Copyright #ERS Journals Ltd 2001 Eur Respir J 2001; 18: Suppl. 32, 93s–100s European Respiratory Journal Printed in UK – all rights reserved ISSN 0904-1850 ISBN 1-904097-01-4

REVIEW

Drug-induced infiltrative lung disease

Ph. Camus, P. Foucher, Ph. Bonniaud, K. Ask

Drug-induced infiltrative lung disease. Ph. Camus, P. Foucher, Ph. Bonniaud, K. Ask. Service de Pneumologie et de Re´anima- #ERS Journals Ltd 2001. tion Respiratoire, Centre Hospitalier ABSTRACT: An increasing number of drugs are recognized to induce distinctive Universitaire de Dijon, et Unite´de patterns of infiltrative lung disease (ILD), ranging from benign infiltrates to life- Pharmacologie Toxicologie Pulmo- naire, Universite´ de Bourgogne, Dijon, threatening adult respiratory distress syndromes. In addition to drugs, biomolecules France. such as proteins and cytokines, and medicinal plants are also capable of inducing , some being severe and/or irreversible. Correspondence: Ph. Camus, Service For several reasons it is difficult to estimate the exact frequency of drug-induced de Pneumologie et de Re´animation infiltrative lung disease (DI-ILD). The risk for DI-ILD and the clinical patterns vary Respiratoire, CHU de Dijon, Dijon, depending on a variety of host and drug factors. France. Although establishing the diagnosis is often difficult, systematic evaluation of the Fax: 33 380293251 possible role of almost any kind of drugs in ILD is warranted, as stopping a drug may Keywords: Drug-induced lung disease favourably influence prognosis. However, prognosis depends on the drug and the type of drugs DI-ILD. may suppress the inflammatory reaction, but for many drugs, lung toxicity proof of the effect of corticosteroids is lacking. patients Advances in prevention and prediction are needed. A user-friendly database of registry respiratory adverse drug reactions was made available on the web, to provide quick web technology information in this area. Eur Respir J 2001; 18: Suppl. 32, 93s–100s.

