Pulmonary Medicine

Non-Chemotherapy-Related Drug-Induced Lung Injury

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What every physician needs to know:

The potential for drugs to cause pulmonary disease has been recognized since Osler’s description of pulmonary edema related to administration of opiates. Drug toxicities are unintended consequences of interventions intended to improve patient health. In cases in which potential adverse effects are known to exist, the healthcare provider and the patient should discuss those risks, as a well-informed patient may be able to identify toxicity before irreparable harm occurs. In some situations, formalized processes for such discussions have been developed--for example, many centers now require patients to sign informed consent before initiating cancer chemotherapy--but in most encounters a brief, informal explanation by the physician suffices. The fundamental premise is that the benefit of the drug will far outweigh its risks, but those risks and potential toxicities should be acknowledged.

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 respiratory system, as distinguishing between primary disease and secondary toxicity may be very 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, many patients take more than one medication, drug interactions may further complicate assessment.

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

This discussion reflects a practical approach based on the concept that, when a patient presents with new respiratory symptoms or chest radiographic abnormalities, a review of his or her medications should be conducted as a matter of routine. Examination of the medications used should include prescribed drugs as well as any over-the-counter, naturopathic, or illicit substances the patient may be using. The question concerning whether the patient’s pulmonary presentation is consistent with described patterns of lung injury for any of those substance exposures should be entertained. This approach is distinct from that of informing patients about potential medication-related toxicities at the time a drug is initiated, as in this situation, the discussion of potential side effects will not be confined to pulmonary toxicities.

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 other sections of this presentation. 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 chemotherapeutic agents, the challenge of evaluating a patient in whom drug-induced lung disease is suspected lies in distinguishing between disease per se 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.

Classification:

An outline of every drug that can possibly cause pulmonary toxicity is impractical, as the list is exhaustive. 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 it 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 included in this discussion are those that have either been associated prototypically with specific pulmonary syndromes of drug toxicities or for which more than twenty cases of toxicity have been reported. One important caveat to the interpretation of frequency of adverse effects is that, while reporting of drug toxicities during the drug development and safety and efficacy trials is mandatory, once a medication is approved for general 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 chemical 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 possible pulmonary drug toxicity may be challenging. In almost all cases, the diagnosis of a drug toxicity reaction 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 complications is unclear, although patients with compromised lung function from primary respiratory disease clearly have less reserve with which to tolerate a drug-related pulmonary complication. When the disease process and the potential complication(s) 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 is varies widely. Most toxicities occur relatively early in the course of exposure; for example, cough related to angiotensin-converting enzyme (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 examination may be completely normal, while progression of toxicity may be heralded by signs related to the type of pulmonary involvement: inspiratory crackles in patients with interstitial pneumonitis, wheezing in patients with airways syndromes or hypersensitivity syndromes, or dullness to percussion or pleural rub in patients with pleuritis or pleural effusion. All of these signs are nonspecific. Radiographic abnormalities are never diagnostic of or specific for drug toxicity.

The presence of persistent pulmonary symptoms, particularly when accompanied by a suggestive abnormal lung examination or radiographic abnormalities, should always raise the possibility of drug toxicity. The decision concerning whether drug toxicity is present is nearly always one of clinical judgment.

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 evaluative step is examination of the patient’s list of prescribed medications and use of non-traditional (herbal, naturopathic) drugs, over-the-counter medications, and illicit substances. Implicit in the question concerning whether any of these medications or substances may be causing the patient’s pulmonary syndrome 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 lung, including the airways, interstitium, vasculature, and pleura, may be adversely affected by medications. 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 diagnostic evaluation and critical in minimizing further exposure. If the clinical syndrome suggests drug toxicity and a potential offending drug to which the patient is exposed 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.

Table 1:

Syndromes Associated with Drug-related Pulmonary Toxicity

The tables included in this discussion address descriptions of clinical syndromes and list the drugs that are usually implicated (as prototypes or by frequency of reporting with each syndrome). The tables are not intended to be exhaustive catalogues.

Drug-induced Airways Disease

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

Cough

Pharmaceutical agents cause cough via a variety of postulated 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.

Table 2:

Drugs Associated with Airways Disease

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

ACE-inhibitor-associated cough, which is nonproductive and persistent, typically 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-inhibitor-induced cough is not clear, but it 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.

