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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2019  |  Volume : 30  |  Issue : 4  |  Page : 974-977
Thalidomide-induced bronchiolitis obliterans organizing pneumonia in a patient with multiple myeloma


1 Department of Hemodialysis, Tahar Sfar Hospital, Mahdia, Faculty of Medicine, Monastir University, Monastir, Tunisia
2 Department of Nephrology, La Rabta Hospital, Tunis, Tunisia
3 Department of Pneumology, La Rabta Hospital, Tunis, Tunisia
4 Department of Research Laboratory of Kidney Diseases (LR00SP01), Charles Nicolle Hospital, Faculty of Medicine, Tunis El Manar University, Tunis, Tunisia

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Date of Submission30-Aug-2018
Date of Acceptance01-Oct-2018
Date of Web Publication27-Aug-2019
 

   Abstract 


Thalidomide, which is an angiogenesis inhibitor and immunomodulator that reduces tumor necrosis factor-alpha, has regained value in the treatment of multiple myeloma. Serious pulmonary complications due to thalidomide use remain relatively uncommon. We describe a case of bronchiolitis obliterans organizing pneumonia (BOOP) due to thalidomide. A 51-year-old man with IgG lambda myeloma was treated with thalidomide and dexamethasone. Seven days after the beginning of chemotherapy, the patient presented a fever and a persistent cough. Auscultation revealed crackles in both pulmonary bases. The chest X-ray showed a diffuse bilateral alveolar–interstitial syndrome. Computed tomography scan revealed bilateral pulmonary involvement, with bilateral interstitial alveolar infiltration and ground-glass pattern consolidations. Pulmonary infection, malignant tumor, and lung involvement of multiple myeloma were excluded through various tests. Thalidomide-induced BOOP was suspected, and the drug was withdrawn and replaced by Melphalan. The patient had complete resolution of his symptoms and radiologic pulmonary involvement on discontinuation of the drug. In the absence of other etiologies, physicians should be cognizant of this potential complication in patients receiving thalidomide who present with respiratory symptoms.

How to cite this article:
El Ati Z, Lamia R, Cherif J, Jbali H, Fatma LB, Mami I, Khedher R, Smaoui W, Krid M, Hamida FB, Beji S, Zouaghi MK. Thalidomide-induced bronchiolitis obliterans organizing pneumonia in a patient with multiple myeloma. Saudi J Kidney Dis Transpl 2019;30:974-7

How to cite this URL:
El Ati Z, Lamia R, Cherif J, Jbali H, Fatma LB, Mami I, Khedher R, Smaoui W, Krid M, Hamida FB, Beji S, Zouaghi MK. Thalidomide-induced bronchiolitis obliterans organizing pneumonia in a patient with multiple myeloma. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Nov 18];30:974-7. Available from: http://www.sjkdt.org/text.asp?2019/30/4/974/265477



   Introduction Top


Thalidomide was considered as an antiemetic drug in the 1950s and started to induce teratogenic effects, so its use was proscribed.[1] Since 1998, based on the fact that this drug had antiangiogenic and immunomodulatory effects,[2] it has been used worldwide as a first-line treatment for multiple myeloma.[3] Prevalent reported side effects of thalidomide included constipation, vertigo, edema, fatigue, emotional change, and peripheral neuropathy.[4]

Pulmonary undesirable effects are unusual, whereas the use of thalidomide alone or in combination with steroids has been lately reported to cause pulmonary embolism, non-specific interstitial pneumonia and bronchio-litis obliterans organizing pneumonia (BOOP).[3] Here, we report a patient with multiple myeloma, who developed a BOOP, rapidly after the use of thalidomide.


   Case Report Top


We report a case of a 51-year-old man, who was admitted to the cardiology hospital for the management of a hypertrophic myocardio-pathy. On admission, investigations revealed an anemia at 7 g/dL, a renal failure with serum creatinine at 2.3 mg/dL, and a monoclonal hypergammaglobulinemia in the serum protein electrophoresis. Hence, he was transferred to the nephrology unit for further management.

