CONTENTS
- Preamble – Limitations on the data
- Medications
- Antibiotics
- Cardiovascular
- Checkpoint inhibitors ➡️
- Immunosuppressives:
- Substance use:
- Questions & discussion
abbreviations used in the pulmonary section: 8
- ABPA: Allergic bronchopulmonary aspergillosis 📖
- AE-ILD: Acute exacerbation of ILD 📖
- AEP: Acute eosinophilic pneumonia 📖
- AFB: Acid-fast bacilli
- AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
- ANA: Antinuclear antibody 📖
- ANCA: Antineutrophil cytoplasmic antibodies 📖
- ARDS: Acute respiratory distress syndrome 📖
- ASS: Antisynthetase syndrome 📖
- BAL: Bronchoalveolar lavage 📖
- BiPAP: Bilevel positive airway pressure 📖
- CEP: Chronic eosinophilic pneumonia 📖
- CF: Cystic fibrosis 📖
- COP: Cryptogenic organizing pneumonia 📖
- CPAP: Continuous positive airway pressure 📖
- CPFE: Combined pulmonary fibrosis and emphysema 📖
- CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
- CTEPH: Chronic thromboembolic pulmonary hypertension 📖
- DAD: Diffuse alveolar damage 📖
- DAH: Diffuse alveolar hemorrhage 📖
- DIP: Desquamative interstitial pneumonia 📖
- DLCO: Diffusing capacity for carbon monoxide 📖
- DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
- EGPA: Eosinophilic granulomatosis with polyangiitis 📖
- FEV1: Forced expiratory volume in 1 second 📖
- FVC: Forced vital capacity 📖
- GGO: Ground-glass opacity 📖
- GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
- HFNC: High flow nasal cannula 📖
- HP: Hypersensitivity pneumonitis 📖
- IPAF: Interstitial pneumonia with autoimmune features 📖
- IPF: Idiopathic pulmonary fibrosis 📖
- IVIG: Intravenous immunoglobulin 📖
- LAM: Lymphangioleiomyomatosis 📖
- LIP: Lymphocytic interstitial pneumonia 📖
- MAC: Mycobacterium avium complex 📖
- MCTD: Mixed connective tissue disease 📖
- NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
- NSIP: Nonspecific interstitial pneumonia 📖
- NTM: Non-tuberculous mycobacteria 📖
- OHS: Obesity hypoventilation syndrome 📖
- OP: Organizing pneumonia 📖
- OSA: Obstructive sleep apnea 📖
- PAP: Pulmonary alveolar proteinosis 📖
- PE: Pulmonary embolism 📖
- PFT: Pulmonary function test 📖
- PLCH: Pulmonary Langerhans cell histiocytosis 📖
- PPFE: Pleuroparenchymal fibroelastosis 📖
- PPF: Progressive pulmonary fibrosis 📖
- PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
- RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
- RP-ILD: Rapidly progressive interstitial lung disease 📖
- TNF: Tumor necrosis factor
- UIP: Usual interstitial pneumonia 📖
general concepts of drug-induced lung disease
- Discussing drug-induced lung disease is impossible to do in a rigorous, evidence-based fashion, for several reasons:
- Drugs may cause a variety of different histopathological patterns of lung disease. Therefore, even if a patient undergoes surgical lung biopsy or complete autopsy, it is still often unclear whether the patient truly has drug-induced lung disease. There is no definitive laboratory or histopathological test for the presence of drug-induced lung disease.
- Since there is no definitive test for drug-induced lung disease, case report(s) are difficult to interpret. Reports abound linking various drugs to pulmonary toxicity, but are these causal relationships or coincidence? It's generally impossible to know in the absence of drug rechallenge (which rarely occurs, for safety reasons).
- Once a drug has been labeled as being problematic, there is a cognitive bias to attribute lung disease to it. This may serve to amplify reports of lung toxicity due to some agents, while ignoring lung toxicity due to other agents.
- The following chapter will attempt to wade through this topic, but please be warned – what follows are intended as general guideposts only, not definitive truths.
