Objectives

The objectives of the present article are as follows:

1. Become familiar with the epidemiology of and etiologic contexts for drug-induced respiratory diseases (DIRDs) and iatrogenic respiratory disease.
2. Examine the risk factors for DIRD.
3. Outline the different patterns of DIRDs, which are often radiographically and pathologically distinctive.
4. Assess causality in DIRD using established diagnostic criteria, including:
   • Exposure to the drug (this can be difficult to evaluate when the patient has been exposed concomitantly to multiple potentially pneumotoxic drugs and to radiation therapy);
   • The notion of a compatible clinical-radiographic-pathologic picture, according to the literature and sources such as Pneumotox; and
   • Disappearance of symptoms upon withdrawal of the agent (a rechallenge is rarely performed because of risks, but might confirm a drug-induced etiology).
5. Provide guidelines for the practical management of DIRD, including thoughtful drug withdrawal and, in some patients, treatment with corticosteroids.

Familiarity with epidemiology, etiology, and risk factors may help predict the occurrence of DIRD.

Key words

adverse effects; drug-induced lung disease; drug-induced respiratory disease; iatrogenic; lung; pleura; radiation therapy; respiratory disease; respiratory system; toxicity

Abbreviations

APRV = airway pressure release ventilation; FIO₂ = fraction of inspired oxygen; HFV = high-frequency ventilation; I:E = inspiratory to expiratory; NIH = National Institutes of Health; PEEP = positive end-expiratory pressure; PPV = positive pressure mechanical ventilation; PV = pressure volume; TNF-a = tumor necrosis factor a; VILI = ventilator-induced lung injury; VT = tidal volume

ACEI = angiotensin-converting enzyme inhibitor; ANCA = antineutrophil cytoplasmic antibody; CO = carbon monoxide; CSF = colony-stimulating factor; DIRD = drug-induced respiratory disease; NSAID = nonsteroidal anti-inflammatory drug; NSIP = nonspecific interstitial pneumonia; TRALI = transfusion-related lung injury

The term iatrogenic encompasses diseases of the respiratory system resulting from the adverse effects of drugs, substances with therapeutic interest, ionizing radiation, and various medical, surgical, or imaging procedures. Among iatrogenic diseases, those that are induced by drugs and affect lung parenchyma (ie, drug-induced lung diseases) have emerged as the most prevalent. Over the years, a huge amount of literature on iatrogenic and drug-induced respiratory disease (DIRD) has accumulated. This literature includes many review articles.^1-78 Numerous case reports or case series have been gathered in the authors' website, Pneumotox (http://www.pneumotox.com⁶⁵), to which the interested reader is referred. Because of their availability through Pneumotox and other sources,⁷⁶ articles describing cases will not be referenced here. Because of space constraints, pathology pictures will not be displayed, as they are also available from other sources.^37,48,79,80

Although this topic will not be covered here, drugs such as methotrexate, corticosteroids, other immunosuppressive agents, and infliximab can enhance the susceptibility of the host to opportunistic infections. Patients treated with these drugs over the long term can develop bacterial, viral, and mycotic infections, including Pneumocystis carinii.^81,82

Care is taken in this text to provide statements substantiated by scientific evidence or by the literature. While we refrain from conveying any personal views, a few statements are made that are supported by our unpublished personal experience. These statements are marked accordingly.

Common Features of DIRD

Epidemiology

Iatrogenic respiratory disorders account for approximately 7% of all iatrogenic events and are outnumbered by skin and liver reactions. There are six main causes of iatrogenic respiratory diseases: approved drugs (called "drugs" in this article), blood or proteins, dietary compounds, illicit drugs, ionizing radiation, and medical procedures (Table 1).

Here, we shall concentrate on the adverse respiratory effects of approved (as opposed to illicit) drugs. Adverse effects of illicit drugs will be mentioned only where appropriate, and the interested reader is referred to other sources.^54,61,75 Nowadays, history taking should systematically include the use of recreational and illicit drugs and dietary supplements, which have repeatedly been cited as causes of respiratory disease.

About 340 drugs are capable of injuring the lung and ancillaries. A continuously updated list of pneumotoxic drugs recognized as causing lung damage, including those recalled in the past, has been made available on Pneumotox.

Using the number of published articles as a rough estimate of incidence, anticancer agents including methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), amiodarone, and angiotensin-converting enzyme inhibitors (ACEIs) have emerged as the drugs that most frequently cause adverse respiratory reactions. The incidence of DIRD ranges from < 1 per million (see drugs marked with one asterisk in Pneumotox), and up to several percent of the treated population (see drugs marked with four asterisks in Pneumotox). Patients receiving chemotherapy and chemoradiotherapy are at greater risk of developing iatrogenic respiratory disease as a result of the high toxicity of these treatments. For example, in one study, up to 64% of women receiving chemotherapy for breast carcinoma developed signs suggestive of drug-induced pneumonitis,⁸³ an unacceptable toxicity rate. A significant risk of developing DIRD has also been seen in cardiology, rheumatology, and gastroenterology patients, with the use of amiodarone, ACEIs, gold, methotrexate, NSAIDs, and two drugs used for bowel diseases, sulfasalazine and mesalamine. Although the risk is less than in an oncology setting, it does exist in virtually every medical field, including family practice. Thus, proper knowledge and early recognition of DIRD by health professionals is warranted.

Although the oral and parenteral routes of administration are most frequently cited, drugs can induce DIRD via almost any route, including ophthalmic, gynecologic, intravesical, and intrathecal.

Patterns of Involvement

Drugs may adversely affect all constituents of the respiratory system including, in decreasing order of frequency, the lung parenchyma, large or small airways, pleural surfaces, pulmonary circulation, neuromuscular system, and mediastinum. Correspondingly, this results in drug-induced parenchymal lung disease, airway involvement, pleural effusion/thickening, pulmonary hypertension, respiratory failure, or mediastinal changes (Table 2 and Table 3).

Table 2 - Sites of Anatomical Involvement in DIRDs*

Table 3–Clinical-Imaging-Pathologic Patterns of DIRDs*

Some drugs or drug categories tend to induce the same pattern of respiratory involvement in all patients who develop adverse effects. For example, methotrexate induces an acute and distinctive form of hypersensitivity pneumonitis, NSAIDs induce eosinophilic pneumonia or acute bronchospasm, and ergot drugs induce pleural thickening and effusion. In such situations, chances are that the patient will develop a similar adverse event if exposed to another drug of the same therapeutic class, a phenomenon known as cross-reactivity. Caution should be exercised accordingly.