In the relatively recent past, conventional (i.e. gathered [15], and made available to the clinician, as nonillicit) drugs (as opposed to medical or surgical regards which drugs can cause adverse effects in the procedures) have emerged as relatively common and lung, and what pattern of lung reaction can be significant inducers of diffuse infiltrative lung disease expected with the use of a given drug [1–4, 14, (ILD) [1–5], as well as of pleural and pulmonary 16–18]. During that period of time, accrual of vascular disease [5–7]. Here, the term "infiltrative" will information has been almost relentless [15]. In be preferred to "interstitial", as drugs can induce addition, novel patterns of respiratory involvement alveolar filling processes, in addition to affecting the and newer offending compounds have been described, interstitium [8–10]. Drugs as aetiological agents of as new drugs or combinations were made available to ILD are interesting for two main reasons: 1) they offer the clinician, and postmarketing experience on drugs a coherent explanation to a sizeable number of ILD expanded. cases seen in clinical practice [11]; and 2) early In the past, information on DI-ILD was essentially withdrawal of the causative drug will often lead to available in the form of conventional articles [1–5]. improvement or even cure of the ILD. A supplemental source of information was recently In addition to the utility of a catalogue of causative provided, in the form of the free and continuously drugs and clinical pictures, at present [5, 11], it is updated Pneumotox1 website [11]. The site was necessary to look ahead, and to ask further questions designed and constructed to provide the interrogator in order to prepare the future of iatrogenic lung with quick and easy access to formatted data, and disorders. It is beyond the scope of the present paper relevant literature on drug-induced respiratory dis- to review all drug-induced respiratory diseases [11–13], ease. At the time of writing, the site9s database but rather to point out novel aspects, and raise contained 4,320 references on DI-ILD available questions that need to be addressed. For a more com- on-line. An overview of this accumulated literature plete overview of drug-induced respiratory diseases, 1 shows marked heterogeneity in reports. This illus- refer to the Pneumotox website [11] and to com- trates the need to improve existing diagnostic criteria prehensive review articles [1–3, 14]. [19] and to provides publication guidelines for all reports on DI-ILD in the future. Data Processing In addition to drugs, biomolecules can also induce ILD, and include the following. 1) Interferons (used From 1950 onwards, a considerable amount of in the treatment of chronic myelogenous leukemia information on drug-induced (DI)-ILD has been and of hepatitis C), which have been linked to the 94s PH. CAMUS ET AL. development of cutaneous or thoracic pulmonary toxicity syndrome" seen in this context [20–23] or obliterans with organizing remains to be delineated [50–53]. 4) Estimates of DI- (BOOP) [24]; this is of interest to the ILD frequency would require systematic notification general understanding of the pathogenesis of these of drug-induced adverse effects to centralized drug- diseases. 2) Immunoglobulins and anti-thymocyte monitoring agencies (as performed in several coun- globulin, which may induce pulmonary infiltrates or tries, including France; but a Europe-wide reporting pulmonary oedema [25, 26]. 3) Substances which system is needed), and estimates of the number of modulate the growth, release or maturation of blood exposed patients. Therefore, any estimate of the cells or progenitors, which have been shown to induce frequency of DI-ILD is probably an underestimate. severe ILD, and even the acute respiratory distress syn- drome (ARDS); examples include all-trans-retinoic acid (ATRA) [27, 28], used in the management of pro- Risk factors myelocytic leukemia, and granulocyte (G)- or granulo- cyte monocyte (GM)-colony stimulating factor (CSF) A major, but largely unresolved question is why, [29, 30], used to restore white blood cell counts in out of the treated population of patients, only some patients with bone marrow hypoplasia, mainly of individuals will develop DI-ILD (see the report by iatrogenic origin. 4) Transfusions, which can induce NEMERY et al. [54] in this Supplement). A limiting dose the transfusion-related lung injury (TRALI) syn- has only been identified for a few drugs [55]. For drome, which consists of the rapid development of amiodarone and bleomycin, toxicity was once con- pulmonary infiltrates or pulmonary oedema, follow- sidered likely only if high doses had been adminis- ing transfusion of blood or blood products containing tered, but several recent reports of side-effects after antileukocyte or antihuman leukocyte antigen (anti- low doses of these drugs tend to suggest that there is HLA) antibodies of donor origin [31, 32]. 5) A novel no real safe dose [56, 57]. For most drugs there is no pattern of pulmonary complications has been des- apparent role of dosage or duration of treatment in cribed following stem cell transplantation, in the form relation to the likelihood of developing adverse of pulmonary cytolytic thrombi originating from effects, i.e. development remains largely unexpected donor cells [33]. and idiosyncratic. Thus, whereas DI-ILDs were formerly regarded as Other explanations for the unequal risks among interstitial tissue reactions to drugs, the three latter patients include the following. 