- This chapter will focus on more commonly used medications, about which more information is available (notably omitting chemotherapeutics). For a more comprehensive listing of adverse reactions, the reader is referred to pneumotox.com.
epidemiology
- Interstitial pneumonia is the most common pulmonary toxicity encountered with amiodarone.
- This usually develops after 6-12 months of therapy.
- The risk may be ~2%. (30192735)
- Risk factors:
- Daily dose >400 mg is the strongest risk factor.
- Long treatment duration.
- Age >60 years old.
- Pre-existing lung disease might increase the risk of disease, but this might also relate to earlier manifestation due to reduced pulmonary reserve (e.g., hazard ratio of 2.5 among COPD patients). (Fishman 2023)
presentation
- Chronicity:
- Presentation is usually insidious (over a period of several months).
- Onset may also be rapidly progressive, mimicking pneumonia.
- Dyspnea and nonproductive cough are most common. This will often be initially attributed incorrectly to heart failure.
- Fever may be seen in half of patients. Other constitutional symptoms are less common (e.g., malaise, weight loss).
radiology
- As a very rough approximation, imaging is variable but may resemble the radiology of COP (cryptogenic organizing pneumonia) and/or NSIP (nonspecific interstitial pneumonia).
- Distribution:
- Infiltrates may be diffuse or unilateral.
- Upper lobe predominance may occur, which can help differentiate this from heart failure. (Shepard 2019)
- Ground-glass opacities may have a peripheral, subpleural distribution. (Fishman 2023)
- Various features may include:
- Ground-glass opacity.
- Thickened interlobular septa.
- Solitary or multiple peripheral areas of consolidation and/or nodules may occur. (Shepard 2019)
- Traction bronchiectasis and honeycombing can occur. (35332071)
- High attenuation:
- High attenuation may be seen in consolidation, nodules, or pleuropulmonary lesions. (Shepard 2019)
- Amiodarone accumulation in tissues increases the density of lung tissue, spleen, and liver (this is simply a reflection of amiodarone exposure).
bronchoscopy
- Bronchoscopy is predominantly useful for excluding alternative diagnoses.
- Foamy macrophages:
- The presence of foamy macrophages is nonspecific, since these are seen in half of patients on amiodarone without lung pathology. (35332071)
- The absence of any foamy macrophages can exclude the diagnosis of amiodarone pulmonary toxicity. (Murray 2022)
- Bronchoalveolar lymphocytosis may indicate more rapid onset, suggesting potential benefit from steroid. (ERS handbook 3rd ed.)
diagnostic process
- Amiodarone-induced lung toxicity is a diagnosis of exclusion. Clinical, radiologic, and bronchoscopic data may support the diagnosis, but they are unable to prove the diagnosis.
- Other less common pulmonary complications of amiodarone:
- AEP (acute eosinophilic pneumonia) is more common than CEP (chronic eosinophilic pneumonia).
- ARDS and/or diffuse alveolar hemorrhage have been attributed to amiodarone in some cases, but it's unclear to what extent these are truly caused by amiodarone.
- Other differential diagnostic processes to consider often include:
- Heart failure.
- Pneumonia.
- Eosinophilic pneumonia (amiodarone may cause acute or chronic eosinophilic pneumonia).
- Exogenous lipoid pneumonia.
- Bronchoalveolar carcinoma.
- Lymphoma.
treatment
- Withdrawal of amiodarone is the cornerstone of therapy. However, the half-life is >1 month, so simply discontinuing amiodarone will take ~1-3 months to take effect.
- Steroid may be useful in more severe cases. A common starting point in most cases is 0.5-1 mg/kg/day (40-60 mg) prednisone. (Fishman 2023; 30192735) Therapy may be required for at least two months, due to the long half-life of amiodarone. (Murray 2022)
prognosis
- The mortality may be as high as 10%. (30192735)
pleural effusion
- May develop 2-12 months after initiation of therapy.
- Fever and pleuritic chest pain may occur.
- Pleural fluid is usually an eosinophilic exudate with normal glucose.