Other drugs, in contrast, can induce variegated clinical-pathologic patterns of respiratory disease. For example, amiodarone or bleomycin can cause subclinical involvement (in the form of asymptomatic shadows on chest imaging or a diminution of carbon monoxide [CO] transfer on pulmonary function tests), symptomatic pulmonary infiltrates with or without eosinophilia, organizing pneumonia, multiple shaggy lung nodules, ARDS, or irreversible pulmonary fibrosis. Pneumotox is also organized to indicate what pattern(s) may result from exposure to a given drug.⁶⁵

Follow-up Screening

The development of DIRD is difficult to predict. Indeed, most studies that have addressed that subject failed to demonstrate a significant benefit from systematic clinical, imaging, or functional follow-up of patients exposed to drugs, even when drugs that commonly cause adverse respiratory effects were studied (eg, amiodarone, bleomycin).⁸⁴ Patients treated with such drugs should, however, be instructed to report respiratory symptoms promptly, with the hope that earlier diagnosis will translate into better prognosis.

Although there are no data on the cost-effectiveness, a chest radiograph is often obtained systematically in patients undergoing a 3-weekly or monthly chemotherapy regimen, looking for pulmonary infiltrates.

Also, it seems advisable to measure pulmonary function at the beginning of treatment with potentially harmful drugs, for the purpose of future comparison.

Risk Factors

Only a few risk factors for the development of DIRD have been identified.

Drug dosage. Only a few drugs, such as amiodarone or nitrosoureas, and radiation therapy have demonstrated dose-related toxicity. Knowing the threshold dose above which significant toxicity develops may help the clinician identify patients at risk.⁸⁵ The reputation of amiodarone and bleomycin as causing dose-related toxicity has recently been challenged, in view of cases of definite toxicity following exposure to low dosages of these drugs.⁸⁶

Combinations of therapeutic regimens. Simultaneous or delayed combinations of several chemotherapeutic agents, or of chemotherapeutic agents with elevated inspired concentrations of O₂, radiation therapy (chest or total body), or colony-stimulating factors (CSFs) may prove more toxic than any of the therapeutic modalities considered separately. Doses of chemotherapeutic agents or radiation therapy considered to be safe may unexpectedly elicit a severe pulmonary reaction. On the other hand, chemotherapeutic agents given months after radiation therapy may elicit severe skin and lung damage within the previously irradiated volume, a phenomenon known as recall pneumonitis/dermatitis.⁸⁷ Accordingly, doses of radiation and/or chemotherapy may need to be tailored down preventively.

Rapid infusion. Rapid infusion, as suggested with the use of bleomycin, may be a risk factor for DIRD.

Renal failure. Renal failure increases the toxicity of bleomycin.

Chronic intake of b-blocking agents in the asthmatic. If a delayed anaphylactic reaction to food, other drugs, insect sting, or radiographic contrast media develops in an asthma patient receiving b-blockers over a long term, chances are that management of the accident will be complex. Indeed, the pharmacologic response to b-agonists used to treat the anaphylactic reaction is likely to be dampened or abolished by prior exposure to the b-blocker. It is therefore good clinical practice to avoid b-blockers in patients with a history of atopy, asthma, or anaphylaxis. Studies indicate that this simple measure is not consistently implemented.⁸⁸

Timing

Temporally, DIRD can develop within minutes after the first exposure to the drug (for instance in drug-induced bronchospasm or anaphylaxis, or in hydrochlorothiazide-induced pulmonary edema), or after many years of taking the drug (eg, as in amiodarone pneumonitis, chemotherapy lung, drug-induced systemic lupus erythematosus, or ergot-induced pleural thickening). Generally, however, DIRD will develop after at least a few weeks or months of treatment with the drug. In rare instances, DIRD develops after termination of treatment, and the time from end of treatment to onset of the iatrogenic respiratory diseases may range from a few weeks (eg, amiodarone) to several years (eg, chemotherapy regimens or radiation therapy).⁸⁹ Sometimes the apparent onset of DIRD is noted at adolescence, possibly because of increased respiratory needs in that period of life.

Signs and Symptoms

Clinical signs and symptoms common to most DIRD (Table 2 and Table 3) include dyspnea, which may be wheezy in drug-induced bronchospasm or laryngeal edema, a dry cough, and sometimes elevated fevers. Chest pain and hemoptysis are unusual features. Acute drug-induced adverse events (eg, catastrophic bronchospasm, acute interstitial pneumonia, acute pulmonary edema, ARDS) are associated with prominent respiratory symptoms, and are more likely to lead to acute respiratory failure.

The severity of drug-induced respiratory disease is variable, and ranges from asymptomatic decrements in pulmonary function, minor shadows on imaging, or derangement of BAL cell populations, to a picture of "white lungs" with severe respiratory failure. Severity is inherent for certain drugs (eg, methotrexate, chemotherapeutic agents, amiodarone) or clinical patterns (eg, drug-induced bronchospasm, acute interstitial pneumonia, edema, or ARDS). Other factors governing severity include continuation of the drug while symptoms are developing (authors' personal experience), inadvertent rechallenge with the drug or a congener, and deleterious association of mutually potentiating drugs, such as chemotherapeutic agents with oxygen, radiation therapy, or CSFs, as mentioned above.

Extrapulmonary symptoms may occasionally be noted in the course of DIRD. These include a cutaneous rash, which has been described in association with methotrexate pneumonitis, and disturbances in liver chemistry, which are thought to reflect concomitant drug-induced liver toxicity. In rare instances, systemic disease is present in association with the lung involvement, and the drug-induced adverse reaction can mimic systemic syndromes. Systemic angiitis resembling Wegener's granulomatosis may be seen after the use of propylthiouracil.⁹⁰ Churg-Strauss syndrome may be seen after treatment with antileukotrienes. Polymyositis may occur with the use of statins. Systemic lupus erythematosus may develop with the use of b-blockers or hydralazine, among many other drugs. The drug-induced rash and eosinophilia systemic syndrome, or DRESS, is the combination of cutaneous, hepatic, cardiac, neurologic, abdominal, hematologic, lymphatic, and pulmonary manifestations, in the context of obtundation and constitutional symptoms.⁹¹

These drug-induced systemic diseases are of great interest to the pulmonologist and internist, as they may closely mimic the idiopathic variant of these syndromes, and because withdrawal of the causative drug will often be quickly curative.