If an ACE inhibitor causes cough, withdrawal of the medication 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 this class of drugs is also associated with cough. When ACE inhibition is deemed necessary, successful symptomatic treatment of cough may be possible using 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 in the treatment of airway reactivity may themselves cause cough or bronchospasm, presumably related to particulates or materials used in their preparation. Severe, even explosive, coughing has been described with use of propofol or fentanyl. The mechanism with fentanyl appears to involve a pulmonary chemoreflex with activation of pulmonary J-receptors.

Bronchospasm

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-adrenergic antagonists (beta blockers), aspirin, and NSAIDs. Drug-induced bronchospasm is of particular concern in patients with asthma or any pre-existing airways disease.

The use of beta blockers in patients with asthma or COPD remains controversial. As beta-adrenergic agonists are used for the treatment of bronchospasm, it follows that beta adrenergic blockade may cause bronchospasm. When nonselective beta blockers were first introduced, numerous cases were reported of severe or fatal asthma exacerbations in asthmatics after oral, intravenous, or even ophthalmic administration.

These cases resulted in a general recommendation to avoid beta blockade in patients with asthma or COPD. However, there is substantial evidence that beta blockers render significant clinical benefit to patients with coronary artery disease, hypertension, and heart failure; a general prohibition of this treatment in patients with coexistent cardiac disease and asthma or COPD is problematic, as coronary disease and COPD frequently coexist. Furthermore, the prohibition may be unwarranted with development of cardioselective beta adrenergic antagonists.

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

Subsequently, two meta-analyses were conducted, the first of which included nineteen studies of single-dose and continued treatment with cardioselective beta blockers in patients with asthma or COPD who had a reversible component. While a 7 percent reduction in FEV1 was seen with single-dose treatment, no difference in FEV1 was noted in patients treated for 3-28 days or in FEV1 response to beta agonist administration. In the second meta-analysis, pooled results from twenty studies of single-dose or longer duration (up to twelve weeks) on the use of cardioselective beta blockade in patients with COPD were analyzed. No significant change in FEV1 or respiratory symptoms were demonstrated compared to placebo, and no changes were seen in patients with severe airways obstruction.

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

Aspirin and NSAIDs are well known to produce bronchoconstriction in a small percentage of the general asthmatic population. NSAIDs may result in IgE-mediated allergic reactions, including urticaria, angioedema, or anaphylaxis; however, the more common inflammatory 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 ingestion. Aspirin or NSAID sensitivity may be present in up to 40 percent of patients with asthma or rhinosinusitis. Sensitivity of this type is an acquired condition, as most patients present in young adulthood with a prior history of uncomplicated use of these medications. Symptoms, which are typically acute, occur within minutes or hours after ingestion and range from mild nasal congestion to severe bronchospasm. Leukotriene modifying agents should be administered to these patients in addition to standard guideline-based asthma management. If aspirin or NSAID use is deemed medically necessary, aspirin desensitization should be considered.

Drugs Associated with Interstitial Lung Disease

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

Table 3:

Drugs Associated with Interstitial Lung Disease

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 in a more insidious fashion, with progressive cough, dyspnea, and fibrotic radiographic changes. The pathologic spectrum of pulmonary interstitial disease related to drug toxicity includes all the major histopathologic forms of interstitial disease, 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 pneumonitidies, may represent manifestations of underlying inflammatory diseases like the connective tissues diseases, or may represent infiltrative or granulomatous lung diseases like sarcoidosis. The clinical challenge lies in distinguishing progression of the underlying disease despite treatment from superimposed pulmonary toxicity that is due to medication.

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

The evaluation of potential toxic effects of drug in the lung is complicated by the fact that medications may cause more than one type of adverse reaction. A single drug may be able to precipitate more than one type of interstitial abnormality or may also result in airways disease or pleural effusion. Many drugs and classes of drugs, including aspirin, NSAIDs, nitrofurantoin, ACE inhibitors, and penicillamine, demonstrate an array of pulmonary complications.

One of the best-recognized examples is amiodarone, which may cause pulmonary disease in several forms: chronic interstitial pneumonitis, organizing pneumonia with or without bronchiolitis obliterans, acute respiratory distress syndrome, or even solitary pulmonary masses. To add yet another layer of complexity, amiodarone has a half-life of several weeks and persists in tissues and the circulation long after the drug is discontinued. What's more, the drug is typically used for serious cardiac arrhythmias, so withdrawal is not without potential severe clinical consequences.

