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Therapeutic Strategies for DLI: How Should DLI Be Treated?

  • Sakae HommaEmail author
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Part of the Respiratory Disease Series: Diagnostic Tools and Disease Managements book series (RDSDTDM)

Abstract

The lungs are vulnerable to toxins because of their large surface area and act as a metabolic site for some substances. Drugs may induce specific respiratory reactions, or the lungs may be affected as part of a generalized response. Drug-induced lung injury (DLI) can involve the airways, lung parenchyma, mediastinum, pleura, pulmonary vasculature, and/or the neuromuscular system. The most common form of DLI is drug-induced interstitial lung disease. There are no disease types specific to DLI, and DLIs are diagnosed on the basis of clinical findings, chest CT images, and histopathologic findings. The first principle of management of DLI is early detection and cessation of treatment with the suspected drug. Response to corticosteroid therapy depends on the histopathologic pattern of drug-induced interstitial lung disease. Prognosis depends on the specific drug and underlying clinical, physiologic, and pathologic severity of lung disease. To minimize DLI morbidity and mortality, all health-care providers should be familiar with the possible adverse effects of medications they prescribe. Individual variability in drug response is an important concern in clinical practice and drug development. Such variability is multifactorial and includes extrinsic factors such as environmental features and genetic and intrinsic factors that affect the pharmacokinetics and pharmacodynamics of drugs.

Keywords

Therapeutic strategy Drug-induced lung injury (DLI) Drug-induced interstitial lung disease (DILD) Treatment 

9.1 Introduction

The number of drugs that cause lung disease will continue to increase with the development of new agents, such as biologics and immune checkpoint inhibitors [1, 2, 3, 4]. Drug-induced lung injuries (DLIs) can affect the airways, lung parenchyma, mediastinum, pleura, pulmonary vasculature, and/or neuromuscular system. The most common form of DLI is drug-induced interstitial lung disease (DILD). Orally and parenterally administered drugs are the most frequent causes of DLI; however, nebulized and intrathecal agents have also been implicated. DLI may result from a direct or indirect drug effect; direct effects may be idiosyncratic or caused by a toxic reaction to the drug or one of its metabolites.

Diagnosis of DLI is difficult because the clinical, radiologic, and histologic findings are nonspecific. The connection with drug use and the development of related inflammatory damage or idiosyncratic toxicities is hard to recognize and quantify, especially in patients using multiple drugs [5].

9.2 Disease Types and Characteristics

There are no disease types specific to DLIs, and DLIs are diagnosed on the basis of clinical features, chest computed tomography (CT) images, and histopathologic findings. The pulmonary lesions, disease types, and corresponding histopathologic findings of DLIs are shown in Table 9.1 [6].
Table 9.1

Pulmonary lesions, disease types, and histopathological findings of DLIs [6]

Pulmonary lesions

Disease types

Histopathological findings

1. Alveolar and interstitial legions

Acute respiratory distress syndrome/acute lung injury (ARDS/ALI)

Diffuse alveolar damage (DAD) (clinically severe)

Acute interstitial pneumonia (AIP)

Diffuse alveolar damage (DAD) (clinically severe)

Idiopathic pulmonary fibrosis (IPF)

Usual interstitial pneumonia (UIP)

Nonspecific interstitial pneumonia (NSIP)

Nonspecific interstitial pneumonia (NSIP)

Desquamative interstitial pneumonia (DIP)

Desquamative interstitial pneumonia (DIP)

Cryptogenic organizing pneumonia (COP)

Organizing pneumonia (OP)

Lymphocytic interstitial pneumonia (LIP)

Lymphocytic interstitial pneumonia (LIP)

Eosinophilic pneumonia (EP)

Eosinophilic pneumonia (EP)

Hypersensitivity pneumonia (HP)

Hypersensitivity pneumonia (HP)

Granulomatous interstitial lung diseases

Granulomatous interstitial pneumonia

Pulmonary edema

Pulmonary edema

Capillary leak syndrome

Pulmonary edema

Pulmonary alveolar proteinosis

Alveolar proteinosis

Diffuse alveolar hemorrhage

Alveolar hemorrhage

2. Airway

Bronchial asthma

Bronchial asthma

Bronchiolitis obliterans syndrome (BOS)

Constrictive bronchiolitis obliterans (CBO)

3. Blood vessels

Vasculitis

Vasculitis

Pulmonary hypertension

Pulmonary hypertension

Pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease

4. Pleura

Pleuritis

Pleuritis

9.2.1 DLI Disease Types and Major Causative Drugs

Representative drugs reported to cause DLIs are listed in Table 9.2 [7].
Table 9.2

Pulmonary lesions and causative drugs of DLIs [7]

Pattern of DLIs

Causative drugs

Diffuse alveolar damage (DAD)