Diagnostic Modalities

Beyond nonspecific increases in erythrocyte sedimentation rate, few changes in blood chemistry are of diagnostic significance in DIRD. Blood eosinophilia is found in many patients with pulmonary infiltrates and eosinophilia, but not in all. A positive test for antinuclear and antihistone antibodies is a characteristic finding in the drug-induced lupus syndrome, but anti-DNA antibodies are typically absent. Circulating antineutrophil cytoplasmic antibodies (ANCAs) with a perinuclear staining pattern can be found in patients with propylthiouracil-induced angiitis, but ANCAs can also be found in nontoxic patients taking the drug. The possible diagnostic contribution of lymphocyte proliferation or migration tests in establishing the diagnosis of DIRD remains unclear.

Abnormalities in pulmonary function are those usually found in the corresponding clinical-pathologic pattern, with restrictive lung function defect, impaired CO transfer, and hypoxemia as the most common findings. Obstruction to airflow is typically found in patients with drug-induced small airways disease, or as the nonspecific result of prior smoking.

BAL is a useful adjunct to the diagnosis of drug-induced parenchymal lung diseases because it will reasonably rule out an infection and will often show changes in cell populations suggestive of the drug-induced etiology. These changes will be discussed below under specific headings.

Diagnostic Criteria

Five criteria are needed for establishing the diagnosis of DIRD: (1) Definite exposure to the drug must be identified. (2) Clinical, imaging, and pathologic patterns should fit earlier observations with the drug. (3) Other causes for the lung disease should carefully be ruled out. (4) Lasting improvement should follow cessation of exposure to the drug. (5) Symptoms should recur if the patient is rechallenged with the drug.

Definite Exposure

There should be, or have been, definite exposure to the drug. In this regard, careful history taking is essential, and may save time and unnecessary investigations. Recognized pitfalls in that area include the following:

• Patients may omit mentioning drugs that are available over the counter or considered to be minor.
• It is also difficult for the patient, and occasionally the physician, to admit that drugs taken for many years may unexpectedly induce respiratory problems.
• Chemotherapeutic agents and radiation therapy can induce slowly progressive lung disease, which can be diagnosed long after exposure has ceased.
• History taking may be difficult in regard to exposure to illicit drugs. This requires the interviewing physician to have special knowledge and skills.
• The patient may be obtunded or comatose. Asking the referring physician, family, social worker, or pharmacist is essential.

Examples of drugs that may easily be overlooked when taking the patient's exposure history include illicit/recreational compounds, laxatives containing mineral oil, aspirin, hydrochlorothiazide, and nitrofurantoin.

Of note, long-term use of steroids (eg, in rheumatoid arthritis or oncology patients) does not prevent drug-induced lung disease from developing.

Clinical, Imaging, and Pathologic Patterns

The clinical, imaging, and pathologic patterns should fit earlier observations with the drug.

Clinical. Pneumotox provides a list of patterns of respiratory disease associated with drugs (see also Table 2, Table 3, and Table 4).

Imaging. The imaging pattern is rarely specific for the drug etiology^77,92 except in a few instances, which will be mentioned below.

Pathology. Examination of lung tissue may support, and more rarely confirm, the drug etiology.⁴⁸ Suggestive changes include the pathologic appearances of amiodarone pneumonitis, lipoid pneumonia, nitrofurantoin-induced desquamative interstitial pneumonia, and bleomycin-induced lung nodules. In most other instances, pathologic examination shows a pattern of nonspecific interstitial pneumonia (NSIP), eosinophilic pneumonia, organizing pneumonia, or pulmonary fibrosis, all of which have many causes other than drugs. Despite the frequent lack of specificity of pathologic changes in lung tissue, a lung biopsy (now preferably video-assisted) may be required to rule out alternate diagnoses, such as infection or cancer.

Table 4–Respiratory Complications Induced by Procedures and Nonpharmaceutical Agents

Rule Out Other Causes

Causes for the lung diseases other than exposure to the drug should carefully be ruled out. Most patterns of DIRD resemble patterns that are attributed to other causes or occur idiopathically. Thus, inhalational, infectious, and hemodynamic causes (ie, left ventricular dysfunction) should be discussed in addition to the possibility of pulmonary involvement from the underlying illness for which the suspect drug was given (eg, connective tissue diseases, inflammatory bowel disease, cancer or lymphoma). Careful analysis of imaging studies, BAL fluid, and pathology data is essential. Echocardiography and a diuresis test are frequently advised to narrow down the diagnostic possibilities.

Improvement After Drug Cessation

Durable improvement should follow cessation of exposure to the drug. Caution should be exercised when withdrawal of a critically needed drug is considered. Unwary withdrawal of such drugs as amiodarone, antineoplastic agents, methotrexate, or bowel-disease-modifying drugs in patients with ventricular dysrhythmias, hematologic or solid tumors, rheumatoid arthritis, or ulcerative colitis, respectively, may have devastating consequences. Difficult-to-control and even life-threatening recurrences of the underlying condition may follow, and it is advisable to ask the physician who originally prescribed the drug for clearance to withdraw it.

When the causative drug is easily identified on the basis of a consistent clinical picture and the absence of other pneumotoxic drugs, cessation of the drug is rapidly followed by improvement of respiratory symptoms, especially in patients with recent drug-induced events of mild to moderate severity (eg, mild bronchospasm, interstitial lung disease, or pulmonary edema). In that situation, and provided the disease does not significantly affect lung function, steroids may be postponed or avoided, enabling a straightforward evaluation of the effects of drug cessation.

In patients with acute to hyperacute adverse reactions (eg, catastrophic bronchospasm, methotrexate lung, acute eosinophilic pneumonia, ARDS), the time course of the ongoing adverse event will often seem little or not at all influenced by drug cessation (authors' personal experience). Because of the impending risk of respiratory failure, steroid treatment is often advised in such patients (Table 5), at the expense, however, of satisfactory analysis of the effects of drug cessation.

After cessation of exposure to the drug, it may take several weeks, and sometimes months, to detect a consistent improvement in patients with chronic drug-induced reactions (eg, chronic nitrofurantoin lung, amiodarone pneumonitis, ergot-induced pleural fibrosis).

Finally, there is usually no detectable improvement following drug withdrawal in patients with drug-induced fibrotic disorders, such as interstitial pulmonary fibrosis, bronchiolitis obliterans, or pulmonary hypertension. Some patients will even deteriorate despite cessation of exposure to the drug or the addition of steroids (Table 5). This may result in chronic respiratory failure and death unless transplantation is possible.

Drug cessation is complex in patients with several possible causative agents, in whom withdrawal of all drugs may have an adverse impact on the underlying disease.

Table 5 - Empirical Guidelines for the Use of Steroids in DIRDs*

Rechallenge

Symptoms should recur if the patient is rechallenged with the drug. While there are case histories of positive and harmless rechallenge in patients with drug-induced pulmonary eosinophilia, and in a few patients with methotrexate pneumonitis. However, a publication bias may also be considered; perilous rechallenge histories may not have reached the stage of publication.

