Clinical Radiology (1992) 46, 232-236

Higtl-Resolution Computed Tomography of Drug-Induced Lung Disease S. P. G. PADLEY, B. ADLER, D. M. H A N S E L L * and N. L. M U L L E R

Department of Radiology, University of British Columbia and Vancouver General Hospital, Vancouver, B.C., • Canada and *Department of Radiology, Royal Brompton National Heart and Lung Hospital, Fulham, London In order to determine the potential clinical utility of high-resolution CT (HRCT) in the assessment of drug-induced lung disease, we reviewed the chest radiographs and HRCT scans of 23 patients and five normal controls. The radiographs and H R C T scans were reviewed separately in random order by two independent observers who were not aware of the relative numbers of patients and controls. Abnormal findings were detected in the affected patients in 17/ 23 radiographs compared to 23/23 H R C T scans. The patients included five cases of bleomycin toxicity, five cases of nitrofurantoin toxicity, two cases each of penicillamine, busulphan, B C N U and amiodarone toxicity, and one case each of cyclophosphamide, procainamide, mitomycin and methotrexate toxicity. The H R C T appearances could be grouped into four categories according to their dominant pattern and distribution of disease. These include fibrosis with or without consolidation ( n = 12), ground-glass opacities ( n = 7 ) , widespread bilateral consolidation ( n = 2 ) , and bronchial wall thickening with areas of decreased attenuation (n = 2). The results of this study indicate that H R C T is more sensitive than the radiograph in the detection of drug-induced lung disease. The appearances demonstrated by HRCT reflect the pathological mechanisms of drug-induced lung disease. Padley, S.P.G., Adler, B., Hansell, D.M. & Mfiller, N.L. (1992). Clinical Radiology 46, 232-236. HighResolution Computed Tomography of Drug-Induced Lung Disease

Accepted for Publication 14 May 1992 Many drugs are known to be toxic to the lungs, with cytotoxic agents having the highest incidence of adverse effects [ 1]. The development of toxicity is not always easily recognized. Although in some patients there is a clear temporal relationship between the onset of symptoms and the introduction of drug therapy, in others there may be a lag time of several years and intake of the responsible drug is not always disclosed in the history. Drug toxicity may go unrecognized particularly in immunosuppressed patients following chemotherapy, being masked by other pulmonary complications such as opportunistic infections or relapse of the underlying malignancy. The radiographic appearances of various drug-induced lung diseases have been described [2,3]. A small number of studies have assessed the CT and high-resolution CT (HRCT) findings [4 7] but these studies have not assessed the sensitivity of H R C T in the detection of drug-induced lung disease. The aim of this study was to compare the sensitivity of H R C T with the chest radiograph in the detection of drug-induced lung disease and to further characterize the H R C T findings. P A T I E N T S AND M E T H O D S The chest radiographs and H R C T scans of 23 patients with drug-induced lung disease and of five normal controls were reviewed by two independent observers (SP and BA). The observers knew only the age and sex of the patients and were unaware of the relative numbers of patients and controls. The age range of the patients was Correspondence to: Nestor L. Mfiller, Department of Radiology, Vancouver General Hospital, 855 West 12th Avenue, Vancouver, B.C., Canada V5Z 1M9.

23 81 years (mean, 50 years). The controls were patients scanned for suspected bronchiectasis or interstitial lung disease in whom no abnormality had been found. They were matched for age. Patient details, means of diagnosis and drug exposure are presented in Table 1. The length of exposure varied from 2 weeks (bischloronitrosourea, BCNU) to over 10 years (nitrofurantoin) (median 6 months). The chest radiographs and H R C T scans were reviewed in randomized order on separate occasions. The observers recorded the findings using a modification of the ILO format for assessment of pneumoconiosis. Chest radiographs were obtained using a high kV technique (19 patients and five controls), or advanced multiple beam equalization radiography (AMBER) (n = 2) or in the erect anteroposterior projection using a mobile unit (n = 2). The H R C T examinations were performed on one of two scanners. Eighteen patients and controls were examined on a GE9800 (GE Medical Systems, Milwaukee, WI) with scans at 1.5 mm collimation and 10 mm intervals through the chest. The remaining 10 patients were examined on an Elscint 2002 (Elscint, Hackensack, NJ) with scans at 3 mm collimation and 10 mm intervals. All images were reconstructed using a highspatial-frequency algorithm and large field-of-view and photographed at the appropriate windows and levels for assessment of lung parenchyma and mediastinal structures. The maximum time interval between the chest radiograph and the H R C T scan was 1 week, with the majority of examinations being obtained on the same day. The diagnosis of drug-induced lung disease was established by a variety of methods. In 14 cases the diagnosis was made based on a combination of clinical history, pulmonary function tests, differential white cell count, bronchoalveotar lavage, serology, lung D T P A clearance, lymphocyte transformation, or response to withdrawal of