Amiodarone, cyclophosphamide (CPA), gefitinib, erlotinib, cetuximab, panitumumab, methotrexate (MTX), and others

Organizing pneumonia (OP)

Bleomycin (BLM), MTX, CPA, gold drugs, amiodarone, salazosulfapyridine (SASP), penicillamine, and others

Nonspecific interstitial pneumonia (NSIP)

Amiodarone, MTX, penicillamine, gold drugs, hydralazine, and others

Hypersensitivity pneumonia (HP)

Beta-blockers, azathioprine, busulfan, procarbazine, nitrofurantoin, and others

Eosinophilic pneumonia (EP)

Loxoprofen, acetylsalicylic acid, acetaminophen, MTX, penicillins, levofloxacin, phenytoin, imipramine, hydralazine, amiodarone, shosaikoto, and others

Pulmonary edema (NCPE)

Cytarabine arabinoside (Ara-C), gemcitabine (GEM), MTX, amphotericin B (AMPH-B), acetazolamide, aspirin, morphine, and others

Bronchial asthma

Beta-blockers, NSAIDs, aspirin, and others

Bronchiolitis obliterans

Penicillamine, ampicillin, salazosulfapyridine, sauropus androgynus, and others

Pulmonary thromboembolism

Estrogen preparations, contraceptives, olanzapine, risperidone, and others

Alveolar hemorrhage

Heparin sodium, rivaroxaban, dabigatran etexilate, aspirin, clopidogrel sulfate, propylthiouracil, and others

Pulmonary hypertension

Aminorex, cocaine, methamphetamine, and others

Pleuritis

Amiodarone, procarbazine, methotrexate, infliximab, and others

9.2.1.1 DILD

DILD must be differentiated from diffuse lung diseases, including idiopathic interstitial pneumonias (IIPs), interstitial pneumonia associated with connective tissue disease, acute and chronic hypersensitivity pneumonia (HP), eosinophilic pneumonia (EP), acute lung injury (ALI)/acute respiratory distress syndrome, and Pneumocystis jiroveci pneumonia (PCP). However, it is particularly difficult to determine whether a new shadow detected in a diagnostic image of the lungs is attributable to primary disease or a drug.

Drugs reported to induce diffuse alveolar disease (DAD), organizing pneumonia (OP), nonspecific interstitial pneumonia (NSIP), and HP include amiodarone, cyclophosphamide (CPA), gefitinib, erlotinib, cetuximab, panitumumab, methotrexate (MTX), bleomycin (BLM), gold drugs, salazosulfapyridine (SASP), penicillamine, hydralazine, beta-blockers, azathioprine, busulfan, procarbazine, and nitrofurantoin, among others.

9.2.1.2 Eosinophilic Pneumonia (EP)

Drug-induced EP is a collective term for diseases with respiratory manifestations—including dyspnea—that develop as a consequence of lung tissue damage caused by eosinophilic infiltration during drug treatment. Drugs that have been reported to induce EP include loxoprofen, acetylsalicylic acid, acetaminophen, MTX, penicillins, levofloxacin, phenytoin, imipramine, hydralazine, amiodarone, shosaikoto, and others [8, 9].

9.2.1.3 Pulmonary Edema

Drug-induced pulmonary edema is typically non-cardiogenic pulmonary edema (NCPE). However, if the causative drug has a direct effect on the cardiovascular system that leads to decreased left ventricular function, the pathology is similar to cardiogenic pulmonary edema. Drugs reported to induce NCPE include cytarabine arabinoside (Ara-C), gemcitabine (GEM), MTX, amphotericin B (AMPH-B), acetazolamide, aspirin, morphine, and others [10, 11].

9.2.1.4 Airway Lesions

Drug-induced asthma or bronchospasm is broadly divided into three disease types, according to the causative agent, as follows: disease induced by beta-blockers; disease induced by nonsteroidal anti-inflammatory drugs, as in aspirin-induced asthma; and disease induced by inhalation of powdery substances, as in occupational asthma [7]. Bronchiolitis obliterans is induced by penicillamine, ampicillin, salazosulfapyridine, and Sauropus androgynus, among other drugs [12, 13, 14].

9.2.1.5 Pulmonary Vessel Lesions

Pulmonary Thromboembolism

Because estrogen preparations and oral contraceptives promote blood coagulation, their use is considered a risk factor for pulmonary thromboembolism. Numerous studies have reported that the use of psychotropic drugs to treat psychiatric disorders, including schizophrenia, was associated with pulmonary thromboembolism development [15].

Alveolar Hemorrhage

Drug-induced alveolar hemorrhage occasionally occurs during the use of antithrombotic drugs, such as anticoagulant, antiplatelet, and thrombolytic drugs, or as a complication of vasculitis related to antineutrophil cytoplasmic antibodies, which are typically present in patients treated with antithyroid drugs [16].