Both amiodarone and its active metabolite, monodesethylamiodarone, 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 requires treatment.

Interstitial lung disease may arise as the result of illicit drug use or from exposure to substances other than medications. Vascular 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.

The “toxic oil syndrome” in Spain in 1981 was characterized by multi-organ system abnormalities that were eventually attributed to contaminated rapeseed oil. Cough and respiratory distress were common pulmonary symptoms, and late sequelae included pulmonary fibrosis and pulmonary hypertension. The epidemiology of this outbreak was notable for the extent and rapidity with which the contaminated food product affected many communities, a situation that is mirrored in epidemics of disease related to contaminated drugs.

Drug-induced Eosinophilic Lung Disease

Eosinophilic lung disease is identified by documentation of an increased number of eosinophils in bronchoalveolar lavage (BAL), by the demonstration of eosinophilic infiltration in histologic specimens, 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 (particularly with parasites and fungi), acute or chronic eosinophilic pneumonia, simple eosinophilic pneumonia (Loeffler's syndrome), Churg-Strauss syndrome, idiopathic hypereosinophilic syndrome, allergic bronchopulmonary aspergillosis (ABPA), and malignancy.

Drug-induced pulmonary eosinophilia usually presents as an acute eosinophilic pneumonia with symptoms of cough and dyspnea and chest radiographs that show infiltrates that are sometimes migratory. In contrast to what is observed in patients with acute idiopathic eosinophilic pneumonia, drug-induced disease is characterized more often by peripheral eosinophilia, fever, and rash. Churg-Strauss syndrome has been described in the setting of leukotriene modifier use, where distinction of idiopathic from drug-induced disease may be very difficult.

Many prescriptive drugs are associated with pulmonary eosinophilia; the most common of these are listed in Figure 4. Eosinophilic drug-induced pulmonary toxicity also provides a prototypical example of a non-prescriptive medication that causes serious medical illness. Contaminants of L-tryptophan marketed in the 1980s for insomnia and depression were the cause of the eosinophilia-myalgia syndrome, characterized by peripheral eosinophilia and severe myalgias and often accompanied by cough, dyspnea, respiratory muscle weakness, pulmonary parenchymal infiltrates, and pleural effusion. Pulmonary biopsies in these cases were notable for lymphocytic and eosinophilic infiltration and small and medium-vessel vasculitis. Severe cases of eosinophilia-myalgia syndrome resulted in respiratory failure and persistent pulmonary hypertension.

Table 4:

Drugs Associated with Pulmonary Eosinophilia

The approach to the patient with 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 obtained. Pulmonary fungal infection with Aspergillus species or, in the United States, with Coccidioides immitis, should be considered. Churg-Strauss syndrome, ABPA, and bronchocentric granulomatosis all may cause pulmonary or peripheral eosinophilia in patients with asthma.

A history of prolonged respiratory symptoms and radiographic abnormalities is more consistent with chronic idiopathic eosinophilic pneumonia than with acute drug-induced eosinophilic pneumonitis. Laboratory evaluation is usually nonspecific, although a very elevated IgE level may be more suggestive of ABPA than it is of drug-associated disease. Similarly, chest radiography is rarely diagnostic. Bronchoscopy, which may be useful in identifying BAL eosinophilia, is helpful in excluding other underlying lung diseases, particularly infection and malignancy.

In most cases, withdrawal of drug results in resolution of eosinophilia and symptoms, but in some cases, such as that of drug-induced Churg-Strauss syndrome, corticosteroids or other immune-suppressive interventions may be necessary.

Drugs Associated with Noncardiogenic Pulmonary Edema and Acute Respiratory Distress Syndrome

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 abnormalities or in severe cases may present with acute respiratory distress syndrome (ARDS). These features are indistinguishable from other causes of pulmonary edema or ARDS, although the absence of typical radiographic findings of congestive heart failure, such as cardiomegaly or pulmonary vascular redistribution, should raise the possibility of noncardiogenic causes.

Table 5:

Drugs that Cause Noncardiogenic Pulmonary Edema or Acute Respiratory Distress Syndrome

Osler described pulmonary edema as being a result of opiate toxicity. Several narcotics, particularly morphine and methadone, have been implicated, as have drugs of abuse like cocaine and heroin. Aspirin as a well-described cause of pulmonary edema appears to correlate to some extent with the level of salicylate intoxication. A number of cardiovascular drugs, including calcium channel blockers, epinephrine, and phenylephrineare, 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 described as causing noncardiogenic pulmonary edema; in these cases, contributing 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 drug and supportive care typically result in prompt resolution of abnormalities (within hours to days), except when drug toxicity occurs as acute and severe respiratory distress, in which case mechanical ventilation or intensive supportive care may be required.