HRcT OF DRUG-'INDUCED LUNG DISEASE Table

1 - Drug-induced

233

lung disease

No.

Age

Sex

Drug

Exposure

Primary means of diagnosis

1

51

M

Bleomycin

Postmortem examination

2

26

M

Bleomycin

360 mg and 120 mg 2 years and 3 months before 600 mg, 4 years before

3 4 5 6

57 26 51 55

M M F F

Bleomycin Bleomycin Bleomycin Nitrofurantoin

270 mg, 4 months before 540 mg, 5 years before 270 mg, 6 months before 1 course, 1 week before

7

60

F

Nitrofurantoin

2 years of daily exposure

8 9 l0 11 12

81 62 53 42 44

F F F M M

2 years of daily exposure 14 months daily exposure Several years use 2 years repeat exposure 1 week, chemotherapy

13

37

M

Nitrofurantoin Nitrofurantoin Nitrofurantoin Busulphan Busulphan/ cyclophosphamide Amiodarone

14

58

M

Amiodarone

2.5 years, 400 mg/day

15 16 17 18 19 20

69 67 49 23 28 49

F F F F F M

Cyclophosphamide Penicillamine Penicillamine BCNU BCNU Gold

I year; 100 rag/day 1 year daily exposure 18 months daily exposure Exposure 2 months previously Exposure 1 week previously 5 months, 3 years before

21 22 23

67 46 58

M M F

Procainamide Mitornycin-C Methotrexate

6 months daily exposure 1 month 1.25 mg/day for 2 years

2 years, 400 mg/day

DTPA clearance, PTF, response to steroids, temporal sequence DTPA clearance, PFT, temporal sequence TBB, response to steroids Postmortem examination Temporal sequence, rash, lung eosinophilia, response to withdrawal Temporal sequence, hmg eosinophilia, response to steroids and withdrawal TBB, response to steroids and withdrawal Response to withdrawal Lung eosinophilia, PFT, response to withdrawal Temporal sequence, PFT, effect of reintroduction Open lung biopsy, temporal sequence High attenuation parenchymal changes, temporal sequence High attenuation parenchymal changes, temporal sequence Open lung biopsy, temporal sequence PFT, temporal sequence, response to withdrawal PFT, temporal sequence PFT, temporal sequence, BAL PFT, temporal sequence Open lung biopsy, lung eosinophilia, lymphocyte transformation test Temporal sequence, response to withdrawal and steroids Postmortem examination Transbronchial biopsy

PFT, Pulmonary function tests; TBB, transbronchial biopsy; BAL, bronchoalveolar lavage; BCNU, bischloronitrosourea. Table 2 - Pattern

of radiographic

abnormality

according

to drug type

No. Pattern of response Fibrosis/ Ground- ARDS Bronchiolitis consolidation glass obliterans

Bleomycin Nitrofurantoin Penicillamine Busulphan BCNU Amiodarone Gold Cyclophosphamide Procainamide Mitomycin Methotrexate Total

5 5 2 2 2 2 1 1 1 1 1

4 4 -1 -2 1 -----

1 1 --2 --1

23

12

----

--2

I

--

----

----

1

--

--

1

---

1

--

--

7

2

2

ARDS, Adult respiratory distress syndrome; BCNU, bischloronitrosourea.

the i m p l i c a t e d d r u g . I n the r e m a i n i n g n i n e cases the d i a g n o s i s w a s also s u p p o r t e d by h i s t o l o g y f r o m t r a n s bronchial biopsy (n--3), open lung biopsy (n=3) or p o s t m o r t e m e x a m i n a t i o n (n = 3). F u l l details are g i v e n in T a b l e 2.