1) Prior respiratory patterns suggest that they may also result from reactions to the drug, to a congener, or to unrelated damage to pulmonary vessels, during the transit, compounds. Beyond occasional mentions in case aggregation and/or sequestration of activated blood reports [58–62], little data are available in that area. cells or progenitors within the pulmonary circulation. 2) Type of underlying disease for which the drug is Treatments with natural products, such as herbs being given. Diseases such as rheumatoid arthritis [63] and other "dietary supplements", will also require or ulcerative colitis [50], may increase the relative close attention, as they increasingly appear capable of risk of developing respiratory disease from disease- causing serious diseases [34–37]. Well-documented modifying drugs. 3) Occupational factors, such as expo- examples are the association of the intake of ephedra sure to asbestos, which may potentiate the noxious with death from cardiovascular causes, of comfrey with respiratory effects of ergot drugs [64–66]. 4) Activa- hepatic veno-occlusive disease, of germander with tion and detoxication pathways of drugs and che- acute hepatitis, of aristolochic acid in a chinese herb micals, which differ quantitatively and qualitatively with urothelial cancer [36, 37], and of shrub leafs among individuals [67]; also, some ethnic groups may containing Sauropus androgynus with bronchiolitis be at increased risk of developing adverse reactions obliterans [38–42]. to drugs [46, 68–70]. 5) Hepatic or systemic reactions to drugs were occasionally linked to acetylator or HLA phenotype [71], but in contrast to these, very Demographics and epidemiology few studies have addressed the possibility of such a relation in patients with DI-ILD. The overall rarity It is difficult to estimate the exact frequency of and scattering of cases may be an explanation of why DI-ILD for several reasons, including the following. such analysis has not yet been possible. 6) The role of 1) The use of plain chest radiography is likely to drugs taken concomitantly may be important, via underestimate subclinical forms of DI-ILD, compared their possible impact on cytochrome P450 systems, on with high-resolution computed tomography (HRCT) detoxication pathways, or via altered pharmacoki- [43]. This has been exemplified by asymptomatic netics of the offending drug [72]. More information is patients taking amiodarone [44], who may have needed in this area. 7) Hazardous associations have opacities detectable at HRCT or at autopsy [45]. 2) been reported, such as the concurrent administration Many drugs that induce ILD are used primarily by of several chemotherapeutic agents, of chemotherapy nonrespiratory physicians [46–49], and underdiagnosis and radiation, and of chemotherapy (even remote) is possible. 3) In oncology patients, where DI-ILD is with high inspired concentrations of oxygen. Inad- common and the differential diagnosis is broad, the vertent mixing of potentially pneumotoxic treatments ultimate diagnosis will often remain presumptive, may lead to an unexpected pulmonary toxicity, known because the severe clinical status of the patient as recall [73–76], which may develop at precludes the use of invasive diagnostic techniques. doses of each offending agent individually considered The role of drugs in the pathogenesis of the "delayed to be safe and nontoxic. 8) Bleomycin may exhibit DRUG-INDUCED INFILTRATIVE LUNG DISEASE 95s enhanced pulmonary toxicity in a patient with renal follows the exposure to anticonvulsants [60, 94, 95, failure [77]. On the other hand, a slow, as opposed to a 97, 98]. 3) Drug-induced alveolar haemorrhage with rapid infusion, may decrease the likelihood of bleo- concomitant renal failure from penicillamine [99]. mycin pulmonary toxicity [78]. 4) ANCA-positive drug-induced angiitis with or Although these risks are well recognized, it is un- without pulmonary capillaritis and haemorrhage, clear that all these hazards are really taken into ac- recently related to the use of the antithyroid drug count and implemented sufficiently in clinical practice. propyl-thiouracil [100–105], in addition to a few other There are also examples of individuals who differ in compounds [106–109]. 5) The drug-induced Churg- their risk of developing pulmonary disease following Strauss syndrome, occasionally described in the past an apparently similar pulmonary insult [79]. For following the use of aspirin [110], macrolides [111, instance, why only a fraction of patients with defi- 112], and more recently described in patients nite amiodarone pneumonitis will ultimately develop on leukotriene antagonists [111–114]. irreversible pulmonary fibrosis, while others will Children may also develop DI-ILD [115]. Chemo- recover, remains largely unexplained. therapy, radiotherapy or their combination in early Despite identification of some risk factors, predic- childhood, for instance for brain tumours or lym- tion of a DI-ILD remains difficult. Only for a limited phoma, may lead to a pattern of progressive number of drugs (bleomycin, nitrosoureas, amiodar- pulmonary retraction and fibrosis [116]. The pulmo- one), is monitoring of patients who receive the drug nary maldevelopment may be aggravated with advisable, but even this is debatable [80]. growth, and lead to impaired lung function and loss of functional reserve, resulting in lung transplantation in adolescence, or in early adulthood. Clinical patterns