Several issues complicate the use of rechallenge: (1) Doses to be used in rechallenge tests (incremental doses, full therapeutic doses?) have not yet been delineated. (2) Tools to monitor recurrence (imaging, pulmonary function tests, BAL?) and criteria for a positive rechallenge remain unclear. Parenthetically, some of these investigational tools are not devoid of risks. (3) Duration of reexposure to the drug before a rechallenge is considered negative remains unknown, as time to recurrence may be several weeks. (4) The risks of rechallenge are significant. For example, although some believe that methotrexate can be reintroduced without undue risks after an episode of methotrexate pneumonitis, careful analysis of the literature has shown that fatalities have occurred after reexposure to that drug.⁹³ (5) Finally, in drug-induced pulmonary fibrotic reactions such as pulmonary fibrosis, bronchiolitis obliterans, pulmonary hypertension, or pleural fibrosis, short-term rechallenge may seem negative because the lesions are already at end stage or because too much time may be required for further damage to develop. Because the pulmonary changes in those conditions are largely irreversible, rechallenge is deemed unethical.

Taken together, these issues do not support rechallenge as a diagnostic tool in infiltrative lung disease and even more so in presumed drug-induced bronchospasm.

However, rechallenge may be discussed and implemented, if three conditions are fulfilled: (1) The drug is the only therapeutic choice, and it is essential to the management of the patient. (2) Doubt remains about the causative role of the drug. (3) No mortality has been recorded in patients rechallenged with the drug (a literature survey, asking drug monitoring systems, including that of the manufacturer, and contacting Pneumotox are warranted).

If these conditions are fulfilled, then small increasing doses of the drug may be given under strict medical supervision, and if no symptom has developed after some days, the patient may be discharged with proper instructions to report any warning sign, no matter how slight.

In patients in whom several drugs may have caused the lung disease, indirect rechallenge may be performed (authors' personal experience) as follows: drugs are sequentially readministered, starting with the drug least likely to have caused the syndrome, according to context, literature, and Pneumotox, while, ultimately, the most likely causative drug is not reintroduced. Here, too, reintroduction should be performed under close medical supervision so that any recurrence is detected in time.

Desensitization is a therapeutically oriented form of rechallenge.⁶⁹ In aspirin-, NSAID-, or sulfa-sensitive individuals (who happen to need these drugs for the treatment of underlying inflammatory or rheumatic conditions, for instance), a minute dose of the drug is given under close monitoring, and the amount of drug is progressively increased in a stepwise fashion every day, until the full therapeutic dose is reached. If no adverse effect has occurred, the patient is thought to have acquired tolerance to the drug. This state will remain as long as the drug is taken daily at therapeutic doses, with no interruption. A few days of not taking the drug would rapidly restore the state of intolerance, with the same adverse consequences if the drug were readministered later.

Clinical–Pathologic Patterns of Drug-Induced Respiratory Diseases

The variegated clinical patterns of DIRD and causative drugs are given in Pneumotox, and corresponding clinical presentations are presented in Table 2 and Table 3. Among the clinical-pathologic patterns of involvement, infiltrative parenchymal lung disease has emerged as the most prevalent one. Two main patterns of infiltrative lung disease (interstitial and alveolar) have been identified, according to the predominant anatomical site of involvement. However, there is some overlap between the two conditions (for instance, in diffuse alveolar damage or ARDS).

Drug-Induced Infiltrative Lung Disease With a Predominantly Interstitial Pattern

Several papers have reviewed drug-induced infiltrative lung disease with a predominantly interstitial pattern.^49,55-59,93 Radiographic and CT appearances of this variant are shown in Figure 1 and Figure 2.

Figure 1. Mild, diffuse drug-induced infiltrative lung disease in a young woman receiving chronic methotrexate therapy for molar pregnancy. The pattern is hazy and micronodular. The drug was taken as a single agent, which eases the diagnostic process. BAL should be performed to rule out an infection and the drug should be withdrawn, if possible. Diffuse infiltrative lung disease is caused by > 80 different drugs. Frequently, methotrexate lung may quickly evolve to acute respiratory failure requiring mechanical ventilation.

Figure 2. CT scan appearance of mild drug-induced pneumonitis, in this case caused by nilutamide. The CT pattern may closely resemble that of hypersensitivity pneumonitis caused by inhaled antigens.

Classic drug-induced pneumonitis. Classic drug-induced pneumonitis (formerly called hypersensitivity pneumonitis or alveolitis) is typically caused by chrysotherapy, methotrexate, nilutamide, and nitrofurantoin, among about 80 other causative drugs. Amiodarone causes a distinctive pattern of pneumonitis that will be discussed in a specific section below. Classic drug-induced pneumonitis usually develops after medium- to long-term exposure to the drug, usually a few months to a few years, but cases have been reported after only a few days to a few weeks of drug treatment. Clinical onset is progressive over a few weeks, except with methotrexate pneumonitis, which may develop over only a few days. Usually, no triggering factor is identified. Symptoms include dyspnea, a dry cough, and fever. A skin rash or mild changes in liver chemistry may be present. Rarely, patients present with multiorgan dysfunction. The disease usually follows a mild course, except with methotrexate pneumonitis, which typically produces acute respiratory failure.

On imaging, pulmonary infiltrates of drug-induced pneumonitis are usually bilateral and roughly symmetrical. A miliary pattern is a distinctly unusual feature. Topographically, the infiltrates may be localized in bases or mid-zones of the lungs, scattered, or diffuse. Localization in the apices is unusual, and should suggest a diagnosis of eosinophilic pneumonia (see below). Chest radiographic density may range from a discrete and barely visible haze to a pattern of diffuse dense bilateral condensation in which air bronchograms can be visualized. Although there is a rough correlation between the chest radiographic density and impact on lung function, some patients are severely hypoxemic even though the chest radiographic abnormalities remain modest. Pleural effusion or mediastinal lymphadenopathy are occasionally seen in the course of methotrexate pneumonitis. On CT examination, lines, ground-glass opacities, a crazy-paving pattern, and alveolar shadows have been described.

A restrictive pattern and hypoxemia of variable intensity are found on pulmonary function tests, with hypoxemia being often particularly profound in methotrexate pneumonitis. Fiberoptic bronchoscopy and BAL are essential to rule out opportunistic infections, especially in patients receiving long-term immunosuppressive therapy. Examination of the BAL fluid typically reveals elevated proportions of lymphocytes. The lymphocyte CD4+/CD8+ ratio is variable, depending on when it is performed with regard to clinical onset and whether the patient has received corticosteroids before.