- Following discontinuation, symptomatic improvement usually occurs within days, but complete resolution of the effusion may take months. (Murray 2022)
basics
- Leflunomide has antimetabolite properties that allow it to be utilized as an immunosuppressive agent. It is metabolized into teriflunomide, which inhibits dihydroorotate dehydrogenase, thereby inhibiting pyrimidine biosynthesis.
epidemiology
- Leflunomide only rarely causes pulmonary toxicity (0.1-0.5% incidence).
- Risk factors for pulmonary toxicity may include: (25549032)
- Prior diagnosis of interstitial lung disease.
- History of smoking.
- Use of a loading dose on initiation of therapy.
- Body weight <40 kg.
manifestations
- Leflunomide may cause various pulmonary manifestations:
- Interstitial pneumonitis with eosinophilia.
- DRESS (drug reaction with eosinophilia and systemic symptoms) is rarely reported.
- Organizing pneumonia.
- Diffuse alveolar damage.
management
- (1) Steroid is often utilized (although clear evidence is lacking).
- (2) Clearance of leflunomide:
- Normally, leflunomide has a half-life of about 15 days due to enterohepatic circulation.
- If toxicity occurs, oral cholestyramine may be used to reduce enterohepatic circulation and thereby accelerate drug clearance (e.g., at a dose of 8 grams, three times daily). (25549032)
basics
- This disorder has parallels to hypersensitivity pneumonia. Pathology shows poorly formed granulomas and infiltration of lung tissue by eosinophils.
epidemiology
- Some newer data questions the incidence of this reaction, suggesting that many cases historically attributed to methotrexate might actually have represented other forms of lung disease. (Shah 2019)
- Typically, this occurs 10 days – 4 months after starting methotrexate (although it may occur years after starting methotrexate).
- Major risk factors: (Fishman 2023)
- Diabetes (odds ratio 35).
- Hypoalbuminemia (odds ratio 19).
- Rheumatoid pleuroparenchymal disease (odds ratio 7).
symptoms
- Usually, there is a subacute onset (over days to weeks).
- Fever, dry cough, dyspnea, and arthralgias may occur.
labs
- Peripheral eosinophilia is seen in ~30% of patients. (Fishman 2023)
imaging
- Most often:
- Patchy airspace disease with scattered ground-glass opacities.
- Thickened interlobular septa (which, combined with patchy airspace disease, may generate a crazy-paving pattern).
- Poorly-defined centrilobular nodules may be seen. (35332071)
treatment
- Discontinue methotrexate.
- Steroid may accelerate recovery.
prognosis
- Rarely fatal.
- May cause a hypersensitivity pneumonitis (HP)-like reaction.
- May cause eosinophilic pneumonitis.
acute nitrofurantoin pulmonary toxicity
- Epidemiology:
- Symptoms:
- Dyspnea, dry cough, pleuritic chest pain.
- Fever.
- Maculopapular rash (~20%).
- Laboratory studies
- Peripheral eosinophilia (>350/uL) and lymphopenia (<1,000/uL) usually occur. (Murray 2022)
- Leukocytosis may be seen.
- Chest imaging:
- A mixed alveolar/infiltrative pattern is usually seen, but chest imaging can be normal.
- Small pleural effusion occurs in about a third of patients.
- Management:
- Discontinue nitrofurantoin. Improvement usually occurs within 1-4 days. (Murray 2022)
- Occasionally, steroid may be used.
chronic nitrofurantoin pulmonary toxicity
- This largely mimics IPF (idiopathic pulmonary fibrosis), including identical pathology. It develops after at least one month of therapy. (35332071)
- Symptoms may include dyspnea, dry cough, fatigue, and weight loss. Acute-onset symptoms may occur in the context of chronic nitrofurantoin use. (34295398)
- Labs may show low-level elevation of ANA and rheumatoid factor.
- Chest imaging shows bilateral interstitial infiltrates. Pleural effusion occurs in <10% of patients. (Murray 2022)
- Treatment includes drug withdrawal and possibly steroid (if there is no improvement).
range of pulmonary complications related to sympathomimetics
- Airway:
- Asthma or COPD exacerbation (snorting or smoking).
- Foreign body aspiration.
- Epiglottitis (due to thermal injury; especially cocaine).
