Introduction

Drugs have been known to cause adverse respiratory reactions since at least 1880, when Sir William Osler published an autopsy report of a fatal case of opioid-related alveolar edema [1, 2]. Since then, the literature on iatrogenic and drug-induced respiratory disease has expanded to over 30,700 Medline searchable articles. Therapeutic drugs, substances of abuse, contrast media, chemicals (solid, liquid, or gases), solvents, household compounds, waterproo ng agents, air conditioner fuid, glue, irradiation, and medical, imaging or surgical procedures can all cause respiratory injury (Tables 42.1 and 42.2). To date, 1650 drugs, chemicals, agents, and procedures (up from 920 listed in the last edition of this chapter) can cause injury in the form of any of the 784 clinical, imaging, bronchoalveolar, and histopathologic patterns of involvement identi ed so far. Since 1997, drugs, patterns of injury, and the speci c literature are indexed in Pneumotox, a set of daily updated web service and Apps [3, 4] (Table 42.3, Figs. 42.1, 42.2, 42.3, 42.4, 42.5, and 42.6).

Adverse iatrogenic and drug reactions can target any anatomical site of the respiratory system, including the lung parenchyma, central, large or small airways, serosal surfaces, pulmonary circulation, cardiovascular system, respiratory muscles and/or nerves, central nervous system, chest wall or blood (i.e., hemoglobin) alone or in combination. Drugs may also elicit such systemic conditions as lupus, vasculitis or sarcoid-like reactions with involvement of the lung, pleura, heart, or pulmonary circulation. Drugs can cause acute reactions which may be life-threatening within minutes. Large

P. Bonniaud

Reference Constitutive Center for Rare Lung Diseases, University Hospital, Dijon, France

e-mail: philippe.bonniaud@chu-dijon.fr

P. Camus (*)

Department of Respiratory Medicine, University of Dijon, Dijon, France

effusions of blood, fuid, chyle, or air/gas in the pleural, pericardial, mediastinal or the retropharyngeal space can cause life-threatening or fatal vessel, airway or organ compression in addition to the consequences of blood or body fuid losses. Pneumotox was developed as a resource for practicing clinicians, to provide freely available and immediate access to iteratively re ned and updated information on drugs and the adverse event patterns that they produce [3, 4].

Drug-induced respiratory disorders (DIRDs) have become a common diagnostic consideration in adults and children with new respiratory symptoms and exposure to a compatible drug. Distinguishing DIRDs from idiopathic conditions can be dif cult, since drug-induced respiratory reactions often mimic idiopathic conditions (Table 42.4). Early consideration of DIRD is important, however, since delaying the detection, diagnosis, management, and drug removal can be detrimental, exposing patients to superfuous investigation, off-target therapies, and progressive lung injury.

The time from starting treatment with a drug to onset of the reaction varies widely, from a few seconds or minutes with drug-induced bronchospasm, anaphylaxis, pulmonary edema, or angioedema, to days, months or years for pulmonary brosis, pulmonary hypertension or pleural effusion. Occasionally, DIRD will manifest months or years after cessation of exposure to the drug, creating signi cant challenges for establishment of a causal link. Diagnostic criteria (Table 42.3) and grading systems for DIRD have been published [5–7] and are available on the frontpages of Pneumotox. An accurate diagnosis rests on a meticulous drug history, identi cation of the causal drug, evaluation of drug timing, matching drug or drugs and pattern or patterns of involvement, exclusion of other causes and improvement or resolution with drug withdrawal.

Interstitial/in ltrative lung disease (ILD) is the main pattern of drug-induced (DI) lung injury, accounting for two-­ thirds of the cases of parenchymal lung involvement due to drugs. DI interstitial lung disease (DILD) can be subsumed into the majority of patterns of ILD, including (1) interstitial pneumonias (cellular or brotic), including nonspeci c

Table 42.1  Patterns of involvement from drugs—classic purveyor drugs—incidence

736

Camus .P and Bonniaud .P

ATRA: tretinoin—all trans retinoic acid—As2O3: arsenic trioxide, C = condition, CSF: colony-stimulating factors, DRESS: the syndrome of drug rash, eosinophilia and systemic symptoms, DW: drug therapy withdrawal (“dechallenge test”). To be done with caution as regards the underlying condition, that may fare up, ECMO extracorporeal membrane oxygenation, FFP: fresh frozen plasma, HUS: hemolytic and uremic syndrome, ICI: immune checkpoint inhibitors, LVDF left ventricular dysfunction or failure, PAN: polyarteritis nodosa, PIE: pulmonary inltrates and eosinophilia, RCC: renal cell carcinoma, RR: risk ratio of developing the condition vs. untreated subjects (when data available), TKI: tyrosine kinase inhibitors

w: weeks, y: years, min: minutes, d: days, mo: months

Reactions Induced-Drug Emergent and Rare, Unusual, on Emphasis With Disease: Respiratory Induced/Iatrogenic-Drug  42

