What every physician needs to know:

Drug induced lung injury is not uncommon and the association of potential drug induced lung injury is described with increasing frequency for medications previously assumed not to be associated with such injury.

The patient with non-chemotherapy drug induced lung injury presents with protean manifestations from mild to severe. The approach to a patient with pulmonary disease in whom drug-induced lung toxicity is of concern can be challenging because of a number of complicating factors. First, nonspecific symptoms, radiographic findings, and laboratory data are the norm, rather than the exception, and symptoms often overlap with the clinical presentation of the underlying disease. This is particularly challenging when the patient’s disease process involves the lungs, as distinguishing between primary disease and secondary toxicity may be difficult.

Second, clinical and radiographic patterns of drug-related effects vary, and neither dose nor duration of exposure typically predicts occurrence. Third, a single drug may exhibit more than one potential pattern of toxicity. Since most patients take more than one medication, drug interactions may further complicate assessment.

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Fourth, patients may choose to not acknowledge their use of non-traditional medications (over-the-counter, alternative, or herbal preparations) or illicit substances. Finally, new drugs, some with undefined long-term risks, are constantly being introduced into practice. The evaluation for pulmonary drug toxicity requires an ever-present awareness that
drugs are potential culprits.

Hence, when a patient presents with new respiratory symptoms or radiographic abnormalities, a review of their medications should be routine. Evaluation of the medications used should include prescribed drugs as well as over-the-counter, naturopathic, or illicit substances the patient may be using. A thorough history should also include medications or substances to which the patient was exposed preceding the development of symptoms.

When a patient presents with specific pulmonary abnormalities, it is useful to understand the broad categories of clinical patterns that are described in association with drug-induced toxicities, as described in the sections below. These clinical, radiographic, and histopathologic syndromes may occur as a consequence of drug exposure, but they may also result from an underlying, independent pulmonary disease process.

As with chemotherapy, the challenge of evaluating a patient in whom drug-induced lung disease is suspected lies in distinguishing between the disease itself and complications of disease or treatment. Pulmonary complications of drug treatment may result in severe morbidity and mortality. Recognition of toxicity at early stages may abrogate potential harm, so an appreciation of the spectrum of such complications is essential.


An outline of every drug that can possibly cause pulmonary toxicity is impractical as the list is exhaustive and growing. The Groupes d’Etudes de la Pathologie Pulmonaire Iatrogène (GEPPI) maintains an active website listing of drugs that have been associated with pulmonary toxicity (www.pneumotox.com). The listing is extensively referenced and frequently updated, and is a remarkable resource for descriptions of adverse pulmonary effects of individual drugs and for identification of drugs that may cause various toxic syndromes. The GEPPI website also lists frequencies with which toxicities have been associated with individual drugs.

The medications listed in the tables attached are those that have either been associated prototypically with specific pulmonary syndromes of drug toxicities or for which > 20 cases of toxicity have been reported. One important caveat to the interpretation of frequency of toxicity is that while reporting of drug toxicities during drug development and safety and efficacy trials is mandatory, once a medication is approved for clinical use, reporting of side effects is largely voluntary. Typically, after several case reports or case series, published reports of a known adverse effect cease; therefore, the exact frequency of post-release toxicities may never be accurately identified.

Individual agents in pharmacologic groups of drugs may be associated with idiosyncratic reactions, but drugs in a given group may cause similar toxicities. Symptoms are driven by drug-related injury and the underlying disease process. When the actual disease process involves the lungs or heart, differentiating between the underlying process and pulmonary drug toxicity may be challenging. In almost all cases, the diagnosis of drug toxicity is one of exclusion.

Are you sure your patient has a non-chemotherapy-related drug-induced lung injury? What should you expect to find?

General Considerations

The clinical, radiographic, and even histopathologic manifestations of drug-induced pulmonary toxicity are usually nonspecific. Whether the presence of underlying lung disease predisposes patients to medication-related pulmonary toxicity is unclear, but patients with compromised lung function from primary respiratory disease clearly have less reserve to tolerate a drug-related pulmonary complication. When the disease process and potential complications overlap, the independent effect of the underlying disease on the risk of drug toxicity may be impossible to define. When the primary disease involves the lung and the use of a drug with known potential pulmonary toxicity is determined to be medically preferable, patients should be informed of the risks so they can be mindful of symptoms that warrant medical attention.

