High-resolution computed tomography of amiodarone pulmonary toxicity

Abstracts

OBJETIVO: Avaliar as principais alterações identificadas na tomografia computadorizada de alta resolução do tórax em pacientes com toxicidade pulmonar pela amiodarona. MATERIAIS E MÉTODOS: Foram avaliadas dez tomografias computadorizadas de alta resolução de tórax de pacientes com pneumonite pela amiodarona, seis desses pacientes do sexo masculino e quatro do sexo feminino, com idade média de 73,5 anos. RESULTADOS: Os achados tomográficos mais relevantes foram opacidades lineares ou reticulares em seis casos (60%), pequenos nódulos com densidade elevada em seis casos (60%), consolidações densas em três casos (30%) e aumento da densidade do parênquima hepático em cinco de oito casos em que havia estudo tomográfico do abdome superior (62,5%). CONCLUSÃO: A tomografia computadorizada de alta resolução é um exame importante na avaliação de pacientes com toxicidade pulmonar pela amiodarona, devendo ser realizada sempre que houver suspeita deste diagnóstico. O achado de espessamento de septos interlobulares associado a lesões com aumento de densidade é altamente sugestivo deste diagnóstico.

Tomografia computadorizada; Amiodarona; Toxicidade pulmonar

ORIGINAL ARTICLE

High-resolution computed tomography of amiodarone pulmonary toxicity^*

Daniela Peixoto Consídera^I; Edson Marchiori^II; Arthur Soares Souza Jr.^III; Gláucia Zanetti^IV; Dante L. Escuissato^V; Emerson L. Gasparetto^VI; César de Araújo Neto^VII; Ronaldo de Souza Leão Lima^VIII; Sérgio Salles Xavier^VIII; Roberto Coury Pedrosa^VIII

^IMD Resident at the Radiodiagnostic of the Universitary Hospital Clementino Fraga Filho

^IITitular Professor of Radiology at Universidade Federal Fluminense, Assistant Coordinator Course of Post-Graduation in Radiology, Universidade Federal do Rio de Janeiro

^IIIAdjunct Professor of Radiology, Faculdade de Medicina de São José do Rio Preto

^IVTeacher of Pneumology, Faculdade de Medicina de Petrópolis

^VAssistant Professor of Radiology, Universidade Federal do Paraná

^VIMD Researcher, Institute of Radiology, Clinics Hospital, Faculdade de Medicina da Universidade de São Paulo

^VIIAssistant Professor of Radiology, Faculty of Medicine, Universidade Federal da Bahia

^VIIIMD at the Service of Cardiology of the Universitary Hospital Clementino Fraga Filho

^{Mailing address}

ABSTRACT

OBJECTIVE: To evaluate the main findings of chest high-resolution computed tomography in patients with amiodarone pulmonary toxicity.

MATERIALS AND METHODS: Ten patients % six male and four female, average age of 73.5 years % with amiodarone-induced pneumonitis have undergone chest high-resolution computed tomography.

RESULTS: The most relevant tomographic findings were linear or reticular opacities in six cases (60%), small high density nodules in six cases (60%), dense consolidations in three cases (30%) and increased density in the hepatic parenchyma in five of eight cases in which there was a superior abdomen CT scan (62.5%).

CONCLUSION: The high resolution computed tomography is a valuable non-invasive test for evaluating patients with amiodarone pulmonary toxicity and should always be performed when one suspects of the presence of this disease. The finding of interlobular septa thickening associated with increased density of lesions is highly suggestive of this diagnosis.

Keywords: Computed tomography; Amiodarone; Pulmonary toxicity.

INTRODUCTION

The amiodarone is a pharmacological agent that has been clinically utilized since the early sixties in Europe. Initially, it was used due its vasodilative and antianginal properties and, later, as an antiarrhythmic agent. Presently, the amiodarone is used to control atrial and ventricular arrhytmias, especially those that are life-threatening^(1,2).

Practically all the patients using this drug for a long period of time develop side effects⁽³⁾. The amiodarone is known for having the capability of causing adverse reactions in virtually any system of the organism. The most frequent side effects are: cutaneous, ocular, cardiac, gastrointestinal, thyroidal, neurologic, hepatic and pulmonary reactions. In the majority of the patients such side effects are well tolerated and usually can be attenuated by means of the drug dosing reduction, so that the amiodarone discontinuation rarely becomes necessary⁽⁴⁾.

Of all amiodarone adverse effects, the pneumonitis is the most severe side effect and that restricts more significantly its clinical use^(1,2,5,6). About 5% to 15% of patients treated with this drug may develop signs and symptoms consistent with pulmonary toxicity, and such complication may lead to death of 10% to 25% of these patients⁽³⁾.

