Drug-Induced Pulmonary Toxicity Clinical Presentation

Drug-induced lung disease is usually considered a diagnosis of exclusion (eg, after excluding infectious and other causes). Discontinuance of the offending agent is often followed by spontaneous improvement, whereas failure to appreciate the causal relationship between the drug and the pulmonary disease can lead to irreversible lung injury.

Importantly, drug-induced lung diseases have no pathognomonic clinical, laboratory, physical, radiographic, or histologic findings. Unfortunately, certain aspects of drug-induced disease can hinder the recognition of this cause-and-effect relationship. Although many drugs can cause diffuse infiltrative lung disease, very few of the patients who receive such drugs experience this disease. In the case of cytotoxic drug-induced disease, the onset of respiratory symptoms can occur many weeks after the last exposure to the offending agent. Finally, the drugs that cause diffuse infiltrative lung disease are often prescribed for conditions that are themselves associated with an increased risk for the disease.

Thus, clinicians evaluating patients with possible drug-induced pulmonary symptoms must obtain a thorough drug exposure history, maintain a high index of suspicion, and use a systematic diagnostic approach to make the correct and firm diagnosis. Irey^[7] defined the following set of criteria for the diagnosis of drug reactions:

• Correct identification of the drug, its dose, and its duration of administration
• Exclusion of other primary or secondary lung diseases
• Temporal eligibility - Appropriate latent period (exposure to toxicity)
• Recurrence with rechallenge (a practice not commonly performed)
• Singularity of drug (ie, other drugs the patient is taking)
• Remission of symptoms with removal of the drug
• Characteristic pattern of reaction to a specific drug (perhaps previous documentation)
• Quantification of drug levels that confirm abnormal levels (especially for overdoses)
• Degree of certainty of drug reaction (ie, causative, probable, or possible)

The physical findings of drug-induced lung disease are nonspecific. The patient may have crackles in the case of NCPE, wheezes in the case of bronchospasm, and decreased breath sounds in pleural effusion. Furthermore, bibasilar Velcro crackles may be audible in cases of drug-mediated interstitial lung disease.

The major clinical syndromes associated with drug-induced lungs disease are discussed below.

NCPE/capillary leak syndrome

A variety of drugs can cause NCPE. It is a less common pattern of drug-induced involvement than pneumonitis and fibrosis. Drugs can cause pulmonary edema by 2 mechanisms. First, some drugs cause injury to the capillary endothelium, leading to leakage of fluid and protein into the interstitium of the lungs. Second, certain drugs depress the central nervous system, resulting in neurogenic pulmonary edema.

The clinical features of acute pulmonary edema (with no evidence for left ventricular dysfunction or overload) manifest as an acute onset of dyspnea with tachypnea, tachycardia, hypoxemia, diffuse crackles upon physical examination, and fluffy infiltrates on the chest radiograph.

Drugs that cause NCPE include heroin, interleukin 2, MTX, cocaine, tocolytic therapy, hydrochlorothiazide, cyclophosphamide, and iodine radiographic contrast agents.^[8]

Hypersensitivity reaction

Drug hypersensitivity results from interactions between a pharmacologic agent and the human immune system. These reactions are commonly associated with nitrofurantoin, MTX, beta-blockers, and procarbazine. Drug-mediated hypersensitivity reactions manifest as an acute syndrome consisting of dyspnea, fever, and nonproductive cough. Peripheral eosinophilia may be present, and the chest radiograph shows localized or bilateral alveolar infiltrates.

Bronchiolitis obliterans-organizing pneumonia

BOOP is a distinctive pattern of lung response to a few drugs. Histology reveals interstitial inflammation superimposed on the dominant background of alveolar and ductal fibrosis. Drugs that can cause BOOP include acebutolol, amiodarone, amphotericin B, bleomycin, and carbamazepine.

Pulmonary vascular disease

Drugs can affect the pulmonary vascular circulation by causing venous thromboembolism, pulmonary hypertension, vasculitis, or pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease is characterized by chronic congestive changes, mild-to-moderate arterial hypertensive changes, and obstruction of small veins. Oral contraceptives, bleomycin, and carmustine (BCNU) have been reported to cause this rare disorder.

