Chapter 17 Drug-Induced and Iatrogenic Respiratory Diseases

For both many older and newer therapeutic agents, the risk-benefit ratio is clearly in favor of treatment of many neoplastic conditions, rheumatoid arthritis, systemic or pulmonary hypertension, and cardiac dysrhythmias. In a small fraction of patients exposed to drugs taken at normal dosage to treat these conditions, adverse respiratory effects may develop. It is the duty of practitioners in oncology, cardiology, rheumatology, primary care, emergency medicine, pathology, and respiratory medicine to be cognizant of drug-induced respiratory diseases.

Recognition that a respiratory problem has been caused by the administration of a drug or a combination of drugs is of primary importance in the clinical setting. Patients may be spared unnecessary invasive evaluation including lung biopsy and/or empirical corticosteroid therapy for an alternative condition pending the results of a dechallenge-challenge test, which can be diagnostic. Further damage usually can be prevented if use of the offending agent is stopped early. Measures should be taken so that the underlying illness for which the drug was given is managed appropriately using other medications and so that the patient is not unduly reexposed to the culprit agent. In each individual case, careful exclusion of another cause is warranted, and considerations in the differential diagnosis will vary with the clinical presentation, pattern of respiratory injury, specific drug, and underlying illness.

An ever-increasing number of therapeutic drugs (n = 455), hormones, and investigational compounds have been associated with severe adverse respiratory reactions in adults, children, health care professionals, and persons who work in the drug industry or otherwise handle drugs, as well as in companion animals, horses, and cattle. A periodically updated online list of causal drugs is maintained on the Pneumotox website (www.pneumotox.com), sponsored by the GEPPI (Groupe d’Etudes de la Pathologie Pulmonaire Iatrogène) investigators. Agents of recent interest or concern are listed in Table 17-1. Adverse effects of drugs such as amiodarone, antineoplastic chemotherapy agents, nitrofurantoin, or nonsteroidal antiinflammatory drugs (NSAIDs) are still commonly observed. Owing to their less trendy nature, however, the number of publications dealing with these medications represents an underestimate of the true incidence. With the recently renewed interest in nitrofurantoin for use as a urinary antiseptic agent, a resurgence of new cases of nitrofurantoin lung may potentially be expected. The same holds true for thalidomide. The clinical problem of drug overdose, although capable of producing severe pulmonary edema, is beyond the scope of drug-induced lung disease in this chapter.

Table 17-1 Drugs/Drug Families Recently Implicated as Agents of Respiratory Injury

Some presentations of drug-induced respiratory disease (DIRD) are distinctive clinically, radiologically, or histopathologically, and in such cases the evidence points almost unequivocally to the drug itself as the cause. Drug-induced anaphylaxis, angioedema, bronchospasm, noncardiac pulmonary edema (NCPE), diffuse alveolar hemorrhage (DAH), amiodarone-induced pulmonary toxicity, exogenous lipoid pneumonia, and the rare diffuse pattern of pulmonary calcification are classic examples of conditions highly suggestive of drug-induced injury.

A few drugs produce gender-specific adverse respiratory reactions because they are reserved for treating diseases that are more prevalent in or specific to one or the other gender (e.g., nilutamide and amiodarone in men, trastuzumab and nitrofurantoin in women). Still other drugs capable of causing lung damage, such as gold salts, penicillamine, or methyldopa, have been supplanted by novel agents and are falling out of favor. In addition, certain drugs—including aminorex, benfluorex, fenfluramine, dexfenfluramine, hexamethonium, L-tryptophan, and mecamylamine—have been recalled from the pharmaceutical lineup for the reason of respiratory or other adverse effects. Rare sporadic cases of adverse reactions from these agents are still being reported.

One of the greatest challenges in determining drug toxicity in suspected cases is that most patients are taking multiple medications to treat complex underlying conditions, and more than one drug may be capable of causing respiratory damage. Diagnosing drug-induced disease in this situation can be problematic, particularly if the underlying disease also manifests with interstitial lung disease (ILD) or is associated with opportunistic pulmonary infections. For instance, patients with rheumatoid arthritis may receive methotrexate or leflunomide in addition to an anti–tumor necrosis factor (TNF) agent; cardiac patients may receive anticoagulants, antiplatelets, and amiodarone; and patients with neoplastic conditions typically are exposed to several drugs, including chemotherapy agents, all capable of causing lung damage.