Potentially life-threatening ARDS as a toxic drug reaction is more often described with chemotherapeutic, rather than nonchemotherapeutic, 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 an urgent or even elective 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 acute, severe respiratory failure.

Drugs Associated with Pulmonary Vascular Disease

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

Diffuse Alveolar Hemorrhage

Diffuse alveolar hemorrhage (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. Churg-Strauss vasculitis has been described in asthmatics who receive leukotriene modifiers.

Table 6:

Drugs Associated With Pulmonary Vascular Disease

Direct injury to the alveolar capillary basement membrane, resulting in the histologic pattern of diffuse alveolar damage, may occur with amiodarone, nitrofurantoin, or cocaine. Bland pulmonary hemorrhage is seen, albeit rarely, in the setting of anticoagulation, thrombolytic therapy, or platelet inhibition. Patients usually present with acute, progressive respiratory insufficiency, although subacute progression may occur. As with other causes of alveolar hemorrhage, hemoptysis is usually, but not always, present. In such cases, BAL is an important diagnostic intervention.

Pulmonary Hypertension

Pulmonary hypertension as a result of drug toxicity is uncommon, but its development has been associated with several well-defined 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.

Even more notoriously, ingestion of various appetite suppressants has been associated with pulmonary hypertension. An epidemic of “primary” pulmonary hypertension in Germany and Austria in the late 1970s was eventually linked to use of aminorex fumarate, an amphetamine derivative. Like amphetamine, aminorex appears to exert its anorexigenic effect through release of catecholamines, including dopamine; this is a feature of many drugs of addiction. Awareness of the addictive potential of aminorex limited its use in other countries and may have prevented a more widespread outbreak of pulmonary hypertension.

The next generation of appetite suppressants included fenfluramine and its racemate, dexfenfluramine. These compounds are structurally similar to aminorex, but they appear to be anorexigenic by causing depletion of intracellular stores of serotonin, so they are less likely to cause addiction. Fenfluramine and dexfenfluramine were marketed and used broadly in Europe and the United States throughout the 1980s, but the agents were withdrawn from clinical use in the mid-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 with aminorex, fenfluramine, or dexfenfluramine did not typically experience reversal of the vascular abnormality after the drug was withdrawn. At the time these drugs were used, little effective therapy was available to reverse disease or prevent progression.

Drug-induced Organizing Pneumonia and Bronchiolitis Obliterans

Organizing pneumonia, which is characterized by fibromyxoid connective tissue plugs that fill distal airspaces and alveoli with mild or moderate interstitial inflammation, is typically termed bronchiolitis obliterans organizing pneumonia (BOOP) when observed in the setting of drug toxicity. Several classes of medications, including antimicrobials, cardiovascular drugs, chemotherapeutic agents, and anti-inflammatory drugs, are associated with BOOP (Figure 7).

Table 7:

Drugs Associated with Bronchiolitis Obliterans Organizing Pneumonia

Clinical presentation parallels that of the idiopathic form of disease, cryptogenic organizing pneumonia: symptoms of dry cough and dyspnea and, less commonly, systemic symptoms, including fever and rash. Chest radiographs usually demonstrate bilateral patchy infiltrates that may wax and wane even if the 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 BOOP, which has been described in a number of cases of amiodarone toxicity, does not appear to be dose-dependent. In contradistinction to many drug reactions that are relatively acute and temporally related to exposure, amiodarone-related pulmonary toxicity may appear even after several years of treatment. In a number of cases, amiodarone-related BOOP has been described to have progressed to respiratory failure and death.

Drug-induced Alveolar Hypoventilation

Besides drugs used therapeutically in critical care or operative settings to induce neuromuscular blockade, 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, pulmonary toxicity may present as depressed level of consciousness, altered mental status, hypercapnea, and hypoxemia.

Table 8:

Drugs that Cause Alveolar Hypoventilation

Drug-Induced Pleural Disease

Medication-related pleural disease is usually recognized in the context of drug-induced lupus. While many medications are described as potential causes of this syndrome, only a handful have a strong association (Figure 9).