Oral contraceptives^[9] also cause a 4- to 7-fold increased risk of venous thromboembolism.^[10] The mechanism responsible for this effect is not known, but estrogens are well known to increase platelet adhesiveness and decrease venous tone and can cause a procoagulant effect. Other implicated drugs include phenytoin, procainamide, and retinoic acid.

Appetite suppressants (eg, amphetamines, fenfluramine) are associated with an increased risk of pulmonary hypertension. Clinicians should remain vigilant because most over-the-counter appetite suppressants contain fenfluramine and dexfenfluramine. Prescription medications such as aminorex, beta-blockers, and mitomycin C have been reported to cause pulmonary hypertension.

Pulmonary vasculitis is caused by several drugs, including nitrofurantoin, sulfonamides, penicillins, phenytoin, and propylthiouracil. This disorder is likely a form of hypersensitivity pneumonitis.

Drug-induced pulmonary hemorrhage is a rare drug-related complication. Patients usually present with hemoptysis, dyspnea, and hypoxemia. Diffuse alveolar hemorrhage is characterized by bilateral infiltrates in the context of anemia of recent onset and hypoxemia. Several anticoagulants and cytosine arabinoside can produce diffuse alveolar hemorrhage.^[11] Penicillamine, amiodarone, cocaine, hydralazine, mitomycin C, nitrofurantoin, abciximab, MTX, carbamazepine, and moxalactam disodium are recognized as inciting agents. Treatment is withdrawal of the offending drug and control of the bleeding. The diagnosis is confirmed by bronchoalveolar lavage (BAL), which shows increased blood staining in sequential aliquots.

Interstitial pneumonitis

Interstitial pneumonitis is inflammation of the lung interstitium, such as alveolar septa. It is the most common manifestation of drug-induced lung disease. A wide array of drugs can cause interstitial pneumonitis. Some of the agents implicated are azathioprine, bleomycin, chlorambucil, MTX, phenytoin, statins, amiodarone, and sulfasalazine.^[12]

Time to onset is from a few days to years into treatment and is unpredictable. The onset of the disease may be progressive over a few weeks, with isolated fever followed by the insidious development of respiratory symptoms, or the onset may be abrupt, especially in patients with MTX lung. Signs and symptoms include increasing dyspnea, dry cough, high fevers, and, sometimes, a rash. The spectrum of severity ranges from mild symptoms and ill-defined pulmonary opacities to extensive consolidation and respiratory failure.

Bronchospasm

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can induce bronchospasm. In rare cases, this reaction can lead to death in aspirin-sensitive persons with asthma. Of adult persons with asthma, 8-20% experience bronchospasm following the ingestion of aspirin and other NSAIDs. Asthma and aspirin sensitivity may develop in the months following initial exposure to aspirin or NSAIDs. The acute asthmatic reaction occurs within 20 minutes to 3 hours after ingestion of aspirin or an NSAID.

Patients initially present with an acute episode of vague malaise, sneezing, nasal obstruction, rhinorrhea, and, often, a productive cough. These symptoms resolve in a few weeks but may be followed by persistent rhinitis and the development of nasal polyps. Spirometry typically shows a variable obstructive ventilatory defect.

Bronchospasm has been reported with the use of inhaled pentamidine, amphotericin B, amiodarone, angiotensin-converting enzyme (ACE) inhibitors, dipyridamole, nitrofurantoin, beta-blockers, and penicillamine.

Because HIV disease is now better controlled and patients are treated for many years, further study of antiretroviral therapy (ARVT) and lung function will determine if bronchospasm reverses after cessation of ARVT. In one study on pulmonary function abnormalities in patients with HIV receiving ARVT, the reversibility was defined only as no response to bronchodilators at the time of pulmonary function testing.^[13]

Pleural involvement

Pleural effusions can develop in patients undergoing treatment with MTX, nitrofurantoin, amiodarone, procarbazine, carmustine, and cyclophosphamide. Pleural effusions can also occur in drug-induced lupus. Medications that cause pleural effusions in this setting include hydralazine, procainamide, phenytoin, nitrofurantoin, and ACE inhibitors. Positive serum testing for antinuclear and histone antibodies aids in the diagnosis of this disorder.