- Emphysema (intravenous methylphenidate may cause panlobular emphysema).
- Bronchiolitis obliterans (cocaine).
- Pleural:
- Pneumothorax.
- Pneumomediastinum.
- Parenchymal:
- Noncardiogenic pulmonary edema (“crack lung,” predominantly with smoked cocaine).
- Cardiogenic pulmonary edema (e.g., acute myocardial infarction, chronic cardiomyopathy, endocarditis).
- DAH (diffuse alveolar hemorrhage).
- AEP (acute eosinophilic pneumonia).
- Organizing pneumonia (cocaine).
- Lipoid pneumonia (crack cocaine mixed with petroleum jelly).
- Vascular:
- Pulmonary hypertension.
- Talc granulomatosis related to intravenous administration of crushed tablets (REF).
- Vasculitis (related to levamisole adulterant in cocaine).
crack lung
basics
- Crack lung is roughly defined as acute pulmonary symptoms with parenchymal infiltrates occurring within ~2 days of heavy cocaine smoking. Although termed “crack lung,” it's probable that a similar phenomenon could result from smoking other sympathomimetics (e.g., crystal meth). (33717751)
- The pathophysiology isn't clear. Pathologically this could represent a variable superimposition of several different histopathological injury patterns (e.g., diffuse alveolar hemorrhage, eosinophilic pneumonia, organizing pneumonia).
symptoms
- Dyspnea.
- Cough, which may include hemoptysis or melanoptysis (production of black sputum).
- Fever.
- Pleuritic chest pain is very common.
laboratory studies
- Toxicology studies may help establish exposure to cocaine (if this is unclear).
imaging
- Radiologic abnormalities are variable.
- Diffuse, bilateral infiltrates are generally expected.
- CT scan may show a characteristic inhalational distribution, with sparing of the peripheral lung (figure below).
bronchoscopy
- Bronchoscopy is often unnecessary. In patients with a clear temporal association between crack utilization and acute parenchymal infiltrates, bronchoscopy is unlikely to affect management.
- If performed, bronchoscopy may demonstrate high levels of eosinophils (>25%), diffuse alveolar hemorrhage, and/or black soot within the bronchi.
treatment
- The mainstay of therapy is supportive care and cessation of crack smoking.
- For patients with substantial illness severity (e.g., significant oxygen requirement), steroid administration is rational.
range of pulmonary complications related to inhaled marijuana and synthetic cannabinoids
- Airway:
- Thermal epiglottitis.
- Asthma exacerbation.
- Chronic bronchitis.
- Upper lobe bullae (“bong lung”), primary spontaneous pneumothorax (may relate to breath holding and Valsalva maneuvers).
- Pleura:
- Pneumothorax and/or pneumomediastinum.
- Parenchyma:
- EVALI (E-cigarette or vaping use-associated lung injury).
- Noncardiogenic pulmonary edema.
- Diffuse alveolar hemorrhage.
- Acute eosinophilic pneumonia.
- Aspergillus fumigatus infection (smoking marijuana).
range of pulmonary complications from opioid use
- Airway
- Bronchospasm, asthma exacerbation (inhalation or snorting).
- Pleural
- Pneumothorax (multiple mechanisms: inhalation, subclavian IV injection, right-sided endocarditis with septic emboli).
- Wooden chest syndrome.
- Pulmonary vasculature
- Talc granulomatosis related to intravenous administration of crushed tablets.
- Parenchyma
- Noncardiogenic pulmonary edema. 📖
- Aspiration pneumonitis or pneumonia.
- Acute eosinophilic pneumonia (smoking heroin).
- Septic pulmonary emboli (due to endocarditis or infected thrombophlebitis).
noncardiogenic pulmonary edema due to opioid intoxication
basics
- Acute intoxication with opioid may cause transient pulmonary edema due to capillary leak.
- The pathophysiology of this entity is unclear, but it may have some parallels to neurogenic pulmonary edema. Indeed, it is conceivable that neurogenic pulmonary edema could share some common pathophysiologic triggers with pulmonary edema due to opioid intoxication (e.g., cerebral edema, respiratory acidosis, and hypoxia).
epidemiology
- May occur with any opioid.