The patient reported asthenia and a history of 6 kg weight loss evolving for a year. Clinical examination demonstrated weight of 66 kg and blood pressure of 120/70 mm Hg, and urinary strip did not show proteinuria and hematuria. Further investigations showed a chronic renal failure with serum creatinine at 2.4 mg/dL. Albumin was at 34 g/L, gamma globulin at 27.6 g/L, lactate dehydrogenase at 165 U/L, calcium at 93 mg/L, hemoglobin at 7.7 g/dL, and platelets at 161,000/mm3. Proteinuria was at 0.88 g/24 h and Bence Jones proteinuria was positive. Immunoelectrophoresis in the blood showed type lambda monoclonal IgG in the gamma region on electrophoresis. Diagnosis of multiple myeloma Durie Salmon Stage III B was established by a diffuse plasmocyts infiltration at 67% in the bone marrow aspirate. Chest X-ray was normal and renal echo graphs showed normal-sized kidneys. Treatment with thalidomide (200 mg/day) and dexamethasone (20 mg/m2/day) was initiated. Seven days after the beginning of chemotherapy, the patient presented with cough and fever and he had developed diffuse erythe-matous skin lesions. On physical examination, he had a body temperature of 38°C, a blood pressure of 130/70 mm Hg, a heart rate of 65 beats/min, and a respiratory rate of 22 breaths/ min. Auscultation revealed crackles in both pulmonary bases. Electrocardiogram found normal sinus rhythm. Laboratory investigations showed hemoglobin - 8 g/dL; total white cell count - 6.4 × 103/μL (differential count - 64% neutrophils, 21.8% lymphocytes, 13% mono- cytes, and 0% eosinophils); platelet count - 167 x 103/μL; erythrocyte sedimentation rate - 112; serum creatinine - 3.1 mg/dL; liver function tests and autoantibodies were negative. D-dimer was normal. Multiple cultures of the blood and urine were negative for microorganisms. Serology for human immunodeficiency virus (HIV) and hepatitis viral were negative. Chest X-ray demonstrated a diffuse bilateral alveolar–interstitial syndrome predominantly in the lower lobes. Computed tomography (CT) scan revealed bilateral pulmonary involvement, with bilateral interstitial–alveolar infiltration and ground-glass pattern consolidations and an absence of neither pulmonary embolism nor adenomegaly [Figure 1] and [Figure 2]. Bronchoscopy with bronchoalveolar lavage (BAL) was negative for Pneumocystisjirovecii and malignant cells. Bacterial, viral, and fungal cultures were negative. The Golde score ruled out intra-alveolar hemorrhage. We started levofloxacin® (500 mg/day) and Cymevan® (250 mg × 2/day), but as the symptoms progressively worsened, thalidomide-associated BOOP syndrome was suspected and the drug was withdrawn and replaced by Melphalan (0.15 mg/kg/day for four days). Outcome was spontaneously favorable and the patient’s symptoms and radiologic findings improved. Follow-up CT scan of the chest two weeks showed improvement in the bilateral pulmonary infiltrates. No relapse occurred during the follow-up.
Figure 1: Computed tomography scan of the lung showing multifocal parenchymal opacities.

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Figure 2: Computed tomography scan of the lung showing multifocal parenchymal opacities and interstitial-alveolar infiltration with ground- glass appearance on both lower lobes.

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   Discussion Top


Thalidomide, initially a sedative-hypnotic drug, has been used in the multimodality treatment of hematologic malignancies and solid tumors,[1],[2],[5] due to its antiangiogenic, immuno-modulation, and anticytokine actions. Anti-angiogenesis, intervention with stromal cell or myeloma adhesive properties and stimulation of natural killer cells are considered to be the mechanisms by which it takes action in multiple myeloma.[6] Side effects related to arterial and venous complications are well described. However. pulmonary complications due to thalidomide use are not common. The most frequent pulmonary side effect is nonspecific dyspnea. reported in 4%–54%.[7] This often improves on cessation of the drug. Pulmonary embolism and vein thromboses are the most severe pulmonary complications.[8],[9] and their incidence increase when combined with dexamethasone and other chemothera-peutic drugs.[10] although organizing pneumonia is very rare.[11],[12] BOOP is an inflammatory lung disease involving the distal bronchioles. respiratory bronchioles. bronchiolar ducts. and alveoli. It may happen in relationship with connective disease, variable immunodeficiency syndrome. HIV infection. hepatitis viral infection. bacterial infections. bone marrow transplant. lung tumors, ulcerative colitis, and drug toxicity.[13],[14] Twenty medications are associated with drug-induced organizing pneumonia; nevertheless. thalidomide is not listed as a potential causative agent.

Pathogenesis studies found an increase in lung microenvironment in the quantity of activated T-lymphocytes. indicative of an immune response. and hence the production of cyto-kines and growth factors.[15] Mast cell hyper-plasia and extracellular release of tryptase have been found on BAL fluid.[16]

To diagnose thalidomide-induced organizing pneumonia, it is imperative to rule out other infections and malignant tumors and also have to suspect that the symptoms may be induced by specific drugs. In fact, when patients taking thalidomide have persistent respiratory symptoms without an exact cause. drug-induced BOOP should be considered, although rare, and appropriate examinations and management of this disease should be established.

