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Case Report |
1
Department of Radiology, Duke University Medical Center, Box 3808, Durham, NC
27710.
2
Department of Internal Medicine, Duke University Medical Center, Durham, NC
27710.
3
Department of Pathology, Duke University Medical Center, Durham, NC
27710.
Received November 17, 2000;
accepted after revision January 8, 2001.
Address correspondence to J. G. Ravenel.
Introduction
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At presentation, she denied illicit drug use for the past 20 years but was
smoking approximately two cigarettes per day and was on bupropion
hydrochloride for depression. She had received interferon therapy for 2 years
before presentation. Initially treated with 3 million units of interferon
-2b subcutaneously three times per week and 1g of ribaviran every day,
she required higher dose therapy (15 µg) with interferon alfacon-1
(Infergen; Amgen, Thousand Oaks, CA) subcutaneously every day on two occasions
for relapse. Two months before presentation, she was placed back on her usual
interferon -2b and ribaviran maintenance doses.
Physical examination at presentation revealed crackles at both lung bases but was otherwise unremarkable. Pulmonary function testing showed normal lung volumes with forced expiratory volume 1 sec, 82%; forced vital capacity, 81%; and total lung capacity, 87% of predicted. Diffusing lung capacity was decreased at 49% of predicted.
Chest radiographs obtained at presentation showed very subtle diffuse heterogeneous opacities in both lungs. These findings were a change from those on a radiograph obtained 1 year before onset of symptoms. There was no evidence of lymphadenopathy or pleural effusion. Thin-section CT showed scattered 1- to 2-mm nodular opacities in an upper lobe distribution (Figs. 1A and 1B). No linear opacities, ground-glass opacities, or air-filled cysts were seen. Small nonenlarged lymph nodes were observed throughout the mediastinum.
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A video-assisted thoracoscopic lung biopsy was performed. Histopathologic specimens taken from the right upper lobe showed abundant noncaseating granulomas composed of tightly arranged epithelioid histiocytes and occasional multinucleated giant cells in the pulmonary interstitium, findings typical of sarcoidosis (Fig. 1C). Polarized light microscopy showed no birefringent material in the granulomas. Findings on cultures for viral, fungal, and mycobacterial organisms were negative.
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The patient recovered well and was discharged home on the second postoperative day. Interferon was discontinued. One month later, the patient presented with hypercalcemia (serum calcium level, 14.4 mg/dL) thought to be caused by sarcoidosis. Twenty milligrams of methylprednisolone, administered every day, resolved the hypercalcemia. Chest radiographs obtained at that time showed no change. Her dose of methylprednisolone was gradually withdrawn, and she has done well clinically without any respiratory difficulties since the discontinuation of interferon. Diffusing lung capacity has improved to 76% of predicted.
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TopIntroductionCase ReportDiscussionReferences |
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for advanced renal
cell carcinoma [2]. Since 1986,
several other case reports have suggested an association between interferon
treatment and development (or recurrence) of sarcoidosis
[1,
3,
5]. In the largest series to
date, four (6.7%) of 60 patients treated with interferon -2a developed
sarcoidosis [1]. As further
evidence of a causal relationship, all symptoms of clinically apparent
sarcoidosis in this series regressed with the discontinuation of interferon.
Overall, prognosis for interferon-induced sarcoidosis seems to be good when
the medication can be
discontinued.
,
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Sarcoidosis is a granulomatous disease of uncertain cause. Although any organ system can be involved, the lung and mediastinal lymph nodes are the most frequent sites of disease. Sarcoidosis is classically manifested on chest radiographs with bilateral hilar and right paratracheal lymphadenopathy. Lung disease, when present, can manifest with fine nodular opacities (miliary pattern), reticular opacities, reticulonodular opacities, or, less commonly, air-space opacities. These findings typically predominate in the mid-to-upper lungs. On thin-section CT, a similar spectrum of findings may be seen. CT frequently shows a distinctly bronchovascular distribution of abnormalities, however. Similar radiologic findings have been described in cases of interferon-induced sarcoidosis [1].
The pathologic hallmark of sarcoidosis is the presence of noncaseating
granulomas in the interstitium, typically involvin the lymphatics that invest
the bronchovascular bundles. Infectious agents such as histoplasmosis must be
carefully excluded by culture and staining for organisms of affected tissue
specimens. Although the exact pathogenesis of sarcoidosis remains in doubt, a
number of immune modulators have been implicated, including interferons.
Interferons are a group of cytokines that serve to up-regulate the immune
system and enhance the immune response. However, the exact role of interferons
in the pathogenesis of sarcoidosis is poorly understood. Interferon-
has been noted at sites of disease activity in sarcoidosis and is produced by
CD4-positive TH1 cells. Production of interferon- along with
other lymphokines induces uncommitted CD4-positive T cells to differentiate
into TH1 effector cells and, in turn, greater production of
interferon. This continuous inflammatory feedback loop may ultimately result
in the granulomatous response
[6].
Sarcoidosis may occur after lung transplantation despite immune suppression with cyclosporine. Although recurrences are often self-limited, do not require specific therapy, and often show no abnormal findings on radiography, a fine nodular appearance similar to that in our patient has been previously described [7]. Development of sarcoidosis after highly active antiretroviral therapy for HIV has also been noted in two patients [8]. It is postulated that this response is the result of restoration of the immune system during therapy. The pattern of disease, however, was different from that of our patient with either adenopathy or larger (greater than 1 cm) peribronchovascular and cavitary nodules.
The differential diagnosis for the radiologic findings in our patient includes IV talc granulomatosis, extrinsic allergic alveolitis, pneumoconiosis, and disseminated infection, particularly tuberculosis. The size and distribution of nodules were quite consistent with that reported in patients with talc granulomatosis from IV drug abuse [9]. However, most patients with clinical and radiologic evidence of talc granulomatosis have a substantial history of ongoing drug abuse and repeated exposure to talc. The history of IV drug abuse in our patient was quite remote, making this possibility less likely. Subacute extrinsic allergic alveolitis may also be depicted on CT in this fashion. However, the nodules seen in patients with extrinsic allergic alveolitis are typically somewhat larger, more poorly defined, and more distinctly centrilobular in distribution than those seen in our patient [10]. Silicosis and coal workers' pneumoconiosis can also be manifested on CT with scattered upper lobe fine nodular opacities. The age of our patient and the lack of appropriate occupational history made these entities unlikely. Finally, disseminated infection, particularly tuberculosis, must be considered. However, patients with miliary tuberculosis or fungal infection are typically more severely ill at presentation than our patient was.
Diagnosis of sarcoidosis is sometimes made on radiographic and clinical grounds alone. However, when pathologic confirmation is required, the diagnosis is usually made by fiberoptic bronchoscopy and transbronchial biopsy—a procedure that has a high diagnostic yield for sarcoidosis (particularly in the presence of lung disease documented on CT). Thoracoscopic lung biopsy is usually not required for diagnosis.
In conclusion, interferon therapy for malignant and nonmalignant conditions may cause sarcoidosis. Sarcoidosis should be considered in the differential diagnosis of a patient who develops pulmonary disease or adenopathy while undergoing interferon therapy. It is important that radiologists recognize this unusual, but clinically important, complication of interferon therapy so that less invasive means of diagnosis may be used.
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TopIntroductionCase ReportDiscussionReferences |
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therapy for chronic hepatitis C. J
Hepatol 1998;28:1058
-1063[Medline]
therapy
associated with the development of sarcoidosis. Chest
1999;116:569
-572
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