In addition to the usual over-the-counter and prescription drugs, numerous agents including whole blood, platelets, plasma concentrates, parenteral nutrition solutions, substances of abuse (e.g., cocaine, heroin, morphine, marijuana, propofol, anesthetic gases), herbal preparations (e.g., Sauropus), drug excipients (e.g., crospovidone, talc, cornstarch, lipids, sesame oil) present in therapeutic drugs, adulterants used in street drugs (e.g., brodifacoum, levamisole), illegally used chemicals such as fluid silicone or paraquat, and external or internal radiation therapy may injure the respiratory system by similar pharmacologic-cytopathic mechanisms.

Virtually any route of administration of drugs may be associated with increased risk for DIRD. The oral, parenteral (intramuscular, intravenous), inhaled, dermal, and topical routes are cited most often. Drugs instilled into the pleural space, coronary artery, hepatic artery, urinary bladder, uterine cavity, myometrium, subcutaneous fat, or vertebral body, or given intrathecally or aspirated into the bronchial tree, also can cause respiratory injury.

With reference to respiratory disease, the term iatrogenic encompasses pulmonary damage from medical or surgical procedures such as liposuction, chest tube placement, coronary artery bypass graft, and insertion of pacemaker leads or central venous line, as well as retained foreign bodies (also known as gossypibomas), all of which may cause potentially serious respiratory compromise.

Interstitial-infiltrative lung disease (i.e., ILD) is the most common clinical-imaging-pathologic pattern of respiratory involvement from drugs, accounting for about two thirds of all cases of DIRD. Conversely, drugs account for about 3% of all ILD cases. The relative preponderance of ILD must not overshadow other, less common DIRD patterns such as involvement of the upper or lower airways, pleural membrane, pericardium, heart, heart valves, pulmonary circulation, mediastinum, respiratory muscles and nerves, central respiratory oscillator, and hemoglobin, which may have detrimental clinical consequences.

DIRD may be detected at a subclinical stage on imaging or bronchoalveolar lavage (BAL) fluid analysis, or it can be clinically evident and serious, requiring prompt recognition, immediate drug withdrawal, and emergent management aimed at securing airway patency, restoring gas exchange, and correcting hemoglobin dysfunction. DIRD presentations that portend particular severity (Table 17-2) include drug-induced anaphylaxis, angioedema, and bronchospasm, which may cause acute airway obstruction; NCPE; diffuse alveolar damage (DAD); DAH; extensive ILD, including eosinophilic pneumonia; opportunistic infections including Pneumocystis and viral pneumonias; massive pleural effusion; methemoglobinemia; neuromuscular failure; and multiorgan dysfunction. Drug-induced and iatrogenic events that occur intraoperatively, including drug-induced explosive coughing, curare- or latex-induced anaphylaxis, opiate-induced pulmonary edema, transfusion-related acute lung injury (TRALI), protamine-induced acute pulmonary hypertension, or negative-pressure pulmonary edema, raise difficult diagnostic and management issues. Awareness and emergent management are essential; however, some DIRDs are not survivable (see Table 17-2).

Table 17-2 Life-Threatening Drug-Induced Respiratory Conditions Requiring Emergent Management

Several drugs within certain pharmacologic classes—curares, opiates, angiotensin-converting enzyme (ACE) inhibitors, β-adrenergic receptor blockers, antidepressants, appetite suppressants (anorectics), anticonvulsants, antineoplastic chemotherapy agents, ergots and ergolines, leukotriene receptor antagonists (LTRAs), mTOR (mammalian target of rapamycin) inhibitors, NSAIDs, and statins—may cause similar kinds of DIRD, suggesting a common pharmacologic cytopathic mechanism (Table 17-3). Furthermore, patients who exhibit an adverse reaction from one drug are at risk for cross-reaction if challenged with another drug of the same family. In the case of anticonvulsants, relatives of patients with the syndrome of drug rash, eosinophilia, and systemic symptoms (DRESS) may be at risk for development of a similar complication with exposure to this class of medications.

