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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]
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(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
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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
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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.
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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
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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.
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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-
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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
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