demonstrated by an exaggerated interferon- g production when stimulated with phorbal myristate acetate/ionomycin from both CD4 and CD8 T cells. The proportion of major histocompatibility complex class 2 (CD11c hi HLA-DR 1 ) cells were, however, reduced (2% of all mononuclear cells) compared with a control experiment (12%).
We speculate that AHR is independently regulated from the eosinophilic and neutrophilic infl ammatory response in this patient. Although there was no luminal infl ammation, we cannot absolutely rule out tissue infl ammation, par-ticularly mononuclear cells. AHR may be mediated by an interaction between T lymphocytes and airway smooth mus-cle cells or inherent NF- k B activity in muscle or epithelial cells. 9 The exaggerated interferon- g activity probably indi-cates that the recurrent viral and bacterial infections, as opposed to allergic stimulus, contributed to the observed NF- k B activity in the patient. This is not unexpected given her two associated immunodefi cient conditions.
In summary, this case history illustrates the dissociation between AHR and cellular bronchitis, and the impor-tance of recognizing the various components of airway diseases that contribute to symptoms. 10 Quantitative cell counts in sputum help to identify the minimum dose of antiinfl ammatory treatment needed to maintain asthma con-trol. Presently, we do not have any therapeutic strategies specifi cally to improve AHR.
Acknowledgments Financial/nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: Dr Nair is listed on a patent for a “sputum fi ltration device” and has acted as a scientifi c advisor for a University spin-off company “Cellometrics Inc.” He has received grant support for investigator-initiated studies from GlaxoSmithKline Canada. The remaining authors have reported that no potential confl icts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.
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Organizing Pneumonia as a Side Effect of Ipilimumab Treatment of Melanoma
Igor Z. Barjaktarevic , MD ; Nida Qadir , MD ; Anu Suri , MBBS ; Jean T. Santamauro , MD, FCCP ; and Diane Stover , MD, FCCP
Ipilimumab is one of the newly developed human mono-clonal antibodies used in the treatment of metastatic melanoma. Its primary mechanism of action is a spe-cifi c blockade of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a T-cell receptor responsible for inhibition of lymphocyte activation. By blocking CTLA-4, ipilimumab enhances immune responses against tumor cells, but also exposes normal tissues to an increased risk of autoimmune phenomena as a potential side effect. In this report, we describe the case of a 58-year-old woman with metastatic mela-noma who was treated with ipilimumab in the weeks prior to the onset of severe nonresolving dyspnea and cough. Extensive workup revealed organizing pneu-monia as the cause of her hypoxemic respiratory failure and treatment with steroids led to a resolu-tion of her pulmonary disease. To our knowledge, this is the fi rst report of pulmonary toxicity caused by ipilimumab, which manifested on pathology as orga-nizing pneumonia. CHEST 2013; 143 ( 3 ): 858 – 861
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Figure 1. A, Chest radiograph on admission with bilateral patchy infi ltrates, predominant in lower lung regions. B, Representative CT scan of chest 24 h after the admission showing extensive bilateral consolidation. C, Transbronchial biopsy specimen from right middle lobe showing intraalveolar granulation tissue with myofi broblasts and collagen consistent with organizing pneumonia; Masson bodies can be seen in the insert image (hematoxylin and eosin, original magnifi cation 3 100; inset, 3 200 ). D, Repeat CT scan of chest 6 weeks after the admission with signifi cant improvement of parenchymal changes.
melanoma. Here we report a case of organizing pneumo-nia as a side effect of treatment with ipilimumab.
Case Report
A 58-year-old white woman was admitted to our hos-pital with complaints of cough and dyspnea starting 2 weeks previously . Despite a 7-day course of azithromycin, her cough persisted and she developed worsening shortness of breath. Past medical history was signifi cant for recently diagnosed melanoma of the foot with metastasis to the inguinal lymph nodes, cryptogenic cirrhosis, hypertension, hyperlipidemia with a history of stroke, and a positive anti-
cardiolipin antibody. Home medications included ursodiol, citalopram, aspirin, amlodipine, ezetimibe, and metoprolol. Her only cancer treatment to date was ipilimumab, which was started 2 months earlier. She had no known drug aller-gies or environmental exposures and denied any tobacco, illicit drug, or alcohol use.
