Drug-induced infiltrative lung disease

CHAPTER 16

Drug-induced infiltrative lung disease V. Cottin*, P. Bonniaud# *Universite´ de Lyon, Universite´ Lyon I, UMR754 INRA, IFR128, Hospices civils de Lyon, Hoˆpital Louis Pradel, Service de pneumologie – centre de re´fe´rence des maladies orphelines pulmonaires, Lyon, and # Universite´ de Bourgogne, Hoˆpital du Bocage, Service de Pneumologie et Re´animation Respiratoire, Pneumotox, Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) 866, Dijon, France. Correspondence: V. Cottin, Hoˆpital Louis Pradel, 69677 Lyon (Bron) Cedex, France. E-mail: vincent. [email protected]

Infiltrative lung diseases, or more broadly diffuse parenchymal lung diseases, encompass a wide and heterogeneous group of disease processes characterised by diffuse lung parenchymal opacities on chest imaging, which often but not always correspond to interstitial lung disease (ILD) on histopathology, with diffuse infiltration of the lung interstitium by cells and/or excess of extracellular matrix. Drug-induced lung disease may affect the airways, the lung parenchyma, the pulmonary circulation, the pleura, the thoracic lymph nodes and the neuromuscular system. Drug-induced ILD (DI-ILD) thus represents one of the many possible manifestations of drug-induced thoracic or lung disease. DI-ILD is characterised by a wide range of severity (from asymptomatic drug-induced manifestation to lifethreatening acute respiratory distress syndrome (ARDS)), imaging patterns, pathology and causative drugs. The diagnosis may be hampered by the lack of specificity of the clinical, imaging and pathological features of DI-ILD, which are often similar to those of ILD due to other causes or to idiopathic ILD. One drug may cause several patterns of clinical radiological manifestations [1]. Occasionally, however, some typical presentations may especially prompt the search for a causative drug. DI-ILD may present in three main clinical settings: 1) some patients taking a drug for several months (or years) for the treatment of chronic disease progressively develop increasing dyspnoea with cough and mild fever; 2) in asymptomatic patients, the ILD may be discovered by systematic chest radiograph; 3) some patients present with acute ILD sometimes requiring mechanical ventilation. Associated extrapulmonary iatrogenic manifestations may be present, especially cutaneous rash, hepatitis, fever or nausea. The search for a causative drug should be systematic in the diagnostic process of any ILD, because it may lead to discontinuation of the responsible drug and frequently to administration of corticosteroids. All the drugs taken in the weeks or months preceding the clinical syndrome must be carefully recorded in any patient presenting with ILD, including illicit drugs (cocaine, heroin or cannabis), the intake of which is often denied by the patient. Here, we review both the main patterns of DI-ILD and the most frequently encountered and most recently described drugs causing ILD, with the exclusion of illicit drugs and the effect of radiation therapy.

Eur Respir Mon, 2009, 46, 287–318. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2009; European Respiratory Monograph; ISSN 1025-448x.

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Pathophysiology of drug-induced infiltrative lung disease Risk factors It is almost impossible to predict which patients will react to certain drugs. However, a number of risk factors have been identified. Dose-related toxicity appears for a few drugs, including amiodarone, bleomycin (500 units), carmustine (BCNU; 1,500 mg?m-2), mitomycine (50 mg?m-2) or radiation therapy. However, the importance of cumulative dose is somewhat theoretical as DIILD may occur unpredictably after lower doses of these agents [2]. The intravenous route and importantly the administration rate may increase the risk of developing DIILD (bleomycin, amiodarone, IV salbutamol, etc.). Combination of several pneumotoxic drugs, as in patients receiving multidrug chemotherapy for malignant conditions, significantly increases the risk of developing DI-ILD. Several early clinical trials using multi-agent chemotherapy regimens were terminated because of unacceptable pulmonary toxicity [3]. The addition of radiation therapy to the chest is a classical synergistic risk factor. High oxygen concentrations may increase both the occurrence rate and the severity of DI-ILD, leading to overt ARDS, as described with amiodarone, bleomycin or radiation therapy [4]. Ethnicity or genetic background may be a risk factor [5] because of the variability in detoxification mechanisms (acetylator phenotype, human leukocyte antigen group). For example, Japanese people are more likely to develop ILD induced by gefinitib than are other populations. History and past exposures to aerocontaminants as well as underlying conditions possibly affecting the lung must be taken into account. For instance, a background of pulmonary involvement due to rheumatoid arthritis or pneumonectomy may be prone to the development of DI-ILD. Incidence also depends on the frequency of drug prescription. Accordingly, amiodarone, bleomycin and chemotherapy agents (and we anticipate possibly statins in the future) account for the greatest number of published cases. Finally, the greatest risk is deliberate or inadvertent rechallenge, which may lead to relapse with an increased clinical severity. For this reason, rechallenge is not advisable for diagnostic purposes.

Mechanisms of DI-ILD The mechanisms that lead to DI-ILD are unclear. Drugs causing ILD are generally transported to the lungs in the bloodstream, whatever the initial route of administration (oral, intravenous, intraocular, etc.). The delivery of drugs directly through the respiratory tract is rarely responsible for ILD; this is the case, however, in exogenous ‘‘lipoid’’ pneumonia with direct involuntary inhalation of especially laxative oil. Although the liver is the main organ of drug metabolism, the lung contains a rich enzymatic system and is also an actor of drug biotransformation and bioactivation. Thus, toxicity to the lung may occur because of the drug itself, its metabolites, or the products of its bioactivation (i.e. toxic oxygen species). The main toxic mechanisms are listed in table 1, with examples.

Diagnosis and assessment of causality Establishing the diagnosis of DI-ILD requires the exclusion of other causes of ILD. There is usually no specific test to confirm the diagnosis of DI-ILD. However, it is 288

DRUG-INDUCED INFILTRATIVE LUNG DISEASE

Table 1. – Main toxic mechanisms leading to drug-induced interstitial lung disease Mechanism Direct toxic effect of the drug or its metabolites Oxidant injury Phospholipidosis Immune system-mediated injury Vascular damage Direct biological effect of the drug Indirect biological effect of the drug Apoptosis

Examples The lung has a very low level of bleomycin hydrolase, thus bleomycin cannot be inactivated in the lung and therefore causes direct DNA damage Nitrofurantoin or chemotherapy drugs increase oxygen radical production, leading to inflammatory and fibrotic reactions The amphophilic drug amiodarone impairs phospholipidic catabolism with resulting phospholipidosis in alveolar macrophages (foamy macrophages) [6] Drugs may act as an adjuvant activating the immune system, as in drug-induced systemic lupus or in other general symptoms like the DRESS syndrome [7]; methotrexate can induce hypersensitivity reactions IL-2 is responsible for a capillar leak syndrome Common with new therapeutic agents, e.g. IFN-a-induced sarcoidosis is probably related to its propensity to induce a predominant Th1-like immune response, which is considered the main immunological event in granuloma formation [8] Complement activation and cytokine release (TNF-a, IL-6 and IL-8) could be the causative factors of early acute lung injury after rituximab infusion [9] Apoptosis of various cells (alveolar cells, macrophages, etc.) may also be involved in lung toxicity as described in radiation pneumonitis or bleomycin-induced lung fibrosis in animal models

DRESS: drug rash with eosinophilia and systemic symptoms; IL: interleukin; IFN: interferon; Th1: T-helper cell type 1; TNF: tumour necrosis factor.

essential to consider the possibility of DI-ILD in every patient with ILD, as the worst scenario would be to misdiagnose DI-ILD and continue the causal drug. We propose the following steps.

History of exposure to the drug In the presence of ILD, a meticulous inquiry into drug exposure is necessary. The diagnosis of DI-ILD is easier to establish in patients exposed to a single pneumotoxic drug. However, most of the time: 1) patients are exposed to more than one possible causal drug (e.g. patients with a background of rheumatic, cardiac or neoplasic conditions); and 2) patients may not report all drugs they are taking only occasionally. The intrinsic risk of toxicity is not correlated to the apparent usual toxicity/efficacy of the drug, and patients may fail to mention that they are being exposed to nitrofurantoin taken to treat recurrent urinary infection, to b-blockers in eye-drops, to mineral oil for constipation, or to aspirin for headhache. Any route of administration may be responsible (i.e. ocular, intra-vesical, intra-vaginal, etc.). Asian herbs, other ‘‘nonapproved’’ drugs or abused substances also have to be assessed carefully.

Timing of drug exposure The temporal relationship of the drug history is of great importance. This can be difficult to collect, particularly in oncology or elderly patients on multiple treatment regimens, in patients with psychiatric conditions or in illicit drug abusers. The patient’s general physician or pharmacist has to be consulted to help to establish the drug history. Generally the disease develops in a few weeks to a few months after starting treatment, and the patient is still being exposed to the drug at the time of onset of the ILD. Acute or subacute forms of DI-ILD are often easier to diagnose than chronic forms. DI-ILD may develop along a suggestive time schedule. For example, hydrochlorothiazide-induced pulmonary oedema develops within minutes of exposure [10] and minocycline-induced ILD typically develops after a few weeks, on average [7]. 289


Occasionally, DI-ILD develops or may be diagnosed only after cessation of exposure to the drug, for instance a few weeks after amiodarone has been stopped, or months or years after receiving antineoplasic chemotherapy in patients treated by radiation therapy to the chest (‘‘recall pneumonitis’’).

