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clinical problems in cardiopulmonary disease Progressive Infiltrates and Eosinophilia With Multiple Possible Causes* Eric B. Milbrandt, MD; William Byron, Jr, MD, FCCP; and Bruce Davis, MD (CHEST 2000; 118:230 –234) Key words: amiodarone; drug-induced lung disease; eosinophilic lung disease; leukotriene; zafirlukast Abbreviations: CEP ⫽ chronic eosinophilic pneumonia; CSS ⫽ Churg-Strauss syndrome Case Presentation man presented with a 10-week hisA 60-year-old tory of nonproductive cough, malaise, and a 40-pound weight loss. He denied fever, chills, night sweats, arthralgias, skin rash, hemoptysis, effort dyspnea, or chest pain. He had a 40 pack-year history of smoking, but had quit 4 years ago when he experienced a myocardial infarction. He denied exposure to toxic dusts, fumes, asbestos, or silica. He had not been exposed to any birds and had not recently traveled outside of the Midwest. His medical history included asthma, COPD, hypertension, coronary artery disease, and congestive heart failure caused by a dilated cardiomyopathy. Two years ago, his cardiologist started him on amiodarone after a workup for dizziness revealed episodes of nonsustained ventricular tachycardia. His other medications were zafirlukast, allopurinol, ipratropium inhaler, furosemide, losartan, aspirin, potassium, and extendedrelease isosorbide mononitrate. He initially sought care from his primary-care physician. A chest radiograph at that time revealed cardiomegaly and patchy infiltrates in the right upper and middle lung fields without lymphadenopathy *From the Division of Pulmonary Critical Care Medicine (Dr. Milbrandt), Vanderbilt University Medical Center, Nashville, TN; Department of Medicine (Dr. Byron), St. Vincent Hospital and Health Services, Indianapolis, IN; and Section of Pulmonary Diseases (Dr. Davis), Medical College of Georgia, Augusta, GA. Manuscript received September 27, 1999; revision accepted September 28, 1999. Correspondence to: Eric B. Milbrandt, MD, Vanderbilt University Medical Center, Division of Pulmonary Critical Care Medicine, Room T-1217 Medical Center North, 1161 21st Ave. South, Nashville, TN 37232-2650; e-mail: [email protected] 230 (Fig 1, top). A CT scan of the chest was performed, which confirmed this finding (Fig 1, bottom). These abnormalities were not present on a chest radiograph obtained 1 year earlier (Fig 2). A skin test and sputum smears for tuberculosis were negative. When he failed to improve with antibiotics, a fiberoptic bronchoscopy was performed and was reported as normal, although no biopsies were obtained. A CTguided needle biopsy was subsequently obtained from a mass-like area of infiltration in the right lung. The specimen was reported as “eosinophilic coagulum.” He was referred back to his cardiologist for possible amiodarone toxicity. The amiodarone was stopped, and pulmonary consultation was requested. Physical examination revealed a well-developed man in no apparent distress. His temperature was normal; heart rate, 66 beats/min; respiratory rate, 16 breaths/min; and BP, 94/60 mm Hg. Head and neck examination results were normal, and the jugular veins were not distended. The lungs were free of wheezes, crackles, or rubs. Examination of the heart disclosed normal sounds without gallops or rubs. There was a grade I/VI short systolic murmur heard at the left sternal border and apex. Abdominal examination was negative for organomegaly, masses, or tenderness. His peripheral pulses were full and symmetric. There was no clubbing, cyanosis, edema, arthritis, lymphadenopathy, or rash. A chest radiograph was obtained, which demonstrated further progression of the pulmonary infiltrates, which were now diffuse and bilateral (Fig 3). Pulmonary function tests showed mild restriction and a markedly decreased diffusion capacity. A diffusion capacity obtained before initiation of amiodarone therapy was normal. An ECG showed normal sinus rhythm with a left intraventricular conduction defect that was unchanged from previously obtained tracings. The following laboratory studies were obtained (normal values are in parentheses): hemoglobin, 13.5 g/dL (14 to 18 g/dL); platelet count, 312 ⫻ 103 cells/L (150 to 350 ⫻ 103 cells/L); and WBC Clinical Problems in Cardiopulmonary Disease Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21949/ on 05/11/2017 Figure 3. Chest radiograph (February 1998) demonstrating further progression of the pulmonary infiltrates, which are now diffuse and bilateral. Figure 1. Top: Chest radiographs (December 1997) showing cardiomegaly with patchy interstitial infiltrates in the right upper and lower lung. Bottom: Chest CT showing the same. count, 11.8 ⫻ 103 cells/L (4.5 to 11 ⫻ 103 cells/L) with 20% (2 to 4%,) eosinophils. Electrolyte levels, including calcium, were within normal limits, but the BUN and creatinine measurements were elevated at 28 mg/dL (7 to 18 mg/dL) and 1.4 mg/dL (0.6 to 1.3 mg/dL), respectively. Serum transaminase levels were elevated to 2 to 3 times normal, and the erythrocyte sedimentation rate was 97 mm/h (⬍ 20 mm/h). Thyroid function test results were normal except for a slightly elevated thyroid-stimulating hormone at 5.48 mIU/mL (0.47 to 5.00 mIU/mL). Antineutrophil cytoplasmic antibody and fungal immunodiffusion test results were negative, but a serum angiotensin-converting enzyme concentration was elevated at 108 U/L (8 to 52 U/L). Additionally, collagen vascular studies were abnormal, with a weakly reactive rheumatoid factor assay and antinuclear antibodies present in a speckled pattern at a titer of 1:160 (⬍ 1:40). Questions for the Pulmonary Expert 1. What is your initial differential diagnosis? 