The time course for development of pulmonary drug toxicity varies widely. Most toxicities occur relatively early in the course of exposure; for example, cough related to ACE inhibitors typically appears within the first few months of treatment. However, many drugs, such as amiodarone and nitrofurantoin, may cause acute and subacute toxicities or present with chronic interstitial lung disease years into treatment.

Respiratory symptoms like cough, dyspnea, and chest discomfort, as well as systemic symptoms like weight loss and fatigue, are nonspecific. These symptoms may be difficult to distinguish from symptoms related to the underlying disease or other unrelated pulmonary processes, such as infection. Failure to consider medication-associated pulmonary toxicity may allow adverse drug effects to progress.

Early in the course of disease, the lung exam may be completely normal, while progression of toxicity may be heralded by signs related to the type of pulmonary involvement: inspiratory crackles in interstitial pneumonitis, wheezing in airway/hypersensitivity syndromes, or dullness to percussion or pleural rub in pleuritis or pleural effusion. All of these signs are nonspecific.

Pulmonary Syndromes Associated with Drug Toxicity

The possibility of drug-related toxicity should always be considered in a patient with clinical or radiographic abnormalities that suggest a new or worsening respiratory process. The first step is examination of the patient’s list of prescribed medications and non-traditional (herbal, naturopathic) drugs, over-the-counter medications, and illicit substances. Implicit in the evaluation of drug induced lung injury is the exclusion of other causes of the patient’s pulmonary decompensation—particularly inflammatory processes including infection, and progression of the patient’s underlying disease.

All components of the respiratory system, including the airways, interstitium, vasculature, and pleura may be adversely affected by drugs. Drug-related pulmonary toxicity may present as a number of well-recognized syndromes (Figure 1); while none are pathognomonic for a given medication, recognition of the possibility of drug toxicity based on clinical patterns is integral to the evaluation and critical in minimizing further exposure. If the clinical syndrome suggests drug toxicity and a potential offending drug is identified, the clinical indication for that drug, the medical necessity for it, and the severity of the toxicity will inform the decision regarding whether it should be discontinued. An alternate therapy can be found for most drugs.

The tables included in this section address descriptions of clinical syndromes and list the drugs that are usually implicated (as prototypes or by frequency of reporting with each syndrome).

Drug-induced Airways Disease

Major findings of drug-induced airways disease include cough and bronchospasm.


Medications cause cough via a variety of proposed mechanisms (Figure 2). In many cases, cough may be an early symptom of parenchymal pulmonary toxicity, but it may also present in an isolated fashion.

ACE inhibitors (ACE-I) are perhaps the most common agents associated with cough, which occurs in approximately 5-20% of all patients treated with this drug class. The cough is of sufficient severity to mandate discontinuation of therapy in a small, but significant, percentage.

ACE-I associated cough is typically non-productive and persistent and appears within the first several months of drug initiation. Women are disproportionately affected, and patients with congestive heart failure also have a higher frequency and earlier manifestation of cough.

The mechanism of ACE-I induced cough is unclear, but may involve direct airways irritation and increased airway reactivity. ACE inhibition results in reduced metabolism of bradykinins and substance P, and an increase in these neuropeptides may stimulate nerve fibers through J receptors. ACE inhibition also appears to result in activation of the arachidonic acid pathway, and the resulting increased levels of thromboxane may cause bronchospasm.

In ACE-I induced cough, withdrawal of the drug typically results in resolution within days to weeks, but rechallenge or treatment with other ACE inhibitors usually causes recurrence. Angiotensin II receptor blockers may be less cough-provoking, although they are also associated with cough. When ACE inhibitors are deemed necessary, successful treatment of cough may be achieved with sodium cromoglycate, theophylline, ferrous sulfate, or indomethacin.

