AJR 2000; 175:1019-1024
© American Roentgen Ray Society
Drug-Induced Lung Disease
High-Resolution CT Findings
Samantha J. Ellis1,
Joanne R. Cleverley and
Nestor L. Müller
1
All authors: Department of Radiology, Vancouver General Hospital, University
of British Columbia, 899 W. 12th Ave., Vancouver, B.C., V5Z 1M9, Canada.
Received February 3, 2000;
accepted after revision March 21, 2000.
Address correspondence to N. L. Müller.
Introduction
Adverse drug reactions are an important cause of morbidity and mortality,
accounting for an estimated 5% of all hospitalizations and 0.3% of hospital
deaths [1]. Recognition of
drug-induced lung disease is difficult because the clinical, radio-logic, and
histologic findings are nonspecific
[1,
2]. The diagnosis is based on a
history of drug exposure, histologic evidence of lung damage, and exclusion of
other causes of lung injury. High-resolution CT is superior to radiography in
the depiction of the presence and distribution of parenchymal abnormalities.
In one study of 23 patients with drug-induced lung disease, abnormal findings
were detected on high-resolution CT in all patients and on radiography in 17
patients (74%) [3].
Abnormalities most commonly overlooked on radiography included ground-glass
opacities and mild fibrosis
[3].
We illustrate the spectrum of abnormalities seen on high-resolution CT in
patients with drug-induced lung disease.
Chemotherapeutic Drugs
As many as 10% of patients receiving chemotherapeutic agents will develop
an adverse drug reaction in their lungs
[2]. The most common drugs
resulting in lung toxicity are bleomycin, methotrexate, carmustine, busulfan,
and cyclophosphamide.
Chemotherapeutic drugs can result in four main types of lung reaction:
interstitial pneumonitis and fibrosis, hypersensitivity reaction, acute
respiratory distress syndrome, and bronchiolitis obliterans organizing
pneumonia [3].
The high-resolution CT findings of chemotherapeutic drug—induced lung
disease reflect the histologic findings
[3]. Interstitial pneumonitis
and fibrosis result in ground-glass opacities, focal areas of consolidation,
and irregular linear opacities that tend to involve the lower zones of the
lungs (Fig. 1). This is the
most consistent finding with cytotoxic chemotherapeutic agents, particularly
bleomycin [3]. Hypersensitivity
reaction can result in a pattern that resembles hypersensitivity pneumonitis,
with ground-glass opacities and poorly defined centrilobular nodules
[3]
(Fig. 2). Hypersensitivity
reaction, particularly to methotrexate, can also result in extensive bilateral
air-space consolidation
[4].
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Fig. 1. —61-year-old man with interstitial fibrosis; patient was receiving
chlorambucil for chronic lymphocytic leukemia. High-resolution CT scan shows
irregular linear opacities and ground-glass opacities in predominantly
subpleural distribution. Differential diagnosis includes drug toxicity,
opportunistic infection, and leukemic opacities. Diagnosis was confirmed at
lung biopsy.
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Fig. 2. —47-year-old woman with hypersensitivity reaction; patient was
receiving bleomycin for Hodgkin's disease. High-resolution CT scan of chest
shows extensive bilateral ground-glass opacities and poorly defined
centrilobular nodules (arrows). Primary diagnostic considerations are
drug toxicity, opportunistic infection, and pulmonary hemorrhage. Diagnosis
was confirmed at open lung biopsy.
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Acute respiratory distress syndrome results in bilateral predominantly
dependent air-space consolidation with onset occurring within days of
chemotherapy administration [3]
(Fig. 3). Less commonly,
chemotherapeutic drugs result in a bronchiolitis obliterans organizing
pneumonia—like reaction. This type of reaction has been described with a
variety of drugs, especially bleomycin
[5]. Bronchiolitis obliterans
organizing pneumonia—like reactions commonly result in peribronchial or
subpleural areas of consolidation
[1]
(Fig. 4).
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Fig. 3. —57-year-old man with drug-induced adult respiratory distress
syndrome; patient was receiving bleomycin for non—Hodgkin's lymphoma.