Table 9:

Drugs Associated with Pleural Disease

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

In contrast to spontaneous SLE, hematologic abnormalities, renal involvement, and central nervous system disease are uncommon in patients with drug-induced lupus. Serologic evaluation of autoantibodies may help differentiate between the two entities. Anti-histone antibodies are present in the vast majority of patients with drug-induced lupus, while other autoantibodies are typically absent. In particular, anti-Sm and anti-double-stranded DNA antibodies that are highly consistent with, if not pathognomonic for, SLE are rarely seen with drug-induced lupus. The mechanisms by which drugs may induce anti-histone antibodies are unclear.

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

Other than drug-induced lupus, drug-induced pleural disease is uncommon. Pleural fluid eosinophilia, with or without peripheral eosinophilia, has been described in case reports of patients treated with valproic acid, propylthiouracil, isotretinoin, nitrofurantoin (usually in the 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 among drug-related toxicity, progression of underlying disease, and other complications, including infection, may be difficult.

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

Factors that predispose patients to development of drug-induced pulmonary disease are unclear. Important considerations that may complicate drug management with regard to pulmonary concerns are presented in the discussion of individual agents or drug classes.

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 medication-related pulmonary complications is unclear, although patients with compromised lung function from primary respiratory disease have less reserve with which to tolerate a drug-related pulmonary complication. When the disease process and the potential complication(s) overlap, the independent effect of the underlying disease on the risk of drug toxicity may be impossible to define.

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

The diagnosis of drug-induced pulmonary toxicity is usually made clinically, predominantly by the exclusion of other causes of respiratory symptoms and radiographic abnormalities. The first sign of toxicity is often the development of nonspecific symptoms like cough or shortness of breath, or abnormal signs on physical examination, including rhonchi or crackles. These findings should lead to chest imaging using plain radiography or computed tomography (CT); while CT scanning is more sensitive in identifying interstitial abnormalities, the findings are nonspecific.

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

Infection and fluid overload often complicate patient care; malignancy also needs to be considered.

Patterns of presentation (Figure 1) may be useful in considering drug toxicity, as a single agent may present with pulmonary drug toxicity in a variety of ways. When drug therapy is used to treat an underlying lung disease, distinguishing between disease progression and drug toxicity may be particularly challenging. Ultimately, resolution of the clinical process after withdrawal of the potential offending drug is the most definitive evidence of a causal association.

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

A plain chest x-ray and chest CT scan are usually useful in establishing an underlying disease process when the lung parenchyma or pleural space is involved. Radiographic studies may not be helpful for diagnosing drug-related airways disease or pulmonary vascular disease.

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), which provides an objective measurement of pulmonary physiology, may be helpful in identifying airflow obstruction or parenchymal lung disease. As is the case with laboratory and radiographic evaluation, PFT abnormalities are not specific; they 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 patients with airflow obstruction, measurements of lung volumes and diffusion capacity in patients with pulmonary parenchymal abnormalities, and assessment of maximal inspiratory and expiratory pressures in patients with 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. It requires a careful examination of the patient’s medication list, and every syndrome outlined in Table 1 (Figure 1) is associated with a broad differential diagnosis. In most cases in which drug toxicity is a strong consideration, an alternative to a specific medication is available, and substitution for a drug of concern is often the simplest approach.

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 that of a patient in whom the differential diagnosis includes progression of underlying pulmonary disease for which a medication is prescribed, pulmonary infection, drug toxicity, and, in some, metastatic disease to the lungs.

Consider as an example a patient with a solid-organ transplant who is taking an immune-suppressing regimen, including sirolimus, who develops cough, low-grade fever, and interstitial pulmonary radiographic abnormalities. Infection is a strong consideration, but sirolimus pulmonary toxicity should also be considered. Since empiric withdrawal of sirolimus might result in rejection of the transplant, distinguishing between infection and drug toxicity is critical to both the acute and the long-term care of the patient. In such a case, a diagnostic procedure--usually bronchoscopy or surgical lung biopsy--is often warranted.

Bronchoscopy may be very useful in patients who have suspected pulmonary drug toxicity. While the primary utility of the procedure is often exclusion of infection, additional information may be derived. For example, BAL eosinophilia strongly suggests eosinophilic pneumonia, while a progressively hemorrhagic lavage would raise concern for alveolar hemorrhage. 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 usually do not yield adequate tissue to identify other interstitial processes.