Cough related to direct airway irritation may occur with any inhaled medication and may be alleviated by pre-medication with inhaled bronchodilators. For example, short-acting beta agonists are routinely given prior to nebulization of pentamidine or amphotericin.

Inhaled medications used to treat airway reactivity may themselves cause cough or bronchospasm, presumably related to particulates used in their preparation. Severe coughing has been described with propofol or fentanyl especially during induction of anesthesia. The mechanism of fentanyl induced cough appears to involve a pulmonary chemoreflex with activation of pulmonary J-receptors.


As a drug-related phenomenon, bronchospasm may present in an isolated fashion or as a component of anaphylaxis. Many drugs are associated with bronchospasm (Figure 2), but the prototypic medications of concern are beta-blockers, aspirin, and NSAIDs. Drug-induced bronchospasm is of particular concern in patients with asthma or pre-existing airways disease.

The use of beta-blockers in patients with asthma or COPD remains controversial. As beta-agonists are used to treat bronchospasm, it logically follows that beta-blockade may cause bronchospasm. When nonselective beta-blockers were introduced, numerous cases were reported of severe or fatal asthma exacerbations after oral, IV, or even ophthalmic administration.

These cases resulted in recommendations to avoid beta-blockade in patients with asthma or COPD. However, there is abundant evidence that beta-blockers have significant clinical benefit in coronary disease, hypertension, and heart failure; a general avoidance of this therapy in those with coexistent cardiac disease and asthma or COPD is problematic, as the conditions frequently coexist. Moreover, this approach may be unwarranted with newer cardioselective beta-blockers.

In a review of 16 trials evaluating the use of nonselective beta-blockers in patients with airways disease, pooled analysis demonstrated that regular use of nonselective beta-blockers resulted in a 14% reduction in FEV1 compared to placebo and a 23% decrease in FEV1 response to beta-2 agonists, suggesting a potential risk for adverse outcomes in an asthma exacerbation.

Two meta-analyses evaluated the effects of cardioselective beta-blockers among patients with asthma or COPD with reversibility. Despite an FEV1 reduction following single-dose of a beta-blocker, no sustained effect on FEV1 was seen with prolonged administration at days 3-28 nor was there a significant change in response to inhaled beta-agonist. Similarly among patients treated for up to 12 weeks with a beta-blocker, there was no change in respiratory symptoms compared to placebo and no changes were seen in those with severe airway obstruction. Several retrospective studies of patients with concomitant coronary disease and COPD have demonstrated an association with decreased hospitalization risk, COPD exacerbation, and all-cause mortality among patients with significant airflow obstruction treated with beta-blockers.

In practice, the risks of bronchospasm should be routinely discussed with all patients who have airways disease, but in general cardioselective beta blockade should not be withheld from patients with coronary disease, hypertension, or heart failure and concomitant asthma or COPD.

Aspirin and NSAIDs are known to cause bronchoconstriction in a small percentage of asthmatics. NSAIDs may result in IgE-mediated allergic reactions, including urticaria, angioedema, or anaphylaxis; however, the more common mechanism relates to inhibition of the cyclooxygenase (COX) pathway. Aspirin inhibits COX-1, and NSAIDs inhibit both COX-1 and COX-2, so their administration diverts arachidonic acid metabolism toward the 5-lipoxygenase pathway and may result in leukotriene-mediated airway inflammation.

The classic Samter’s triad describes patients with asthma, chronic rhinosinusitis with nasal polyposis, and symptom exacerbation with aspirin. Aspirin or NSAID sensitivity may be present in up to 40% of patients with asthma or rhinosinusitis. Sensitivity of this type is acquired as most patients present in young adulthood with a history of uncomplicated use of these medications. Symptoms are typically acute, occur within minutes or hours after ingestion of aspirin or NSAIDs and range from mild nasal congestion to severe bronchospasm. Leukotriene modifying agents should be administered to these patients along with standard asthma management. If aspirin/NSAID use is deemed medically necessary, aspirin desensitization should be considered.