2. What further studies would you require to arrive at a diagnosis? 3. What would be your overall management strategy from this point on? 4. Would you have recommended that the amiodarone be stopped, even if it were the only pharmacologic agent capable of controlling the arrhythmia? Response of the Pulmonary Expert Dr. Bruce Davis, Augusta, GA Figure 2. Baseline chest radiograph (November 1996) with cardiomegaly but otherwise normal. The striking peripheral blood eosinophilia (20% eosinophils, 2.4 ⫻ 103 eosinophils/L) and the “eosinophilic coagulum” on needle biopsy report suggest that the patient had developed one of the CHEST / 118 / 1 / JULY, 2000 Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21949/ on 05/11/2017 231 eosinophilic lung diseases. Differential diagnosis should include Churg-Strauss syndrome (CSS), chronic eosinophilic pneumonia (CEP), drug-induced lung disease, and interstitial lung disease. The patient probably has CSS, although some of his clinical findings are atypical of that disorder. CSS, or allergic angiitis and granulomatosis, is a vasculitis of small arteries and veins. There is prominent pulmonary involvement with asthma and eosinophilic inflammation. As in this case, asthma may appear to be relatively quiescent as the full-blown vasculitic disorder becomes clinically manifest. The chest radiograph and chest CT findings in this patient showing patchy interstitial infiltrates are compatible with CSS. Patients with CSS should have findings of a multisystem disorder. Although this patient had impressive weight loss, a high sedimentation rate, mild renal insufficiency, and elevated serum transaminase levels, he did not manifest some of the more common nonpulmonary manifestations of CSS. He did not have upper airway abnormalities (nasal polyps, allergic rhinitis, sinusitis) or skin lesions (nodules, purpura, urticaria), and did not manifest neurologic disease such as mononeuritis multiplex. The absence of these latter findings makes the diagnosis of CSS problematic. In addition, the antineutrophil cytoplasmic antibody measurement was negative in this patient. About 50% of CSS patients will have a positive antibody finding, usually in the perinuclear form. The atypical presentation of CSS in this patient suggests that he may have developed a CSS-like illness caused by the leukotriene inhibitor zafirlukast. The clinical association between CSS and leukotriene inhibitors has recently generated widespread interest. Although it remains possible that zafirlukast can directly cause CSS, most evidence favors a mechanism by which the leukotriene inhibitor improves asthma control allowing for a lowering of corticosteroid dosage. This lowering of corticosteroid dosage unmasks an underlying eosinophilic infiltrative disorder leading to the clinical recognition of CSS. The case history does not mention the duration of zafirlukast therapy and does not provide information about prior use of corticosteroids. The patient could have CEP. He has cough, malaise, and weight loss, all of which are common symptoms of this disorder. He also has a history of asthma, which is present in about 50% of patients with CEP. The chest radiograph and chest CT findings of patchy infiltrates in a more peripheral location are certainly compatible with CEP. The patient had a low titer of rheumatoid factor, a finding that has previously been noted in CEP. The antinuclear antibody and the elevated angiotensin-converting enzyme results are probably nonspecific findings. 232 Although CEP is possible, CEP occurs more commonly in middle-aged atopic women with a female to male ratio of 2:1. In addition, CEP does not usually have extrapulmonary involvement. The patient was taking a total of nine different medications. Thus, drug-induced lung disease with peripheral blood and lung tissue eosinophilia could explain his illness. Drugs can cause eosinophilic lung disease that varies in presentation from a mild illness with fleeting pulmonary infiltrates to a severe form of lung injury resembling acute eosinophilic pneumonia. The possible role of zafirlukast in producing a disease simulating CSS has been discussed. His other medications, including allopurinol, ipratropium bromide, furosemide, losartan, aspirin, potassium, and isosorbide are unlikely causes of eosinophilic lung disease. Finally, the patient had been taking amiodarone for 2 years. Although amiodarone was discontinued in the patient because of the development of lung disease, it seems unlikely that it was the culprit. Amiodarone use results in a characteristic BAL and lung biopsy pattern that is not associated with eosinophils. Finally, the patient could have developed one of the many forms of interstitial lung disease, although this seems unlikely. Peripheral blood eosinophilia occurs in a small minority of patients with sarcoidosis, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, and bronchiolitis obliterans organizing pneumonia. The level of blood eosinophilia in this patient (20% eosinophils) would be very unusual for these disorders. Additional history about the course of the patient’s