Drug-Induced Lung Disease

Table II.

Cytotoxic drugs

A. Cytotoxic antibiotics1. Bleomycin2. Mitomycin3. Zinostatin

B. Nitrosureas1. Carmustine2. Other nitrosureas

C. Alkylating agents1. Busulfan2. Cyclophosphamide3. Chlorambucil4. Melphalan

D. Antimetabolites1. Methotrexate2. Azathioprine and 6-Mercaptopurine3. Cytosine arabinoside

E. Other cytotoxic drugs1. Procarbazine2. Etoposide3. Vinca alkaloids

Non cytotoxic drugs

A. Antibacterials1. Nitrofurantoin2. Sulfasalazine3. Other antibiotics

B. Analgesics1. Acetylsalicylic acid (aspirin)2. Tricyclic antidepressants

C. Anticonvulsants1. Phenytoin2. Carbamazepine

D. Anti-arrhythmics1. Amiodarone2. Lidocaine3. Tocainide

E. Anti-rheumatic drugs1. Penicillamine2. Gold salts 3. Colchicine

F. Sympathomimetics1. Terbutaline2. Ritodrine

G. Other non-cytotoxic drugs

2. Emergency Management

Early recognition and termination of the offending agent are the keys in management. Recognition of drug-induced lung injury is often difficult because the clinical, radiographic and histological findings are often non-specific. In addition, because there are no specific markers available to establish the presence of drug-induced pulmonary toxicity, health care providers are able to make the diagnosis only when they are aware of the manifestations of medication-induced pulmonary injury.

3. Diagnosis

Establishing the diagnosis

Intersitial pneumonitis/fibrosis

Interstitial pneumonitis/fibrosis is the most common clinical manifestation associated with drug-induced pulmonary damage. Many cancer chemotherapeutic drugs can cause interstitial pneumonitis/fibrosis, while several non-cytotoxic drugs have also been implicated. Clinically symptoms usually begin insidiously, progressing over weeks to months with a non-productive cough, exertional dyspnea, fatigue, malaise and weight loss. Bibasilar end-inspiratory rales are commonly appreciated on examination. There are more acute forms of this syndrome, occurring within hours to days after exposure to the offending agents.

This syndrome of acute pneumonitis is typically associated with nitrosoureas, cyclophosphamide and the mitomycin/vinca alkaloid combination. It has also been decribed with amiodarone and biologicals. On chest radiography, interstitial pneumonitis frequently manifests as bilateral bibasilar reticular or nodular infiltrates. Pleural effusions are frequently absent but have been described in association with mitomycin, nitrofurantoin, amiodarone and gold salts.

Occasionally the chest radiograph may be normal, even in the presence of significant symptoms or pulmonary physiological impairment. Patients with interstitial pneumonitis will commonly have a restrictive defect with a reduced diffusion capacity on pulmonary function testing. Diagnosis is often confirmed with bronchoscopy and transbronchial biopsy.

Hypersensitivity pneumonitis

The syndrome of hypersensitivity pneumonitis occurs following exposure to various agents and often progresses subacutely. It typically is characterized by dyspnea, non-productive cough, chills, myalgias and a headache. On examination, fever and inspiratory crackles are common. A skin rash is present in up to half of patients. Laboratory findings may include eosinophilia (in 40% of cases).

More specific testing includes the lymphocyte transformation test (LTT) to the offending drug. Signs of hepatitis have been reported in a few cases. Radiographic manifestations of hypersensitivity pneumonitis include diffuse alveolar infiltrates or diffuse reticular infiltrates. Pleural effusions are seen more commonly than in interstitial pneumonitis.

Non-cardiogenic pulmonary edema

As with other forms of non-cardiogenic pulmonary edema such as ARDS, clinical manifestations occur acutely, within minutes to hours. Patients present with severe dyspnea and hypoxemia. Non-cardiogenic pulmonary edema is typically associated with an overdose of the offending agent, suggesting that high-serum levels of the offending agent is important in the development of pulmonary capillary leak. The prognosis for non-cardiogenic pulmonary edema tends to be quite good upon withdrawal of the offending agent.