IV use of crushed methylphenidate (Ritalin) tablets has been associated with lower lobe emphysema and airways obstruction similar to that seen in alpha-1 antitrypsin deficiency. The disease is thought to be related to acute destruction of lung parenchyma from the talc used to stabilize the active medication in tablet form. Despite withdrawal of the medication, affected patients have persistent and progressive obstructive lung disease.

Drugs Associated with Interstitial Lung Disease

Interstitial lung disease (ILD) is one of the most common presentations of medication-related pulmonary toxicity (Figure 3). Drug toxicity should be considered in the differential diagnosis of patients with ILD before classifying the process as idiopathic.

Acute or subacute pneumonitis may present abruptly with shortness of breath and radiographic abnormalities that may be mild but that may progress rapidly to respiratory failure. Chronic pneumonitis occurs more insidiously, with progressive cough, dyspnea, and fibrotic radiographic changes. The pathologic spectrum of interstitial disease related to drug toxicity includes all major histopathologic forms of ILD, including usual interstitial pneumonitis (UIP), nonspecific interstitial pneumonitis (NSIP), lymphocytic interstitial pneumonia (LIP), eosinophilic pneumonia, hypersensitivity pneumonitis, vasculitis, and granulomatous inflammation.

Drug toxicity may be difficult to identify in patients with underlying disease processes that may have interstitial lung involvement. Pulmonary interstitial abnormalities may be the result of idiopathic pneumonitis, may represent manifestations of underlying inflammatory diseases such as connective tissues diseases, or may represent infiltrative or granulomatous lung diseases such as sarcoidosis. Clinically, the challenge lies in distinguishing between progression of the underlying disease versus superimposed pulmonary toxicity due to medication.

Treatment of rheumatoid arthritis (RA) exemplifies the diagnostic complexity of interstitial disease. RA is associated with many pulmonary complications, including interstitial pneumonitis, pleural effusion, pulmonary nodules, and bronchiectasis, and patients on immunosuppression are also at high risk of pulmonary infection. Many drugs used to treat RA, including tumor necrosis factor (TNF) alpha inhibitors (etanercept, infliximab), methotrexate, leflunomide, azathioprine, gold, and penicillamine, are also known causes of interstitial pneumonitis. Distinguishing between progressive RA-ILD and drug-related lung toxicity in patients with RA and new or worsening interstitial abnormalities may be difficult, as symptoms, radiographic findings, and even histology may be indistinguishable between the two conditions.

The multiple different presentations of pulmonary toxicity seen for a single drug make the evaluation more challenging. A single drug may precipitate more than one type of interstitial abnormality or may also result in airways disease or pleural effusion. Many drugs including aspirin, NSAIDs, nitrofurantoin, ACE-I, and penicillamine, demonstrate an array of pulmonary complications.

One example is amiodarone, which may cause pulmonary disease in several forms: chronic interstitial pneumonitis, organizing pneumonia +/- bronchiolitis obliterans, ARDS, or pulmonary masses. The lengthy half-life of amiodarone (multiple weeks) suggests the toxic effects of the drug can linger following medication discontinuation. Given the frequent use of amiodarone in cardiac arrhythmias, withdrawal is also not without potential clinical consequences.

Both amiodarone and its active metabolite are amphiphilic compounds that accumulate in macrophages and type II alveolar cells, which may contribute to amiodarone’s propensity to injure the lung. While rapidly progressive respiratory failure may occur in the setting of peri-operative use of amiodarone, pulmonary toxicity usually occurs insidiously months to years after therapy is initiated, when clinical suspicion of drug-related complications may be relatively low. Since no test pathognomonically identifies amiodarone toxicity, suspicion of drug toxicity must be maintained as long as the patient is on treatment.

ILD may arise as the result of illicit drug use or from exposure to substances other than medications. IV injection of drugs intended for oral use, including narcotics or stimulants like amphetamines, may be accompanied by unintentional injection of particulates—most notably talc—with subsequent granulomatous inflammation and pulmonary fibrosis.