RESULTS Pulmonary parenchymal abnormalities were detected o n H R C T by b o t h o b s e r v e r s in all 23 p a t i e n t s c o m p a r e d to 17/23 c h e s t r a d i o g r a p h s . T h e six cases in w h o m the c h e s t r a d i o g r a p h w a s n o r m a l b u t the H R C T r e v e a l e d a b n o r m a l i t y i n c l u d e d t h r e e cases w i t h i r r e g u l a r l i n e a r

opacities (bleomycin (n=2) and busulphan), two with g r o u n d - g l a s s o p a c i t y ( B C N U ) (Fig. 1) a n d o n e w i t h p a t c h y areas o f d e c r e a s e d a t t e n u a t i o n a n d b r o n c h i a l wall thickening (penicillamine). In 10 o u t o f 17 p a t i e n t s w i t h a b n o r m a l r a d i o g r a p h s , HRCT demonstrated various other parenchymal abnorm a l i t i e s w h i c h w e r e n o t a p p a r e n t o n the r a d i o g r a p h . T h e s e i n c l u d e d : g r o u n d - g l a s s o p a c i t i e s (n = 5), i r r e g u l a r l i n e a r o p a c i t i e s (n = 2), b r o n c h i a l wall t h i c k e n i n g (n = 2), n o d u l e s (n = 2) a n d a p n e u m o t h o r a x (n = 1). U p to t h r e e a d d i t i o n a l f e a t u r e s w e r e a p p a r e n t in a n y o n e p a t i e n t . In the r e m a i n i n g seven p a t i e n t s H R C T a d d e d n o f u r t h e r significant i n f o r m a t i o n . T h e p a r e n c h y m a l a b n o r m a l i t i e s o n H R C T c o u l d be g r o u p e d i n t o f o u r d i f f e r e n t c a t e g o r i e s a c c o r d i n g to t h e d o m i n a n t p a t t e r n a n d d i s t r i b u t i o n o f d i s e a s e ( T a b l e 2). T h e m o s t f r e q u e n t p a t t e r n was t h a t o f fibrosis w i t h o r w i t h o u t c o n s o l i d a t i o n . T h i s d i a g n o s i s was b a s e d o n the presence of irregular linear opacities with architectural distortion and/or areas of consolidation. Included within this g r o u p w e r e f o u r o f the five cases o f b l e o m y c i n l u n g toxicity. I n t h r e e o f t h e s e the p r o c e s s w a s b i l a t e r a l w i t h a p r e d o m i n a n t l y s u b p l e u r a l b a s a l d i s t r i b u t i o n . I n the o t h e r case a single a r e a o f u n i l a t e r a l u p p e r l o b e fibrosis was present. The fibrosis/consolidation group also included f o u r o f the five cases o f n i t r o f u r a n t o i n toxicity. I n t h r e e o f these t h e d i s t r i b u t i o n o f fibrosis a n d c o n s o l i d a t i o n was p e r i b r o n c h o v a s c u l a r (Fig. 2), whilst in the f o u r t h it was predominantly subpleural. The remaining four causative a g e n t s in this g r o u p i n c l u d e d gold, w i t h a r a n d o m d i s t r i b u t i o n o f fibrosis a n d h o n e y c o m b i n g , a n d b u s u l phan which showed patchy consolidation with associated p l e u r a l t h i c k e n i n g . T h e o t h e r t w o cases w e r e o f a m i o d a r o n e t o x i c i t y a n d s h o w e d a r e a s o f c o n g l o m e r a t e fibrosis a n d c o n s o l i d a t i o n o f g r e a t e r t h a n soft tissue a t t e n u a t i o n

234

CLINICAL RADIOLOGY

(a)

(a)

(b) Fig. 1 (a) Chest radiograph of a 28-year-old female patient 1 week following administration of bischloronitrosourea (BCNU). The patient complained of shortness of breath. The chest radiograph is normal. (b) • 1.5 mm collimation HRCT image through the lower lung zones on the same day showing bilateral ground-glass opacities in the lower lobes in keeping with a hypersensitivity reaction.