Surgical lung biopsy, either open or obtained by video-assisted thoracoscopic surgery (VATS), provides more tissue--enough to identify pulmonary histopathology, which may be particularly helpful in correctly classifying an interstitial process--than does bronchoscopy, although surgical lung biopsy requires general anesthesia and is a much more invasive approach. The pathologic findings do not in isolation establish a diagnosis of drug toxicity; the diagnosis requires interpretation of the biopsy in the context of an identifiable culprit drug and a suggestive clinical course.

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

In the absence of other elements of clinical assessment, pathologic lung findings are insufficient to establish a diagnosis of drug toxicity. However, pathology may 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 to a patient with suspected pulmonary drug toxicity is withdrawal of the drug. While it is sometimes appropriate to continue to expose a patient to a medication that is probably causing harm, these exceptions are rare. In almost all cases, an alternative medication can be identified to replace the potential offender.

When the drug in question has a long half-life or has a long-acting metabolite, such as amiodarone, withdrawal may not result in removal of ongoing exposure. Still, drug withdrawal typically results in improvement, but symptomatic intervention 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 acute respiratory insufficiency may require oxygen or ventilatory support. When drug toxicity manifests as a severe or persistent inflammatory process like BOOP, vasculitis, or drug-induced lupus, corticosteroids may be warranted.

Pulmonary injury related to drug toxicity may not always be fully reversible. Certain drug-induced processes, such as severe interstitial lung disease from any drug and pulmonary hypertension related to fenfluramine, may never resolve, leading to chronic impairment or death. Early recognition of the symptoms and signs that suggest 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 the drug is withdrawn, but the earlier toxicity is recognized, the less likely it is that irrevocable pulmonary injury will occur. Patients with chronic, long-standing drug toxicity, usually in the form of interstitial pneumonitis, may have irreversible pulmonary parenchymal changes, emphasizing the need to maintain awareness of the possible toxicity. Pulmonary injury from drug toxicity may, in rare cases, progress despite removal of the offending agent,.

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

Given the many different presentations of drug-induced lung injury, and the potential severity of clinical consequences if injury is unrecognized, an awareness of the possibility of toxicity must be maintained for all patients undergoing pharmacologic interventions.

What’s the evidence?

Babu, K, Marshall, B. "Drug-induced airway diseases". Clin Chest Med. vol. 25. 2004. pp. 113-122.

(This article reviews the drugs that can result in cough, bronchospasm, and other airways syndromes.)

Borchers, AT, Keen, CL, Gershwin, ME. "Drug-induced lupus". Ann N Y Acad Sci. vol. 1108. 2007. pp. 166-182.

(This review discusses the clinical patterns of drug-induced lupus and suggests guidelines for diagnosis.)

Brenot, F, Herve, P, Petitpretz, P. "Primary pulmonary hypertension and fenfluramine use.". Br Heart J. vol. 70. 1993. pp. 537-541.

(The relationship between the anorexigen fenfluramine and pulmonary hypertension is explored in this retrospective study of fifteen patients who used fenfluramine and subsequently developed severe pulmonary hypertension.)

Camus, P, Martin, WJ, Rosenow, ED. "Amiodarone pulmonary toxicity". Clin Chest Med. vol. 25. 2004. pp. 65-75.

(As reviewed in this report, amiodarone pulmonary toxicity may present in a variety of clinical and radiographic patterns, with variable outcomes.)

Epler, G. "Drug-induced brochiolitis obliterans organizing pneumonia". Clin Chest Med. vol. 25. 2004. pp. 89-94.

(This review discusses that bronchiolitis obliterans organizing pneumonia occurs in a variety of clinical settings, including as a consequence of drug toxicity.)

Flieder, D, Travis, W. "Pathologic characteristics of drug-induced lung disease". Clin Chest Med. vol. 25. 2004. pp. 37-45.

(This is a useful review of the varying pulmonary histopathologic patterns that may accompany drug toxicity reactions.)

Foucher, P, Camus, P. "The drug-induced lung diseases: Groupes d’Etudes de la Pathologie Pulmonaire Iatrogène". http://pneumotox.com..

(GEPPI maintains this active and well-referenced listing of drugs associated with pulmonary toxicity. The site is particularly useful in that it provides frequencies of cited toxicities for individual drugs. Drugs are also grouped by the clinical patterns of toxicity they share.)

Good, JT, King, TE, Antony, VB. "Lupus pleuritis. Clinical features and pleural fluid characteristics with special reference to pleural fluid antinuclear antibodies.". Chest. vol. 84. 1983. pp. 714-718.