asthma and prior use of corticosteroids would have been very helpful in diagnosis of CSS. An IgE level and urinalysis would also have been helpful. IgE is elevated in most cases of CEP and is often present in very high concentrations in CSS in which it may correlate with disease activity. A urinalysis might show active urinary sediment supporting the diagnosis of vasculitis. Most of the eosinophilic lung diseases respond dramatically to systemic corticosteroids. Although a compelling argument can be made for stopping zafirlukast use and adding prednisone, I would avoid this “wait and see” approach. The patient should have open lung biopsy. He has a serious lung disease and has comorbid conditions that could complicate treatment of the lung disease. A diagnosis of CSS, for example, would prove the need for vigorous corticosteroids and even immunosuppressive therapy. It would also mandate that zafirlukast be stopped and other asthma medications instituted. I believe the patient should be prepared for a lung biopsy procedure, preferably a video-assisted thoracoscopic surgery. Zafirlukast use should be stopped Clinical Problems in Cardiopulmonary Disease Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21949/ on 05/11/2017 and the patient begun on asthma therapy with inhaled corticosteroids and inhaled bronchodilators. His cardiopulmonary condition does not seem severe enough to prevent surgical biopsy. If possible, systemic corticosteroids should be withheld to prevent their deleterious effects on wound healing and to preserve the findings on lung biopsy. The striking peripheral blood eosinophilia in this case does not suggest amiodarone lung toxicity. The lung biopsy would be helpful in confirming the presence of an eosinophilic lung disease with a morphologic pattern very different from amiodarone toxicity. If amiodarone use had not already been discontinued, I would have recommended that it be continued for its excellent antiarrhythmic efficacy as the patient proceeds through surgery. Comments by the Treating Pulmonary Consultants Dr. Eric B. Milbrandt, Nashville, TN, and Dr. William Byron, Jr, Indianapolis, IN With peripheral eosinophilia, pulmonary infiltrates, and the medication history noted, our initial differential included CEP, amiodarone pulmonary toxicity, and zafirlukast-associated CSS. A bronchoscopy with transbronchial biopsies was performed. The transbronchial biopsies revealed focal areas of eosinophilic interstitial infiltrates with extension into alveolar spaces (Fig 4). Scattered foamy histiocytes were also noted. A well-developed organizing pneumonia was not apparent, nor was there evidence of granulomatous inflammation, vasculitis, or malignancy. Results of special studies for acid-fast bacteria, fungi, and Pneumocystis were negative. The zafirlukast use was stopped, and the patient Figure 4. Low- (top) and high-power (bottom) photomicrographs of right lower lobe transbronchial biopsy. Eosinophilic interstitial infiltrates are present (curved arrow) with extension into alveolar spaces. Scattered foamy histiocytes also were noted (straight arrow; hematoxylin-eosin, original ⫻ 100 [top], original ⫻ 400 [bottom]). Figure 5. Chest radiograph (March 1998) with complete resolution of infiltrates after 1 month of prednisone use. CHEST / 118 / 1 / JULY, 2000 Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21949/ on 05/11/2017 233 had already discontinued the amiodarone. Prednisone, 60 mg/d orally, was initiated with rapid resolution of his symptoms and complete clearing of the pulmonary infiltrates (Fig 5) and peripheral eosinophilia. The prednisone administration was continued and then slowly tapered and discontinued after 11 months. He has not taken corticosteroids for 8 months and remains free of recurrence. He has not resumed amiodarone use because, according to his cardiologist, there was not a strong indication for its continued use. Amiodarone pulmonary toxicity may present in many ways, but typically manifests with insidious onset of cough, dyspnea, weight loss, interstitial infiltrates, and decreased total lung and diffusing capacities on pulmonary function testing.1 However, peripheral and pulmonary interstitial eosinophilia is uncommon. CSS has been reported in steroid-dependent asthmatics treated with zafirlukast.2 Characteristically, patients have fever, dyspnea, wheeze, rash, interstitial infiltrates, and worsening obstruction on pulmo- 234 nary function testing. Histologic examination reveals eosinophilic infiltrates, necrotizing vasculitis, and interstitial granulomas. Our patient had no symptoms or ventilatory findings suggestive of asthma, no histologic evidence of vasculitis or granulomas, and had never been previously treated with corticosteroids. The patient’s clinical presentation, pulmonary and peripheral eosinophilia, pulmonary function tests and transbronchial biopsy findings, rapid and complete response to prednisone treatment, and absence of recurrence on withdrawal of this agent lead us to believe that the patient most likely had CEP. References 1 Fishman AP. In: Fishman’s pulmonary diseases and disorders. 3rd ed. New York, NY: McGraw-Hill, 1998; 1020 –1021 2 Wechsler ME, Garpestad E, Flier SR, et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA 1998; 279:455– 457 Clinical Problems in Cardiopulmonary Disease Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21949/ on 05/11/2017