Bronchiolitis obliterans organizing pneumonia (BOOP)

BOOP is a rare complication of non-cytotoxic drug exposure and has been reported with the use of gold salts, sulfasalazine and penicillamine. The association of BOOP to the medication is controversial since similar pulmonary manifestations can be seen with the underlying disease, particularly with rheumatoid arthritis. However, in the reported cases there appears to be a temporal association between the onset of drug institution and the onset of clinical symptoms. The clinical presentation is similar to that seen in pneumonitis, with an insidious onset of exertional dyspnea, non-productive cough and weight loss.

Bronchospasm

Drug-induced bronchospasm may occur in conjunction with a type I hypersensitivity reaction. Non-cytotoxic drugs frequently are implicated as the cause. Frequent offenders are NSAIDs and beta blockers. NSAIDs exacerbate bronchospasm in asthmatics either by inhibition of the COX pathway, leading to increased production of leukotrienes, or by reducing the production of bronchodilating prostanoids. Beta blockers may cause bronchospasm by inhibition of beta receptors on airway smooth muscle cells.

Pulmonary-renal syndrome

Pulmonary-renal syndrome is a rare complication of penicillamine therapy that has been reported in four patients. The syndrome develops after 1-2 years of therapy and is characterized by acute onset of hemoptysis, pleuritic chest pain and uremia. Chest radiography may demonstrate diffuse alveolar or reticular infiltrates. The prognosis is poor, with only one patient surviving after treatment with plasmapheresis and aziathioprine.

Drug-induced lupus

Drug-induced SLE accounts for 5-12% of the cases of SLE. In SLE the lungs or pleura are affected in 50% of cases, whereas a much higher involvement is seen in drug-induced lupus. Acetylator status is important in cases of hydralazine- or isoniazid-related SLE, as cases of hydralazine- and isoniazid-induced SLE are more frequently seen in slow acetylators of these drugs. Common clinical manifestations include pleural effusions with or without pleuritic chest pain and interstitial pneumonitis. Chest radiographs in drug-induced SLE typically show pleural thickening, pleural effusions or pulmonary fibrosis.

Pulmonary vascular disease

Illicit drugs of abuse are able to produce pulmonary angiitis and pulmonary hypertension when administered intravenously. Alpha-adrenergic nasal sprays have been reported to cause interstitial fibrosis as well as pulmonary vascular involvement. There have also been reports implicating oral contraceptives as a cause of primary pulmonary hypertension in patients taking the medication for more than 6 months. Pulmonary veno-occlusive disease is commonly idiopathic but also can be seen as a complication of chemotherapeutic drug use with bleomycin, carmustine, gemcitabine, mitomycin and vinca alkaloids.

Diffuse alveolar hemorrhage (DAH)

DAH is a clinical-pathological syndrome characterized by the accumulation of red blood cells in the alveolar spaces. DAH as a direct consequence of medical therapy may represent an immune or hypersensitivity reaction to a medication, an injury to the alveolar capillary basement membrane or a coagulation defect induced by a medication.

Typically chest X-ray and CT scan are non-specific, demonstrating diffuse alveolar infiltrates or ground glass opacity. Patients typically do not have clinically evident hemoptysis, although they sometimes do. Diagnosis of suspected cases can typically be made by bronchoscopy, where increasingly bloody BAL fluid is seen on serial aliquots.

Histological findings

The pulmonary histological findings in drug-induced lung injury show a common characteristic feature, with type I pneumocyte destruction and type II pneumocyte proliferation with dysplastic changes. Additionally, interstitial and alveolar inflammatory cell infiltration with mononuclear and polymorphonuclear leukocytes are seen as well. Finally, pulmonary tissue from such patients demonstrates marked interstitial fibrosis with thickening of the interstitial space.

The pulmonary histological findings in hypersensitivity lung disease are characterized by interstitial and alvolar eosinophila. Fibrosis is an uncommon finding. With nitrofurantoin and methotrexate, a mononuclear cell infiltrate with granuloma formation may be seen.

Pulmonary histology in BOOP is similar to the idiopathic form of BOOP, with characteristic obliteration of bronchioles and surrounding areas of inflammation and fibrosis. In a few cases of BOOP from sulfasalazine and penicillamine, significant alveolitis has also been reported.

Pulmonary vascular disease (PVOD)

Histology from patients with injection drug abuse may show foreign body granulomatosis. Alpha-adrenergic nasal spray may result in obliterated pulmonary vessels. Oral contraceptive use can show thickened arterial walls with occasional evidence of thrombosis. Pulmonary veno-occlusive disease is characterized by fibrous obliteration of pulmonary venules and small pulmonary veins. PVOD in the setting of chemotherapeutic drugs is considered to be a result of immune or hypersensitivity reaction as opposed to a direct toxic effect of the medication itself.