737

interstitial pneumonia (NSIP), organizing-pneumonia, acute or chronic eosinophilic-pneumonia, desquamative interstitial-­pneumonia (DIP), lymphocytic interstitial pneumonia (LIP), giant cell interstitial pneumonia (GIP), and usual interstitial pneumonia or brotic nonspeci c interstitial pneumonia; (2) alveolar lling disorders (phospholipidosis or alveolar proteinosis (PAP)), exogenous lipoid pneumonia, amiodarone pulmonary toxicity, pulmonary edema, alveolar hemorrhage. The list of histopathological patterns is available under heading “XVI” in Pneumotox [3, 4]. Other mechanisms and patterns of injury include airway-, pleural-, mediastinal-, and neuromuscular involvement, drug-induced vasculopathies, systemic reactions induced by drugs, and a potpourri of variegated and unusual patterns of drug-induced injury [3, 4]. Drugs can also cause cardiac

injury in the form of valvular heart disease, cardiomyopathy, myocarditis, pericarditis, pericardial effusion, arrhythmias, coronary heart disease, coronary spasm, or heart block. Consequent drug-induced left ventricular dysfunction may cause cardiogenic pulmonary edema [3, 4]. Pneumotox lists >70 patterns of drug-induced cardiac involvement, and 50 drugs capable of causing cardiogenic pulmonary edema. The App Cardiotox is free and available for download [8].

DIRD as a whole are rare. Relatively common causative drugs include (Table 42.4) angiotensin-converting enzyme inhibitors (ACEI), amiodarone, anticoagulants, beta-­blockers, chemo agents (bleomycin, busulfan, cyclophosphamide, and nitrosoureas, among many others), antibiotics (daptomycin, minocycline, penicillin, trimethoprim-­sulfamethoxazole [9]), methotrexate (although the incidence of pulmonary compli-

Table 42.3  Check list for diagnosing drug-induced/iatrogenic respiratory disease or reactions

Absence of pulmonary disease prior to therapy with the suspected drug

Respiratory event is unlikely to develop in the course of the underlying disease

Con rmed exposure to the drug

Eligible drug (Drug singularity?)

Absence of prodromal signs and symptoms prior to exposure to the drug

Appropriate timing (latency time, time to onset) relative to taking the medication

Pattern appropriate for the drug under scrutiny

Con rmatory data in the literature (qualitative = consistency. Quantitative = magnitude)

Suggestive/Supportive symptoms, imaging (CXR, HRCT, nuclear medicine), laboratory data, BAL, pathology

Laboratory evidence including plasm levels, UDS

Reasonable exclusion of other causes including an infection and the adverse effect of comedications

Improvement, abatement or resolution with discontinuation of the drug, preferably without recourse to corticosteroids

Lack of recurrence of signs and symptoms is patient not rechallenged with the druga

Relapse following rechallenge with the drugb

aDrug-induced organizing pneumonia may show replicas despite drug discontinuation

bRechallenge can be hazardous or lethal

Fig. 42.1  Acute severe cellular ILD and pulmonary edema with acute respiratory failure (con rmed by open lung biopsy). Young lady. Methotrexate lung (note chest tube on left side post-lung biopsy). It is generally impossible to anticipate the exact histopathologic pattern of involvement from data on chest imaging. The disease resolved in a few weeks following drug withdrawal and corticosteroid therapy (i.v. then p.o.)