High-resolution CT scan reveals extensive bilateral ground-glass opacities
primarily involving dependent lung regions. Differential diagnosis includes
opportunistic infection, drug toxicity, and pulmonary hemorrhage. Diagnosis
was confirmed at open lung biopsy.
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Fig. 4. —58-year-old man with bronchiolitis obliterans organizing pneumonia;
patient was receiving busulfan and cyclophosphamide chemotherapy for multiple
myeloma. High-resolution CT scan shows peripheral areas of consolidation. Note
striking left-sided predominance. Differential diagnosis includes bacterial or
fungal pneumonia and adverse drug reaction. Diagnosis was confirmed at lung
biopsy.
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Cardiovascular Agents
The most common cardiovascular agent resulting in pulmonary abnormalities
is amiodarone. Approximately 6% of individuals receiving amiodarone develop
pulmonary toxicity [6].
The most common clinical presentation consists of subacute onset of dyspnea
that manifests on high-resolution CT as diffuse interstitial thickening or,
less commonly, as nodular areas of subpleural consolidation (bronchiolitis
obliterans organizing pneumonia) (Fig.
5). Another less common presentation consists of acute onset of
dyspnea associated with fever; this presentation appears on high-resolution CT
as areas of dependent consolidation (Fig.
6).
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Fig. 5. —60-year-old man with bronchiolitis obliterans organizing pneumonia;
patient was receiving amiodarone for ischemic heart disease. High-resolution
CT scan of right lung shows irregular linear opacities, ground-glass
opacities, and focal areas of consolidation. Differential diagnosis includes
pneumonia, adverse drug reaction, and pulmonary edema. Diagnosis was confirmed
at lung biopsy.
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Fig. 6. —77-year-old man with bronchiolitis obliterans organizing pneumonia;
patient was receiving amiodarone for treatment of cardiac arrhythmia.
High-resolution CT scan shows extensive bilateral ground-glass opacities and
dependent areas of consolidation. Diagnostic considerations include pneumonia,
pulmonary edema, and adverse drug reaction. Diagnosis was confirmed at lung
biopsy.
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Amiodarone is an iodine-containing compound; therefore, parenchymal lesions
often show high attenuation, with a range from 82 to 174 H
[6] (Fig.
7A,7B).
Although this finding is helpful in suggesting amiodarone-induced pulmonary
toxicity, it is not pathognomonic.
Antibiotics
Antibiotics known to cause pulmonary disease include nitrofurantoin,
amphotericin B, sulfonamides, and sulfasalazine. Adverse drug reactions caused
by antibiotics include interstitial pneumonitis and fibrosis, hypersensitivity
reaction, acute respiratory distress syndrome, and bronchiolitis obliterans
organizing pneumonia.
Nitrofurantoin is a urinary antiseptic used in the treatment of urinary
tract infections. Pulmonary reactions occur in fewer than 1% of patients
receiving the medication [5];
however, it remains an important cause of adverse drug reaction. The most
common manifestation consists of an acute hypersensitivity reaction. Clinical
symptoms include dyspnea, cough, fever, and skin rash. High-resolution CT
shows air-space consolidation with a basilar predominance, a pattern
consistent with noncardiogenic pulmonary edema
[6]. Pleural effusions may be
present. Less commonly, chronic pneumonitis and fibrosis may ensue. This
occurs after years of continuous therapy and presents clinically with the
insidious onset of dyspnea and nonproductive cough. On high-resolution CT,
this appearance mimics idiopathic pulmonary fibrosis with bilateral,
predominantly basilar, reticular opacities
[6]
(Fig. 8). Occasionally a
bronchiolitis obliterans organizing pneumonia-like reaction may also be seen
[1]
(Fig. 9).
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Fig. 8. —74-year-old woman with interstitial fibrosis; patient was receiving
nitrofurantoin for recurrent urinary tract infections. High-resolution CT scan
shows predominantly basal subpleural reticular and ground-glass opacities.
Differential diagnosis includes adverse drug reaction, unrelated interstitial
lung disease, and pneumonia. Diagnosis was confirmed at open lung biopsy.
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Fig. 9. —81-year-old woman with bronchiolitis obliterans organizing
pneumonia; patient was receiving nitrofurantoin for recurrent urinary tract
infections. High-resolution CT scan shows bilateral areas of consolidation in
predominantly peribronchial and subpleural distribution. Primary diagnostic
considerations are bronchopneumonia, idiopathic bronchiolitis obliterans
organizing pneumonia, and adverse drug reaction. Diagnosis was confirmed at
transbronchial biopsy.