Drugs reported to induce alveolar hemorrhage include heparin sodium, rivaroxaban, dabigatran etexilate, aspirin, clopidogrel sulfate, and propylthiouracil, and others.

Pulmonary Hypertension (PH)

Drug-induced PH is reported to account for approximately 10% of all PAH cases and is induced by aminorex, cocaine, and methamphetamine, among other drugs [17].

9.2.1.6 Pleural Lesions

Drug-induced pleural lesions are rare. To date, over 40 drugs have been reported to induce pleural lesions, including amiodarone, procarbazine, methotrexate, infliximab, etanercept, and others [18, 19].

9.3 Current Status of and Response to DLI Treatment

9.3.1 Current Status of Treatment

The first principle of management for DLIs is early detection and cessation of treatment with the suspected drug. The primary goal of treatment is suppression of the inflammatory response and prevention of lung fibrosis.

Acute episodes of DLIs usually resolve within 24–48 h after drug discontinuation, but chronic syndromes take longer. Because hypoxemia is common in DLIs, supplemental oxygen therapy is often provided. If a cytotoxic DLI is severe or appears to progress despite drug discontinuation, empirical administration of corticosteroids is advisable.

If continued treatment is necessary, the suspected drug should be replaced by a drug that is less likely to induce DLIs. Antineoplastic drugs therapy, however, should not be resumed until the injury has resolved. Recent evidence indicates that treatment approaches for everolimus- or temsirolimus-induced interstitial pulmonary disease and immune-related adverse events should be based on disease severity (Table 9.3) or grade (Table 9.4).
Table 9.3

Disease severity and treatment strategy for DLIs [6]

Degree of severity

PaO2 (room air)

Treatment strategy

Mild

≥80 Torr

Discontinuation of the suspected drug

Moderate

60 to <80 Torr

Discontinuation of the suspected drug Corticosteroid therapy

Severe

<60 Torr (PaO2/FiO2 < 300)

Discontinuation of the suspected drug. mPSL pulse therapy for 3 days and then continuous corticosteroid therapy

Table 9.4

Management of DILD caused by immune checkpoint inhibitors [4]

Grade 1 (mild)

Grade 2 (moderate)

Grade 3 (severe)

Grade 4 (life threatening)

Asymptomatic; clinical or diagnostic observations; no intervention needed: delay drug administration. Consider steroids (e.g., prednisone 1 mg/kg/day PO or methylprednisolone 1 mg/kg/day IV). Follow-up: reassess management after 3 weeks—if completely resolved or non-drug-related continue treatment. If worsens treat as grade 2 or grade 3/grade 4

Symptomatic; medical intervention indicated; limits instrumental ADLs: delay drug administration. Consider hospitalization, daily monitoring of symptoms. Steroids recommended (e.g., prednisone 1–2 mg/kg/day PO or methylprednisolone 1–2 mg/kg/day IV). Consider empiric antibiotics (if suspicious for concurrent infections). Follow-up: reassess management every 1–3 days. If improving, taper steroids and continue treatment if symptoms resolve completely. If it worsens treat as grade 3/grade 4

Severe symptoms; limits self-care ADLs; oxygen indicated: discontinue drug administration. Hospitalization. High-dose steroids with methylprednisolone (e.g., 1 g/day IV). Add prophylactic antibiotics for opportunistic infections. Consider bronchoscopy with biopsy. Reassess management daily. If not improving after 48 h or worsening, administer additional immunosuppressive therapy (e.g., infliximab, mycophenolate, immunoglobulins). If improving, taper steroids. Discontinue treatment permanently

Life-threatening respiratory compromise; urgent intervention indicated (e.g., intubation): as per grade 3. Intensive care support required

Patients with a moderate DLI should be treated with corticosteroids at a dose equivalent to 0.5–1.0 mg/kg/day of prednisolone (PSL), depending on the suspected drug and condition of the patient, in addition to discontinuation of the suspected drug. Treatment at the initial dose should be continued for 2–4 weeks and then gradually tapered. Patients with a severe DLI should be treated with methylprednisolone (mPSL) pulse therapy consisting of an mPSL dose equivalent of 500–1000 mg/day for 3 days, followed by treatment with corticosteroids at a dose equivalent to 0.5–1.0 mg/kg/day of PSL for 2–4 weeks, which is then tapered. If lung injury and hypoxemia resolve immediately, corticosteroid therapy can be ceased after 1–2 months (Fig. 9.1).
Fig. 9.1

Treatment strategy for DLIs [6]

Recent research on the side effects of the immune checkpoint inhibitor nivolumab showed that DILD was less frequent in patients with melanoma (approximately 2–5%) than in those with renal cancer or non-small cell lung cancer (NSCLC) (approximately 5%). Treatment-related deaths from DILD have been reported, and the frequencies of such deaths were similar in melanoma and NSCLC patients receiving pembrolizumab. Ipilimumab monotherapy results in pneumonitis in up to 5% of patients, although the percentages of patients with dyspnea and cough are higher. Combination administration of ipilimumab and nivolumab is associated with the highest rate of ILD (5–10% for any grade and 2% for grade 3/grade 4) [4, 20, 21, 22, 23, 24, 25, 26].