Bilateral pleural thickening is a distinctive form of late cyclophosphamide toxicity. Pneumothorax can complicate late stages of drug-induced pulmonary changes and has been reported in association with bleomycin, carmustine, and retinoic acid.

Mediastinal involvement

Phenytoin, bleomycin, and carbamazepine can induce enlargement of hilar and mediastinal lymph nodes. In addition, a pseudosarcoidosis syndrome can develop with interferon alfa and beta.

Mediastinal lipomatosis is the accumulation of excess unencapsulated fat within the mediastinum. It may be seen in patients with Cushing disease or those treated with steroid therapy. The usual appearance on the chest radiograph is a smooth widening of the anterior and superior mediastinum without any deformity of the trachea. The fat pads in the costophrenic angles are also often enlarged. The diagnosis is made based on chest CT scanning findings. The treatment is cessation of steroid therapy.

Selected important cytotoxic, cardiovascular, anti-inflammatory, antimicrobial, illicit, and miscellaneous drugs that cause pulmonary toxicity are discussed below.

Cytotoxic drugs

Bleomycin

The rate of bleomycin-induced pulmonary toxicity is approximately 10% (varies from 2-40%). Bleomycin is very useful in the treatment of head and neck carcinomas, germ cell tumors, and lymphoma.

Risk factors for lung toxicity include old age; cumulative dose greater than 450 total units (10% mortality if >550 total U); concomitant or prior radiation therapy (lung injury may not be confined to radiation port); exposure to high supplemental fraction of inspired oxygen (>0.25-0.3),^[14] which can lead to the development of ARDS 18-36 hours after exposure; combination therapy with cyclophosphamide or granulocyte-colony stimulating factor; and renal failure.^[15]

A wide variety of adverse reactions to bleomycin have been reported, including chronic interstitial fibrosis, hypersensitivity-type disease, and BOOP. Clinically, bleomycin toxicity manifests acutely or subacutely with dyspnea and chest pain.^[16] Pneumonitis with pulmonary fibrosis^[17] can develop 6-8 weeks after the onset of treatment.^[18] Crackles may be present upon auscultation of the chest and precedes radiographic changes.

Chest radiographs may show reticulation, ground-glass opacity, and, sometimes, consolidation with a predominant subpleural and lower lobe predominance.^{[19, 20]} Often, generalized loss of lung volume occurs.^[21] Lung toxicity can cause multiple pulmonary nodules,^[22] which may mimic metastatic disease^[23] but have the histologic characteristic of BOOP.

Pulmonary function test (PFT) results typically reveal a restrictive ventilatory defect and reduced diffusion capacity for carbon monoxide (DLCO) that predates the onset of overt toxicity by weeks. The BAL cytologic pattern is neutrophilic.^[24] Tissue eosinophilia is uncommon but has been reported in patients with bleomycin-induced lung toxicity.^[25]

Management includes withdrawal of the drug. Corticosteroids are generally administered to all patients with clinically significant toxicity and then are slowly tapered according to the patient’s clinical response. Clinical improvement typically occurs within weeks, but the condition may take 2 years to completely resolve. The overall mortality rate varies from 10-83%.

Mitomycin C

The rate of pulmonary mitomycin C toxicity is approximately 3-12%. This medication is used in the treatment of breast, gastrointestinal, gynecologic, and lung carcinomas. Pulmonary disorders that have been described with mitomycin toxicity include acute pneumonitis, hemolytic-uremic–like syndrome with acute lung injury, chronic pneumonitis with the insidious development of diffuse parenchymal lung disease, and exudative pleural exudative effusions.