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Antiinflammatory Drugs
Antiinflammatory drugs are probably the most commonly used medications
worldwide and include drugs such as acetylsalicylic acid, nonsteroidal
antiinflammatory agents, methotrexate, and penicillamine. Acetylsalicylic acid
is the most common salicylate associated with adverse reactions. An acute
respiratory distress syndrome picture is described in salicylate toxicity
[5].
Methotrexate is currently used as an antiinflammatory agent in the
treatment of rheumatoid arthritis, psoriasis, and, more recently, asthma. A
low-dose regime is typically used; nevertheless, pulmonary toxicity has been
reported in approximately 4% of patients
[4]. Methotrexate toxicity is
most commonly subacute with a hypersensitivitylike reaction
(Fig. 10). High-resolution CT
reveals interstitial pneumonitis and occasionally centrilobular nodules or a
localized nodular airspace filling pattern
(Fig. 11).
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Fig. 10. —52-year-old man with hypersensitivity reaction; patient was
receiving methotrexate for rheumatoid arthritis. High-resolution CT scan shows
poorly defined centrilobular nodules (arrows) and extensive areas of
ground-glass attenuation. Differential diagnosis includes interstitial
pneumonitis related to rheumatoid arthritis, opportunistic infection, and
adverse drug reaction. Diagnosis was confirmed at open lung biopsy.
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Fig. 11. —70-year-old man with bronchiolitis obliterans organizing pneumonia;
patient was receiving methotrexate for temporal arteritis. High-resolution CT
scan shows bilateral ground-glass opacities, linear opacities, and patchy
areas of consolidation. Primary differential diagnosis includes opportunistic
infection, drug-induced lung disease, or unrelated interstitial pneumonitis.
Diagnosis was made at open lung biopsy.
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Illicit Drugs
The use of illicit drugs is increasing, and these drugs may now be the most
common cause of drug-induced pulmonary disease
[7].
IV injection of talc in sufficient quantities may result in talcosis (IV
drug abuser's lung). High-resolution CT shows diffuse micronodularity
resulting from a foreign body granulomatous response. The micronodules may
become confluent and progress to conglomerate parahilar masses, which tend to
have high attenuation caused by talc accumulation (Fig.
12A,12B).
Ground-glass attenuation has also been described
[7].
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Fig. 12A. —27-year-old female IV drug abuser with talcosis. High-resolution CT
scan shows magnified view of left lung. Conglomerate mass is seen on
background of fine micronodular interstitial pattern.
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Fig. 12B. —27-year-old female IV drug abuser with talcosis. Same image as
A obtained with mediastinal windows confirms high attenuation of
consolidative mass caused by talc accumulation. Findings are virtually
diagnostic of talcosis.
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IV injection of methylphenidate may result in talcosis and in severe
panlobular emphysema (Fig.
13). In one review of the autopsy findings of seven
methylphenidate abusers, all patients had severe lower lobe panacinar
emphysema [7].
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Fig. 13. —63-year-old man with panacinar emphysema and long history of IV
methylphenidate abuse. CT scan (3-mm collimation) shows severe lower lobe
panacinar emphysema. Identical appearance may be seen in patients with
 1-antitrypsin deficiency.
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IV heroin and cocaine may result in acute pulmonary edema with an onset
occurring within a few hours of injection. The edema is presumably caused by
direct alveolar capillary injury
[6].
Conclusion
The high-resolution CT manifestations of drug-induced lung disease imitate
other entities such as infection, pulmonary fibrosis, and disease recurrence.
The diagnosis should be suspected in patients receiving one or more drugs
known to be potentially damaging to the lung and with radiologic findings
consistent with interstitial pneumonitis and fibrosis, hypersensitivity
reaction, acute respiratory distress syndrome, or bronchiolitis obliterans
organizing pneumonia. The main value of high-resolution CT is in the depiction
of parenchymal abnormalities in symptomatic patients who have normal or
questionable findings on chest radiography.
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Introduction
Chemotherapeutic Drugs