The clinicoradiographical correlates of DI-ILD Histopathology range from subclinical opacities [81] to a picture of white lungs with the criteria of ARDS [11, 82, 83]. Reports of DI-ILD in which histological data were Several drugs (including amiodarone, bleomycin, obtained (v10% of those published to date [11]) colony stimulating factors, methotrexate, mitomycin, indicate that drugs can induce many distinctive nitrofurantoin) [11], and several histopathological histopathological patterns of ILD (table 1). In the patterns (acute cellular-type nonspecific interstitial constellation of ILD patterns described [140–142], pneumonia, acute , acute most can be induced by drugs. Only giant-cell organizing pneumonia (alternatively called BOOP), interstitial pneumonia and respiratory bronchiolitis- acute pulmonary oedema or alveolar haemorrhage) interstitial lung disease have not (yet) been related may lead to the clinicoradiographical and gas- to exposure to drugs. While drugs can trigger the exchange pattern of ARDS [11]. Accordingly, pul- development of such conventional patterns of ILD monary physicians should inform their colleagues in as nonspecific interstitial pneumonia (cellular or the intensive care field, that drugs can cause life- fibrotic), eosinophilic pneumonia [59], or pulmonary threatening and ARDS. fibrosis [143], drugs can also elicit less usual patterns In the patient with migratory opacities with or such as organizing pneumonia (OP, previously desig- without chest pain that could be suggestive of nated BOOP) [86, 122, 144], or desquamative inter- organizing pneumonia, a careful drug history should stitial pneumonia (DIP) [124]. The two latter patterns also be taken, as this clinical pattern may relate to have such a limited number of other recognized causes exposure to drugs, or radiation [84–86]. that the iatrogenic cause for the ILD is sometimes Among the mild forms of DI-ILD, transient suspected as a result of the histological report. Other infiltrates have been described following administra- than mineral oil pneumonia [145] and, sometimes, tion of drugs (such as hydrochlorthiazide, nitro- amiodarone pneumonitis [146], the histopathological furantoin, novel anticancer agents) [87], proteins appearance of DI-ILD is almost indistinguishable [26], colony stimulating factors [29], and blood from that of their counterparts occurring idiopathi- products [31]. Understandably, the histopathological cally, or from other causes. background of these transient and benign infiltrates While some drugs (e.g. minocycline, nitrofurantoin) remains almost unknown [88], as no biopsy was taken induce quite stereotyped reactions in the lung (eosi- in these cases. nophilic pneumonia and the cellular type of non- While in most instances, the pulmonary reaction in specific interstitial pneumonia, respectively) [11], other DI-ILD is confined to the lung, or restricted to the drugs (e.g. amiodarone, bleomycin), can induce a lung and liver [89], it may occasionally be part of a palette of variegated histopathological patterns in generalized and systemic syndrome [60, 90–95]. different patients [11]. As an example, patterns Examples, include the following. 1) The drug-induced described under the term "amiodarone pneumonitis" systemic lupus erythematosus syndrome [96], which may include nonspecific interstitial pneumonia (cel- may result from exposure to a wide array of drugs [11] lular or fibrotic type), alveolar filling by foamy (e.g. hydralazine, beta blockers, nonsteroidal anti- macrophages, organizing pneumonia, diffuse alveolar inflammatory drugs and many others). 2) Drug-induced damage, interstitial lung fibrosis, a pattern of "usual hypersensitivity syndromes, with involvement of liver, interstitial pneumonia", or any combination thereof brain, heart, digestive system, bone marrow, lymph depending on the patient and, possibly, the site of nodes or any combination of these, which mostly the lung biopsy [11, 146]. The reasons why some drugs 96s PH. CAMUS ET AL.