A fraction of inspired oxygen value greater than 50% increases the risk for pulmonary mitomycin C toxicity. Coadministration with vinca alkaloids (eg, vinblastine, vincristine) can cause bronchospasm and hypoxia.

Symptoms of pulmonary mitomycin C toxicity typically begin after the third or fourth course of chemotherapy. Chest radiographs may reveal a reticular pattern and opacities. These pulmonary opacities may clear, or they may persist in patients who progress to the development of chronic interstitial lung disease.

Approximately two thirds of the patients develop chronic respiratory symptoms that respond to corticosteroids. The mortality rate is high, up to 50%.

Nitrosourea (BCNU, carmustine)

The rate of pulmonary toxicity is 20-30%, with a mortality rate of 90%. BCNU readily crosses blood-brain barriers and is often used in patients with central nervous system malignancies. BCNU causes pulmonary toxicity more often than any other nitrosourea.

Factors that increase the risk of toxicity are younger age, preexisting lung disease, smoking habit, and a dose greater than 525 mg/m² (50% affected at dose >1500 mg/m²). BCNU may have synergy with other drugs (eg, cyclophosphamide) and radiation therapy in producing pulmonary toxicity.

Symptoms may develop as soon as 1 month after treatment or up to more than 10 years after treatment.^[26] Patients presenting with BCNU-induced pulmonary toxicity typically have nonproductive cough and dyspnea associated with reticular nodular interstitial infiltrates on their chest radiographs.^[27] PFT results demonstrate reduced forced vital capacity (FVC), total lung capacity (TLC), and DLCO values. The reduced DLCO value can occur in patients with normal chest radiographs.

Treatment of BCNU-induced pulmonary toxicity is corticosteroids.^[28] Patients presenting early with acute pulmonary toxicity due to BCNU are more responsive to corticosteroid therapy and have a better prognosis. In contrast, late toxicity is characterized by pulmonary fibrosis and a poor therapeutic response. A long-term complication with BCNU toxicity is the development of upper lobe fibrosis

Cyclophosphamide

The rate of cyclophosphamide-induced pulmonary toxicity is generally less than 1%. Cyclophosphamide is an alkylating agent used in the treatment of various forms of leukemias and lymphomas and as a conditioning agent prior to bone marrow or stem cell transplantation.

Risk factors for cyclophosphamide lung toxicity include concomitant radiation therapy, use of other cytotoxic agents known to be associated with lung toxicity (eg, bleomycin), and exposure to high oxygen concentrations.

The 2 distinct clinical patterns of pulmonary toxicity associated with cyclophosphamide are (1) an acute pneumonitis that occurs early in the course of treatment and (2) a chronic, progressive, fibrotic process that may occur after prolonged therapy. If diagnosed early, the acute form of cyclophosphamide pulmonary toxicity is largely reversible upon removal of the drug and institution of corticosteroid therapy. Chronic cyclophosphamide pneumonitis takes the form of progressive pulmonary fibrosis with respiratory failure and, sometimes, digital clubbing. Chronic cyclophosphamide pneumonitis is typically irreversible, even with drug withdrawal and the institution of corticosteroid therapy.^[29]

Bilateral reticular or nodular diffuse opacities are the hallmark of both early- and late-onset pulmonary toxicity. In the case of early-onset pneumonitis, CT scanning of the chest reveals ground-glass opacities predominantly in the periphery of the upper lungs. The radiographic opacities of late-onset pneumonitis have a more fibrotic appearance on CT scans, involving mostly mid and upper lung regions. Pneumothorax may develop late in the course of the disease. Patients with cyclophosphamide pulmonary toxicity typically display a restrictive pattern with a reduced diffusing capacity on PFT results.

Importantly, rule out infection, particularly Pneumocystis jiroveci pneumonia, when evaluating a patient for cyclophosphamide-induced pulmonary toxicity. Infections can coexist in persons with cyclophosphamide pneumonitis. In general, treatment of cyclophosphamide-induced pulmonary toxicity is largely supportive, but lung transplantation may be considered.