Observation and continued treatment with the suspected drug are acceptable for patients with asymptomatic DILD; however, development of symptoms warrants interruption of immune checkpoint delivery and initiation of corticosteroid treatment (Table 9.4).

9.3.2 Responses to Treatment

The response to corticosteroid therapy depends on the histopathologic pattern of DILD. Histopathologic changes for most drug reactions are nonspecific, but some drugs (e.g., amiodarone) have a characteristic histopathologic pattern of involvement that enables almost instant recognition of the causative agent. Methotrexate, for example, causes acute granulomatous DILD, which mimics an opportunistic infection [27].

Drugs can produce nearly all histopathologic patterns of interstitial pneumonia, including HP, OP, DAD, nonspecific interstitial pneumonia (NSIP), EP, pulmonary hemorrhage, and granulomatous pneumonitis. Most drugs in a comparable class induce a similar pattern of pulmonary involvement, which suggests a common cytopathic mechanism. However, some drugs produce more than one pattern of histopathologic involvement in the same patient. These reactions may be acute, subacute, or chronic (Table 9.2).

DLIs caused by allergic reactions and EP, HP, cellular NSIP, and OP associated with DILD generally respond to corticosteroids. However, DAD caused by cytotoxic mechanisms may not respond to corticosteroids. With respect to histopathologic findings, the following types of DLI cases will likely respond to corticosteroids: (1) cases in which histopathologic findings indicate inflammation characterized by lymphocyte infiltration or development of granulomatous lesions with no, or very limited, tissue damage or fibrosis and (2) cases in which histopathologic findings suggest EP or organic changes in alveoli. However, cases of DAD and those involving advanced fibrosis are unlikely to respond to corticosteroids.

Patients with OP, EP, or HP and normal serum KL-6 levels respond to corticosteroids; thus, those with DLIs and normal KL-6 levels are also likely to respond to corticosteroids, as long as the injury corresponds to any of the OP or HP clinical disease types for DLIs [28].

Treatment planning must carefully consider the severity of DLI and the morbidity associated with failure to treat the underlying disease. Alternative agents, if available, should be used. Because many patients with DILD are treated with immunosuppressive medications, which modestly increase the risk of infection, patients with DILD should receive the pneumococcal vaccine and yearly influenza virus vaccine. Furthermore, the incidence of tuberculosis is highly associated with antitumor necrosis factor monoclonal antibody therapy. The increased risk associated with early antitumor necrosis factor treatment and lack of an optimal chemopreventive treatment favor reactivation of latent tuberculosis.

9.4 Prognosis

Prognosis is favorable when acute DLIs are diagnosed early, and complete recovery can be expected in such cases. However, undiagnosed DLIs are associated with substantial morbidity and mortality. Prognosis depends on the specific drug and underlying clinical, physiologic, and pathologic severity of lung disease. Typical complications of DLIs are pulmonary fibrosis and respiratory failure requiring mechanical ventilation. Unfortunately, if the initial injury or abnormal repair of injury is not stopped, progressive tissue damage can lead to worsening physiologic impairment and even death.

The prognosis for DILD varies in relation to the frequency of the DAD pattern. Thus, it is important to determine whether the presenting DILD has a DAD pattern. Histopathologic examination is required for diagnosis. However, patients often present in serious condition, when it is difficult to perform a lung biopsy. In such cases, high-resolution CT is helpful in determining the DILD pattern. In general, the suspected drug should be immediately discontinued and re-administration avoided.

9.5 Conclusions

DLIs can involve the airways, lung parenchyma, mediastinum, pleura, pulmonary vasculature, and/or the neuromuscular system. The first principle of management of DLIs is early detection and cessation of treatment with the suspected drug. Response to corticosteroid therapy depends on the histopathologic pattern of DILD. Prognosis depends on the specific drug and underlying clinical, physiologic, and pathologic severity of lung disease. In addition, the clinical and radiographic features of DILD are often difficult to distinguish from those of other causes of DILD (e.g., infections, lung involvement of an underlying disease, pulmonary edema, connective tissue disease), and no signs, symptoms, or laboratory or radiologic findings are considered pathognomonic. Therefore, it is essential for physicians to be familiar with iatrogenic diseases that may affect their patients. In addition, clinical and genetic risk stratification may improve prevention of DILD in the future.

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Respiratory MedicineToho University Omori Medical CenterTokyoJapan

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