Drug-induced Eosinophilic Lung Disease

Eosinophilic lung disease is identified by evidence of an increased number of eosinophils in bronchoalveolar lavage (BAL), by the finding of eosinophilic infiltration in histologic samples, or by inference because of peripheral eosinophilia in patients with pulmonary symptoms or radiographic findings. As is the case whenever a drug reaction is of concern, exclusion of underlying diseases that can cause peripheral or pulmonary eosinophilia is necessary.

The differential diagnosis of eosinophilic lung disease includes infection (e.g., parasites, fungi), acute or chronic eosinophilic pneumonia, simple eosinophilic pneumonia (Loeffler’s syndrome), eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome), idiopathic hypereosinophilic syndrome, allergic bronchopulmonary aspergillosis (ABPA), and malignancy.

Drug-induced pulmonary eosinophilia typically presents as an acute eosinophilic pneumonia with cough, dyspnea, and chest imaging that demonstrates infiltrates that are sometimes migratory. In contrast acute idiopathic eosinophilic pneumonia, drug-induced disease is more often characterized by peripheral eosinophilia, fever, and rash. Eosinophilic granulomatosis with polyangiitis has been associated with initiation of leukotriene receptor antagonists, where distinction of idiopathic from drug-induced disease may be very difficult.

Many drugs are associated with pulmonary eosinophilia; the most common are listed in Figure 4. Eosinophilic drug-induced pulmonary toxicity also provides a good example of toxicity from non-prescription medications. Contaminants of L-tryptophan, marketed for insomnia and depression, results in an eosinophilia-myalgia syndrome characterized by peripheral eosinophilia and severe myalgias, often accompanied by cough, dyspnea, respiratory muscle weakness, pulmonary infiltrates, and pleural effusion. Lung biopsies were notable for lymphocytic and eosinophilic infiltration and small and medium-vessel vasculitis. Severe cases of eosinophilia-myalgia syndrome result in respiratory failure and pulmonary hypertension.

The approach to eosinophilic lung disease must first exclude causes other than drugs. Since parasitic infections are the most common cause of eosinophilia worldwide, a travel history should be taken. Fungal pulmonary infections with Aspergillus species or Coccidioides immitis should be considered. Eosinophilic granulomatosis with polyangiitis, ABPA, and bronchocentric granulomatosis all may cause pulmonary or peripheral eosinophilia in patients with asthma.

A history of prolonged respiratory symptoms and imaging abnormalities is more consistent with chronic idiopathic eosinophilic pneumonia than acute drug-induced eosinophilic pneumonitis. Lab evaluation is usually nonspecific although a very elevated IgE level may be more suggestive of ABPA. Chest imaging is also rarely diagnostic. Bronchoscopy is helpful in identifying eosinophilia on BAL and in excluding other lung diseases such as infection and malignancy.

In most cases, withdrawal of drug results in resolution of eosinophilia and symptoms, but in some cases, such as drug-induced eosinophilic granulomatosis with polyangiitis, corticosteroids or other immunosuppressive medications may be necessary.

Drugs Associated with Noncardiogenic Pulmonary Edema and ARDS

Noncardiogenic pulmonary edema is a toxic complication of a number of drugs (Figure 5). Patients may demonstrate dyspnea, tachypnea, and hypoxia associated with mild interstitial or alveolar-filling radiographic findings or in severe cases may present with ARDS. These features are indistinguishable from other causes of ARDS.

Several narcotics, particularly morphine and methadone, have been implicated in development of pulmonary edema, as have illicit drugs like cocaine and heroin. Aspirin as a well-described cause of pulmonary edema appears to correlate with the level of salicylate intoxication. A number of cardiovascular drugs, including calcium channel blockers, epinephrine, and phenylephrine are also associated with this form of pulmonary toxicity. Several classes of neuropsychiatric drugs, including phenothiazines and tricyclic antidepressants, have also been identified.

Tocolytic agents are also known to cause noncardiogenic pulmonary edema; in these cases, risk factors include prolonged or high doses of tocolytic administration, underlying anemia, twin or multiple gestations, and sustained tachycardia, all of which add hemodynamic stress to the increased cardiac output imposed by pregnancy.