Busulfan

The rate of busulfan lung toxicity is approximately 5%. Busulfan is an alkylating agent used to treat myeloproliferative disorders. Currently, this drug is almost exclusively administered as part of preparative regimens prior to stem cell transplantation.

Risk factors for toxicity are synergistic pulmonary damage when exposed to oxygen, radiation, or other cytotoxic chemotherapeutic drugs. The time of onset of busulfan lung toxicity is from a few months to 10 years. Patients with busulfan-induced pulmonary injury commonly report cough, progressive dyspnea with exertion, fever, weight loss, and brownish pigmentation of the skin.

Chest radiographs may be normal or may reveal bibasilar reticular opacities. Busulfan toxicity can cause a radiological pattern similar to that of alveolar proteinosis.^[30] PFT results show a restrictive ventilatory defect and a reduced DLCO.

Treatment is withdrawal of the drug and corticosteroid therapy. Anecdotal reports describe responses to corticosteroids, but no controlled studies are available. The prognosis, in general, is poor, with a mortality rate from 50-80%.

Methotrexate

The incidence of MTX pulmonary toxicity varies from 0.3-12%. MTX is an antifolate that is part of several antineoplastic chemotherapy regimens.

Risk factors for MTX-induced lung toxicity include age older than 60 years, rheumatoid pleuropulmonary involvement, previous use of disease-modifying antirheumatic drugs, hypoalbuminemia (either before or during therapy), diabetes mellitus, daily rather than weekly drug administration, preexisting lung disease, abnormal PFT results prior to therapy, and decreased elimination of MTX (eg, renal failure).

In contrast to many other cytotoxic agents, MTX often results in reversible abnormalities. Symptoms usually develop within weeks of the onset of treatment and include fever, dyspnea, persistent nonproductive cough, and/or rash. Patients may also have fatigue and weight loss. Then, typically, the disease accelerates, producing a brisk development of infiltrative lung disease, resulting in respiratory failure. Severe hypoxemia is consistently present. Mild peripheral eosinophilia is present in 40% of patients.

Nonspecific interstitial pneumonia (NSIP) is the most common manifestation of MTX-induced lung disease. Other histopathologic patterns include BOOP, NCPE, and non-Hodgkin (B-cell) lymphoma. Interestingly the non-Hodgkin lymphoma usually regresses after cessation of MTX therapy.

Chest radiographs reveal ill-defined reticular opacities, ground-glass opacity, or consolidation.^[31] A basal prominence is typical. High-resolution CT scanning may show ground-glass changes as prominent abnormalities.

PFTs in patients who can tolerate the procedure reveal restrictive ventilatory defects with a low diffusing capacity. Hypoxemia may be present on arterial blood gas (ABG) analysis. BAL may be helpful for excluding an infectious etiology such as P jiroveci pneumonia^[32] and in supporting the diagnosis of MTX pneumonitis. Lymphocytic predominance with an increase in the number of helper T lymphocytes and the helper/suppressor T-cell ratio is observed in the BAL fluid of patients with MTX pneumonitis.^{[33, 34]}

The diagnosis of MTX-induced lung toxicity must be made on the basis of the clinical setting, clinical manifestations, radiographic abnormalities, and BAL results. Occasionally, lung histopathology is necessary. The diagnostic criteria proposed by Searles and McKendry^[35] for MTX-induced toxicity consist of major and minor criteria, as follows:

• Major criteria

  • Hypersensitivity pneumonitis based on histopathology, without evidence of pathogenic organisms
  • Radiologic evidence of pulmonary interstitial or alveolar infiltrates
  • Blood cultures (if febrile) and initial sputum cultures (if sputum is produced) that are negative for pathogenic organisms
• Minor criteria

  • Nonproductive cough
  • Shortness of breath for less than 8 weeks
  • Oxygen saturation less than or equal 90% on room air at the time of initial evaluation
  • DLCO less than or equal to 70% of predicted for age
  • Leukocyte count less than or equal 15,000 cells/µL

Definitive diagnosis of MTX pneumonitis can be made if the patient has 1 or 2 major criteria in conjunction with 3 of the 5 minor criteria.