Table 1. – Types of infiltrative lung disease which may be induced by drugs (pulmonary oedema was omitted) Type of infiltrative Prototypic drug(s) Frequency Severity Literature Number of lung disease causative drugs [11]

NSIP-cellular Methotrexate, nilutamide Common Mild [18, 46] 89 Granulomatous IP BCG, methotrexate Uncommon Mild [18, 117, 118] 8 Pseudo-sarcoidosis Interferons (antiretroviral therapy?) Uncommon Mild [20, 23, 119] 3 Eosinophilic pneumonia Antibiotics, NSAID, ACE inhibitors Common Can be severe [58, 120, 121] 95 Organizing pneumonia Amiodarone, bleomycin, interferons, Common Can be severe [83, 84, 23 nitrofurantoin, radiations, statins 122, 123] DIP Nitrofurantoin Rare Moderate [124] 3 LIP Phenytoin Very rare? Mild [125] 1 NSIP-fibrotic, or IPF-like Amiodarone, chemoptherapy, ergots Quite Severe [8, 48, 126] 34 common AIP/DAD Chemotherapy, gold, methotrexate* Quite Usually [127–132] 10 and most common severe chemotherapies Alveolar filling process with Amiodarone, mineral oil Quite Variable [9, 10, 45] 2 foamy macrophage common Alveolar haemorrhage Anticoagulants, fibrinolytic agents, Unusual Variable [133–137] 25 pulmonary haemosiderosis** penicillamine, PTU Proteinosis-like Busulfan Rare ? [138, 139] 1 NSIP: nonspecific interstitial pneumonia; IP: interstitial pneumonia; DIP: desquamative interstitial pneumonia; LIP: lymphocytic interstitial pneumonia; IPF: idiopathic pulmonary fibrosis; AIP: acute (or accelerated) interstitial pneumonia; DAD: ; PTU: propyl-thiouracil; BCG: bacille Calmette-Gue´rin; NSAID: nonsteroid anti- inflammatory; ACE: angiotensin converting enzyme. *: as per gold or methotrexate, it may be difficult to distinguish "hyperdense" cellular NSIP, from true DAD; **: in addition, alveolar haemorrhage may complicate most cases of acute cellular interstitial pneumonia; ?: too few data available. are capable of inducing several patterns of ILD, Future outlook and why a given patient will develop a given pattern remain unknown. In order to improve current knowledge of DI-ILD, A notable clue that suggests the drug as a cause, is and to have it move beyond the purely descriptive art, the fact that the ILD (e.g. nonspecific interstitial which was necessary up to now, it is necessary to: 1) pneumonia, organizing pneumonia) will demonstrate refine and homogenize the diagnostic criteria of all a relative refractoriness to steroids, or will recur while forms of drug-induced respiratory diseases among the patient is still receiving relatively high dosages of steroids [124]. different countries, to give future publications a com- Of note, long-term treatment with steroids, which mon and interpretable framework; 2) help develop are occasionally needed to control severe DI-ILD, and serve drug monitoring systems, in conjunction expose the patient to significant risks, including that with responsible agencies, be they country-based or of severe opportunistic infections in the lung or European, with the objective of exhaustively collecting elsewhere. and formatting data on drug-induced adverse res- piratory reactions; 3) collect data on associated or other risk factors, including genetic profile, occupa- Imaging tional exposure, history (even remote) of exposure to drugs [151]; and 4) evaluate the long-term conse- The pattern and topographic distribution of opa- quences of drug-induced respiratory diseases, in order cities in patients with DI-ILD are highly variable. to better guide pulmonary physicians in the manage- Occasionally, imaging features are very suggestive, if ment (including the handling of steroids) and follow-up not pathognomonic, of certain types of DI-ILD. of afflicted patients. Examples include the "foamy" opacities of lipidic With these data at hand in the future, broader density seen on HRCT of patients with mineral oil understanding, better prevention, earlier detection, pneumonia [9], and the asymmetrical, nonsegmental and overall reduction of the severity of drug-induced opacities common to many patients with amiodarone infiltrative lung disease should follow. This may help lung [147]. Other imaging features are suggestive of a lawmakers to accurately delineate fields of responsi- given histopathological pattern of DI-ILD, like the bility, and prepare ways to compensate patients migratory, occasionally painful opacities of BOOP adequately. [85], the "melted candlewax-like" opacities in nitro- furantoin lung or in some OP cases [43, 148], the image of "photographic negative of pulmonary oedema" of eosinophilic pneumonia [149], and the distinctive Acknowledgements. The authors wish to mosaic pattern of desquamative interstitial pneumo- thank C. Sartini-Camus for invaluable help in nia [150]. refining the manuscript. DRUG-INDUCED INFILTRATIVE LUNG DISEASE 97s

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