(b)

Fig. 2 - 81-year-old female patient with 2 years of daily intake of nitrofurantoin. 1.5 mm collimation H R C T image at the level of the carina shows the peribronchovascular distribution of the fibrosis/ pneumonitis reaction.

Fig. 3 - ( a ) 58-year-old male patient with a 2.5 year history of amiodarone intake. 1.5 mm collimation HRCT image through the right upper lobe on lung windows shows areas of irregular consolidation with irregular linear opacities suggestive of fibrosis. (b) On mediastinal windows the areas of consolidation have greater than soft tissue attenuation, presumably due to iodine accumulation.

HRCT OF DRUG-INDUCED LUNG DISEASE

V

Fig. 4 55-year-old female patient with 1 week intake ofnitrofurantoin. 3 m m collimation H R C T shows patchy areas of ground-glass opacification in both lungs. The vessels are still visible.

5

Fig. 5 46-year-old female patient 1 week following mitomycin-C therapy. 1.5 m m collimation H R C T scan at the level of the carina shows consolidation mainly in the posterior aspects of the lungs in keeping with ARDS.

Fig. 6 - 49-year-old female patient with rheumatoid arthritis on penicillamine therapy. Pulmonary function tests showed a severe airway obstruction. 1.5 m m collimation H R C T scan demonstrates abnormally dilated bronchi in the right lower lobe (arrows) in keeping with the diagnosis of bronchiolitis obliterans.

235

(Fig. 3), which in one case mimicked rounded atelectasis. The second most frequent pattern was that of patchy bilateral areas of ground-glass opacification. This was seen in association with a variety of drugs including methotrexate, Neomycin, nitrofurantoin (Fig. 4), cyclophosphamide and BCNU. Small localized areas of airspace consolidation were also present in some cases. Eosinophilia in the bronchoalveolar lavage fluid or peripheral blood was seen in three of the six patients with these ground-glass opacities. Widespread bilateral consolidation was seen in two cases. One of these patients had undergone recent therapy with mitomycin-C (Fig. 5) and the other with busulphan. Airspace consolidation was widespread in a patchy distribution in association with multiple 5-10 m m poorly defined nodular opacities. The final pattern was one of patchy areas of decreased attenuation and hypovascularity seen in two cases of penicillamine-associated lung disease. In one case there was associated bronchiectasis (Fig. 6). Both of these patients were being treated for rheumatoid arthritis. The control cases were all correctly identified as normal by both observers on the chest radiographs and H R C T scans. On only two occasions were there major differences between the two observers. These concerned the presence or absence of subtle ground-glass opacities on the chest radiographs. Both of these cases were of bleomycin toxicity. Although the observers agreed about the presence of other abnormalities on the chest radiographs, one observer also felt that there was a ground-glass pattern present. H R C T revealed a mild ground-glass pattern and otherwise unrecognized basal fibrosis in both. On no occasion was there significant discrepancy between the observers on the H R C T findings. DISCUSSION The results of our study suggest that H R C T may be helpful in the diagnosis of drug-induced lung disease. The most important role of H R C T is the detection of abnormalities in patients with normal chest radiographs. The presence of disease may be suspected on the basis of the patient's symptoms or abnormal pulmonary function tests. The diagnosis of drug-induced lung disease is primarily clinical. There is no true gold standard test available, and even biopsy is not completely diagnostic if taken in isolation [8]. This was the case in the eight patients in our series who had undergone biopsy. The only instances in which a definitive diagnosis would have been made in the absence of a history of drug ingestion were in the cases of amiodarone toxicity, where high attenuation deposits were present within the lung parenchyma on CT, although this may not be seen in all cases and may be related to the overall dose of the drug. Although the mechanisms by which drugs induce lung disease have yet to be fully elucidated, four main patterns of lung response to drug injury are currently accepted [13]. We feel that the four H R C T patterns ofparenchymal abnormality seen in our series may reflect the four pathological responses. The most c o m m o n response is that of pneumonitis and fibrosis. This is seen most consistently in association with cytotoxic chemotherapy, particularly bleomycin [5,9,10]. The pathological appearances may be similar to usual interstitial pneumonia with a predominantly basal and