Clinical and imaging pattern The patterns should match the literature of ILD induced by the suspected drug. An updated list of drugs causing lung disease with the corresponding patterns is available on the Pneumotox website [11]. Almost every ILD pattern has been described. Finger clubbing is classically absent in DI-ILD. High-resolution computed tomography (HRCT) and bronchoalveolar lavage (BAL), depending on the condition of the patient, are useful to distinguish the pattern of ILD. Blood tests are usually of limited interest, although peripheral blood eosinophilia may be present. Previous lung function tests and imaging performed prior to drug administration are always helpful. In certain underlying diseases or with some drugs, they may preclude the initiation of the medication (e.g. amiodarone, rheumatoid arthritis). Lung biopsy theoretically can exclude the presence of pulmonary involvement from underlying disease or infection. However, apart from amiodarone pneumonitis (where it may be difficult to differentiate amiodarone pneumonitis from amiodarone exposure at histopathology) and exogenous ‘‘lipoid’’ pneumonia, the histopathological pattern of DI-ILD is not entirely pathognomonic but rather suggestive or nonspecific for a drug reaction. Thus lung biopsy cannot be recommended to confirm the diagnosis.

Exclusion of other causes for ILD One of the key steps is to rule out other aetiologies of ILD with a high level of confidence. Imaging, chronology and biology are necessary here. The other main diagnostic categories are as follows. 1) Infections (and especially Pneumocystis jiroveci): this is one of the main reasons to perform a BAL systematically. 2) Heart failure: echocardiography, measurement of serum N-terminal pro-brain natriuretic peptide or diuretic therapy may help, although diuretics may temporarily be beneficial in other diagnoses such as lymphangitic carcinomatosis or even DI-ILD. 3) The underlying disease: this may be particularly challenging in connective tissue disease (i.e. rheumatoid arthritis), cardiac and neoplastic conditions.

Improvement following drug discontinuation This is a key feature in the diagnostic process. When the drug is essential for the patient, discontinuation has to be carefully considered, and choosing a replacement drug may need the help of other specialists in the underlying disease. Usually, discontinuation of the drug is followed by improvement in symptoms. However, in the presence of multiple suspected drugs, discontinuation of the offending drug may be difficult and depends on the severity of the pattern. It is advisable to first withdraw the drug most likely causing the syndrome. Drugs that are not really essential also have to be withdrawn for safety. Additionally, when the presentation is severe and the respiratory prognosis is poor, all suspected drugs have to be withdrawn at the same time. In acute interstitial pneumonitis or pulmonary fibrosis, corticosteroids are often given concomitant with drug discontinuation. 290


Recurrence of symptoms after rechallenge with the drug Although it would be the best evidence of causality, rechallenge is rarely advised for diagnostic purposes, as it may be dangerous and even lethal. It should be appreciated that recurrence may follow exposure to a drug of the same pharmacological class, as cross-reactions may occur.

Drugs most frequently causing ILD In this section we will describe drugs causing DI-ILD according to the underlying disease for which the drug has been given. Then some of the new drugs responsible for DI-ILD will be described in further detail.

Drugs used in cardiovascular conditions Amiodarone. Amiodarone is the most widely prescribed anti-arrhythmic. Amiodarone pulmonary toxicity (amiodarone pneumonitis or amiodarone lung) was first described in 1980 and is one of the most frequent and severe forms of DI-ILD [12]. The cumulative prevalence of pulmonary toxicity ranges from 0.1 to 0.5% of patients who take 200 mg?day-1 but can reach up to 15% of patients taking i500 mg?day-1 [13]. The likelihood of developing lung toxicity increases, not only with dose, but also with duration of treatment. Most cases do occur within the first 18 months of treatment, but ILD may develop within a few days (after a loading dose) or after more than a decade in some cases. Because of the extended storage of amiodarone in tissue, the disease may, rarely, develop a few weeks (ƒ3 months) after treatment cessation. Recognised risk factors or triggers are an increase in the daily dose of amiodarone, high inspiratory oxygen fraction (FI,O2) and possibly respiratory infections [14]. A low initial diffusing capacity of the lung for carbon monoxide (DL,CO) and heart failure are suspected risk factors. Severe acute amiodarone pneumonitis has been described following pneumonectomy or lobectomy [15], probably because amiodarone is commonly used due to a high incidence of post-operative atrial fibrillation in these patients with a background of chronic obstructive pulmonary disease and poor ventilatory reserve after lung surgery. Today, although respiratory physicians are well aware of the drug-related disease, the diagnosis is still often delayed. The mode of presentation is insidious in about 55% of cases (over a period of 1–3 months); it may simulate a rapidly evolving infectious disease in 40% of cases (acute amiodarone pneumonitis); and it is asymptomatic in 5% of cases. Clinical symptoms include dyspnoea, asthenia, dry cough, moderate fever and, rarely, pleuritic chest pain [16]. There is no pathognomonic biological marker; an increase in lacticodehydrogenase level is frequent. Common imaging findings include alveolar opacities (the most frequent, as illustrated in figure 1), interlobular thickening, lobular opacities, nodules or masses simulating cancer, or a fibrotic pattern. Opacities may migrate. Infiltrates can involve any part of the lungs, may be diffuse, unilateral or may predominate on one side [17]. Pleural effusion is common and is often associated with contiguous pleural thickening. Pulmonary function tests typically show a restrictive pattern and typically a defect in DL,CO. Many of these patients, particularly because of a history of congestive heart failure (and sometimes coronary bypass), might already have a restrictive syndrome at baseline and impairment in the DL,CO. Therefore, it is considered useful to perform pulmonary function tests before initiating amiodarone therapy [12]. The BAL pattern can be neutrophilic, lymphocytic, mixed, or normal in 20% of cases. There is no correlation between the presence of neutrophils and prognosis. 291


Lymphocytes usually indicate acute presentations of acute pulmonary toxicity. The classical presence of foamy macrophages in BAL is a sign of exposure, not toxicity [18]. The cardiologist has to approve the withdrawal of amiodarone and substitution with another anti-arrhythmic agent. Some of these may also cause DI-ILD, as shown in figure 2. Corticosteroids are often required if there is significant functional impairment and/or no improvement 1 month after amiodarone withdrawal. They are very effective, particularly in acute amiodarone pneumonitis, with improvement of clinical symptoms, and later of chest opacities within 1–3 months. The duration of steroid treatment must be extended over 6–12 months, or more, and tapered progressively and cautiously. Normalisation of imaging and lung function is obtained in 80% of cases. In 15% of patients, symptoms and pulmonary function improve, while only stabilisation of chest imaging is obtained [17]. In ,5% of cases, amiodarone pneumonitis worsens to ARDS or progresses to chronic pulmonary fibrosis and death [18]. Relapse is frequent upon involuntary reintroduction of amiodarone or too early or abrupt withdrawal of steroids [19]. The prognosis is better if the diagnosis is made early. Screening, however, is not recommended.

Statins and angiotensin-converting enzyme inhibitors. These drugs rarely lead to DIILD, but are so commonly prescribed that the number of cases may be significant. This is the case with inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) and angiotensin-converting enzyme inhibitors. Statin-induced ILD is emerging as a new side-effect of statin therapy [1]. Presentation is variable, including lupus-like syndrome, a)

b)

c)

Fig. 1. – Amiodarone pneumonitis. a and b) An 86yr-old male developed rapidly increasing dyspnoea, fever, crackles and a severe hypoxaemia while he was treated with amiodarone. Amiodarone was withdrawn and corticosteroids were given. c) After 6 months, dyspnoea and hypoxaemia disappeared, with only slight residual lung infiltrates.

292


Fig. 2. – Drug-induced interstitial lung disease in a patient receiving flecainide.

organising pneumonia (OP), pleuritic chest pain, lung fibrosis [20], eosinophilic pneumonia or ARDS with or without the feature of dermatomyositis. The mechanism of ILD induced by statins remains unclear but appears to be linked to a class effect of these compounds. Discontinuation of the drug is necessary and rechallenge is hazardous and can be lethal. Angiotensin-converting enzyme inhibitors, apart from the well-known cough and angio-oedema, may induce eosinophilic pneumonia, subacute interstitial pneumonia and, rarely, drug-induced lupus syndrome [21].

Other drugs used in cardiology. Acetylsalicylic acid, clopidogrel, oral anticoagulant, heparin, fibrinolytics and more recently the GP IIb/IIIa inhibitor, abciximab, may contribute to alveolar haemorrhage [22]. Occasionally, b-blockers have been involved in acute and subacute interstitial pneumonitis (fig. 3) and can also cause pleural and pericardial thickening. Hydrochlorothiazide may induce acute noncardiogenic pulmonary oedema, as does ingestion of high dosages of aspirin [10]. Diltiazem or prostacyclin infusions may produce pulmonary oedema in patients with pulmonary veno-occlusive disease.

Antibiotics Nitrofurantoin. Nitrofurantoin is an antimicrobial used to treat acute or recurrent urinary tract infection. ‘‘Nitrofurantoin lung’’ primarily occurs in females and may present in an acute or chronic form. The acute form occurs within a few days (1– 2 weeks) following initiation of the antibiotic or, rarely, after a single dose in patients with prior sensitisation to the drug. The illness may present as a pattern of ARDS, but frequently symptoms are out of proportion compared with the minimal radiographic changes. The drug must be discontinued, giving clear and rapid benefits. In patients with acute respiratory failure, adjunctive corticosteroid therapy is often necessary. Rechallenge is not acceptable because relapse is inevitable [23], and should be prevented 293


Fig. 3. – Drug-induced interstitial lung disease presenting as subacute fibrosing interstitial lung disease in a patient receiving a b-blocker.

by patient information. The chronic form presents as interstitial pneumonitis, lung fibrosis or a distinctive pattern of desquamative interstitial pneumonia [24]. Drug withdrawal and corticosteroids are also required in this setting.