Table 17-3 Specific Agents/Drug Families Implicated in Drug-Related Respiratory Disease

Certain antineoplastic agents may cause acute or subacute lung injury when used in a single-drug regimen (e.g., azathioprine, bleomycin, busulfan, chlorambucil, cyclophosphamide, dasatinib, imatinib, methotrexate, nitrosoureas). Typically, however, these agents are given as part of a multiagent regimen, so that it is difficult to discern which drug caused the reaction, unless pulmonary toxicity is observed to occur only after addition of a specific drug to an otherwise nonpneumotoxic regimen. Toxicity in this latter setting has been documented for bleomycin, gemcitabine, methotrexate, radiation therapy, and rituximab. Combinations of certain chemotherapy agents, such as gemcitabine and bleomycin, or of drugs and radiation therapy may be particularly toxic, dramatically increasing the incidence of severe pulmonary toxicity. Oxygen also synergizes the pulmonary toxicity of chemotherapy agents, amiodarone, and radiation therapy. Radiation therapy may synergize chemotherapy-induced lung damage, causing augmented toxicity or rebound pneumonitis in the previously treated patient. Several antineoplastic agents of the newer generation—erlotinib, gefitinib, imatinib, dasatinib, everolimus, trastuzumab, temozolomide, temsirolimus, thalidomide, lenalidomide, omalidomide, and topotecan—may cause acute pneumonitis, DAD, pulmonary fibrosis, organizing pneumonia (the preferred designation for bronchiolitis obliterans organizing pneumonia [BOOP]), infusion reactions, bronchospasm, anaphylaxis, capillary leak, methemoglobinemia, and pulmonary hemorrhage. In addition to subacute and acute presentations, antineoplastic agents may cause subtle insidious pneumonitis or fibrosis particularly in children, typically noted years after completion of therapy, in the form of indolent or progressive restrictive lung dysfunction. In a few such patients, lung transplantation may be necessary.

Diagnosing Drug-Induced Respiratory Disease

Diagnosing DIRD accurately is essential with regard to decisions to discontinue or continue the presumptively offending agent, because inappropriate drug withdrawal may have a negative impact on outcome, and because rechallenge may lead to fatal relapse. Issues regarding the diagnosis of DIRD and the corresponding differential diagnosis differ according to the underlying illness and specific clinical context (Table 17-4). Particularly difficult issues arise in patients with solid tumors, hematologic malignancies, or rheumatoid arthritis and in recipients of bone marrow or hematopoietic stem cell transplants, who are immunosuppressed under the combined influence of the underlying condition and the drugs (including corticosteroid therapy) and the radiation used to treat it.

Table 17-4 Diagnosis and Differential Diagnosis of Drug-Induced Respiratory Disease

Although the expression of bacterial and fungal pulmonary infections on imaging studies often is distinctive, viral and Pneumocystis pneumonias resemble drug-induced ILD, with no clinical or radiographic discriminator to separate these two entities. Therefore, meticulous examination of BAL and other body fluids is indicated. Further complicating the issue, recipients of hematopoietic stem cell transplants may develop diffuse nonspecific pulmonary complications unrelated to drugs, such as acute pulmonary edema, DAH, the periengraftment respiratory distress syndrome, and idiopathic pneumonia syndrome, leading to substantial diagnostic confusion. Drug-induced ILD also is difficult to diagnose in patients with rheumatoid arthritis and in those with certain other systemic conditions, for several reasons: such patients often receive more than one DMARD (e.g., NSAID, methotrexate, an anti-TNF drug, cyclophosphamide, or rituximab) each having the potential to cause lung damage. In addition, the underlying rheumatic or systemic condition itself may manifest with progressive ILD. Furthermore, opportunistic infections can occur as a consequence of the underlying disease and/or therapy with corticosteroids and anti-TNF agents. Similarly, ILD in cardiac patients who are taking amiodarone raises complex issues, because amiodarone-induced pulmonary toxicity must be reliably and noninvasively separated from heart failure and from any incidental ILD.