If the drug-induced etiology cannot be firmly established on the basis of clinical history, pattern of exposure to the drug, imaging, and BAL, a lung biopsy may be required in an attempt to confirm the drug-induced etiology and rule out other diagnoses. Histologic examination shows cellular interstitial pneumonia (now called NSIP), which consists of a dense interstitial infiltrate of mononuclear cells, along with mild to moderate interstitial edema. Interstitial fibrosis is generally inconspicuous. There is some correlation between chest radiographic density or clinical severity, on the one hand, and magnitude of the cellular infiltrate on the other. Alveolar edema may occasionally be found in patients with severe respiratory failure (eg, methotrexate lung). Alveolar hemorrhage, as an associated feature, is a rare finding. Pulmonary granulomas are also rarely found, except following the use of methotrexate, interferons, highly active antiretroviral therapy, or intravesical bacille Calmette-Guérin therapy. A pattern of desquamative interstitial pneumonia can be found in some patients chronically exposed to nitrofurantoin (see below).

Drug withdrawal should be discussed as early as possible under the guidance of the prescribing physician; otherwise, there is the possibility of a flare-up of the underlying illness, which may complicate the management of the drug-induced lung disease. Upon withdrawal, symptoms and pulmonary opacities clear within a few weeks, but it may take longer for pulmonary function to normalize fully. Corticosteroids are generally given to patients with significant respiratory failure, provided an infection has been ruled out (Table 5). Doses and duration of treatment with steroids should be titrated against the clinical, chest radiographic, and functional response (usually, 1 to 3 months is required). The overall prognosis of classic drug-induced pneumonitis is favorable and mortality remains the exception, provided the drug has been withdrawn early. Irreversible pulmonary fibrosis following classic drug-induced pneumonitis is extremely unusual.

Drug-induced pulmonary eosinophilia. Drug-induced pulmonary eosinophilia^50,94 can be caused by several dozen drugs, mainly ACEIs, antibiotics (eg, minocycline), and NSAIDs, to name a few. Occasionally, eosinophilic pneumonia is the result of inhalation of drugs or illicit substances. The diagnosis rests on the combination of pulmonary opacities with eosinophilia in blood or BAL fluid. An elevated proportion of eosinophils may be present in association with eosinophilia in the BAL fluid. Peripheral eosinophilia may be lacking, however, possibly because eosinophils are trapped in tissues, or if steroids have inadvertently been given prior to diagnosis. One single administration of corticosteroids may indeed normalize blood eosinophils, at least temporarily. The clinical picture ranges from asymptomatic pulmonary opacities on the chest radiograph to a pattern of acute respiratory failure with the features of acute eosinophilic pneumonia. Mild constitutional symptoms are frequent, and wheezing may be related to associated eosinophilic bronchitis. In practice, the most common and typical form of eosinophilic pneumonia is the acute eosinophilic lung disease of young persons receiving minocycline for acne vulgaris.⁵⁰

On imaging (Fig 3), the nearly pathognomonic pattern of biapical symmetrical subpleural opacities known as the "photographic negative of pulmonary edema" is inconstant, and opacities may be basilar, focal, scattered, or diffuse. Radiographically, eosinophilic pneumonia may sometimes be difficult to distinguish from organizing pneumonia or the Churg-Strauss syndrome, and the issue may be resolved only through histologic examination. Occasionally, hilar or mediastinal adenopathies are visualized.

Figure 3. Chest radiograph of a patient with eosinophilic pneumonia (in this case, induced by an ACEI). In addition to the classical pattern of biapical, peripheral pulmonary opacities, pulmonary infiltrates may be diffuse or be localized elsewhere in the lungs.

A restrictive or mixed lung function defect is found on pulmonary function testing, with hypoxemia of variable severity.

A lung biopsy is rarely needed in this essentially benign condition, but if needed, histologic study would show an interstitial infiltrate of mononuclear cells and eosinophils. The eosinophilic infiltrate may aggregate around pulmonary arterioles, and occasional foci of organizing pneumonia may be found.

Drug withdrawal may be sufficient in patients with mild eosinophilic pneumonia. Steroids are useful in patients with respiratory failure, provided a parasitic etiology has been ruled out (Table 5).

In the past, a particular brand of the dietary supplement L-tryptophan contained trace amounts of a contaminant and induced the eosinophilia-myalgia syndrome. The syndrome is a distinctive constellation of constitutional symptoms, fever, blood eosinophilia, eosinophilic pneumonia, pulmonary hypertension, scleroderma-like skin changes, and liver, heart, or neurologic dysfunction. Although the drug was recalled, a cohort of patients still suffer from disabling symptoms long after drug withdrawal.

Amiodarone pneumonitis or "amiodarone lung." Amiodarone pneumonitis or "amiodarone lung"⁶⁸ is a common disease of uncertain prognosis that has distinctive clinical, imaging, and pathologic characteristics (Fig 4). Amiodarone is widely and increasingly used to control various forms of ventricular or atrial arrhythmia. Incidence figures for amiodarone pneumonitis range from a few percent in patients taking low-dose amiodarone (< 200 mg/d) up to 40% in patients takign elevated doses (eg, 1,200 mg/d for refractory ventricular arrhythmias). Time to onset of amiodarone pneumonitis averages 2 1/2 years, correlates negatively with daily dosage, and is rarely shorter than a few weeks. Although formerly thought to develop only in patients receiving elevated dosages of the drug, there is no real safe dose below which amiodarone pneumonitis will not develop.⁹⁵

Figure 4. Chest imaging in amiodarone pneumonitis. Pulmonary infiltrates in amiodarone pneumonitis disease are often asymmetrical. Chest radiographic density may range from a discrete haze, especially in patients with a background of emphysema (top), to denser opacities (middle) or ARDS. On CT (bottom), pleural effusion is a common finding, and opacities usually show no segmental distribution.

The onset of amiodarone pneumonitis is usually insidious, with dyspnea, mild fever, weight loss, and crackles on auscultation. Occasionally, onset is rapid (or patients become rapidly aware of their symptoms). Some patients develop the features of acute respiratory failure or ARDS, mainly following coronary or open-heart surgery.^95,96

On imaging,⁹⁷ there are scattered or diffuse bilateral, asymmetrical, interstitial or alveolar infiltrates with no clear-cut segmental or lobar distribution. An associated pleural effusion is common. Other patterns include unilateral lobar or segmental consolidation, rapidly migrating opacities (which usually correspond to the pathologic pattern of organizing pneumonia), diffuse consolidation, or multiple shaggy nodules. With little doubt, some of these patterns are misleading.