Diffuse alveolar hemorrhage (DAH)

Histologically the most common finding is a small vessel vasculitis known as pulmonary capillaritis that occurs after treatment with Dilantin, propylthiouracil and all-trans-retinoic acid. Pulmonary capillaritis is most commonly seen in systemic vasculitis and connective tissue disease. It is characterized by neutrophilic infiltration and edema of the interstitium, edema and fibroid necrosis of the alveolar walls with red blood cell and neutrophil infiltration of the alveolar spaces.

Other pulmonary hypersensitivity reactions that may result in DAH include the hemolytic uremic syndrome (HUS) that complicates mitomycin treatment, Goodpasture’s-like syndrome seen after treatment with penicillamine, sulfasalazine-induced necrotizing granulomatous vasculitis and Churg-Strauss syndrome seen after treatment with leukotriene antagonist. Drugs that produce lesions of diffuse alveolar damage may also cause DAH syndrome. Histologically diffuse alveolar damage is characterized by inflammation and edema of the alveolar walls with formation of intra-alveolar hyaline membranes.

DAH may occur during this exudative phase of diffuse alveolar damage. Several chemotherapeutic drugs and illicit use of crack cocaine can result in this form of injury. The final end reaction that results in DAH is red blood cells in the alveolar spaces. Agents that inhibit the coagulation cascade can lead to DAH. Heparin, thrombolytics, warfarin, abciximab and clopidogrel have all been associated with DAH. In addition, severe thrombocytopenia, which is frequently caused by medications, can also lead to this syndrome.

4. Specific Treatment

Discontinuation of potential offending medications is critical in treating cases of suspected medication-induced lung disease.

Interstitial pneumonitis/fibrosis

In cases of interstitial pneumonitis/fibrosis corticosteroids are frequently used. Although there have not been any controlled clinical trials, several case studies document favorable response in interstitial fibrosis associated with mitomycin, amiodarone and gold salt therapy.

Hypersensitivity pneumonitis

The prognosis of hypersensitivity pneumonitis is usually good. Most patients will make a complete recovery with discontinuation of the drug and institution of corticosteroid treatment. Only a minority of patients will have residual chest radiographic abnormalities that persist months after clinical recovery. Hypersensitivity from methotrexate has a poorer prognosis, with a reported mortality rate of up to 10%.

BOOP

Treatment of BOOP is typically with corticosteroids. The prognosis of drug-induced BOOP is typically poor, with a mortality rate of approximately 50% of reported patients. Residual pulmonary function abnormalities are common in survivors despite discontinuation of the drug and institution of corticosteroids.

Bronchospasm

Bronchodilators are obvious treatment options for drug-induced bronchospasm. For cases of beta blocker-induced bronchospasm, inhibition of beta receptors on airway smooth muscle promotes bronchodilation through downregulation of cholinergic pathways. As a result, inhaled anticholinergic agents also may be useful.

Drug-induced SLE

The prognosis of drug-induced SLE is typically favorable, with resolution of the pleuropulmonary manifestation following withdrawal of the inciting agent. Occasionally corticosteroids may be necessary.

DAH

Treatment of DAH again involves the withdrawal of the offending agent, reversal of any coagulation defect and corticosteroids for severe cases.

5. Disease monitoring, follow-up and disposition

Any patient with suspected drug-induced lung disease should be monitored closely. Dyspnea, cough, fever and other systemic symptoms should be followed closely, as well as chest imaging, pulmonary function testing and clinical examination. The response to treatment also should be carefully monitored.

Pathophysiology

Pulmonary toxicity secondary to drugs may be due to a variety of mechanisms, including oxidant injury, deposition of phospholipids within the cells, immune system-mediated injury and central nervous system depression.

Oxidant injury

Certain drugs, such as cyclophosphamide, amiodarone, carmustine, nitrofurantoin and bleomycin, are able to generate free oxygen radicals when metabolized. These oxidant species include the superoxide anion, hydrogen peroxide, hydroxyl radical and hypochlorous acid. All have been implicated in the pathogenesis of numerous pulmonary injuries, including ARDS, emphysema, pulmonary oxygen toxicity and radiation pneumonitis.