Minocycline. The example of minocycline is remarkable. This antibiotic, commonly used for acne vulgaris in teenagers and young adults, may induce acute or chronic eosinophilic pneumonia or, less often, the systemic pattern of involvement known as DRESS syndrome (drug rash with eosinophilia and systemic symptoms; fig. 4). The DRESS syndrome can cause considerable morbidity, with eosinophilia, hepatosplenomegaly, enlarged lymph nodes and multiple, severe visceral disturbances (especially hepatitis or renal failure). The lung can be affected with hypoxaemic pneumonia and bilateral alveolar opacities. Drug withdrawal is urgently required; corticosteroids are often prescribed but their efficacy is unknown. The slow improvement can be worrisome. Anticonvulsants and several other drugs are also responsible for the DRESS syndrome [7].

Drugs used in the treatment of neoplastic conditions The ‘‘chemotherapy lung’’. This frequent side-effect occurs with chemotherapy agents used to treat solid tumours or haematological malignancies [25]. Drugs involved are in ever-increasing numbers and include the following: antineoplastic antibiotics (bleomycin, mitomycin C), alkylating agents (busulfan, cyclophosphamide, chlorambucil, melphalan, nitrosamines), antimetabolites (azathioprine, aracytine, gemcitabine, fludarabine, 6-mercaptopurine, methotrexate) podophyllotoxines (etoposide), taxanes (docetaxel, paclitaxel), tyrosine kinase inhibitors (erlotinib, gefitinib, imatinib), irinotecan, retinoic acid and ionising radiation. Immune modulatory agents used to treat malignancy (interferons (IFNs), interleukin (IL)-2, tumour necrosis factor (TNF)-a) 294


Fig. 4. – Lung involvement is rarely observed in the DRESS syndrome (drug rash with eosinophilia and systemic symptoms). This 19-yr-old male had been treated for acne vulgaris with minocycline for 28 days when he was admitted to the intensive care unit for acute respiratory distress with fever, lymph node enlargement, hepatomegaly, splenomegaly and peripheral blood eosinophilia (1,640 cells?mm-3). Skin lesions appeared 3 days later.

may also be involved [11]. The pulmonary adverse effects may develop within the first days of treatment, or later into the course of therapy. High-concentration oxygen therapy or concomitant lung irradiation may favour the onset of chemotherapy-induced ILD, or increase its severity. Clinical examination is usually not specific, with dyspnoea, inconstant but frequent fever and slight bilateral pleural effusion. Finger clubbing is classically absent. There is no characteristic imaging pattern corresponding to the involvement from a given chemotherapy agent [26]. The multiplicity of treatments in cancer therapy requires careful consideration of all administered treatments. Cardiac function must be evaluated and, above all, an exhaustive search for the infectious agent including BAL must be conducted, as patients are immunosuppressed by the chemotherapeutic agents and also by the underlying disease. The lung biopsy, which is more invasive than BAL, has no clear-cut benefit in this setting. If performed, it may demonstrate cellular infiltration, alveolar oedema and diffuse alveolar damage, with hyaline membranes or fibrin-rich interstitial fibrosis. By definition, malignant cells are not found on histopathological examination. Despite discontinuation of the suspected drug and the initiation of corticosteroid therapy, the prognosis of chemotherapyinduced ILD is not predictable, with occasionally severe or rapidly fatal outcome. Early cases respond better to corticosteroids and exhibit a more favourable prognosis. If the diagnosis is delayed, pneumonitis may evolve to respiratory failure with rapidly progressive ARDS, or long-term pulmonary fibrosis with a poor prognosis. Rarely, the onset of DI-ILD is delayed, developing several months or years after the end of treatment. Typically, carmustine (BCNU) and/or cyclophosphamide may induce late or very late upper lobe pleural and pulmonary fibrosis that is insidious in onset and intractably progressive, with recurrence of pneumothoraces [27].

Colony-stimulating factors. Colony-stimulating factors may induce pulmonary infiltrates that tend to occur during neutrophil recovery; a definitive association is unclear [28].

Radiotherapy. Interactions between chemotherapy and radiotherapy are also a source of iatrogenic manifestations. The ‘‘radiation recall’’ syndrome can occur in a previously 295


irradiated territory following chemotherapy. The skin is frequently involved, but many organs can be affected, and pneumonitis has been described after gemcitabine, carmustine, paclitaxel and anthracyclines [3, 29]. OP and, less often, eosinophilic pneumonia are well described complications that are thought to result from breast irradiation. Radiation pneumonitis is beyond the scope of this chapter.

Drugs used in the treatment of rheumatoid arthritis DI-ILD in rheumatoid arthritis is a challenging problem as rheumatoid arthritis itself may cause ILD. Nonsteroidal anti-inflammatory agents have been associated with the development of pulmonary infiltrates with eosinophilia. Patients usually experience rapid resolution of their symptoms upon drug withdrawal. D-penicillamine has been responsible for infiltrative lung disease as well as hypersensitivity pneumonitis and, rarely, pulmonary–renal syndrome. Chrysotherapy-induced acute lung injury or ‘‘gold lung’’ [30] is characterised by the acute onset of dry cough and dyspnoea associated with fever, skin rash and crackles. Interstitial and/or alveolar opacities of recent onset on chest imaging are associated with an impaired diffusing capacity and lymphocytosis on BAL. Prognosis is good.

Methotrexate. Methotrexate is very commonly used in rheumatoid arthritis. The incidence of DI-ILD is estimated to be about 1% of treated patients [31]. Patterns are mainly represented by pulmonary hypersensitivity pneumonitis, less frequently by noncardiogenic pulmonary oedema, diffuse alveolar damage, OP and, rarely, alveolar haemorrhage. Worsening of rheumatoid nodules has been mentioned as a possible consequence of methotrexate therapy. Malignant lymphoma, pleuritic chest pain or pleural effusions have also been described. Pulmonary hypersensitivity to methotrexate occurs even in other indications of the drug. Patients receiving this treatment must be educated to report spontaneously any symptom such as cough, fever or dyspnoea not otherwise explained. There is no correlation with the dose or duration of therapy. However, most events do occur within the first year of treatment [32]. There is no recognised trigger. Risk factors include age, diabetes and hypoalbuminaemia, but the practical value of these findings is limited in clinical practice. Prior abnormalities in lung function (lung volumes or diffusing capacity) or a past history of ILD may lead to earlier respiratory symptoms. Classically, the clinical presentation is characterised by cough, fever and the progressive onset of dyspnoea, often followed by sudden acceleration of the disease, which is associated with severe hypoxaemia. On chest imaging, localised or diffuse areas of ground-glass opacities may be associated with reticulation or nodules. The BAL, which should be free of any microorganism, is typically lymphocytic (initially with predominance of CD4+ then of CD8+ T-cells), but can be rich in neutrophils at onset in some cases. After careful exclusion of an infection (P. jiroveci, viruses, Cryptococcus, Aspergillus, Histoplasma or Candida), management relies on methotrexate withdrawal, frequently with corticosteroid therapy and mechanical ventilation when required. Mortality ranges from 10 to 16%. Evolution towards secondary pulmonary fibrosis is unusual. Rechallenge is dangerous [33]. Leflunomide. The immunomodulatory drug leflunomide is strongly suspected of inducing hypersensitivity pneumonitis or nonspecific interstitial pneumonia [34]. However, it has been demonstrated that there is no excess risk of ILD in leflunomidetreated patients who have no history of methotrexate use and no pre-existing ILD [35]. 296


TNF-a inhibitors. TNF-a inhibitors (etanercept, adalimumab and infliximab), the IL-1 inhibitor anakinra, and the anti-CD20 monoclonal antibody rituximab are the ‘‘modern’’ treatment of rheumatoid arthritis. The US Food and Drug Administration and the European Medicines Agency have approved the three above-mentioned TNF-a inhibitors for the treatment of other rheumatic, digestive and cutaneous diseases, thus increasing the number of patients exposed to these agents. Apart from the increased incidence of pneumonia, including tuberculosis, TNF-a inhibitors can induce auto-antibodies. A majority of patients with positive antinuclear antibodies are asymptomatic but they may also present with vasculitis or lupus-like syndrome. Pleuro-pulmonary involvement is possible but less frequent than in other drug-induced lupus. ILD has been described with infliximab, etanercept and adalimumab in order of decreasing frequency, and this is possibly related to the respective prescription rate of each of these drugs. The mechanism for the development of TNF-a inhibitor-induced ILD remains unclear. DI-ILD varies from severe acute-onset ILD to subacute cellular interstitial pneumonitis. Sarcoidosis, pulmonary haemorrhage and OP have also been described [36]. Several reports have suggested that infliximab and probably other TNF-a inhibitors may potentiate methotrexate-induced ILD [37]. Age .60 yrs and prior lung fibrosis are considered risk factors for developing ILD in patients with rheumatoid arthritis and treated with TNF-a inhibitors [38]. Most cases develop within 3 months of the first infusion of the drug [37, 39]. The prognosis of the early and especially of the late form of ILD induced by TNF-a inhibitors is devastating. Of note, rheumatoid nodules may appear or grow more rapidly in patients receiving etanercept despite adequate control of joint symptoms [40]. Lymphomas (mainly non-Hodgkin lymphoma) have been described or suspected with these new treatments.