On CT,⁹⁸ the opacities may extend across fissures. Air bronchograms may be present within the opacities. Discrete contralateral opacities are frequent in patients with apparently unilateral involvement seen on plain chest radiograph. These areas correspond to diminutive foci of amiodarone pneumonitis, and are a help to diagnosis. A high radiographic density of both the pulmonary opacities and liver parenchyma have been described, and are thought to relate to the iodine in the amiodarone molecule as the drug is accumulated and sequestered in these tissues.

On pulmonary function testing, a restrictive pattern and reduced CO transfer are common, and are often superimposed on a background of airflow obstruction from earlier smoking. There is often severe hypoxemia, which is out of proportion to the chest radiographic abnormalities.

Cellular changes in the BAL fluid are manyfold, with neutrophilia, lymphocytosis, an increase in both cell types, or a normal differential in approximately the same proportion of patients.⁹⁹ Increased lymphocyte counts may point to early-onset amiodarone pneumonitis. The finding of foamy macrophages in the BAL fluid is of little help, as it is also found in nontoxic amiodarone patients.

The diagnosis of amiodarone pneumonitis should be established carefully in order to justify the withdrawal of amiodarone, as this may expose the patient to the risk of arrhythmia recurrence. Other diagnoses to be considered include left ventricular dysfunction and pulmonary edema, and pulmonary embolism or infarction, among others. A trial of forced diuresis with pre- and posttest chest radiograph is a simple and helpful test in this setting. Although there is more severe impairment of pulmonary function in amiodarone pneumonitis than in left ventricular failure, this is not really discriminant in practice.⁶⁷ Ga scan has been reported to be positive in amiodarone pneumonitis cases, and may help in selected cases. The perfusion scan is not helpful, as it may show perfusion defects in amiodarone pneumonitis as well.

In cases in which valve replacement or heart transplantation is planned, the diagnosis of amiodarone pneumonitis must be firmly established or ruled out, and a lung biopsy may be needed. A constellation of histologic findings are suggestive of amiodarone pneumonitis; these include lipid-laden (foam) cells within alveolar spaces, lipidic infiltration of pneumocytes and endothelial cells, a moderate mononuclear cell interstitial infiltrate, interstitial edema, organizing pneumonia, and interstitial fibrosis.⁷⁹

Once the diagnosis of amiodarone pneumonitis is confidently established, amiodarone should be withdrawn, the patient's heart condition permitting. This is followed by slow to very slow resolution of the pulmonary opacities, and although there is no scientific evidence for this, there is an agreement that steroids seem to hasten recovery (Table 5), and may also prevent the development of pulmonary fibrosis, which is not unusual if amiodarone pneumonitis is left untreated for a significant period of time. The duration of treatment with steroids should be at least 6 months to 1 year in order to avoid recurrence linked to the extended retention of amiodarone in lung tissues. Also, steroid tapering should be prudent and gradual; otherwise, difficult-to-control recurrences of the disease may follow. Long-term steroid treatment may be required in patients with amiodarone-induced pulmonary fibrosis. In some patients in whom amiodarone had to be continued because there was no alternate therapeutic choice, the combination of steroids and amiodarone at a reduced dosage has enabled the control of amiodarone pneumonitis.

The outcome of amiodarone pneumonitis is favorable in about three fourths of cases; persistent impairment of lung function, hypoxemia, and decreased CO transfer are common findings. The mortality rate is at least 10 to 15%, with early death resulting from respiratory failure and later deaths from pulmonary fibrosis, recurrence of ventricular arrhythmias, or sudden cardiac events.

Drug-induced organizing pneumonia. Organizing pneumonia (otherwise called bronchiolitis obliterans organizing pneumonia) may be caused by drugs.^100,101 Amiodarone, nitrofurantoin, and breast radiation therapy in women are the most frequent iatrogenic causes of organizing pneumonia, along with 26 other causes. The disease may manifest in the form of pulmonary opacities in a patient with mild constitutional symptoms. Occasionally, patients complain of excruciating chest pain, and acute respiratory failure is possible in extensive forms of the disease.

On chest imaging (Fig 5), the retractile opacities have a lobar or segmental distribution, and sequential imaging typically demonstrates migration of the opacities from base to apex and/or from one side to the other. Intervening periods of normalization of the chest radiographic appearance may occur between episodes of pulmonary opacities, even though the drug is still being taken. Other chest radiographic patterns include fixed lobar consolidation or a mass (eg, with the use of amiodarone), multiple retractile peribronchovascular shadows (eg, with the use of nitrofurantoin), dense subpleural opacities with visible air bronchograms (eg, with the use of mesalamine), multiple shaggy nodules (eg, with the use of amiodarone, bleomycin, or minocycline), or diffuse infiltrates with small lung volumes. There are not enough data yet to indicate a consistent pattern of BAL findings in drug-induced organizing pneumonia.

Figure 5. Chest radiographic (top) and CT scan (bottom) in a patient with drug-induced organizing pneumonia caused by exposure to a statin drug. The most typical pattern of organizing pneumonia on chest imaging is that of multiple, rapidly migratory opacities that commonly show a subpleural distribution, and may occasionate marked chest pain, as in the present case (one of the foci of organizing pneumonia was present anteriorly in the right middle lobe). Other patterns include a mass or diffuse pulmonary involvement with respiratory failure.

Should a biopsy be deemed necessary to confirm the diagnosis, histologic sections of lung tissue will show numerous buds of connective tissue within the distal airspaces, including alveoli. An eosinophilic infiltrate is occasionally seen as an associated feature, and when it is significant, it may raise difficulties concerning the distinction between organizing and eosinophilic pneumonia.

The outcome of drug-induced organizing pneumonia is generally favorable, and withdrawal of the causative agent may suffice to ensure disappearance of the opacities. In patients in whom drug cessation is not sufficient, or in those with amiodarone-induced organizing pneumonia, corticosteroids may be needed to accelerate the clearing of the chest radiograph (Table 5). There may be steroid refractoriness in a small minority of patients with extensive organizing pneumonia complicated by respiratory failure.¹⁰² In some patients in whom the culprit drug was not recognized at the origin of organizing pneumonia and who were given steroids, the opacities were found to recur at elevated dosages of steroids (eg, 40 mg of prednisolone). Only when the causative drug was eventually withdrawn could the patient be weaned from steroids without recurrence of the disease.