To the best of our knowledge. this is the second case of thalidomide causing BOOP. Feaver et al in 2006 reported a case of a 58- year-old who developed an organizing pneumonia after initiating thalidomide.[17] Our patient had a dyspnea, ongoing cough and fever after taking thalidomide. and pulmonary infection, malignant tumor, and lung involvement of multiple myeloma were excluded through various tests. Patient’s clinical course and radiographic and bronchoscopic results support effectively the diagnosis of thalidomide-induced BOOP. The drug was stopped and the symptoms improved.

This case suggests that vigilance is necessary in patients treated with thalidomide. In this context, when patients taking this drug have persistent respiratory symptoms without a definite cause, thalidomide-induced BOOP should be considered, although rare, and appropriate examinations and management of this disease should be considered.

Conflict of interest: None declared.



 
   References Top

1.
Raphael C, Hudson E, Williams L, Lester JF, Savage PM. Successful treatment of metastatic hepatic epithelioid hemangioendothelioma with thalidomide: A case report. J Med Case Rep 2010;4:413.  Back to cited text no. 1
    
2.
Raje N, Anderson K. Thalidomide – A revival story. N Engl J Med 1999;341:1606-9.  Back to cited text no. 2
    
3.
Kang MH, Ju JH, Kim HG, et al. Thalidomide induced nonspecific interstitial pneumonia in patient with relapsed multiple myeloma. Korean J Intern Med 2010;25:447-9. '  Back to cited text no. 3
    
4.
Figg WD, Dahut W, Duray P, et al. A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer. Clin Cancer Res 2001;7:1888-93.  Back to cited text no. 4
    
5.
Gordinier ME, Dizon DS. Dyspnea during thalidomide treatment for advanced ovarian cancer. Ann Pharmacother 2005;39:962-5.  Back to cited text no. 5
    
6.
Zervas K, Dimopoulos MA, Hatzicharissi E, et al. Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): A phase II multicenter study. Ann Oncol 2004;15:134-8.  Back to cited text no. 6
    
7.
Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002;20:4319-23.  Back to cited text no. 7
    
8.
Potenza L, Luppi M, Morselli M, et al. Thrombotic complications associated with thalidomide in multiple myeloma: An old problem with new questions and quandaries in decision-making. Thromb Haemost 2004;91: 834-6.  Back to cited text no. 8
    
9.
Urbauer E, Kaufmann H, Nösslinger T, Raderer M, Drach J. Thromboembolic events during treatment with thalidomide. Blood 2002;99:4247-8.  Back to cited text no. 9
    
10.
Kumar S, Witzig TE, Rajkumar SV. Thalidomid: Current role in the treatment of non-plasma cell malignancies. J Clin Oncol 2004;22:2477-88.  Back to cited text no. 10
    
11.
Camus P, Kudoh S, Ebina M. Interstitial lung disease associated with drug therapy. Br J Cancer 2004;91 Suppl 2:S18-23.  Back to cited text no. 11
    
12.
Iguchi T, Sakoda M, Chen CK, et al. Interstitial pneumonia during treatment with thalidomide in a patient with multiple myeloma. Rinsho Ketsueki 2004;45:1064-6.  Back to cited text no. 12
    
13.
Cazzato S, Zompatori M, Baruzzi G, et al. Bronchiolitis obliterans-organizing pneumonia: An Italian experience. Respir Med 2000;94: 702-8.  Back to cited text no. 13
    
14.
Chakravorty I, Oldfield WL, Gómez CM. Rapidly progressive bronchiolitis obliterans organising pneumonia presenting with pneumothorax, persistent air leak, acute respiratory distress syndrome and multi-organ dysfunction: A case report. J Med Case Rep 2008;2:145.  Back to cited text no. 14
    
15.
Poletti V, Castrilli G, Romagna M, et al. Bronchoalveolar lavage, histological and immunohistochemical features in cryptogenic organizing pneumonia. Monaldi Arch Chest Dis 1996;51:289-95.  Back to cited text no. 15
    
16.
Pesci A, Majori M, Piccoli ML, et al. Mast cells in bronchiolitis obliterans organizing pneumonia. Mast cell hyperplasia and evidence for extracellular release of tryptase. Chest 1996;110:383-91.  Back to cited text no. 16
    
17.
Feaver AA, McCune DE, Mysliwiec AG, Mysliwiec V. Thalidomide-induced organizing pneumonia. South Med J 2006;99:1292-4.  Back to cited text no. 17
    

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Correspondence Address:
Zohra El Ati
Department of Hemodialysis, Tahar Sfar Hospital, Mahdia
Tunisia
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DOI: 10.4103/1319-2442.265477

PMID: 31464258

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