In most cases, drug toxicity manifesting as noncardiogenic pulmonary edema presents relatively rapidly, sometimes within hours. Withdrawal of medication and supportive care typically result in prompt resolution of abnormalities (within hours to days), except when drug toxicity occurs as ARDS, in which case mechanical ventilation or ICU care may be required.

Potentially life-threatening ARDS as a toxic drug reaction is more often described with chemotherapeutic agents. In rare cases, amiodarone and nitrofurantoin may cause ARDS. Amiodarone as a cause of respiratory failure has been reported particularly in the peri-operative setting or with pulmonary angiography. The half-life of amiodarone is long so withholding the drug before a procedure will not eliminate exposure. Most patients who take amiodarone have no difficulty with surgery, but the physician should be aware of the potential for ARDS.

Drugs Associated with Pulmonary Vascular Disease

Drug-induced pulmonary vascular disease may be evident as diffuse alveolar hemorrhage or pulmonary hypertension.

Diffuse Alveolar Hemorrhage (DAH)

DAH as a complication of drug treatment may occur with several types of exposures (Figure 6). A small-vessel vasculitis has been described with phenytoin, propylthiouracil, and all-trans retinoic acid. Eosinophilic granulomatosis with polyangiitis has been described in asthmatics who receive leukotriene modifiers.

Direct injury to the alveolar capillary membrane resulting in diffuse alveolar damage, may occur with amiodarone, nitrofurantoin, or cocaine. Bland pulmonary hemorrhage is seen rarely in the setting of anticoagulation, thrombolytic therapy, or platelet inhibition. Patients usually present with acute respiratory failure although subacute progression may occur. As with other causes of DAH, hemoptysis is often but not always present. Bronchoscopy is important diagnostically.

Pulmonary Hypertension

Pulmonary hypertension as a result of drug toxicity is uncommon, but its development has been associated with several exposures (Figure 6). Development of pulmonary hypertension has been described in conjunction with the eosinophilia-myalgia syndrome and the toxic oil syndrome, which are related to contamination of L-tryptophan and rapeseed oil, respectively.

More notoriously, ingestion of various appetite suppressants has been associated with pulmonary hypertension. An epidemic of “primary” pulmonary hypertension in Europe in the 1970s was linked to use of aminorex fumarate, an amphetamine derivative.

The next generation of appetite suppressants included fenfluramine and dexfenfluramine. The agents were withdrawn from clinical use in the 1990s following case reports and a large French series that demonstrated a probable causal relationship with pulmonary hypertension.

Patients who developed drug-related pulmonary hypertension did not typically experience reversal of disease after the drug was withdrawn. At the time these drugs were used, little therapy was available to treat pulmonary hypertension. Although the majority of affected individuals have been identified, a careful history for potential exposure to dietary medications remains important when assessing a patient with pulmonary arterial hypertension.

Drug-induced Organizing Pneumonia

Organizing pneumonia (OP), characterized by fibromyxoid connective tissue plugs that fill distal airspaces and alveoli with mild or moderate interstitial inflammation, occasionally develops in drug toxicity. Several classes of medications, including antimicrobials, cardiovascular drugs, chemotherapeutic agents, and anti-inflammatory drugs, are associated with OP (Figure 7).

Symptoms include dry cough, dyspnea, and less commonly systemic symptoms including fever and rash. CXRs usually demonstrate bilateral patchy infiltrates that may wax and wane even if offending drug is continued. Since this process appears to reflect a pulmonary inflammatory reaction, corticosteroids are often employed in addition to withdrawal of drug.

Drug-related OP from amiodarone may appear after several years of treatment. In a number of cases, amiodarone-related OP has been reported to progress to respiratory failure and death.

Drug-induced Alveolar Hypoventilation

Several classes of drugs may cause unintentional impairment of respiratory muscle function, resulting in alveolar hypoventilation (Figure 8). Other drugs cause hypoventilation by central suppression of respiratory drive. In these cases, toxicity may present as depressed level of consciousness, altered mental status, hypercapnea, and hypoxemia.