Other recent drugs commonly causing DI-ILD IFNs. IFN-a can induce de novo sarcoidosis (fig. 5) or lead to relapse of pre-existing sarcoidosis. Sarcoidosis has also been described with IFN-b [41], but never with IFN-c. Cutaneous involvement is observed in up to 60% of cases [42]. Symptoms and/or pulmonary imaging abnormalities improve in 85% of cases after cessation or reduction in dosage of the drug, but corticosteroids may be required. While the majority of individuals (.86%) received this therapy for hepatitis C virus infection [8], sarcoidosis also developed in association with other indications for IFN-a therapy such as melanoma [43]. The adjuvant role of the nucleoside analogue ribavirin is debated, but seems unlikely. IFN-a or -b may also be responsible for dense, extensive, nonspecific interstitial pneumonia that can evolve to ARDS. Diffuse or localised OP has also been described. However, the use of IFN-a in patients with pre-existing sarcoidosis and requiring treatment for hepatitis C is possible [44]. IFN-c may potentiate thoracic radiation-induced pneumonitis [45]. Fatal cases of ARDS or acute exacerbation of pre-existing idiopathic pulmonary fibrosis [46] have been described as a result of treatment with IFN-c [46]. However, no further cases have been reported in a recent large international trial.

IL-2. IL-2 is approved for the treatment of metastatic melanoma and renal cell carcinoma. The most serious respiratory adverse effect is the capillary leak syndrome that, in early series, affected up to 20% of treated patients. The clinical picture is represented by nausea, oliguria, hypotension, peripheral oedema, a moderate increase in weight, pulmonary oedema and pleural effusions. This adverse effect profile appears dose dependent and usually improves after drug withdrawal. Preventive steroids, the use 297


Fig. 5. – Interferon (IFN)-a-induced sarcoidosis. A 55-yr-old female was treated with IFN-a for hepatitis C viral infection. After 8 months of treatment she was complaining of severe asthenia and cough. High-resolution computed tomography (HRCT) showed diffuse peribronchial infiltrates. Bronchoalveolar lavage was lymphocytic and nonnecrotising epithelioid granulomas were found in endobronchial biopsies. 4 months after IFN withdrawal, HRCT was normal and the patient had no symptoms.

of lower doses and of the subcutaneous route of administration provide effective prevention. Diuretics are not indicated.

Rituximab. Rituximab is a chimeric human–mouse antibody that targets the CD20 antigen on B-cells. The drug is used for treating malignant lymphomas of B-cell lineage and is currently being tested in autoimmune disorders. More than 50 cases of DI-ILD have already been published with rituximab in monotherapy or in association with chemotherapy [9]. Pulmonary adverse effects following rituximab infusion occur with three different patterns. Acute lung injury with bilateral infiltrates are described within the first 24 h after the first injection and may be fatal [47]. Acute alveolar haemorrhage has occasionally been observed. The mechanism could be linked to a massive ‘‘release’’ of cytokines from lysed neoplastic cells. Most cases of rituximab-induced ILD occur on average 2 months after the first rituximab infusion and 2 weeks after the last rituximab infusion at the time corticosteroids are withdrawn [48]. Symptoms consist of fever, cough, dyspnoea, crackles and hypoxaemia. Chest imaging shows bilateral alveolar infiltrates, and OP has been diagnosed when histopathology is available. Increase in CD4+ lymphocyte count has been noted in the BAL. Withdrawal of rituximab along with corticosteroids is usually very effective. Rechallenge is potentially dangerous. Of note, late-onset and chronic macronodules have been related to rituximab therapy [49]. Imatinib. Imatinib is a tyrosine kinase inhibitor initially used to treat chronic myelogenous leukaemia but with a constantly growing number of other indications. ILD with diffuse opacities, ground-glass or nodules may develop on average 50 days after the initiation of the drug (10–282 days) [50]. BAL shows lymphocytosis or, less frequently, eosinophilia. Withdrawal of the drug with associated administration of corticosteroids leads to improvement or normalisation in .80% of cases. Importantly, corticosteroids may allow continuation of imatimib if the drug is absolutely necessary [51]. However, reintroduction after withdrawal is dangerous, with an estimated risk of relapse in .30% [50].

Dasatinib. Dasatinib is a novel tyrosine kinase inhibitor indicated in the treatment of chronic myelogenous leukaemia. Lung toxicity is frequently revealed by an exudative 298


pleural effusion with or without lung parenchymal abnormalities [52]. Dasatinib toxicity appears to be immune mediated [53]. Lung parenchymal changes are in the form of ground-glass or alveolar opacities. Septal thickening has been described. Lung manifestations resolved in all cases after dasatinib was withdrawn. Dasatinib-related lung involvement may be dose related, as recurrence was not observed in 75% of cases if dasatinib was carefully reintroduced at a lower dose in a recent study [52].

Epidermal growth factor receptor inhibitors. Gefitinib-induced ILD has an incidence of up to 5% of treated persons [54] in the Japanese population and 0.3% outside Japan, suggesting reporting bias and/or genetic predisposition. The main risk factor is preexisting pulmonary fibrosis. Patterns include ARDS with diffuse alveolar damage, acute interstitial pneumonia and alveolar haemorrhage. Erlotinib, another epidermal growth factor receptor tyrosine kinase inhibitor, has been responsible for acute ILD, and was fatal in some cases [55, 56]. A pattern of OP may be found on histopathology. The onset of the disease ranges from 5 days to .9 months after initiating erlotinib treatment [57], and requires the withdrawal of erlotinib.

Sirolimus. Sirolimus, a proliferation signal inhibitor inhibiting the mammalian target of rapamycin has immunosuppressive properties through the reduction of T- and B-cell proliferation. The drug is widely prescribed to prevent solid organ transplant rejection, and has been used successfully to prevent coronary stent stenosis. Sirolimus is a significant inducer of lung adverse effects [58, 59]. Risk factors for sirolimus-induced ILD are daily dosage (.5 mg?day-1), serum concentration (.15 ng?L-1), recent increase in daily dose or loading dose, graft dysfunction, advanced age and male sex [60]. Lung involvement arises a few days to .4 yrs after the initiation of sirolimus therapy and is mainly characterised by lymphocytic interstitial pneumonia, OP or alveolar haemorrhage. Clinical symptoms include cough, fever, dyspnoea and haemoptysis. Chest imaging shows reticular and ground-glass opacities, alveolar consolidation corresponding to OP, or nodules. The lower lobes may be predominantly affected. BAL is typically lymphocytic, sometimes with increased eosinophil cell count, or suggestive of alveolar haemorrhage. Outcome is usually rapidly favourable after sirolimus withdrawal. Corticosteroids may be necessary. Everolimus, which has a molecular structure analogous to sirolimus, may also be responsible for subacute cellular interstitial pneumonitis or OP [61]. However, sirolimus-induced pneumonitis may improve after switching to everolimus [62].

Distinctive patterns of drug-induced infiltrative lung disease Drug-induced subacute or chronic interstitial pneumonia Subacute or chronic (or nonspecific or cellular) interstitial pneumonia is the most common pattern of DI-ILD, and may be caused by a variety of drugs, frequently including b-blockers, methotrexate, chemotherapeutic agents, nitrofurantoin, nilutamide and statins, as well as more than 40 drugs for which imputability criteria have been demonstrated [11, 63, 64]. The responsibility of a drug in inducing the ILD may be easier to suspect in the case of acute or subacute onset than in chronic ILD. As histopathology of the lung is often not available, and the current classification of interstitial pneumonia is used variably in cases reported in the literature, the presentation of chronic ILD cannot be confidently classified in all cases as drug-induced nonspecific interstitial pneumonia or even cellular interstitial pneumonia. A pattern of imaging and 299


histopathological features indistinguishable from that of hypersensitivity pneumonitis can also be found (e.g. methotrexate) [65]. Hence, a broader and somewhat less precise terminology of ‘‘cellular’’ or ‘‘chronic interstitial pneumonia’’ is used in those cases that do not correspond to the other patterns described below (e.g. OP, eosinophilic pneumonia, etc.). This terminology usually corresponds to a clinical radiological presentation of DI-ILD that is largely reversible. The pathophysiology is poorly known, but most cases are idiosyncratic and unpredictable. Drug-induced chronic interstitial pneumonia usually develops in patients who have been receiving the causative drugs for at least several weeks, with a mean delay of 3– 6 months, but the delay may reach up to several years (e.g. methotrexate). No definite relationship can be found with cumulative doses received by the patient, with the exception of amiodarone pneumonitis, which occurs more frequently in patients receiving high doses [63]. Occasionally, DI-ILD may develop after the drug has been discontinued, thereby causing considerable difficulty in establishing the diagnosis (amiodarone, nitrosoureas and, rarely, methotrexate) [64]. Clinical manifestations may vary from subclinical pulmonary infiltrates on chest imaging to ARDS. Dyspnoea and dry cough are the main symptoms, often with fever, and occasionally accompanied by a skin rash or elevation of the serum liver enzymes. Crackles are frequently found at auscultation. Chest imaging demonstrates bilateral infiltrates, with variable predominance of the areas involved, and often with reduced lung volumes. Pleural effusion and/or mediastinal lymphadenopathy may be associated. The diagnostic approach to DI-ILD is not specific to the aetiology. BAL is necessary to rule out pulmonary infection, especially in the context of chemotherapy for solidorgan cancers, and connective tissue diseases treated with immunosuppressive therapy, and should include specific work-up for opportunistic agents. Differential cell counts of BAL show an increased percentage in lymphocytes or a mixed lymphocytic and neutrophilic pattern. Lymphocytic immunophenotyping (CD4/CD8) gives variable results, even for a given causative drug (i.e. methotrexate), and is therefore of limited practical value. Lipid-laden macrophages are frequently found in the BAL of patients receiving amiodarone [18], with or without amiodarone pneumonitis. Although they frequently show histopathological abnormalities [66], transbronchial biopsies are often poorly contributive. Video-assisted thoracoscopic lung biopsy is seldom necessary. When performed, it typically shows dense mononuclear cell infiltration of the alveolar walls, with homogeneous distribution, and usually low-grade interstitial fibrosis, often fulfilling the histopathological criteria of nonspecific interstitial pneumonitis [65, 67, 68]. There is considerable overlap between drug-induced ‘‘pulmonary fibrosis’’, with the histopathological pattern of nonspecific interstitial pneumonia, and subacute-onset interstitial pneumonia, with diffuse inflammatory cell infiltration on histopathology, that may improve with corticosteroids. Notably, prominent infiltration of the alveolar spaces by macrophages may be present, and a histological pattern of desquamative interstitial pneumonia has been reported as presumably caused by nitrofurantoin, amiodarone and, more recently, sirolimus [69]. Noncaseating granulomata are typically not found in DI-ILD, although they have been reported with a limited number of drugs (including methotrexate, IFNs, antiretroviral therapy (as part of immune reconstitution), etanercept and intravesical bacillus Calmette–Gue´rin) [64]. Giant cell interstitial pneumonia related to nitrofurantoin has been reported [65]. In the particular case of amiodarone pneumonitis, histopathology shows lipid-laden macrophages packed in the alveolar spaces, lipid infiltration of endothelial and type-II pneumocytes (that may be found in any patient taking amiodarone), and infiltration by inflammatory cells and fibrosis of the alveolar walls [70]. Subacute or chronic-onset ILD has a generally favourable outcome with cessation of the offending drug and administration of oral corticosteroids, provided that the 300