On examination, the patient was afebrile and in moderate respiratory distress with oxygen saturation of 74% on room air. She had crackles in the lower half of both lung fi elds. Laboratory workup was unremarkable. Chest roentgeno-gram revealed bilateral patchy infi ltrates with predominantly lower-lobe distribution. Chest imaging ( Figs 1A, 1B ) showed extensive, patchy, bilateral, peribronchial consolidation most prominent in the lower lobes.
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The patient received broad-spectrum antibiotics and methylprednisolone IV 2 mg/kg . Fiber-optic bronchos-copy was performed, and cytopathologic and microbiologic analyses showed no evidence of infection. BAL showed lympho cytic alveolitis. Transbronchial biopsy specimens revealed an organizing pneumonia pattern ( Fig 1C ). The patient’s dyspnea and hypoxemia improved, and she was discharged home after 10 days of hospitalization. Systemic steroids were tapered over 6 weeks after discharge. Repeat chest imaging ( Fig 1D ) showed resolution of the infi ltrates 6 weeks later.
Discussion
The CTLA-4 receptor on T lymphocytes is a nega tive regulator of lymphocyte activation that binds to B7 on antigen-presenting cells, resulting in an inhibitory signal to the T cell. 1 Ipilimumab has a high affi nity for CTLA-4, effectively impeding binding to B7, which may potentiate T-cell activation against tumor cells. Ipilimumab has been shown to have a survival benefi t in treating metastatic melanoma 2 and is also being investigated as potential treat-ment of hematologic malignancies, 3 , 4 and advanced pros-tate, 5 , 6 lung, 7 and renal cancers. 8
Ipilimumab treatment results in enhanced immune response not only to tumor cells, but also to normal host tissues, which is the cause of most of ipilimumab’s adverse effects. 9 , 10 A correlation between immune-related adverse effects and the degree of tumor regression induced by ipilimumab has been reported, suggesting that its clinical efficacy is associated with the development of autoim-munity. 11 The most common sites of immune-related adverse effects are the skin and GI tract, followed by the liver and endocrine glands. 12 The majority of these adverse effects occur during or after the treatment period and resolve with systemic administration of corticosteroids, infl iximab, or mycophenolate. 13 - 15
Organizing pneumonia is a known presentation of drug-induced lung injury. The histopathologic changes seen in organizing pneumonia include the proliferation of granu-lation tissue within the alveolar ducts with chronic infl am-mation in the surrounding alveoli. The high lymphocyte count in BAL fl uid and rapid clinical improvement seen with administration of corticosteroid therapy suggest an immune-mediated mechanism of lung injury. Additionally, multiple investigators have seen an increase in the number of activated T cells in the BAL fl uid of patients with orga-nizing pneumonia in comparison with normal control sub-jects, 16 - 18 suggesting that T cells may play an important role in the pathogenesis of this disease.
The patient was treated with ipilimumab for 2 months prior to the onset of symptoms, with the last dose admin-istered 1 week prior to the onset of cough. Extensive microbiologic workup did not reveal any evidence of active pulmonary infection. She had not received any other treatment and was not exposed to any environmental agents known to cause organizing pneumonia. Known pul-monary side effects of her other medications included noncardiogenic pulmonary edema related to amlodipine, metoprolol-induced bronchospasm, and ARDS associated with citalopram 19 - 21 ; none of these medications has been
associated with organiz ing pneumonia specifically. Her respiratory symptoms improved rapidly after systemic steroids were initiated, similar to what has been seen in cases of other nonpulmonary immune-related adverse effects caused by ipilimumab. It is unclear if the patient’s history of cryptogenic cirrhosis and positive anticardiolipin antibody, in the absence of a clinically obvious autoimmune disorder, may have predisposed this patient to an autoim-mune reaction triggered by ipilimumab.
To our knowledge, this is the fi rst report of pulmo nary toxicity caused by ipilimumab. This case highlights the importance of considering ipilimumab pulmonary toxicity in patients presenting with respiratory symptoms or pulmo-nary infi ltrates during or after the administration of the drug.
Acknowledgments Financial/nonfi nancial disclosures: The authors have reported to CHEST that no potential confl icts of interest exist with any companies/organizations whose products or services may be dis-cussed in this article .
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