The evidence base for respiratory disease as being drug-induced is wide-ranging, because the literature on DIRD consists mostly of case reports and is subject to reporting bias. There is a paucity of epidemiologic studies showing a convincing association of exposure to a drug and occurrence of pulmonary events. Investigating a case of possible DIRD requires a high degree of awareness, careful exclusion of conditions that DIRD can resemble (e.g., Pneumocystis or viral pneumonia with use of BAL), cessation of administration of the suspected agent (underlying disease permitting), and discussion of whether corticosteroid therapy is indicated, bearing in mind that corticosteroid therapy itself may complicate evaluation of the effect of drug withdrawal on signs and symptoms (drug withdrawal may be without an effect in patients with explosive or severe presentations). Evidence indicating that a respiratory reaction is drug-induced consists of the following: (1) the likelihood of exposure to a compatible drug, particularly if given as a solo agent, (2) previous conclusive reports of reactions to the drug, (3) pattern of involvement compatible with the specific drug, (4) compatible temporal relationship of exposure and onset and progression of symptoms, best demonstrated in patients who experience an acute reaction such as acute bronchospasm, anaphylaxis, angioedema, or pulmonary edema; (5) abatement of signs and symptoms after cessation of drug administration; (6) supportive findings on BAL fluid and histopathologic analysis; (7) lack of an alternative diagnosis after meticulous investigation using BAL and, in selected cases, lung biopsy; and (8) relapse of signs and symptoms on rechallenge, a potentially hazardous test. Box 17-1 summarizes these diagnostic criteria and presents a useful approach to diagnosis and management of DIRD.

Box 17-1

Approach to Diagnosis and Management of Drug-Induced Respiratory Disease

Diagnostic Criteria

Confirmed exposure to an eligible drug

Confirmatory literature data

Pattern of reaction appropriate for the drug

Appropriate latency period and timing of onset of respiratory symptoms relative to taking the drug

Supportive BAL and histopathologic findings

Resolution of symptoms after dechallenge

Exclusion of any other cause including other drugs

Relapse after rechallenge, if performed

Checklist for Fine-Tuning Diagnosis and Management

In patients with compatible clinical presentation or supportive imaging or histopathologic findings (summarized on the Pneumotox website):

1. Depending on level of consciousness and presence or level of respiratory distress, take history of exposure to drugs, occupational/environmental agents, chemicals, and toxic substances. Confirm drug history from relatives, friends, or pharmacist when needed.

2. Evaluate risks associated with discontinuance of drug for underlying condition. Substitute when appropriate.

3. Arrange for timely evaluation of drug and metabolites in blood and/or urine (e.g., opiates, amiodarone, aspirin, mTOR inhibitors) and a urine drug screen.

4. List patterns of respiratory involvement attributable to an underlying disease if present. Match with pattern of involvement from the drug or drugs under consideration. Check for overlapping features.

5. Check complete blood count, CD4⁺ count, autoimmunity (ANA, ANCA), and HIV serostatus whenever appropriate.

6. Retrieve earlier, pretreatment, and baseline imaging studies, respiratory physiology reports, laboratory data, and autoantibody assay results.

7. List exposure to any drug (even if remote), blood transfusion, blood products, radiation therapy, concealed exposure to illicit drugs, substances of abuse, and chemicals used to synthesize drugs in the household.

8. List possible risk factors related to dosing or blood levels (see text).

9. Examine timing of exposure—discontinuation versus latency period, onset, peak, and resolution of pulmonary symptoms and signs on imaging studies.

10. Match clinical presentation, imaging data, and findings on BAL, laboratory testing, ANA and ANCA assays, and histopathologic analysis (if available) with the drug under study. Contribution of KL-6 glycoprotein assay and in vitro tests is limited.

11. Examine other diagnostic possibilities including Pneumocystis and viral pneumonia and pulmonary involvement from the underlying disease.