diagnosis is made early enough. Clinical manifestations improve within a few weeks, and imaging and pulmonary function abnormalities regress without sequelae within a few months. Corticosteroids in addition to cessation of the drug are not mandatory in mild cases. Death may rarely occur as a consequence of early uncontrollable respiratory failure, recurrence of the underlying disease for which the causative drug had been prescribed (e.g. ventricular arrhythmia after cessation of amiodarone), or long-term progression to pulmonary fibrosis despite corticosteroids (which is distinctly rare) [64]. Prolonged corticosteroid treatment (6–12 months) is required in the case of amiodarone pneumonitis due to extensive accumulation of amiodarone in the lung with very slow clearance upon discontinuation of the drug [63]. Recently, chronic DI-ILD has been reported in patients with rheumatoid arthritis and treatment with the anti-TNF-a agents infliximab, etanercept and adalimumab, mostly within 3 months of initiation of therapy and acute or subacute onset [37, 71, 72]. AntiTNF-a agents may induce acute worsening (so-called exacerbation) of pre-existing pulmonary fibrosis [37, 71, 72], a condition which must be differentiated from infection, methotrexate toxicity, and from ILD due to the connective tissue disease itself [37]. Infliximab is the most frequent causative agent (it is also the most widely used worldwide) [36]. Improvement may be obtained with corticosteroids and discontinuation of the causative agent in about half the cases, but the condition may result in death in 32% of the cases [36].

Pulmonary fibrosis It should first be noted that a causative drug is seldom found in routine evaluation of a patient with pulmonary fibrosis, e.g. with a clinical radiological presentation of chronic fibrosing interstitial pneumonia limited to the lung and demonstration of fibrosis on histopathology when available. However, genuine pulmonary fibrosis may be caused by prolonged therapy with a rather limited number of drugs, including chemotherapeutic agents (bleomycin, busulfan, chlorambucil, cyclophosphamide and nitrosoureas), as well as amiodarone and nitrofurantoin and, less frequently, gold therapy, methotrexate or sulfasalazine [63]. As chronic forms of DI-ILD lack specificity, it is possible that the iatrogenic aetiology is underestimated. Pulmonary fibrosis induced by radiation therapy is beyond the scope of the present chapter. Establishing a causative link between drug exposure and pulmonary fibrosis is generally challenging, because the criterion of regression of disease upon discontinuation of therapy is lacking, in contrast with subacute or acute onset of inflammatory ILD that regresses with corticosteroid treatment and cessation of the causative drug. Clinical and imaging manifestations of drug-induced pulmonary fibrosis are often indistinguishable from those of idiopathic pulmonary fibrosis. When available, histopathology of the lung may demonstrate fibrosis, sparse mononuclear interstitial infiltrates, interstitial oedema and hyperplasic type II pneumocytes [63], which may be classified as nonspecific interstitial pneumonia or more rarely as usual interstitial pneumonia [65], although a precise classification of the histopathological pattern is often lacking in published cases and series. Antinuclear antibodies may be found in patients with ILD induced by prolonged treatment with nitrofurantoin. Honeycombing is infrequently observed. Response to corticosteroid therapy is generally limited in patients with pulmonary fibrosis, and the disease progressively leads to respiratory insufficiency and death with variable delay. A more rapid progression of disease reminiscent of the accelerated variant of idiopathic pulmonary fibrosis has been reported [63]. DI-ILD presenting as recent worsening of exertional dyspnoea may occur in a patient with underlying idiopathic pulmonary fibrosis [73]. 301


Drug-induced eosinophilic pneumonia Eosinophilic pneumonia is a pneumonia where eosinophils are the most prominent inflammatory cells on histopathological examination. The eosinophilic pneumonias may manifest with different clinical radiological syndromes, namely Lo¨ffler’s syndrome with transient pulmonary opacities (mostly due to parasitic infection, as in ascariasis), chronic eosinophilic pneumonia or acute eosinophilic pneumonia, mostly differing from one another by disease onset. Extra-respiratory manifestations may accompany eosinophilic pneumonias, especially in Churg–Strauss syndrome (and in hypereosinophilic syndromes to a lesser extent). More than 80 drugs have been reported to cause eosinophilic pulmonary infiltrates regardless of clinical manifestations. Of these, the causality has been firmly established for fewer than 20 (table 2), which can reliably be considered as a common cause of druginduced eosinophilic pneumonia [74]. Prescription drugs causing eosinophilic pneumonia are mainly nonsteroidal anti-inflammatory drugs and antibiotics, although anticonvulsants, antidepressants and angiotensin-converting enzyme inhibitors may also cause ILD. Possible causes must be thoroughly investigated, as over-the-counter drugs (or illicit drugs that frequently cause eosinophilic lung disease) may not be mentioned spontaneously by the patients. For example, minocycline prescribed for acne vulgaris is a common cause of eosinophilic pneumonia in young subjects with little or no medical history; eosinophilic pneumonia may develop within 2–3 weeks of treatment [75]. Eosinophilic lung disease may manifest clinically by a pulmonary disease of varying severity and onset, ranging from chronic or transient infiltrates with mild symptoms to the acute severe eosinophilic pneumonia resembling acute lung injury or ARDS and necessitating mechanical ventilation. Transient interstitial infiltrates with eosinophilia (Lo¨ffler’s syndrome), chronic eosinophilic pneumonia and acute eosinophilic pneumonia have all been reported as drug-induced manifestations. Presentation is generally nonspecific, with pulmonary manifestations compatible with idiopathic chronic or acute eosinophilic lung disease [76]. Therefore, in any case of ‘‘idiopathic’’ eosinophilic pneumonia, an iatrogenic cause must be systematically considered. The possible association of pleural effusion and extrapulmonary manifestations, especially cutaneous rash, may be a clue for the diagnosis of DI-ILD. Less frequently due to drugs than its acute counterpart, chronic eosinophilic pneumonia manifests with progressive onset over several months of cough, dyspnoea and, often, chest pain, together with asthenia, fever and weight loss. Imaging features are characteristic, with bilateral peripheral consolidation of varying density, which may be migratory, often associated with ground-glass opacities. Peripheral effusion is present in ,10% of cases in the idiopathic form of disease but is more frequently encountered in drug-induced eosinophilic pneumonia. Table 2. – Main drugs causing typical pulmonary eosinophilia Acetylsalicylic acid Captopril Diclofenac Ethambutol Fenbufen GM-CSF Ibuprofen Minocycline Naproxen

Para (4)-aminosalicylic acid Penicillins Phenylbutazone Piroxicam Pyrimethamine Sulindac Sulphamides-sulphonamides Tolfenamic acid Trimethoprim-sulfamethoxazole

Data taken from [74]. GM-CSF: granulocyte-macrophage colony-stimulating factor. 302