The management of MTX pneumonitis includes drug discontinuation. If symptoms and radiographic findings persist despite discontinuation of the drug, corticosteroid therapy is recommended. However, no prospective, randomized, placebo-controlled trials have been performed to support the use of corticosteroids in MTX pulmonary toxicity. Of the affected patients, 85% fully recover. Fibrosis of the lungs after MTX pneumonitis is unusual. The overall mortality rate is 15%. Death is caused by rapidly progressive respiratory failure.

Cardiovascular drugs

Amiodarone

The incidence of amiodarone-induced lung disease is approximately 5-7%. Amiodarone is an antiarrhythmic agent used in the treatment of many types of tachyarrhythmia.

Although no definitive correlation exists between the development of drug toxicity and the duration of therapy or the total accumulative dose, the risk for amiodarone-induced lung disease may be increased if the daily maintenance dose is greater than 400 mg and the patient is elderly or if the duration of therapy exceeds 2 months. Recognized risk factors include preexisting lung disease and a history of thoracic or nonthoracic surgery or pulmonary angiography.

Patients who have developed amiodarone-induced lung toxicity usually present with nonspecific symptoms such as cough, dyspnea, fever, and weight loss. These symptoms may be mistaken for, or obscured by, symptoms of overt cardiac failure in a patient who is critically ill.

Radiologically, amiodarone toxicity can manifest as a focal lesion or similar to diffuse interstitial lung disease. Less commonly, ill-defined nodules or masses that occasionally cavitate can be present.^{[36, 37]}

Bronchoscopy with BAL and biopsy helps exclude infection and typically reveals the presence of foamy macrophages with lamellar inclusions (visualized by electron microscopy). These changes within macrophages are indicative of exposure to amiodarone but do not prove that the drug is the cause of the pulmonary process. Similar changes are seen in asymptomatic persons who are receiving the drug.

Amiodarone pulmonary toxicity is a diagnosis of exclusion. Increased lung attenuation on CT scans, increased gallium uptake, and abnormal PFT results are helpful in the diagnosis but are nonspecific. The combination of high-attenuation abnormalities within the lungs, liver, or spleen is characteristic of amiodarone toxicity. A positive gallium scan result is seen in almost all patients with amiodarone pneumonitis and can help differentiate it from pulmonary embolism and congestive heart failure.

Withdrawal of the drug is the cornerstone of treatment for amiodarone-induced lung disease. Glucocorticoids seem to be useful in more severe or persistent cases. Because of its long elimination half-life (approximately 45 d), pulmonary toxicity may initially progress despite drug discontinuation and may recur upon steroid withdrawal. Radiographic resolution generally occurs over 2 months.

Patients taking amiodarone can develop postoperative ARDS, which begins 18-72 hours after surgery.^[38] A high fraction of inspired oxygen given during the operation and the postoperative period has been postulated to contribute to this complication.^{[39, 40]}

ACE inhibitors

Up to 20% of patients develop a dry cough after taking ACE inhibitors. The exact mechanism of ACE inhibitor cough is unknown, but it is thought to be linked to the accumulation of substances normally metabolized by ACE. These substances include bradykinin or tachykinins (with the consequent stimulation of vagal afferent nerve fibers) and substance P.^{[41, 42, 43, 44, 45]} Patients with ACE inhibitor–induced cough usually have resolution within 1-4 days, but it may take weeks to months. Patients can be switched to an angiotensin receptor blocker, which rarely induces cough. Sulindac has been reported to be of benefit in the management of ACE inhibitor–induced cough. Studies^{[46, 47]} have also suggested that intermediate doses of aspirin (500 mg/d), but not low doses (100 mg/d), can suppress ACE inhibitor cough.^[48]

Although ACE inhibitors are generally safe in most patients with obstructive airways disease, case reports suggest that in a subpopulation of patients, these agents can increase bronchial reactivity, asthma symptoms, or exacerbations.