Drug-Induced Pleural Disease

Drug-related pleural disease is usually described in the context of drug-induced lupus. While many medications have been implicated, only a handful have a strong association (Figure 9).

Patients with drug-induced lupus may present with fever, rash, arthralgias, and serositis, features that overlap with spontaneous SLE. Pleuritis or pleural effusions are common in procainamide- or hydralazine-associated lupus, but they occur less frequently with other drugs.

In contrast to SLE, hematologic abnormalities, renal involvement, and CNS disease are not common in drug-induced lupus. Serologic autoantibodies may help differentiate between the two entities. Anti-histone antibodies are present in the vast majority of cases of drug-induced lupus, while other autoantibodies are typically absent. Anti-Sm and anti-dsDNA antibodies are highly consistent with, if not pathognomonic for SLE but are rarely seen in drug-induced lupus.

Pleural fluid analysis demonstrates exudative features with normal or low glucose, but these characteristics do not distinguish drug-induced lupus from SLE. Drug-induced lupus typically improves after medication discontinuation. In symptomatic patients, anti-inflammatory treatment with NSAIDs or corticosteroids may be beneficial.

Other than drug-induced lupus, drug-induced pleural disease is uncommon. Pleural fluid eosinophilia +/- peripheral eosinophilia has been described in case reports of patients treated with valproic acid, propylthiouracil, isotretinoin, nitrofurantoin (usually in context of parenchymal lung disease), mesalamine, and dantrolene. Pleural fibrosis is also unusual, but it has been described with the beta blockers practolol and oxyprenolol and with amiodarone, methysergide, and bromocriptine.

Beware: there are other diseases that can mimic a non-chemotherapy-related drug-induced lung injury.

The clinical, radiographic, and histopathologic manifestations of drug-induced pulmonary toxicity are usually nonspecific. Distinction between drug-related toxicity, progression of underlying disease, and other complications including infection may be difficult. A detailed history of medication use, including illicit, prescription, over-the-counter, dietary and nutritional supplements, can help distinguish between drug-induced lung disease and other conditions.

How and/or why did the patient develop a non-chemotherapy-related drug-induced lung injury?

Factors that predispose patients to developing drug-induced pulmonary disease are unclear.

Which individuals are at greatest risk of developing a non-chemotherapy-related drug-induced lung injury?

Whether the presence of underlying lung disease predisposes patients to drug-related pulmonary complications is unclear, although patients with compromised lung function have less reserve to tolerate a drug-related pulmonary complication.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Once the possibility of drug toxicity is considered, no pathognomonic lab tests are available to establish the diagnosis definitively. In some cases, lab findings may result in a higher level of clinical suspicion for toxicity, e.g., a positive anti-histone antibody in a patient with a new pleural effusion suggesting drug-induced lupus. However, these and other lab findings may reflect the underlying disease process or a new, superimposed pulmonary process unrelated to either the underlying disease or medication.

What imaging studies will be helpful in making or excluding the diagnosis of a non-chemotherapy-related drug-induced lung injury?

CXR and chest CT are useful in evaluation when the lung parenchyma or pleural space is involved. CT is more sensitive in identifying interstitial abnormalities. Notably radiographic abnormalities are never diagnostic of, nor specific for, drug toxicity.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a non-chemotherapy-related drug-induced lung injury?

Pulmonary function testing (PFT) may be helpful in identifying airflow obstruction or parenchymal disease. As is the case with lab and imaging, PFT abnormalities are nonspecific and may prove more useful as a metric for follow-up monitoring after interventions such as drug withdrawal, are made.

Serial measurements of FEV1 and FEV1/FVC in airflow obstruction, measurements of lung volumes and diffusion capacity in pulmonary parenchymal disease, and assessment of maximal inspiratory and expiratory pressures in neuromuscular dysfunction may be helpful.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a non-chemotherapy-related drug-induced lung injury?

The diagnosis of pulmonary drug toxicity may be challenging and sometimes a presumptive diagnosis is made when patients improve after drug withdrawal.

