.
Inomata M, Kamio K, Azuma A, Matsuda K, Kokuho N, Miura Y, et al.
Pirfenidone inhibits fibrocyte accumulation in the lungs in bleomycin-induced murine pulmonary fibrosis. Respir Res 2014;15:16.
Rimmer MJ, Dixon AK, Flower CD, Sikora K. Bleomycin lung: Computed tomographic observations. Br J Radiol 1985;58:1041-5.
Tanoue LT. Pulmonary toxicity associated with chemotherapeutic agents. In: Fishman AP, editor. Fishman's Pulmonary Diseases and Disorders. New York: McGraw Hill; 1998. p. 1003-16.
Mitani Y, Sato K, Muramoto Y, Karakawa T, Kitamado M, Iwanaga T, et al.
Superoxide scavenging activity of pirfenidone-iron complex. Biochem Biophys Res Commun 2008;372:19-23.
Gon Y, Hashimoto S, Nakayama T, Matsumoto K, Koura T, Takeshita I, et al.
N-acetyl-L-cysteine inhibits bleomycin-induced interleukin-8 secretion by bronchial epithelial cells. Respirology 2000;5:309-13.
Idiopathic Pulmonary Fibrosis Clinical Research Network, Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr., Raghu G. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2093-101.
Behr J, Bendstrup E, Crestani B, Günther A, Olschewski H, Sköld CM, et al.
Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med 2016;4:445-53.
Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, et al.
Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): Two randomised trials. Lancet 2011;377:1760-9.
Nathan SD, Albera C, Bradford WZ, Costabel U, du Bois RM, Fagan EA, et al.
Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: Analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis. Thorax 2016;71:429-35.
Lancaster L, Albera C, Bradford WZ, Costabel U, du Bois RM, Fagan EA, et al.
Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: Integrated analysis of cumulative data from 5 clinical trials. BMJ Open Respir Res 2016;3:e000105.
Bendstrup E, Hyldgaard C, Agerbæk M, Andersen CU, Hilberg O. No effect of pirfenidone treatment in fulminant bleomycin-induced pneumonitis. Respir Med Case Rep 2014;12:47-9.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]