Acute eosinophilic pneumonia (idiopathic) is characterised by acute onset of febrile respiratory manifestations (ƒ1 month duration before consultation), bilateral diffuse infiltrates on chest radiography, hypoxaemia (with arterial oxygen tension (Pa,O2) on room air ,60 mmHg and/or Pa,O2/FI,O2 ƒ300 mmHg and/or oxygen saturation on room air ,90%) and lung eosinophilia (with .25% eosinophils on BAL differential cell count) [77]. On imaging, bilateral pleural effusions, poorly defined nodules and interlobular thickening are often associated with bilateral airspace consolidation and are suggestive of the diagnosis of acute eosinophilic pneumonia in the appropriate context. Interestingly, although the imaging findings of DI-ILD are usually nonspecific, the presence of pleural effusion, hilar lymphadenopathy and reticular densities are frequently observed [78]; however, a formal diagnosis of drug-induced acute eosinophilic pneumonia is not always made. Apart from drugs, acute eosinophilic pneumonia may be caused by a variety of infections, and may especially be triggered by recent onset of tobacco smoking and exposure to other inhaled contaminants [77, 79]. Minocycline-induced ILD is a typical example of drug-induced acute ILD, which usually fits with the criteria of idiopathic acute eosinophilic lung disease [75]. Other drugs that may commonly cause a syndrome corresponding to acute eosinophilic pneumonia [80] notably include amitriptyline [81], nitrofurantoin [82], phenytoin [83], acetaminophen [84], ampicillin [85], pyrimethaminesulphadoxine [86], sulfasalazine [87], venlafaxin [88], L-tryptophan [89], diclofenac [90], trazodone [91], chloroquine [92, 93], granulocyte-macrophage colony-stimulating factor [94] and piroxicam [95]. Drug-induced acute eosinophilic pneumonia is usually easily suspected, as symptoms develop in a timely fashion following drug exposure [76], and skin rash may be concomitant. In some cases, the respective role of recent tobacco smoking and drug exposure may be difficult to assess [88]. Blood eosinophilia .16109 eosinophils?L-1 (and preferably .1.56109 eosinophils?L-1) is of considerable help in establishing the diagnosis of eosinophilic pneumonia. However, it may be absent, especially in patients already taking corticosteroids. On BAL, eosinophilia .25% (and preferably .40%) may be considered diagnostic of eosinophilic pneumonia in a compatible setting. There is currently little if any indication for pulmonary biopsy in the diagnosis of the eosinophilic lung diseases; when lung biopsy is performed, histopathology of drug-induced eosinophilic pneumonia is nonspecific and indistinguishable from other types of eosinophilic pneumonia [77]. It is notable that chest imaging may overlap with that of OP; therefore, differentiating these patterns is based on BAL and occasionally on lung biopsy when needed (also with possible overlapping pathological patterns in some cases). Apart from typical cases of eosinophilic pneumonia due to drug exposure, mild or moderate peripheral blood or alveolar eosinophilia may be present in a patient with DIILD, particularly methotrexate [96]. As in other drug-induced manifestations, drug-induced eosinophilic pneumonia usually resolves with removal from the agent and recurs with rechallenge (which is potentially dangerous and is thus discouraged). The regression of eosinophilic lung disease after stopping the drug is the best clue for an iatrogenic reaction. Other possible causes of eosinophilic pneumonia (especially parasitic or fungal infection) must be excluded. Treatment with corticosteroids may be needed in addition to discontinuation of the offending agent, especially in severe cases [76]. Corticosteroid treatment is particularly effective in eosinophilic pneumonias, with rapid resolution of symptoms and infiltrates. Systemic eosinophilic vasculitis involving the lung and thus closely resembling Churg– Strauss syndrome has also been reported as a result of treatment with diphenylhydantoin or sulphonamides [97, 98]. Severe extra-respiratory manifestations may accompany drug-induced eosinophilic pneumonia, and include systemic reaction, rash, fever, lymph node enlargement, and possibly liver and renal impairment. This condition, 303


referred to as the DRESS syndrome, has been principally reported with minocycline [7], anticonvulsants, aspirin and allopurinol. The responsibility of leukotriene receptor antagonists (montelukast, zafirlukast and pranlukast) in the development of Churg–Strauss syndrome is a matter of continuing debate. Although direct responsibility of this family of drugs has not been established, literature reviews [99] and epidemiological studies [100–102] have concluded that there is an association between the use of leukotriene receptor antagonists and onset of Churg– Strauss syndrome. Conflicting results were obtained when results were controlled for the use of other anti-asthmatic drugs [101, 102], especially since asthmatics receiving leukotriene modifiers may have more severe asthma, and the use of this group of medication has increased over time [100]. Whether the association is coincidental, whether smouldering Churg–Strauss syndrome flares just because of reducing oral or inhaled corticosteroids, or whether the drug exerts a direct role on the pathogenesis of vasculitis, is not exactly known. However, a number of observations were reported in patients who did not have any suggestion of latent disease or smouldering Churg– Strauss syndrome before the onset of treatment, and many showed a definite temporal relationship between drug therapy and onset of disease [99]. In addition, Churg–Strauss syndrome may recur on rechallenge with leukotriene receptor antagonists [103, 104] and may remit upon withdrawal of this medication without modifying the corticosteroid or immunosuppressive therapy [99, 105]. Until further evidence is available, leukotriene receptor antagonists should be avoided in asthma patients with eosinophilia and/or extrapulmonary manifestations compatible with smouldering Churg–Strauss syndrome, and they should be withdrawn should Churg–Strauss syndrome develop [105].

Drug-induced organising pneumonia OP is a pathological pattern consisting of intra-alveolar buds of granulation tissue with fibroblasts and myofibroblasts intermixed with loose connective matrix [106], a process which may also be found in adjacent bronchiolar lumen (hence the now abandoned term of bronchiolitis obliterans with OP). Although OP may be present as an accessory finding in many disorders, a diagnosis of OP is made only in those cases where it represents the major and predominant pathological lesion. When no aetiology is found, the disease is called cryptogenic OP (COP), an entity that has been included in the American Thoracic Society/European Respiratory Society international consensus classification of the idiopathic interstitial pneumonias, although it is not strictly interstitial [67]. The term COP should not be used if there is a known aetiology including drugs. A detailed description of OP may be found elsewhere [107]. COP occurs at a mean age ofy50–60 yrs, more frequently in non- or ex-smokers. The initial manifestations comprise fever, cough, malaise, anorexia and progressive weight loss, with a subacute onset over a few weeks. Dyspnoea is usually mild. Haemoptysis, chest pain and severe dyspnoea are rare. Crackles may be heard on pulmonary auscultation. The diagnosis is often considered after the patients have received antibiotics without improvement. The typical imaging pattern of COP consists of multiple, bilateral, patchy ground-glass or alveolar opacities, predominating at the periphery of the lungs and sometimes migratory. When present, this typical pattern immediately suggests the diagnosis of COP (with idiopathic chronic eosinophilic pneumonia as the main differential). Less frequently encountered imaging patterns include the infiltrative pattern (with interstitial opacities and superimposed alveolar opacities but no honeycombing), and a solitary focal nodule or mass (often located in the upper lobes and usually asymptomatic) that probably represents nonresolving infectious pneumonia in a number of cases [107]. Lung function tests in COP show a 304


mild restrictive ventilatory pattern, and may occasionally be normal. The transfer coefficient for carbon monoxide is within normal limits, while the transfer factor is decreased in proportion to the restrictive defect. Hypoxaemia is usually mild. When present, severe hypoxaemia may be associated with diffuse infiltrative opacities, or with right-to-left shunting in perfused areas of lung consolidation. Blood tests often show increased C-reactive protein and moderate leukocytosis. Performing BAL is especially important to search for infectious agents; fibreoptic bronchoscopy also excludes any bronchial obstruction. The BAL differential cell count in COP often shows a mixed pattern, with increased levels of lymphocytes (20–40%), neutrophils (y10%) and eosinophils (5%); some mast cells and plasma cells may be present. Potential underlying causes of secondary OP include a number of infectious agents (bacteria, viruses, fungi, parasites), drugs, and a variety of conditions such as radiation therapy to the breast after tumorectomy for cancer, connective tissue disease (especially dermatomyositis-polymyositis and rheumatoid arthritis), occult aspiration pneumonia, organ transplantation, inflammatory bowel disease and haematological malignancies. Iatrogenic OP closely resembling COP may be caused by radiation therapy to the breast, and usually develops within 9–16 months of radiation therapy; pulmonary opacities on chest imaging are often initially unilateral and located in the irradiated field, with further progression and ‘‘migration’’ of the opacities [107, 108]. Secondary OP may be caused by a number of drugs (table 3), with relatively convincing histopathological features reported. Medications causing OP (albeit with a different incidence rate) typically include antimicrobials (especially minocycline [109] and nitrofurantoin [110]), anticancer agents (including a recent report with oxaliplatin [111]), cardiac agents (including amiodarone and b-blockers), anti-inflammatory agents [112] and rituximab [48, 49]. The majority of drug-induced OP cases present with computed tomography (CT) features of bilateral ground-glass and/or alveolar opacities similar to the typical presentation of COP. One notable exception is the anticancer agent bleomycin, which causes the focal nodular type of OP in up to 5% of individuals treated with no progression to a more diffuse pattern of OP [113], or may cause multiple pulmonary nodules mimicking pulmonary metastases and consisting of OP at histopathology [114, 115]. The infiltrative pattern of OP may also be caused by a variety of drugs, such as amphotericin B, doxorubicin, amiodarone, phenytoin, etc. (see [11] for an exhaustive list) [112]. As the clinical and imaging pattern of secondary OP and especially drug-induced OP are not specific to its cause and parallel those of COP, the diagnosis of drug-induced OP may be difficult. A careful aetiological inquiry is necessary in any OP without evident cause. All drugs taken in the weeks or months preceding the symptoms must be systematically reviewed. Any drug suspected to be a cause of OP should be withdrawn if Table 3. – Main drugs causing organising pneumonia 5-Aminosalicylic acid Acebutotol Amiodarone Bleomycin Busulfan Carbamazepine Fluvastatin Interferon-a Interferon-b Mesalazine Methotrexate

Minocycline Nilutamide Nitrofurantoin Oxaliplatin Rituximab Sirolimus Sulfasalazine Tacrolimus Thalidomide Trastuzimab