The early diagnosis of the amiodarone-induced pulmonary toxicity is difficult. This condition signs and symptoms are similar to those inherent in the patient's base disease and its onset is insidious⁽²⁾. Additionally, due their non-specificity, supplementary examinations do not provide a definite diagnosis⁽⁷⁾. The chest X-ray demonstrates interstitial and alveolar opacities with variable distribution. The computed tomography, especially the high-resolution computed tomography (HRCT), may show bilateral septa thickening, poorly defined nodular consolidation; pleural effusion, ground-glass opacities, pulmonary masses and, in more advanced stages, findings of fibrosis^(4,7–11).

Therefore, this complication must be always taken into consideration aiming at the early implementation of the main conduct recommended for such cases, that is the interruption of the drug administration^(1,2,10).

The objective of this study is to describe the main alterations identified at chest HRCT in patients with amiodarone-induced pulmonary toxicity.

MATERIALS AND METHODS

In this study we have retrospectively analyzed ten chest HRCT of patients from three different institutions located in three Brazilian states (Rio de Janeiro, São Paulo and Rio Grande do Sul).

The patients were included in the study after exhaustive clinical, radiological and laboratorial evaluation, aiming at excluding other possible diagnoses. Inclusion criteria were: clinical picture, compatible tomographic findings and clinical improvement following an adequate therapeutic conduct. Exclusion criteria were: presence of associated pulmonary diseases, clinical and tomographic investigations incompatible with pulmonary toxicity diagnosis and absence of appropriate therapeutic response.

The chest HRCT were performed in different TC devices, with acquisition of 1 mm to 2 mm thick axial slices and 10 mm increments, taken during deep inspiration, from the apex through the pulmonary bases. Images acquisition was performed on parenchymal windows (width between 1.000 and 1.500 Hounsfield Units (HU) and center between –650 HU and –750 HU) and on mediastinal windows (width between 350 HU and 400 HU and center between 40 HU and 60 HU).

The HRCT analysis was performed independently by two observers and the final results were decided by consensus. The study has included the pulmonary parenchyma evaluation taking into consideration the presence of consolidations, ground-glass opacities, intra and interlobular septa thickening, dense nodular opacities, architectural distortions, pleural effusion or thickening and increased density of the hepatic parenchyma. The criteria for definition of these findings are those presented in the Fleischner Society's Glossary of Terms for CT of lungs⁽¹²⁾ and in the Terminology proposal of the Colégio Brasileiro de Radiologia⁽¹³⁾.

RESULTS

Ten patients were studied, six male (60%) and four female (40%) with ages ranging between 64 and 83 years, averaging 73.5 years.

The analysis of parenchymatous pulmonary alterations has demonstrated a mixed pattern of the disease presentation with pulmonary tracts and interstitial diseases in four patients (40%) presenting linear and reticular opacities and interlobular septa thickening associated with ground-glass opacities and consolidations. Four patients (40%) have presented purely interstitial disease and occupation only of the lung aerial space has occurred in two patients (20%).

At chest HRCT the most frequent findings were linear or reticular opacities (Figures 1 to 6), especially represented by interlobular septa thickening and presence of high density small nodules (Figures 2, 3, ⁵ and ⁶). Each of these findings was observed in six patients (60%). Dense consolidations (^{Figure 6}) were found in three patients (30%). The identification of dense nodules >1 cm occurred in one patient (10%). Ground-glass opacities (Figures 1 and ⁴) were found in three patients (30%). Tomographic signs of architectural distortion were identified in two patients (20%). Bronchiectasis was seen in one patient (10%).

Increased attenuation of parenchymatous lesions, in the form of small nodules and consolidations, was observed in eight of the ten patients studied (80%).

The analysis of the increase of the hepatic parenchyma density was feasible in CT studies including superior abdomen images. This has occurred in eight of the ten patients of our casuistic. Increased attenuation of the liver was observed in five (62.5%) of these eight patients.

Pleural effusion was observed in only one of the patients.

Tomographic alterations have predominated in inferior and posterior portions of the lungs, in eight patients (80%). Both lungs were affected in all these patients.

Tomographic findings are represented in Graphic 1.

DISCUSSION

The amiodarone is a pharmacological agent with several adverse side effects such as pulmonary toxicity; which constitutes the reaction that restricts more significantly its clinical use^(1-6). Conversely to the other side effects of this drug, which can be identified through the patients's clinical history and by means of laboratory tests, the amiodarone-induced pneumopathy requires supplementary evaluation for its diagnosis^(4,7–11). The computed tomography can be used as it presents more specific findings for this diagnosis than the chest x-ray, contributing to the distinction between amiodarone side effects and other possible differential diagnoses. The CT is also very useful in the initial diagnoses and follow-up of patients affected by this disease^{(1,2,9–11,14)}.