Another symptom of ACE therapy is angioneurotic edema (0.68% of patients).^[49] It manifests as swelling of the tongue, lips, and mucous membranes within hours or weeks after initiating treatment and can rapidly evolve into respiratory distress. This complication can be treated with a subcutaneous injection of epinephrine every 15-20 minutes, diphenhydramine, and steroid therapy.

Beta-blockers

Beta-blockers can precipitate bronchospasm in patients with asthma or chronic obstructive pulmonary disease (COPD).^[50] The benefits of using beta-blockers, like any other drug, must be weighed on a case-by-case basis against the risk of adverse effects.

In patients with stable COPD or asthma, beta-blockers can be started at low doses, with careful monitoring for adverse effects. Because of its cardioselectivity, atenolol is the drug of choice for an individual with obstructive airways disease who needs a beta-adrenergic antagonist.

Esmolol is the drug of choice in critically ill patients with asthma or COPD who require a beta-blocker (unstable angina), owing to its beta1 selectivity and extremely short life (9 min).

Importantly, ophthalmic beta-blockers, such as timolol, which are used in the treatment of glaucoma, have produced a number of deaths secondary to exacerbation of COPD and asthma.^[51] Betaxolol may be a safer alternative to timolol.

Anti-inflammatory drugs

Aspirin

Aspirin-induced asthma (AIA) occurs in less than 1% of healthy individuals and up to 20% of asthmatic individuals. The pathogenesis of AIA is mediated by the production of potent inflammatory and bronchoconstrictor leukotriene mediators such as LTC4, LTD4, and LTE4 via activation of the 5-lipoxygenase pathway.

In addition to wheezing, reactions are usually accompanied by nasal and ocular symptoms, including congestion, rhinorrhea, and tearing. Facial flushing, angioedema, and gastrointestinal symptoms can also occur. The treatment of AIA is steroid therapy and discontinuation of aspirin and NSAIDs. The Samter triad is asthma, nasal polyps, and aspirin sensitivity.

Of elderly patients on long-term aspirin therapy, 10-15% develop NCPE. It usually occurs when the serum salicylate level is greater than 40 mg/dL. Treatment is usually supportive, but some patients require hemodialysis. Long-term salicylate ingestion can manifest as pseudoseptic syndrome (fever, tachycardia, elevated white blood cell count, hypotension, ARDS, and altered mental status). Elevated salicylate levels are helpful in diagnosing this condition.

Gold

Gold-induced drug toxicity is uncommon, occurring in 1% of patients. Toxicity occurs within 2–6 months after therapy is started and is associated with mucocutaneous lesions in 30% of patients. DAD and NSIP are the most common manifestations of gold-induced lung disease. Importantly, note that pleural effusion is not associated with gold toxicity.

Gold therapy can result in pulmonary toxicity as well as other organs, such as the skin (dermatitis), the nerves (peripheral neuropathy), and the kidneys (proteinuria). Treatment of gold toxicity is withdrawal of the drug and, in severe cases, steroid therapy. The prognosis is good. Most patients improve after discontinuation of the gold therapy.

Penicillamine

Penicillamine is an anti-inflammatory agent mostly used in the treatment of rheumatoid arthritis. It can cause bronchiolitis obliterans, penicillamine-induced systemic lupus erythematosus, pulmonary-renal syndrome, and pneumonitis. Management includes withdrawal of the drug, supportive therapy, and consideration of a trial of corticosteroids. In general, the prognosis is poor.

Antimicrobial drugs

Nitrofurantoin

Nitrofurantoin, an antibacterial agent used primarily for the treatment of urinary tract infections, is one of the most common causes of drug-induced lung disease. Both acute and chronic pulmonary toxicity can occur, but the acute syndrome is much more common.

The mechanism of the acute nitrofurantoin reaction is unknown and is not dose dependent. The acute pleuropulmonary reaction begins 2-10 days after the initial drug exposure and is manifested by dyspnea and cough. Fever is present in most cases. Pleurisy occurs in one third of patients. The chest radiograph shows a pattern of basilar alveolar or interstitial infiltrates,^[52] sometimes accompanied by a pleural effusion. Peripheral blood eosinophilia and elevation in the sedimentation rate are seen in one third and nearly one half of the patients, respectively. The prognosis is good, with most patients recovering in 1-4 days after discontinuation of nitrofurantoin therapy.