Data taken from [107]. 305


possible, and rechallenge should be avoided. Causality has not been firmly established for many drugs, mainly because only isolated case reports have been published and corticosteroids are frequently given. A further difficulty arises from the frequent association of several possible causes of OP. For example, in a patient treated by bone marrow allograft for haematological malignancy, a syndrome of OP may related to the underlying haematological condition, to graft-versus-host disease, to infections favoured by iatrogenic aplasia, or to several of the drugs received concomitantly. Drug therapy may cause severe OP and severe respiratory failure requiring mechanical ventilation. This rare condition usually represents OP overlapping with diffuse alveolar damage undergoing organisation, acute fibrinous and organising pneumonia, or acute exacerbation of usual interstitial pneumonia (thereby with superimposed diffuse alveolar damage). Amiodarone toxicity to the lung may also manifest as OP associated with interstitial pneumonia with fibrosis [112]. Videothoracoscopic lung biopsy, obtaining specimens of sufficient size for pathological analysis with microbiological analysis, is the gold standard for the diagnosis of OP. When a decision for surgical biopsy is made, it should be done before corticosteroids are initiated. However, it is not always necessary, as the association of a typical clinical radiological pattern and a mixed pattern at BAL is considered highly suggestive of OP (and COP in the appropriate clinical context). Transbronchial lung biopsies contribute to the diagnosis when showing typical buds of granulation tissue within alveoli in patients with typical clinical and imaging profile [116, 117], but their small size does not allow for exclusion of other associated pathological patterns. CT-guided percutaneous tru-cut needle biopsy may be used when transbronchial biopsies are not contributive or as an alternative to obtaining a surgical biopsy specimen; the size is larger than that of transbronchial biopsies but much smaller than surgical lung biopsies [118–120]. As in most cases of primary or secondary OP, corticosteroid therapy is effective. The diagnosis of OP should be reconsidered whenever the outcome is unusual, and especially in the case of an incomplete response to corticosteroids or relapse despite .20– 25 mg?day-1 of oral prednisone, because other, potentially more serious, causes of the radiological pattern, including malignancy and lymphoma, need to be considered. Interestingly, drug-induced OP is a frequent cause of OP not responding to treatment or with early relapse despite continued oral corticosteroids, and a drug potentially causing OP should be thoroughly investigated in any ‘‘difficult COP’’. Corticosteroid treatment results in rapid clinical and imaging improvement in typical COP as well as secondary OP [107]. In the case of drug-induced OP, cessation of the causative drug is mandatory to obtain complete and long-lasting remission of the disease. Prednisone therapy may be initiated at 0.5–1 mg?kg-1?day-1 for several weeks (commonly 0.75 mg?kg-1?day-1 for 4 weeks) then progressively decreased over a minimum of 24 weeks. Pulmonary opacities on chest imaging usually completely resolve within 1 month. In rare cases of severe OP, the response to corticosteroids is not as favourable as in classical COP, and immunosuppressive therapy may be added to corticosteroids with variable outcome. Improvement has also been reported after treatment with macrolides, but with insufficient evidence to justify their use as first-line therapy.

Drug-induced diffuse alveolar haemorrhage Alveolar haemorrhage is defined by pulmonary haemorrhage originating from the pulmonary microcirculation, either focal or diffuse, the latter being caused by a lungspecific or generalised process of damage to the alveolar microcirculation [121]. Diffuse alveolar haemorrhage can be life threatening and may result in acute respiratory failure. The usual presentation typically includes haemoptysis, alveolar infiltrates on chest 306


imaging and acute anaemia, although haemoptysis is not always present even in severe cases. Acute-onset dyspnoea and cough are frequent. Examination may reveal ocular, nasopharyngeal or cutaneous manifestations of systemic vasculitis or connective tissue disease. HRCT shows bilateral and diffuse alveolar infiltrates [122]. Haematocrit may rapidly decrease in conjunction with the alveolar haemorrhage. The diagnosis of diffuse alveolar haemorrhage is generally established by fibreoptic bronchoscopy, demonstrating macroscopically haemorrhagic BAL fluid (increasingly red fluid in true sequential BAL aliquots from the same location) [121]. Quantification of the haemosiderin concentration of alveolar macrophages may be helpful in some cases of occult chronic or subacute alveolar haemorrhage [123]. Surgical lung biopsy is seldom necessary to confirm the diagnosis of diffuse alveolar hemorrhage, and rarely contributes to the identification of the underlying cause [124]. The broad differential diagnosis of diffuse alveolar haemorrhage mostly includes the vasculitides associated with anti-neutrophil cytoplasmic antibodies (essentially microscopic polyangitis and Wegener’s granulomatosis), connective tissue diseases (mostly systemic lupus erythematosus and rheumatoid arthritis) and Goodpasture’s syndrome associated with anti-basement membrane antibodies. Concomitant renal disease (pneumorenal syndrome) is characteristic of vasculitis and Goodpasture’s syndrome. Other important causes include infections (leptospirosis, legionellosis), toxic exposures (isocyanates, trimellitic acid), drug reactions, complication of lung or allogenic bone marrow transplantation, mitral stenosis and, rarely, veno-occlusive disease, pulmonary capillary haemangiomatosis, lymphangioleiomyomatosis, pulmonary metastasis and coagulation disorders [121]. Idiopathic pulmonary haemosiderosis is a diagnosis of exclusion when no cause can be ascertained. Diffuse alveolar haemorrhage is uncommon in patients with drug-induced diffuse parenchymal lung disease [65]. An indicative list of potential causes of drug-induced alveolar haemorrhage is indicated in table 4. The two main drugs causing diffuse alveolar haemorrhage are propylthiouracil and phenytoin. More recently described causes of alveolar haemorrhage include the anti-CD52 antibody alemtuzumab [125], the anti-CD20 antibody rituximab [126], and sirolimus [58, 127, 128]. Alveolar haemorrhage may occur after the causative drug has been discontinued for several months (e.g. mitomycin), and both current and past drug intake should thus be evaluated in a patient with diffuse alveolar haemorrhage. Clinical and HRCT findings are nonspecific of the aetiology, with acute dyspnoea, possible haemoptysis, and bilateral diffuse or disseminated ground-glass and/or alveolar opacities. By definition, renal disease is absent, with normal urine Table 4. – Main drugs causing diffuse alveolar haemorrhage Abciximab Acetylsalicylic acid Alemtuzumab Amiodarone Anticoagulants (oral) Azathioprine Carbamazepine Cyclosporin Cytarabine (cytosine arabinoside) Dextran Epoprostenol Fibrinolytics (including rTPA) Fludarabine Hydralazine

Iodine, radiographic contrast media Methotrexate Mitomycin C Nitrofurantoin Penicillamine Phenytoin Propylthiouracil Quinidine Retinoic acid Rituximab Sirolimus Streptokinase TNF-a

Data taken from [11]. rTPA: recombinant tissue plasminogen activator; TNF: tumour necrosis factor. 307


sediment and serum creatinine level. Anti-neutrophil cytoplasmic antibodies, antiglomerular basement membrane antibodies and markers of connective tissue diseases are absent in drug-induced alveolar haemorrhage, with the notable exception of antineutrophil cytoplasmic antibodies with myeloperoxidase specificity, which may be found in patients treated with propylthiouracil [129], who may also present with skin leukocytoclasic purpura and focal segmental necrotising glomerulonephritis, a syndrome reminiscent of microscopic polyangiitis. Glomerulonephritis associated with diffuse alveolar haemorrhage (thus causing pneumorenal syndrome) has mostly been reported in patients treated with propylthiouracil, penicillamine, hydralazine and carbimazole [130]. Lung biopsy is generally not required, as the diagnosis of diffuse alveolar haemorrhage is usually established on clinical, blood erythrocyte counts, and BAL findings. When performed, lung biopsy does not show histopathological features specific to the iatrogenic aetiology. In addition to alveolar haemorrhage per se, a small-vessel vasculitis (so-called ‘‘capillaritis’’) may be present on histopathology, with oedema and fibrinoid necrosis of the alveolar wall, and destruction of the alveolar capillary basement membrane with ensuing leukocytoclasis. Capillaritis has been reported in systemic vasculitides and connective tissue disease, but also in patients treated with propylthiouracil, diphenylhydantoin or all-trans-retinoic acid [129, 130]. When present, capillaritis due to drug-induced pulmonary reaction may be difficult to distinguish from isolated pauci-immune pulmonary capillaritis, sometimes accompanied by upper respiratory tract symptoms such as rhinitis, sinusitis and otitis media [131]. Alternatively, pulmonary veno-occlusive disease may be observed, especially in patients receiving bleomycin or carmustine after bone marrow transplantation [132, 133]. In addition, alveolar haemorrhage resulting from various causes (including drug therapy and especially chemotherapeutic agents) may occur during the exudative phase of diffuse alveolar damage and cause ARDS [130]. Treatment of drug-induced diffuse alveolar haemorrhage relies on cessation of the causative agent (it is not mandatory for treatment with all-trans-retinoic acid [130]) and administration of high-dose corticosteroids. Plasmapheresis may be used in acute pulmonary disease caused by mitomycin (while fluid overload should be avoided whenever possible) [130]. A syndrome of chronic anaemia, dyspnoea, pulmonary infiltrates and haemosiderinladen macrophages at BAL has been reported in patients treated with anticoagulants, but acute-onset and overt diffuse alveolar haemorrhage is rare. The role of additive cofactors has been discussed on such occasion, including congestive heart failure, infection or use of platelet inhibitors.