However, in some situations, an empiric trial of withdrawal is not advisable either because the specific drug is necessary to the patient’s care and withdrawal may have severe consequences or because the patient’s clinical status is precarious, and exclusion of other causes of a pulmonary syndrome may require more rapid diagnostic intervention. A common scenario clinicians face is a patient in whom the differential includes progression of underlying pulmonary disease for which a medication is prescribed, pulmonary infection, drug toxicity, and even malignancy. In such cases, a diagnostic procedure, e.g., bronchoscopy or surgical lung biopsy is often warranted.

Bronchoscopy may be very useful in those with suspected pulmonary drug toxicity. While the primary utility is often exclusion of infection, additional information may be obtained. For example, BAL eosinophilia suggests eosinophilic pneumonia, while a progressively bloodier lavage would raise concern for DAH. In the appropriate clinical setting, the findings might be sufficient to establish a diagnosis of drug toxicity.

Transbronchial biopsies may also be useful in defining parenchymal processes with distinct pathologic findings, such as granulomatous inflammation; however, transbronchial biopsies often do not yield adequate tissue to identify other interstitial processes.

Surgical lung biopsy, either open or by video-assisted thoracoscopic surgery, provides more tissue for histopathology, which may be helpful in correctly classifying an interstitial process compared to bronchoscopy, although surgical lung biopsy requires general anesthesia and is much more invasive.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a non-chemotherapy-related drug-induced lung injury?

Pathologic findings do not in isolation establish a diagnosis of drug toxicity; diagnosis requires biopsy interpretation in the context of an identifiable culprit drug and a suggestive clinical course. Pathology may also be helpful in ruling out infection or malignancy as the cause of the underlying clinical or radiographic picture.

If you decide the patient has a non-chemotherapy-related drug-induced lung injury, how should the patient be managed?

The usual approach in suspected pulmonary drug toxicity is withdrawal of the offending drug. While it is sometimes appropriate to continue to expose a patient to a drug that is likely causing harm, these exceptions are rare. In almost all cases, an alternative medication can be identified.

When the drug has a long half-life or a long-acting metabolite, such as amiodarone, withdrawal may not result in removal of ongoing exposure. Still, drug withdrawal typically results in improvement, but other interventions may be warranted. For example, patients with airways obstruction may require bronchodilators and corticosteroids, patients with pleural effusion may benefit from anti-inflammatory agents or thoracentesis, and patients with ARDS may require oxygen or ventilatory support. When drug toxicity manifests as a severe or persistent inflammatory process like OP, vasculitis, or drug-induced lupus, corticosteroids are warranted.

Pulmonary injury related to drug toxicity may not always be fully reversible. Certain drug-induced processes, such as severe ILD from any drug and pulmonary hypertension related to fenfluramine, may never resolve, leading to chronic impairment or death. Early recognition of pulmonary drug toxicity is integral to minimizing long-term complications.

What is the prognosis for patients managed in the recommended ways?

Most patients with drug-induced pulmonary toxicity improve once drug is withdrawn, but the earlier toxicity is recognized, the less likely it is that irreversible pulmonary injury will occur. Patients with chronic longstanding drug toxicity, usually in the form of interstitial pneumonitis, may have irreversible pulmonary fibrosis. In addition, pulmonary injury from drug toxicity may rarely progress despite removal of the offending agent.

What other considerations exist for patients with a non-chemotherapy-related drug-induced lung injury?


Table 1:

Syndromes Associated with Drug-related Pulmonary Toxicity

Table 2:

Drugs Associated with Airways Disease

Table 3:

Drugs Associated with Interstitial Lung Disease

Table 4:

Drugs Associated with Pulmonary Eosinophilia

Table 5:

Drugs that Cause Noncardiogenic Pulmonary Edema or Acute Respiratory Distress Syndrome

Table 6:

Drugs Associated With Pulmonary Vascular Disease

Table 7:

Drugs Associated with Bronchiolitis Obliterans Organizing Pneumonia

Table 8:

Drugs that Cause Alveolar Hypoventilation

Table 9:

Drugs Associated with Pleural Disease

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