Chronic toxicity is far less common than the acute reaction and is not associated with systemic symptoms. Chronic pulmonary toxicity typically manifests clinically with an insidious onset dyspnea and cough. Clinically and radiographically, it is indistinguishable from idiopathic pulmonary fibrosis and typically causes no pleural effusion. PFT results demonstrate a restrictive ventilatory defect. If no improvement is noted within 2-3 months after withdrawal of the drug, corticosteroid therapy is indicated.

Sulfasalazine

Sulfasalazine is an antimicrobial drug used for the treatment of inflammatory bowel disease. It can cause eosinophilic pneumonia, desquamative interstitial pneumonitis, NCPE, drug-induced lupus syndrome, and vasculitis, usually after 1-8 months of therapy. Greater than 50% of patients have peripheral eosinophilia. Management includes removal of the drug, and, if necessary, corticosteroids can be added to the treatment regimen.

Illicit drugs

Cocaine

Cocaine is one of the most frequently used illicit drugs in the United States. Smoking cocaine is associated with acute exacerbations of asthma, bronchiolitis obliterans, cardiogenic pulmonary edema, NCPE, interstitial pneumonitis, pulmonary vascular hypertension, pulmonary hemorrhage, talcosis, thermal injury to the airway, pneumothorax, and significant impairment of the diffusing capacity of the lungs. Inhalation of cocaine may result in pneumomediastinum and pneumothorax.^{[53, 54]}

Naloxone

Naloxone is primarily used to reverse respiratory depression induced by heroin. Several case reports describe acute NCPE related to naloxone, although the mechanism remains unknown.

Heroin

Heroin can cause acute NCPE, which can occur with the first intravenous use of the drug. The exact mechanism of heroin-induced NCPE is unknown, but a postulated mechanism is the direct toxic effect of heroin on the alveolar capillary membrane, which leads to increased permeability, and effects on the central nervous system. This, in turn, leads to a hypoxic effect on the alveolar capillary membrane, resulting in increased capillary permeability.

Other complications of heroin use are septic emboli from infected thrombophlebitis or endocarditis and aspiration pneumonia. In persons with long-term heroin abuse, bronchiectasis and narcotizing bronchitis can be observed because of repeated aspiration pneumonia. Treatment is supportive. Naloxone can be used to reverse respiratory depression.

Miscellaneous drugs

Talc

Talcosis is the development of a foreign body granulomatous reaction and is also termed intravenous drug abuser’s lung. It results from intravenous injection of oral preparations containing particulates of talc. Talc can cause granulomatous pulmonary artery occlusion or granulomatous interstitial fibrosis. Patients present with dyspnea, syncope, or signs of right-sided heart failure.

Chest radiographs may be normal in approximately 50% of cases. Chest radiographs can demonstrate diffuse micronodular densities mimicking alveolar microlithiasis. Talc can also cause nodular lesions in the upper lobes, resembling progressive massive fibrosis or pneumoconiosis.

PFT results may reveal a mixed obstructive and restrictive ventilatory defect with decreased DLCO. Funduscopic examination is helpful by disclosing typical changes of talcosis. Talc emboli can be identified near the macula within the small vessels in 50% of the patients.

Tocolytics

Tocolytics (ie, terbutaline, albuterol, ritodrine) are mainly used in the treatment of premature labor. Tocolytics act on the beta-receptors of the vessels and cause peripheral vasodilation. If tocolytics are discontinued abruptly, the vasodilated vessels return to their normal vascular tone and promote large increases in intravascular volume, which causes NCPE.

The risk factors for the development of NCPE include use of corticosteroids, fluid overload, twin gestation, multiparous state, anemia, and silent cardiac disease. Tocolytic-induced NCPE is treated with diuretics and supportive therapy. Corticosteroids are not helpful.