An increasing number of patients who have migratory opacities while taking drugs may not undergo a lung biopsy, and are simply observed after drug cessation (authors' personal experience). This form of management was mainly proposed for patients exposed to drugs that may cause migratory pulmonary opacities, such as amiodarone, b-blockers, and statins (authors' personal experience). If drug withdrawal is followed by durable clearing of the pulmonary opacities, then the drug etiology is supported. However, the exact pathologic nature of the opacities (organizing pneumonia? eosinophilic pneumonia?) will remain unknown. Whether this form of "economical management" is superior to or safer than management that includes a lung biopsy is unknown at this time.

Chemotherapy lung. The chemotherapy lung^103-107 is an aggressive form of rapidly fibrosing lung disease that can develop during or after prolonged or multiple cytotoxic chemotherapy regimens (particularly those containing bleomycin, cyclophosphamide, melphalan, mitomycin C, or nitrosoureas) with or without added radiation therapy. It is generally difficult to sort out the exact responsibility of each of the drugs received, or of radiation therapy. Even with the use of the same drug, the chemotherapy lung may develop rapidly or more insidiously. When it develops late or very late after chemotherapy or radiation, it is called the delayed pulmonary toxicity syndrome. Occasionally, the chemotherapy lung is discovered at adolescence in patients who had received chemoradiotherapy in childhood. The chemotherapy lung may develop after intravesical administration of mitomycin C for bladder carcinoma, but this remains unusual. Possible factors that trigger the onset of the chemotherapy lung include infection and administration of elevated concentrations of O₂, CSFs, or radiation therapy to the chest.

On imaging (Fig 6), patients typically present with symmetrical, basilar or diffuse opacities that are interstitial, alveolar, or mixed, along with volume loss. On CT, there is a combination of dense linear interstitial opacities, diffuse haze, and sometimes subpleural thickening. Honeycombing is unusual early in the course of the disease, but may develop in the long term.

Figure 6. Chest imaging in the chemotherapy lung. Top, in mild cases, the picture is that of diffuse infiltrates and volume loss, without honeycombing (due in this case to busulfan). Sensitivity to steroids is common in cases with early involvement. Some patients may develop ARDS early in the course of the disease. Later (bottom), as seen in this patient with mitomycin-induced chemotherapy lung, there is more extensive involvement, possible honeycombing, restrictive lung physiology, and hypoxemia, which is less sensitive to treatment with steroids.

Severe restrictive lung physiology and markedly altered gas exchange are usually noted in pulmonary function test results. Histologic examination reveals interstitial pneumonitis and fibrosis, a sparse mononuclear cell infiltrate, and diffuse alveolar damage in the form of edema, hyaline membranes, and bizarre dysplastic type 2 pneumocytes lining the alveolar lumens. The respective intensity of these changes depends on the causative agent and on the time at which the biopsy is taken with respect to onset of the disease.

The prognosis is variable. Patients with early disease may demonstrate steroid sensitivity,¹⁰³ and will recover fully. At the other end of the spectrum, patients may develop a picture of progressive respiratory failure that is only modestly or transiently influenced by steroids. A few cases have been treated successfully with lung transplantation.

Severe chemotherapy lung is a particularly frustrating clinical picture in an otherwise stabilized cancer patient.

Thoracic complications of radiation therapy. Many changes may be seen in the chest after radiation therapy.¹⁰⁸ The best-known pattern is that of subacute focal pneumonitis, followed by progressive volume loss within the radiation field. On imaging, changes are restricted to the radiation field, and the late changes show sharply demarcated limits (Fig 7, top). Later in the course of the disease, traction bronchiectasis may develop, and colonization by Aspergillus spp is a possibility. Radiation therapy for lung cancer, breast cancer, or lymphoma is the main context for radiation pneumonitis/fibrosis. In rare instances, pulmonary opacities extend outside the radiation field. This corresponds to acute radiation pneumonitis, which may evolve towards ARDS; in such cases, histologic changes are similar to those associated with the chemotherapy lung.^10,108

Figure 7. Radiographic appearances in respiratory disease associated with radiation therapy. The most classical pattern is that of retractile radiation pneumonitis, limited to the irradiated volume (top, the left upper lobe was irradiated for lung cancer in this case).

Patients who have undergone Y-shaped radiation therapy in the remote past for Hodgkin’s disease, may present with fibrosis of the apices, mediastinum, and heart (bottom). Severe cardiorespiratory failure is a common finding.

Patients treated with older techniques for mediastinal lymphoma or Hodgkin's disease may develop fibrosis of the mediastinum, superior sulci of the lung, pleura, and spine. This particular form of lung damage is visible in the form of a Y-shaped fibrosing process in upper lung and mediastinum (Fig 7, bottom). Pericardial thickening and effusion, fibrosis of heart valves or pulmonary veins, and myocardial dysfunction may all be present in association, and may collectively be responsible for severe and debilitating cardiopulmonary failure that is little amenable to any form of treatment.^109,110

Endobronchial brachytherapy for lung tumors may be complicated by necrosis of the bronchial wall and adjacent vascular structures, with massive and fatal hemoptysis as a possible complication.¹¹¹

Breast radiation therapy may prompt the development of organizing pneumonia, which typically manifests in the form of migratory opacities (see under "Drug-induced organizing pneumonia").

Chemotherapy may "recall" damage to the lungs and skin from prior radiation therapy, even though the doses of each agent were within recommended and presumably safe limits.

Intra-arterial administration of radioactive iodine or yttrium for the treatment of thyroid or liver tumors may induce radioactive material to spill over into the systemic circulation, followed by entrapment of the material within the pulmonary arterial bed. Severe lung damage or ARDS may ensue as early complications. Later on, progressive pulmonary fibrosis of mid-lung zones can develop, in the form of distinctive symmetrical masses located at a distance of both the pleural surface and hila.¹¹²

Other patterns of drug-induced infiltrative lung disease. Desquamative interstitial pneumonia is a distinctive histopathologic pattern of drug-induced lung disease that has almost been exclusively linked to chronic exposure to the antiseptic drug nitrofurantoin.¹¹³ On histologic examination, there is extensive and monotonous filling of alveolar spaces by macrophages, with some interstitial fibrosis. The development of progressive pulmonary fibrosis despite drug withdrawal seems a rare, but definite, possibility (authors' personal experience).