These oxidant molecules are formed within the phagocytic cells and participate in redox reactions, resulting in fatty acid oxidation that leads to membrane instability and autologous cytotoxicity. Typically the antioxidant defense mechanisms counteract the oxidant effects. However, when production of these oxidant free radicals is accelerated, the normal antioxidant protective mechanisms are overwhelmed, resulting in an inflammatory and fibrotic reaction. Why the lungs of some individuals are more susceptible than others remains unknown.

Deposition of phospholipids

Amiodarone, an amphiphilic compound, causes phospholipid accumulation within the macrophages of the lung and other tissues by inhibiting the activity of phospholipase A2.

Immune-mediated injury

Drug-induced SLE is an example of immune-mediated lung injury. Drugs can act as haptens, activating pulmonary resident cells and attracting peripheral inflammatory cells with resulting release of inflammatory mediators. Also, the resulting antibody-antigen immune complex deposition may result in an inflammatory response.

Another proposed mechanism is that damaged endothelial and epithelial cells are able to liberate mediators that activate inflammatory cells. BAL fluid derived from patients with bleomycin, amiodarone, tocainide and phenytoin pulmonary toxicity demonstrates significant neutrophilia, whereas a lymphocytic alveolitis will be seen in methotrexate and nitrofurantoin toxicity.

Central nervous system depression

The medulla is responsible for the activation of the sympathetic nervous system. Any acute neurological insult stimulates the hypothalamus and the vasomotor centers of the medulla, increasing the sympathetic drive, leading to acute neurogenic edema. Pulmonary edema has been described following the administration of intrathecal methotrexate, opiates, major tranquilizers and salicylates.

Epidemiology

The occurence of drug-related pulmonary toxicity remains largely unpredictable and idiosyncratic. Recognizing patients at high risk for drug-induced pulmonary toxicity is important to ensure closer monitoring and other efforts to help prevent disease. Documentation of risk factors may reveal the potential mechanisms of drug-induced lung injury. Risk factors include both patient risk factors and risk factors associated with the medication.

Patient risk factors include pre-existing lung disease, oxygen therapy, age, occupational exposures, exposure to blood transfusion, and concurrent or previous radiotherapy. Medication factors include cumulative or unit dose.

Cytotoxic drugs generally exhibit increasing toxicity with increasing dose. This is believed to be the result of drug accumulation and deposition in the lung tissue. Bleomycin, busulfan and carmustine have all demonstrated such an association. Amiodarone causes an increase in pulmonary toxicity when administered at larger maintenance doses. The incidence of amiodarone-induced lung injury is less common in European nations compared to the United States, where the maintenence dose is much higher (400-600 mg vs. 200-400 mg in Europe).

Exposure to gamma radiation leads to the generation of free oxygen radicals, allowing for the synergistic toxicity seen with this form of therapy with chemotherapeutic agents such as bleomycin and mitomycin. The evidence for this interaction is strongest for bleomycin. Bleomycin may either radio-sensitize or cause a radio-recall phenomenon in which prior radiotherapy lowers the required dose for bleomycin to induce lung injury.

Oxygen will cause injury even in normal lungs if it is administered in high doses for a prolonged period of time. A high fraction of inspired oxygen concentration generates free oxidant radicals. Because drugs such as bleomycin, cyclophosphamide and mitomycin are also capable of producing oxygen free radicals, synergistic drug injury can be seen with these two modes of therapy.

Combination drug regimens can increase the incidence of pulmonary toxicity and lower the dose at which pulmonary damage occurs. Cytotoxic drugs that show an increased incidence of pulmonary toxicity when combined include carmustine, mitomycin, cyclophosphamide, bleomycin and methotrexate.

Typically patients with underlying lung disease are at increased risk for drug toxicity. Carmustine and amiodarone cause clinical pulmonary disease more commonly in individuals with co-existing pulmonary disease. This could be due to earlier manifestation of symptoms or an increased risk following exposure to an already damaged lung.

Advancing age is a risk factor for the development of drug-induced lung injury. A decrease in the antioxidant defense system capability is seen with advancing age. Bleomycin, for example, is more likely to induce pulmonary damage in patients older than 70 years.

Packed red cell transfusion has been shown to cause a clinical syndrome characterized by microangiopathic hemolytic anemia, renal failure and pulmonary edema in patients receiving mitomycin. Amphotericin B has been implicated as a cause of non-cardiogenic edema in patients who received leukocyte transfusions.

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