cations of that drug are not as high as in the past), nitrofurantoin, anticonvulsants, statins, nonsteroidal anti-infammatory drugs (NSAIDs), and salicylate [3, 4]. The current literature does not always refect this, because well-known drug reactions tend to be published less frequently. Emerging drugs and inhaled agents are increasingly implicated in DIRD, including immune checkpoint inhibitors (anti-PD1, -PDL1, -CTLA4) [10], monoclonal antibodies (TNF-alpha-, CD20- (rituximab)) [11], e-cigarette liquids or vapor [12], tyrosineor protein kinase inhibitors (e.g., BCR-ABL, mTOR), anticoagulants (platelet glycoprotein IIB/IIIA receptor-, anti- thrombin-), antiviral drugs (reverse transcriptase inhibitors), substances of abuse (cannabinoids, levamisole), and cosmetic agents (silicone, hyaluronate or autologous fat). Drugs, corresponding patterns of involvement, and literature (minimized for space constraints here) can be easily accessed in Pneumotox [3, 4]. A further dif culty is that treatments with TNF-alpha inhibitors or other targeted agents including immune checkpoint inhibitors can be complicated by opportunistic or non-opportunistic bacterial, mycobacterial (including de novo or reactivation pulmonary or extrapulmonary tuberculosis), viral or fungal infections [13].

Warning symptoms are occasionally present before full-­ blown adverse drug reactions become manifest. However, most drug-induced respiratory reactions occur unexpectedly in patients receiving therapeutic doses of the drug. Overdose of drugs including opioids [14] and drug poisoning [15] is generally considered outside the province of adverse reactions to drugs. However, this will be touched upon when appropriate, as drug overdose can manifest with pulmonary edema, alveolar hemorrhage, ARDS, metabolic acidosis, airway bleeding, acute ventilatory depression, and/or aspiration pneumonia.

Drug overdose can occur with minute amounts of novel hyperpotent drugs of abuse (e.g., carfentanyl, synthetic cannabinoids) or toxic chemicals (e.g., the weaponized “Novichoks” “Hoвичoκ” organophosphates). These can cause acute respiratory failure and death. The corresponding toxidromes [16–18] must be available or known, because medical personnel must be protected, and antidotes are available to counter the pharmacological action of opiates, anticoagulants, methemoglobinemia-inducers, and organophosphates. Care must be taken to have antidotes readily available at all hospitals [19].

Some adverse drug-induced respiratory reactions may result from sequential, downstream or domino adverse effects. Examples include (1) Amiodarone-induced thyrotoxicosis followed by arrhythmias, heart failure, and/or pul- monaryedema[20],(2)amiodarone-inducedhypothyroidism,

Fig. 42.3  (a, b) Acute amiodarone-induced pulmonary toxicity/ Amiodarone lung. (b) CT. This complication often occurs following thoracic or cardiovascular surgery, even after only a few days on the

medication, causing diagnostic dif culties. The trauma or surgery and liberal oxygen therapy may trigger the onset of this complication

Fig. 42.4  Acute drug-(tocolytic agent in this case) induced pulmonary edema. In each patient, it is necessary to separate cardiogenic or overload pulmonary edema from noncardiogenic pulmonary edema using imaging (particularly vascular pedicle size, presence of pleural effusion or effusions, and heart size), cardiac ultrasound, cardiac biomarkers, measurement of lling pressure. Diuretic therapy is reserved for cardiogenic/overload pulmonary edema

Fig. 42.5  Drug-induced alveolar hemorrhage. All anticoagulants can produce alveolar hemorrhage. Brodifacoum (superwarfarins) can also produce this complication. Superwarfarin must be searched actively in plasma. Superwarfarins are now present as an adulterant in many cannabinoid samples

Fig. 42.6  (a, b) Bleomycin-induced ARDS (severe bleomycin pulmonary toxicity). Full list of drugs causing acute ILD, eosinophilic pneumonia, organizing pneumonia, pulmonary edema, alveolar hemorrhage or ARDS is available on Pneumotox. Drug-induced allergic or hypersensitivity-­related emergencies including anaphylaxis, and methemoglobinemia, though life-threatening, may not express themselves

on plain imaging. Drug-induced upper airway obstruction can be visualized on CT or MRI, although emergent cases require immediate endoscopy and securing the airway. Detailed list of imaging patterns (n = 75) of drug-induced/iatrogenic respiratory disease or reactions available on section XVI in pneumotox website and XVII on the App

pericardial effusion, and tamponade [21], (3) epinephrine (adrenaline)- (used to treat drug-induced angioedema) or licorice-induced hypertension, heart failure, and pulmonary edema [22], (4) self-i.v. administration of drugs of abuse

causing right-sided endocarditis followed my metastatic pulmonary embolism and multiple lung abscesses [23] and opioid-­induced ventilatory depression [14] and antidote (naloxone)-induced pulmonary edema [24].