12. Check laboratory findings for involvement of organs other than the lung.

13. If patient has been exposed to more than one drug, assess causality for each specific drug.

14. Examine whether adverse reaction may result from the known pharmacologic effect of the drug

15. Determine pharmacogenetic trait when appropriate.

16. Evaluate whether corticosteroid therapy is indicated in addition to drug withdrawal (as indicated by clinical severity).

17. Schedule follow-up assessment for signs/symptoms and imaging and laboratory abnormalities after drug withdrawal, to confirm positive dechallenge.

18. Ensure proper communication with any health professional so that the patient is not inadvertently rechallenged with the drug.

19. Discuss whether deliberate rechallenge is indicated (reserved for vital drugs for which no substitute is available). This procedure is performed using low doses in a hospital setting close to an ICU. Tolerance can be induced for a limited number of drugs.

20. Report to national/federal drug safety monitoring authorities; plan publication of findings.

ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; BAL, bronchoalveolar lavage; HIV, human immunodeficiency virus; ICU, intensive care unit; mTOR, mammalian target of rapamycin.

The Naranjo scale is well known for grading the evidence. Case histories are heterogeneous in the literature and rarely include all criteria. Patients may give a history of periods on and off the drug, and it is important to correlate timing of these with onset, fading, and recurrence of respiratory signs and symptoms. Although drugs are an important consideration in the differential diagnosis for ILD, video-assisted surgical lung biopsy (VATS) is rarely performed owing to its relative invasiveness and associated risks. The transbronchial approach is a valuable alternative, although the limited size of the sample obtainable with this technique confers a lesser degree of diagnostic certainty than that achieved with the open approach. Although the possibility of drug-induced ILD sometimes is raised by the pathologist on the basis of typical changes in the tissue, lung biopsy usually can be avoided, because lung tissue changes may lack specificity for the drug. Important exceptions include amiodarone pulmonary toxicity, which demonstrates features of dyslipoidosis; chemotherapy lung, characterized by DAD and an abundance of reactive epithelial cells; lung injury from illicit drugs, in which presence of carbonaceous deposits or drug excipient within and around the pulmonary vasculature is typical; exogenous lipoid pneumonia, in which oil is seen lying free in the alveoli and in the tissue; and fluid silicone embolism, associated with distinctive nonstainable vacuoles.

In most other instances, histopathologic examination discloses changes that are consistent with, rather than diagnostic for, the drug etiology. However, the lung biopsy has an important diagnostic role in that it may confidently exclude other potential etiologic disorders, including infection, if appropriate stains and molecular techniques are applied to the specimen.

Patterns of Drug-Induced Respiratory Disease

More than 60 discrete clinical-imaging-pathologic patterns of DIRD have been identified. The most common presentation is one of diffuse or focal pulmonary infiltrates, with or without hypoxemia. This pattern often is referred to as ILD, although histopathologic evidence is rarely available to confirm the diagnosis. Under the influence of cultural differences throughout the world, a given clinical imaging pattern may be named using various descriptor English terms. A recent trend is to ascribe a specific “pathologic diagnosis” to a given pattern on high-resolution computed tomography (HRCT). This should be done with caution, however, because correlation of these two diagnostic modalities can be suboptimal. Drugs can elicit virtually any pattern of naturally occurring ILD, which as noted is a clinical, radiologic, and histopathologic mimic of numerous entities: nonspecific cellular or fibrotic nonspecific interstitial pneumonia (NSIP), eosinophilic pneumonia, BOOP, desquamative interstitial pneumonia (DIP), ILD with a granulomatous component, interstitial pulmonary fibrosis, or pulmonary alveolar proteinosis. Drugs also may cause NCPE, DAD, and DAH.

Other patterns of respiratory involvement include angioedema, bronchospasm, pleural effusion with or without the lupus syndrome, pulmonary vasculopathy with or without pulmonary arterial hypertension, neuromuscular failure, and methemoglobinemia. Although DIRD generally occurs in isolation, concomitant involvement of the liver has been reported with nitrofurantoin, nilutamide, and amiodarone.