Paraffin oil is used as a laxative agent or as a vehicle for nasal decongestants. When taken orally or nasally on a regular basis, the oil may reach the bronchial tree and lung, presumably via physical spreading or microaspiration. This results in "mineral oil," "lipoid," or "lipidic" pneumonia, which manifests as condensation(s) on the chest radiograph. The dependent right lower lobe is classically affected more often than any other area, but case series have shown that the opacities can also localize elsewhere in the lungs.¹¹⁴ On CT, opacities may demonstrate a crazy-paving pattern with mosaic-shaped borders, and the branches of the pulmonary arteries may be spontaneoulsy visible within the area of condensation (spontaneous angiogram). Not surprisingly, opacities have a lipidic density on CT and MRI examination. In addition to careful interview of patient, relatives, and/or caregivers, the diagnosis of lipidic pneumonia can be confirmed by the finding of sputum or BAL-fluid macrophages containing lipid droplets stainable with Sudan black and oil red 0 stain. Further evidence can be obtained, if needed, by performing chromatography on the BAL fluid in parallel with authentic paraffin oil on silica plates. Lipoid pneumonia often has a chronic and debilitating course despite cessation of exposure to the oil, and outcome seems to be influenced little by steroids. Mycobacterial superinfection and the development of lung cancer have been reported as late complications.

Treatment with nitrofurantoin, hydrochlorothiazide, antithymocyte globulin, CSFs, and the newer antineoplastic agents docetaxel, taxotere, and gemcitabine have been associated with transient pulmonary infiltrates.¹¹⁵ Because the opacities are short-lived, may not consistently affect lung function, and are well tolerated, almost no biopsy data are available. Limited evidence obtained in the past indicates that the infiltrates may correspond to transient edema, vasculitis, or interstitial cellular influx. Resumption of the causative drug is discouraged, as it is quickly followed by recurrence of the infiltrates. Whether these infiltrates, if noted during treatment with chemotherapeutic agents, represent an attenuated form of or a prelude to the chemotherapy lung remains unknown at this time. In any event, caution is required if rechallenge is planned after an episode of pulmonary infiltrates.

Pulmonary fibrosis related to treatment with noncytotoxic drugs is a rare event, except with the use of amiodarone. Other noncytotoxic drugs causing pulmonary fibrosis include nitrofurantoin, gold, and sulfasalazine. While the diagnosis of pulmonary fibrosis is generally easy, that of drug-induced pulmonary fibrosis is often elusive, as there is always the possibility of chance association with idiopathic pulmonary fibrosis, a common disease in elderly adults. Normal chest radiograph findings prior to institution of the presumably causative drug and/or sudden onset of symptoms during treatment with the drug may point to the drug etiology, but do not constitute irrefutable proof. In this perspective, a pulmonary work-up before beginning treatment with amiodarone is generally advisable. Onset of the disease is variable, ranging from insidious to rapid or fulminant, with no triggering factor identified in most patients. Dyspnea and a dry cough are the main symptoms. On imaging, there are scattered opacities, with intervening areas of normal lung parenchyma on CT; honeycombing is a late feature. Overall, the clinical, imaging, and pathologic pattern of drug-induced pulmonary fibrosis resembles that of pulmonary fibrosis from other causes, or the chemotherapy lung described above. However, progression of the disease seems less severe than in the chemotherapy lung. On histologic study, there is a combination of fibrosis, sparse mononuclear interstitial infiltrate, interstitial edema, and reactive/dysplastic pneumocytes.⁹⁵ The latter are, however, found less consistently than in the chemo- or radiotherapy lung. When a drug is suspected at the origin of pulmonary fibrosis, cessation of exposure is warranted, if possible. Corticosteroids are beneficial, at least in some patients (Table 5), but the magnitude and duration of the effect of these drugs remain unpredictable. The prognosis is roughly similar to that of pulmonary fibrosis from other causes. However, it is fortunate that some patients seem to stabilize for many years, without apparent progression (authors' personal experience).

DILD With a Predominantly Alveolar Pattern

Drug-induced alveolar reactions often demonstrate alveolar shadows on the chest radiograph, and they may evolve into ARDS.

Drug-induced pulmonary edema. Overload pulmonary edema is a nonspecific complication that may follow generous perfusion or transfusion. Pulmonary edema may also complicate treatments with myocardial depressant drugs such as b-blockers or verapamil.

More specifically, drugs and transfusion of blood or fractions can induce a picture of permeability pulmonary edema. Temporally, drug-induced pulmonary edema is closely related to drug administration–within hours, as opposed to the longer time to onset of infiltrative lung diseases. Aspirin is an exception, as edema may develop during chronic exposure to the drug. For a few drugs (eg, cytosine arabinoside, opiates, or tricyclic antidepressants), the risk relates to drug dosage, and pulmonary edema is a well-known complication of intentional overdoses of opiates, tricyclic antidepressants, or heroin.¹¹⁶

Other drugs, even when taken at recommended dosages, may also induce pulmonary edema. This holds true for both IV-injected agents (eg, b₂-agonists in parturients,¹¹⁷ opiates, vinorelbine, radiographic contrast media, blood transfusion) and orally administered drugs (eg, hydrochlorothiazide, salicylate). At examination, audible crackles and wheeze are present; in severe cases, a cough producing frothy sputum may be present. On imaging (Fig 8), there are bilateral alveolar shadows, along with evidence of pulmonary congestion, such as enlarged septae or fissures or a slight amount of pleural fluid. Drug-induced pulmonary edema is mostly noncardiogenic, with normal pulmonary capillary wedge pressure and echocardiographic findings. In rare instances, histopathologic examination was performed and showed a combination of alveolar flooding by proteinaceous material, hyaline membranes, some hemorrhage, and interstitial edema. In most patients, symptoms and opacities resolved within a few hours or days; however, a few developed ARDS.

Figure 8. Chest radiograph depicting b-agonist-induced pulmonary edema in a young woman. The drug had been administered IV near the end of pregnancy to retard labor. This picture may result from exposure to many other drugs or to blood and blood derivatives (known in such cases as the TRALI syndrome).

Transfusion of blood or blood products, including cells and plasma fractions, or immunoglobulins may be followed by the development of pulmonary edema.^118,119 The edema usually develops within 1 to 2 h in about 1 in 2,000 transfusions, and the syndrome is known as transfusion-related lung injury (TRALI). Mechanistically, TRALI is thought to result from passive transfusion of anti-human leukocyte antigen antibodies of donor origin, which activate complement and elicit leukoagglutination in the recipient's pulmonary circulation. This results in pulmonary infiltrates/edema. A fraction of patients may develop the features of ARDS. Fatalities have been reported, especially in patients in whom the syndrome was not recognized in time. The role of diuretic drugs is controversial, as these drugs may aggravate the syndrome. Proper recognition of TRALI is essential in order to withdraw donors who have antibodies (often multiparous women) from the donor pool. Short of doing so, the index patient or subsequent patients may receive blood from the same donor and develop problems that could otherwise have been prevented. A recent study indicated that the TRALI syndrom