- Often follows acute overdose with heroin or methadone.
clinical presentation
- Usually occurs immediately, or within hours of intoxication.
- Should resolve within hours.
imaging
- If patient is found down, this may produce an asymmetric edema pattern.
- Generally indistinguishable from other types of pulmonary edema:
- Widespread, patchy, bilateral consolidation.
- Often in a perihilar distribution. (Walker 2019)
management
- The prognosis is extremely favorable. With supportive therapy, patients should improve relatively rapidly.
- If resolution doesn't occur within 24-48 hours, this suggests an alternative or additional diagnosis (e.g., aspiration pneumonitis or pneumonia). (Murray 2022)
- Intubation may be needed, but many patients can respond to noninvasive ventilation.
- Naloxone should not be used specifically for management of pulmonary edema (but rather, naloxone should be used as it would generally be utilized – to reverse cerebral effects of opioid intoxication).
To keep this page small and fast, questions & discussion about this post can be found on another page here.
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- 📄 = Link to open-access journal article.
- = Link to supplemental media.
References
- 23127737 Duello KM, Louh IK, Burger CD. 48-Year-old woman with dyspnea, cough, and weight loss. Mayo Clin Proc. 2012 Nov;87(11):1124-7. doi: 10.1016/j.mayocp.2012.05.027 [PubMed]
- 25549032 Hamilton JA, Bishop JM. 69-year-old woman with rheumatoid arthritis presents with shortness of breath and cough. Ann Am Thorac Soc. 2014 Dec;11(10):1653-5. doi: 10.1513/AnnalsATS.201407-306CC [PubMed]
- 30192735 Slostad BD, Prasad M, Anavekar NS. Shortness of breath, fever, cough, and more in an elderly woman. Cleve Clin J Med. 2018 Sep;85(9):685-692. doi: 10.3949/ccjm.85a.18030 [PubMed]
- 32427626 Ullah T, Patel H, Pena GM, Shah R, Fein AM. A contemporary review of radiation pneumonitis. Curr Opin Pulm Med. 2020 Jul;26(4):321-325. doi: 10.1097/MCP.0000000000000682 [PubMed]
- 34295398 Capaccione KM, Tran CV, Leb JS, Salvatore MM, D'souza B. Acute pulmonary function decline and radiographic abnormalities: chronic cause? Breathe (Sheff). 2021 Mar;17(1):200286. doi: 10.1183/20734735.0286-2020 [PubMed]
- 35332071 Spagnolo P, Bonniaud P, Rossi G, Sverzellati N, Cottin V. Drug-induced interstitial lung disease. Eur Respir J. 2022 Mar 24:2102776. doi: 10.1183/13993003.02776-2021 [PubMed]
Books:
- Shah, P. L., Herth, F. J., Lee, G., & Criner, G. J. (2018). Essentials of Clinical pulmonology. In CRC Press eBooks. https://doi.org/10.1201/9781315113807
- Shepard, JO. (2019). Thoracic Imaging The Requisites (Requisites in Radiology) (3rd ed.). Elsevier.
- Walker C & Chung JH (2019). Muller’s Imaging of the Chest: Expert Radiology Series. Elsevier.
- Palange, P., & Rohde, G. (2019). ERS Handbook of Respiratory Medicine. European Respiratory Society.
- Rosado-De-Christenson, M. L., Facr, M. L. R. M., & Martínez-Jiménez, S. (2021). Diagnostic imaging: chest. Elsevier.
- Murray & Nadel: Broaddus, V. C., Ernst, J. D., MD, King, T. E., Jr, Lazarus, S. C., Sarmiento, K. F., Schnapp, L. M., Stapleton, R. D., & Gotway, M. B. (2021). Murray & Nadel’s Textbook of Respiratory Medicine, 2-Volume set. Elsevier.
- Fishman's: Grippi, M., Antin-Ozerkis, D. E., Cruz, C. D. S., Kotloff, R., Kotton, C. N., & Pack, A. (2023). Fishman’s Pulmonary Diseases and Disorders, Sixth Edition (6th ed.). McGraw Hill / Medical.