DIRD may at times manifest as a systemic condition with extrapulmonary and pulmonary involvement. Systemic presentations include the drug-induced lupus syndrome, antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis with DAH, and the Churg-Strauss syndrome. In these conditions, involvement of the skin, kidney, heart, and lung occurs in a manner similar to that seen in the idiopathic conditions. The DRESS syndrome includes a distinctive cutaneous rash and involvement of the liver, kidney, central nervous system, fever, and blood eosinophilia; in a fraction of affected patients, pneumonitis is present. Propythiouracil and anticonvulsants epitomize the culprit agents for drug-induced ANCA–related vasculitis and DRESS, respectively (Table 17-5).

Table 17-5 Systemic Drug-Induced Reactions With Possible Pulmonary Involvement

Parenchymal Patterns

ILD is the most common pattern of DIRD and sometimes is assigned as a “definitive” diagnosis, although lung biopsy is rarely used to confirm this. Severity ranges from the asymptomatic state or mild changes on imaging, to the gas exchange characteristics of acute lung injury (ALI) or adult respiratory distress syndrome (ARDS). If performed, lung biopsy can reveal almost any form of ILD or interstitial and alveolar lung disease including NSIP (the most common reaction), eosinophilic pneumonia, BOOP, DAD, and DAH. Of importance, these patterns may overlap in different areas of a given lung biopsy. The potential for harm versus possible gain with transbronchial or surgical lung biopsy should be weighed in each individual patient, inasmuch as the biopsied tissue may show only nonspecific changes. A state of immunosuppression, severe hypoxemia, and rapidly deteriorating lung function all are contraindications to undertaking an invasive diagnostic procedure.

Nonspecific Interstitial Pneumonia: Cellular Interstitial Pneumonitis

On histopathologic examination, the pattern of NSIP consists of interstitial inflammation with expansion of alveolar septa by a mild to moderate mononuclear cell infiltrate, occasional eosinophils, and interstitial edema. Among the well over 100 drugs that may cause this condition, β-blocking drugs, amiodarone, flecainide, fludarabine, gold salts, imatinib, lenalidomide, methotrexate, mTOR inhibitors, nilutamide, nitrofurantoin, propylthiouracil, statins, sulfasalazine, thalidomide and its congeners, tocainide, and venlafaxine are cited most often (see under categories Ia and Ib on the Pneumotox website). Methotrexate pneumonitis in rheumatoid arthritis seems to typify acute drug-induced NSIP. Collection of evidence for drug relatedness can be done using the approach set forth in Box 17-1.

Onset of signs and symptoms can be insidious or rapid, with a dry cough, dyspnea, fever, fatigue, and malaise (Figure 17-1). In patients who develop this complication with methotrexate and particularly if the drug is continued, the disease may accelerate without notice, causing further shadowing and progressive respiratory failure. The chest radiograph exhibits areas of ground glass attenuation, confluence, or consolidation, which often predominate in the bases, where such changes may extend rather than migrate. In more advanced cases, findings include areas of consolidation with air bronchograms and generalized volume loss, which can be marked. In early or mild cases, HRCT discloses a discrete and diffuse haze, ground glass shadowing, or mosaic attenuation, which may resemble hypersensitivity pneumonitis in appearance. Other signs on imaging include disseminated or diffuse inter- and/or intralobular septal thickening or “crazy paving”; in severe cases, an associated pleural exudate can be present. The BAL fluid typically reveals a CD8⁺-dominant lymphocytosis, except with bacillus Calmette-Guérin (BCG)-induced pneumonitis, and sometimes an associated increase in neutrophils and/or a modest increase in eosinophil counts. The results of BAL fluid analysis are influenced by timing of the test in the course of the disease and whether the patient has received corticosteroids. BAL has an important exclusionary role: It is used to rule out a coincidental or drug-induced infection, the main competing diagnosis in drug-induced ILD. Particularly important is the use of the most recent nucleic acid–targeted molecular techniques to diagnose Pneumocystis jiroveci

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