Drug-induced ARDS ARDS characterised at histopathology by diffuse alveolar damage is a common manifestation of drug-induced lung toxicity. In turn, drug therapy represents one of the many causes of ARDS, including sepsis and shock. ARDS is considered as the common presentation of any severe injury to the lung regardless of its cause (and the term acute interstitial pneumonia is reserved for cases of ARDS of unknown cause) [67]. ARDS may be caused by a number of drugs, among which the chemotherapeutic drugs represent the largest group, when used for the treatment of malignant neoplasms, and to a lesser extent when used at lower doses for the treatment of systemic connective tissue diseases [65]. The majority of cases are observed as a consequence of treatment with a limited number of drugs, e.g. busulfan, cyclophosphamide, carmustine (BCNU), bleomycin [134] and the more recent chemotherapeutic drugs paclitaxel and docetaxel [70] (see [11] for an exhaustive list of causative drugs). Other, nonchemotherapeutic 308


drugs commonly causing ARDS include amiodarone, nitrofurantoin and leflunomide [135]. Most cases of drug-induced ARDS or pulmonary oedema are idiosyncratic reactions and occur independently of drug dosage or duration of therapy, but the exact pathogenetic mechanisms are largely unknown [136]. Drug-induced ARDS occurs with a wide range of age and no sex predominance. Severe exertional dyspnoea develops over a few days, with prominent diffuse crackles at auscultation. Chest imaging shows widespread pneumonic consolidation with air bronchogram and with a patchy distribution and bibasilar predominance. During the exudative or early proliferative phase of diffuse alveolar damage, the most common findings on HRCT are areas of ground-glass attenuation and bronchial dilatation; focal sparing of lung lobules may give a geographic or mosaic appearance. During the later, organising stage of diffuse alveolar damage, traction bronchiectasis and distortion of the bronchovascular bundles are often present. Although the HRCT appearance is not specific for the aetiology of ARDS, a symmetric bilateral distribution of lesions reportedly corresponds more often to acute (idiopathic) interstitial pneumonia than to drug-induced ARDS [137]. When performed, pulmonary function tests show a restrictive pattern, with reduced diffusing capacity and severe hypoxaemia that rapidly worsens despite supplemental oxygen. BAL fluid is predominantly neutrophilic, with frequent haemorrhage and occasionally increased lymphocytes and fragments of hyaline membranes. Diagnostic criteria of ARDS are as follows: Pa,O2/FI,O2 ratio ƒ200 mmHg; diffuse bilateral opacities on chest radiograph; and a pulmonary capillary wedge pressure of ,18 mmHg or no clinical evidence of left atrial hypertension [67, 138]. Exclusion of infection is of utmost importance in the diagnosis of ARDS before drug-induced lung disease may be diagnosed. The key pathological features of diffuse alveolar damage [67, 139] include the diffuse distribution and uniform temporal appearance of the lesions, with alveolar septal thickening due to organising fibrosis (usually diffuse). The exudative phase shows oedema, interstitial acute inflammation, and the hyaline membranes that are a hallmark of diffuse alveolar damage. The organising phase shows mutilating organising fibrosis of the interstitium, with reactive type II pneumocyte hyperplasia. However, lung biopsy is rarely indicated in drug-induced ARDS, as there are no histological features that differentiate drug toxicity from other potential causes of ARDS [65], with the notable exceptions of busulfan- and amiodarone-induced lung disease. In this regard, treatment with busulfan is associated with cytological atypia of bronchiolar and alveolar epithelium (a marker of busulfan treatment regardless of lung toxicity) [140]. Prominent foamy histiocytes and finely vacuolated epithelial cells may be present on histopathology and ultrastructural analysis of the lungs in patients receiving amiodarone [70, 141], a drug that may cause diffuse alveolar damage. As with any cause of ARDS, the lungs may either resolve to normal, or progress to end-stage honeycomb fibrosis causing death. Treatment of ARDS is mostly supportive, and respiratory failure often requires mechanical ventilation with positive endexpiratory pressure, allowing recovery in a proportion of cases [136]. Although they are often prescribed, the therapeutic role of corticosteroids is uncertain.

Drug-induced pulmonary oedema Drug-induced noncardiogenic pulmonary oedema shares clinical and imaging features with ARDS, but the pathological features of diffuse alveolar damage defining ARDS are lacking. In addition, pulmonary oedema due to increased alveolar capillary permeability may be observed through a variety of mechanisms following treatment with hydrochlorothiazide, intravenous b2-agonists in pregnancy, high-dose aspirin, 309


agents used to induce ovulation (ovarian hyperstimulation syndrome), pulmonary vasodilators in patients with veno-occlusive disease, some anticancer drugs (gemcitabine, vinorelbine, paclitaxel), and opiates and tricyclic antidepressants when overdosed in attempted suicides [63]. ILD with fluid retention has been recently reported with the novel multi-targeted anti-tyrosine kinase agent dasatinib in patients treated for chronic myeloid leukaemia, with pleural effusion and septal thickening associated with groundglass opacities and consolidation at chest imaging [52]. Patients present with intense dyspnoea of acute onset, weight gain, alveolar bilateral opacities on chest imaging, and normal echocardiography ruling out cardiac failure. The diagnosis is generally easy because pulmonary oedema occurs very rapidly after the initiation of drug therapy, with the exception of oedema induced by chronic exposure to aspirin [142]. This reversible adverse event of treatment must be differentiated from cardiac failure induced by cumulative toxicity of anthracyclin therapy.

Lipoid pneumonia Exogenous oil (so-called ‘‘lipoid’’) pneumonia caused by laxative agents (paraffin) can cause chronic onset dyspnoea, with basal bilateral pulmonary infiltrates on chest imaging; however, it may also not give rise to symptoms [143]. A condition possibly favouring oil aspiration or inhalation, such as gastro-oesophageal reflux, achalasia and neurological or psychiatric illness, is frequently found. Fever and weight loss may be present, with cough and dyspnoea being the most frequent symptoms. HRCT of the chest demonstrates alveolar consolidation with air bronchogram, together with groundglass opacities of the lower lobes and typically areas of spontaneous angiogram (visualisation of normal branching pulmonary vessels within the consolidated lung in the absence of intravenous contrast injection). Measurement of the density of the alveolar opacities by CT scan reveals a negative density similar to that of subcutaneous adipose tissue and characteristic of ‘‘lipid’’ pneumonia [144]. Resonance magnetic imaging may confirm the presence of fat in the lung, with hypersignal on T1-weighted images [144]. The diagnosis can be further confirmed by BAL, showing numerous large alveolar macrophages with multiple vacuoles stained with Soudan black or red oil O, as well as the presence of mineral oil on lipid chromatography. Lung biopsy is not required. The patient must be advised to stop taking mineral oil. Oral corticosteroid treatment is often poorly effective, and the disease may remain stable for several years.

Alveolar proteinosis and other patterns Pulmonary manifestations compatible with drug-induced secondary pulmonary alveolar proteinosis have been reported with leflunomide [145] and sirolimus [146]. Patchy areas of pulmonary fibrosis have been reported as a result of the use of the haemostatic tissue sealant ‘‘biologic glue’’ [147]. High oxygen concentration may result in acute pulmonary syndrome several years after treatment with bleomycin or amiodarone, a process called oxygen-exacerbated drug pulmonary toxicity [4, 148].

Conclusion Both current and past drug intake should be evaluated very carefully in any patient with diffuse parenchymal lung disease. Because the lung manifestations of drugs may be highly variable, a high index of suspicion is required. Web-based updated lists of drugs causing lung adverse events [11] represent a useful tool when considering possible 310


causative drugs, and drug imputability should be carefully evaluated both in published cases and in clinical practice. Withdrawal of the offending drug may reverse a lifethreatening situation. When imputability is established, adequate information needs to be given to both the patient and the general practitioner and is mandatory to prevent involuntary and hazardous drug re-challenge.

Summary Because the lung manifestations of drugs may be highly variable, a high index of suspicion is required. Both current and past drug intake should be carefully evaluated in any patient with infiltrative lung disease. Drug-induced infiltrative lung disease may manifest as variable clinical radiological patterns, including subacute or chronic interstitial pneumonia, pulmonary fibrosis, eosinophilic pneumonia (presenting as Lo¨ ffler syndrome, or chronic or acute eosinophilic pneumonia), organising pneumonia, diffuse alveolar haemorrhage, acute respiratory distress syndrome, pulmonary oedema, lipoid pneumonia, alveolar proteinosis or sarcoidosis. A variety of drugs have been incriminated, including those used in cardiovascular diseases (amiodarone, statins and angiotensin-converting enzyme inhibitors), antibiotics (especially minocycline and nitrofurantoin), most anticancer drugs and especially chemotherapy, treatment of rheumatoid arthritis (nonsteroidal anti-inflammatory agents, methotrexate, D-penicillamine and tumour necrosis factor-a inhibitors), as well as more recent drugs (interferon, interleukin-2, rituximab, imatinib, dasatinib, gefitinib and sirolimus). Although some risk factors have been identified, the precise mechanisms of drug-induced infiltrative lung disease are largely unknown. The history of exposure to the drug, the timing of drug exposure, the clinical and imaging pattern, the possible improvement following drug discontinuation and the exclusion of other causes of infiltrative lung disease all contribute to the diagnosis and assessment of causality. Although the recurrence of manifestations after patient rechallenge with the drug is considered the best imputability criterion, rechallenge may be dangerous and is discouraged. Web-based updated lists of drugs causing lung adverse events (www.pneumotox.com) represent a useful tool when considering possible causative drugs, and drug causality should be carefully evaluated both in published cases and in clinical practice. Withdrawal of the offending drug and administration of corticosteroids when required may reverse a potentially lifethreatening situation. Keywords: Alveolar haemorrhage, drug-induced, eosinophil, interstitial lung disease, organising pneumonia, pulmonary fibrosis.

Statement of interest None declared. Acknowledgements The authors thank J.F. Cordier (Universite´ de Lyon, Universite´ Lyon I, UMR754 INRA, IFR128, Hospices civils de Lyon, Hoˆpital Louis Pradel, Service de pneumologie – centre de re´fe´rence des maladies orphelines pulmonaires, Lyon, France) and P. Camus (Universite´ de Bourgogne, Hoˆpital du Bocage, Service de Pneumologie et Re´animation Respiratoire, Pneumotox, INSERM 866, Dijon, France) for critical review of the manuscript. 311


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