236

CLINICAL RADIOLOGY

subpleural distribution. Four cases of bleomycin toxicity demonstrated the fibrosis/consolidation pattern in our series, and fibrosis and pneumonitis was confirmed in both cases which were subsequently examined pathologically. Chronic nitrofurantoin toxicity may lead to the development of lung fibrosis; four of our five cases of nitrofurantoin toxicity demonstrated the fibrosis/consolidation pattern on HRCT. This was predominantly peribronchovascular in three patients and subpleurat in one. Amiodarone toxicity can be readily recognized by greater than soft tissue attenuation of the airspace consolidation, as described by Kuhlman et al. [11]. This is presumably due to tissue accumulation of the drug which, being an iodinated compound, acts like a contrast agent [12]. The second response seen with drug-induced lung disease is that of hypersensitivity reaction. In these patients the onset is often more acute, is unrelated to the cumulative dose of the drug, and is associated with generalized systemic effects. A peripheral eosinophilia may be present in up to 40% of cases [13]. Hypersensitivity reaction is commonly described with methotrexate [13-15] and ground-glass opacities have been shown to be the most common finding in patients with hypersensitivity pneumonitis [16,17]. In our study ground-glass opacities were seen with methotrexate and also with bleomycin, nitrofurantoin, cyclophosphamide, BCNU and procainamide. Pathologic confirmation of hypersensitivity reaction was present in the three cases examined histologically. The third kind of lung response to drug-induced injury is adult respiratory distress syndrome (ARDS). On H R C T this results in diffuse airspace consolidation that may have a dependent distribution [18]. In the two patients with this pattern of disease in our series, there was sudden development of abnormality within a few days of chemotherapy, as is typically described in ARDS associated with drug reaction [13]. ARDS was confirmed pathologically in both cases. Other than the temporal relationship to chemotherapy, there are no clinical or • radiological features of drug-induced ARDS that allow it to be differentiated from other causes. In general, the prognosis for drug-induced ARDS is better than when other aetiologies are responsible [ 13] although both of the patients in our series died. ARDS reaction is most frequently seen in association with chemotherapeutic agents such as mitomycin-C and cyclophosphamide, as in our study. It is also associated with many other drugs, most notably narcotic analgesics [13]. The final lung response to drug-induced injury is bronchiolitis obliterans, which has been described most frequently in association with penicillamine therapy for rheumatoid arthritis [19]. The role of penicillamine is controversial. Bronchiolitis obliterans may also be seen in rheumatoid arthritis [20] without any apparent inciting cause and it is unknown whether penicillamine plays a major role or not. Both cases of penicillamine toxicity in our study demonstrated bronchial wall thickening with areas of decreased attenuation, and also fulfilled the clinical criteria for bronchiolitis obliterans as described by Turton et al. [21]. Although bronchiolitis obliterans was not confirmed pathologically, such H R C T appearances and bronchiolitis obliterans have previously been documented to accurately correlate [22]. In conclusion, the results of our study indicate that

H R C T may be useful in the diagnosis of diffuse druginduced lung disease by Confirming the presence of parenchymal abnormality in patients with normal chest radiographs. Furthermore, H R C T allows better characterization of the nature of the abnormality and assessment of extent and distribution of disease. The H R C T findings reflect the main patterns of drug-induced lung disease. REFERENCES

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High-resolution computed tomography of drug-induced lung disease.

In order to determine the potential clinical utility of high-resolution CT (HRCT) in the assessment of drug-induced lung disease, we reviewed the ches...
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