(This report discusses pleural fluid findings and characteristics in pleural effusions related to drug-induced lupus.)

Heffner, JE, Sahn, SA. "Salicylate-induced pulmonary edema. Clinical features and prognosis". Ann Intern Med. vol. 95. 1981. pp. 405-409.

(This report of patients with salicylate intoxication identifies risk factors for the development of salicylate-associated pulmonary edema, including older age, chronic salicylate ingestion, a history of smoking, and elevated serum salicylate levels.)

Jenkins, C, Costello, J, Hodge, L. "Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice". Brit Med J. vol. 328. 2004. pp. 434.

(This systematic literature review demonstrates a 21 percent pooled incidence of aspirin sensitivity in asthmatics.)

Kilbourne, EM, Rigau-Perez, JG, Heath, CW. "Clinical epidemiology of toxic-oil syndrome. Manifestations of a new illness". N Engl J Med. vol. 309. 1983. pp. 1408-1414.

(This report describes the epidemiology of the toxic-oil syndrome caused by contaminated cooking oil, which caused hundreds of deaths and thousands of pneumonia-like illnesses in Spain.)

Lee-Chiong, TJ, Matthay, R. "Drug-induced pulmonary edema and acute respiratory distress syndrome". Clin Chest Med. vol. 25. 2004. pp. 95-104.

(The article provides a comprehensive review of drugs that can be associated with noncardiogenic pulmonary edema.)

Pare, JP, Cote, G, Fraser, RS. "Long-term follow-up of drug abusers with intravenous talcosis". Am Rev Respir Dis. vol. 139. 1989. pp. 233-241.

(This description of six cases of pulmonary complications related to injection of talc-containing drugs provides a long-term clinical, radiographic, and pathologic perspective on talc-induced progressive respiratory disease.)

Ravid, D, Lishner, M, Lang, R. "Angiotensin-converting enzyme inhibitors and cough: a prospective evaluation in hypertension and in congestive heart failure". J Clin Pharmacol. vol. 34. 1994. pp. 1116-1120.

(This prospective study monitored cough in ACE-inhibitor-treated patients followed for at least one year. Cough developed in 18.6 percent of patients. Rechallenge with other ACE-inhibitors caused cough recurrence in almost all cases. Cough necessitated discontinuation of ACE-I treatment in 4 percent of patients with hypertension and in 18 percent of patients with CHF.)

Salpeter, S, Ormiston, T, Salpeter, E. "Cardioselective beta-blockers for chronic obstructive pulmonary disease". Cochrane Database Syst Rev. 2005. pp. CD003566.

(This Cochrane review meta-analysis evaluates the effect of cardioselective beta-adrenergic blockers in patients with COPD after single dose treatment and up to twelve weeks. No change in FEV1 or respiratory symptoms with a single dose or up to twelve weeks of treatment was demonstrated. The conclusion of the meta-analysis was that cardioselective beta blockers should not routinely be withheld from patients with COPD.)

Salpeter, S, Ormiston, T, Salpeter, E. "Cardioselective beta-blockers for reversible airway disease". Cochrane Database Syst Rev. 2002. pp. CD002992.

(This Cochrane review meta-analysis evaluates the effect of cardioselective beta-adrenergic blockers in patients with mild to moderate reversible airways obstruction (asthma or COPD). The conclusion of the meta-analysis was that there were no short-term adverse respiratory effects from treatment on baseline FEV1 or FEV1 response to short-acting beta-2 agonist treatment after a single dose or up to twenty-eight days of use.)

Schwaiblmair, M, Berghaus, T, Haeckel, T, Wagner, T, von Scheidt, W. "Amiodarone-induced pulmonary toxicity, an under-recognized and severe adverse effect?". Clini Res Card. vol. 99. 2010. pp. 693-700.

(This report discusses the evaluation of amiodarone pulmonary toxicity and the proposed pathophysiologic mechanisms of lung injury.)

Varga, J, Uitto, J, Jimenez, SA. "The cause and pathogenesis of the eosinophilia-myalgia syndrome". Ann Intern Med. vol. 116. 1992. pp. 140-147.

(This report provides a review of studies published from 1989-1991 that relate to the eosinophilia-myalgia syndrome caused by contaminants of L-tryptophan, with a comprehensive discussion on the proposed pathopysiologic mechanisms of disease.)
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