Of the ten patients included in this study, six (60%) were male and four (40%) were female. Also in the literature, one observes a higher prevalence of the amiodarone pulmonary toxicity in male patients^{(1,7–9,11,15)}. Patients' age ranged between 64 and 83 years, averaging 73.5 years, similarly to the data presented in the literature^(1,9,11,15). The prevalence of male patients and of a higher age range probably is due to the higher association of elder men with coronary arterial disease and, consequently, with arrhythmias that require the use of amiodarone⁽⁹⁾.

Tomographic manifestations in patients presenting amiodarone pulmonary toxicity are variable. Usually, the patients present associated tomographic findings^(1,15), and this fact has also been observed in our study.

The predominant findings in the patients studied have followed a mixed disease pattern, manifesting in the interstice and in the lung aerial space in four patients (40%), and a purely interstitial pattern, also in four patients (40%), totalling the presence of interstitial manifestation in 80% of the patients studied % either isolatedly or in association with manifestation in the lung aerial space. Only two patients (20%) have presented the disease purely in the lung aerial space. Other authors have reported similar findings^(4,10,11), and Terra Filho⁽¹⁰⁾ has observed mixed or only-interstitial alterations also in 80% of his cases. This preferential onset in the pulmonary interstice is corroborated by the fact that the unusual interstitial pneumonia is the most common histopathologic manifestation in the amiodarone pulmonary toxicity^(1,14).

Among the patients studied, the main tomographic alterations observed were: the linear or reticular opacities (60%), especially represented by interlobular septa thickening; high density small nodules (60%); dense consolidations (30%), dense nodules >1 cm (10%); ground-glass opacities (30%); tomographic signs of architectural distortion (20%); bronchiectasis (10%) and pleural alterations (20%). Eight of these patients had undergone CT scans including the superior abdomen portion % five (62.5%) presented increased density of the hepatic parenchyma. This tomographic alterations distribution is consistent with several studies available in the literature^(1,2,6,10).

Interlobular septa thickening evidenced in 60% of patients, also was reported in several other studies in the literature, resulting in the presence of conjunctive tissue, edema or inflammatory cells, mainly macrophages with spumous cytoplasm infiltrating septa^(1,8,10). The presence of macrophages with spumous or xanthomatous aspect is quite frequent in these patients, but is a non-specific finding^(10,11).

On the other hand, the demonstration of high-attenuation lesions with nodules or consolidations is a well known feature, suggestive of amiodarone pulmonary toxicity, although the percentage of these findings is not reported in the several studies referred to by the authors^(7–9,11,14). In our study, high-density small nodules were observed in six patients (60%), dense consolidations in three patients (30%) and dense nodules >1 cm in one patient (10%). All these findings, in total, were observed in eight patients (80%). These increased-density foci are a result of the high iodine contents in the amiodarone molecule that is incorporated principally by pneumocytes type II⁽¹⁴⁾.

Another aspect observed was the presence of ground-glass opacities found in three patients (30%). The literature reports variable frequencies of this finding. In some studies, the ground-glass opacity is not even described. However, other studies like that of Siniakowicz et al.⁽⁹⁾, report the presence of ground-glass opacities in 40% of the cases, while Vernhet et al.⁽¹¹⁾ report it in 100% of their cases, although this finding is non-specific to this toxicity⁽¹⁰⁾.

Architectural distortion, identified in 20% of the cases, and traction bronchiectasis, seen in 10%, were findings not frequent in our analysis. This data are consistent with the literature^(9,11).

Several authors have indicated the presence of increased density in the hepatic parenchyma as a highly specific sign, although poorly sensitive, of amiodarone pneumopathy. In literature, there are reports on frequencies between 62% and 91%^(1,9,11,14). In our casuistic, the increase in the hepatic attenuation was evidenced in five of the eight patients to whose superior abdomen CT we have gotten access to (62.5%). Therefore, this data is consistent with those presented in the literature.

Our study has demonstrated predominance of findings bilaterally in the inferior and posterior portions of the lung in eight patients (80%). This distribution is comprehensively described in the literature^(2,7,9,10), also as asymmetrical and predominant in the peripheral regions of the lungs.

Finally, the HRCT finding of high density parenchymatous lesions represented by nodules or consolidations, especially when associated with increased density of the hepatic parenchyma, is highly suggestive of amiodarone-induced pulmonary toxicity.

REFERENCES

Received July 1st, 2005.

Accepted after revision July 25, 2005.

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*

Study developed at the Radiodiagnostic Service of the Universitary Hospital Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ.

Publication Dates

• Publication in this collection
  25 May 2006
• Date of issue
  Apr 2006

History

• Received
  01 July 2005
• Accepted
  25 July 2005