Thalidomide-induced organizing pneumonia.

Abstract: Twenty medications are associated with drug-induced organizing pneumonia; however, thalidomide is not listed as a potential causative agent. Thalidomide (Thalomid, Celgene Corp., Summit, NJ), an angiogenesis inhibitor and immunomodulator that reduces tumor necrosis factor-alpha, is used for the treatment of multiple myeloma. We report a case of organizing pneumonia in a 58-year-old male with multiple myeloma treated with dexamethasone and thalidomide.

Key Words: thalidomide, organizing pneumonia, pulmonary toxicity, multiple myeloma

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Organizing pneumonia is diagnosed by its histopathologic pattern of fibroblastic plugs within alveolar ducts and inflammatory changes in the surrounding alveoli with varied bronchiolar involvement. (1) Causes of organizing pneumonia include connective tissue disorders, hypersensitivity pneumonitis, eosinophilic pneumonias, aspiration, inhalational injury, drugs, radiation, infection, and hematologic malignancies. The most common cause of organizing pneumonia is idiopathic in nature, named cryptogenic organizing pneumonia. Presenting symptoms are usually acute or subacute onset of cough and dyspnea. Fever, malaise, anorexia, and weight loss occur, while acute respiratory distress syndrome and respiratory failure are rare. Physical examination findings include fine inspiratory crackles and tachypnea. The chest x-ray can show patchy bilateral alveolar infiltrates or diffuse reticular infiltrates. High resolution chest computed tomography (CT) findings are variable, but most commonly demonstrate patchy areas of ground-glass attenuation with or without linear or reticular opacities. (1)

Case Report

A 58-year-old male with multiple myeloma status post two complete cycles of thalidomide (200 mg/d), plus dexamethasone (40 mg/d on days 1-4, 9-12, 17-20 [odd cycles] and days 1-4 [even cycles]), presented to his oncologist with a one week history of dyspnea on exertion, cough, and low grade fevers. Significant history included an untreated positive PPD along with exposure to a relative with active tuberculosis. He had bibasilar inspiratory crackles on auscultation. Chest x-ray demonstrated reticular opacities in the right upper and middle lobes. The patient's dyspnea rapidly worsened over the ensuing five days. His room air resting Sa[O.sub.2] was 92% and Pa[O.sub.2] was 65 mm Hg. With walking, his Sa[O.sub.2] dropped to 79%. Spirometry showed a restrictive pattern with an FVC of 2.93 L (60% predicted). Due to severe dyspnea and cough induced by deep breathing, he was unable to complete DLCO and TLC evaluations. High resolution chest CT had diffuse ground glass opacities with areas of peripheral consolidation involving all lobes (Fig. la). Thalidomide was discontinued. Sputum cultures and bronchoalveolar lavage for Pneumocystis jejuni, as well as bacterial, fungal, and mycobacterial evaluations, were negative. The bronchoalveolar lavage contained 31% neutrophils, 40% lymphocytes, 8% monocytes, 20% eosinophils and 1% plasma cells. Transbronchial biopsy specimens revealed fibroblastic plugs in the alveolar spaces with surrounding interstial inflammation, diagnostic of organizing pneumonia. There was no evidence of infection or malignancy (Fig. 2). He was treated with IV steroids and discharged on oxygen and prednisone. Within three days, his dyspnea and cough improved and his room air oxygen saturation increased to 99% resting and 94% ambulating. Follow-up spirometry demonstrated marked improvement: FVC 3.85 (79%), DLCO 19.7 (83%), and TLC 6.14 (83%). A chest CT six weeks later documented significant improvement (Fig. 1b). He has had no recurrence of pulmonary symptoms after completion of a three month steroid taper.

Discussion

Thalidomide, introduced in the 1950s as a hypnotic agent, was withdrawn from the market in 1961 when it was recognized as a potent teratogen. After discovery of its immuno-modulating effects, it was cautiously re-introduced in 1998.

Drug-induced organizing pneumonia has been associated with at least 20 medications including antimicrobials (minocycline, nitrofurantoin, cephalosporin, amphotericin-B), chemotherapy agents (busulfan, bleomycin, doxorubicin, methotrexate, mitomycin-c), cardiac medications (amiodarone, acebutolol), anti-inflammatory agents (gold, sulfasalazine), and others (carbamazepine, interferons, ticlopidine, phenytoin, L-tryptophan, FK 506, and cocaine). (2)

Drug-induced organizing pneumonia occurs within weeks to months of starting the medication. Symptoms resolve rapidly with cessation of the medication; corticosteroids may be required in severe or refractory cases. Bronchoalveolar lavage demonstrates a neutrophilia in drug-induced organizing pneumonia versus a lymphocytosis in cryptogenic organizing pneumonia (COP), Re-introduction of the offending medication causes near immediate recurrence of symptoms. (2)

Pulmonary toxicity has been reported with thalidomide. Respiratory symptoms were reported in one case series of three patients receiving thalidomide and docetaxel for prostate cancer. Radiographic evidence of interstitial lung disease was present in one patient. (3) A recent case described a patient receiving thalidomide for multiple myeloma who developed interstitial pneumonitis based on CT findings. (4) In this case, the patient was rechallenged with thalidomide and her symptoms recurred. The final reported case of pulmonary toxicity associated with thalidomide described a patient with respiratory insufficiency and an interstial pattern on chest x-ray; no other studies were reported in this patient. (5) In none of these cases was a tissue diagnosis of interstial lung disease reported.

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In our case, infection and malignancy were excluded as causes of this patient's dyspnea and organizing pneumonia. His symptoms, physical examination, radiologic findings, histopathology, and rapid improvement after the cessation of thalidomide therapy all confirm the diagnosis of organizing pneumonia. Although it is possible that the patient had COP, his rapid improvement with cessation of thalidomide is most consistent with drug-induced organizing pneumonia. His bronchoalveolar lavage fluid demonstrated a mixed inflammatory cell population. While the treatment with corticosteroids before the patient's clinical improvement is a potential confounding factor, his clinical stability without recurrent symptoms after such a short course of therapy argues against COP.

Conclusion

The tissue diagnosis in our case raises the suspicion that the growing reports of pulmonary toxicity associated with thalidomide may be potentially due to organizing pneumonia. Since thalidomide can cause interstial lung disease, organizing pneumonia should be considered in patients who develop respiratory symptoms while on this medication.

Acknowledgments

Pathologic specimen and photograph of organizing pneumonia provided by CPT Harlan I. Rumjahn, MD, MC, USA, Department of Pathology, Madigan Army Medical Center. Evaluation of bronchoalveolar lavage with differential cell count provided by CPT Novae Simper, MD, MC, USA, Department of Pathology, Madigan Army Medical Center.

References

1. Ryu JH. Myers JL, Swensen SJ. Bronchiolar disorders. Am J Respir Crit Care Med 2003;168:1277-1292.

2. Epler GR. Drug-induced bronchiolitis obliterans organizing pneumonia. Clin Chest Med 2004;25:89-94.

3. Behrens RJ, Gully JL, Dahut WL. Pulmonary toxicity during prostate cancer treatment with docetaxel and thalidomide. Am J Ther 2003;10:228-232.

4. Onozawa M, Hashino S, Sogabe S, et al. Side effects and good effects from new chemotherapeutic agents: case 2: thalidomide-induced interstitial pneumonitis. J Clin Oncol 2005;23:2425-2426.

5. Carrion Valero F, Bertomeu Gonzalez V. Lung toxicity due to thalidomide. Arch Bronconeumol 2002;38:492-494.

Everybody likes to go their own way--to choose their own time and manner
of devotion.
--Jane Austen

Ashley A. Feaver, DO, CPT, MC, USA, David E. McCune, MD, LTC, MC, USA, Angela G. Mysliwiec, MD, MAJ, MC, USA, and Vincent Mysliwiec, MD, MAJ, MC, USA

From the Department of Medicine at Madigan Army Medical Center, Fort Lewis, WA.

Reprint requests to Ashley Feaver, 3710 Vassar Loop SE, Lacey, WA 98503. Email: [e-mail]

No financial support was attained for this case report from any source outside Madigan Army Medical Center. The views expressed herein are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.

Accepted May 1, 2006.

RELATED ARTICLE: Key Points

* Thalidomide is increasingly used in the treatment of multiple myeloma.

* Known pulmonary toxicities of thalidomide include pneumonia and venous thromboembolism; evaluation for intersitial lung disease should be included in the assessment of patients with respiratory symptoms.

* Thalidomide should be added to the list of medications that can cause interstitial lung disease.