Drug-induced lung disease

Introduction to drug-induced lung disease The drug plays an extremely important role in the prevention, treatment and diagnosis of the disease, but on the other hand, it can cause damage to various organs of the body due to its toxic side effects, although William Osler observed excessive morphine as early as 1880. It caused acute pulmonary edema, but it was not until 1972 that Rosenow systematically discussed 20 drugs that were definitely associated with lung injury. Since then, there have been more and more reports on drugs and lung diseases, and more and more people have paid attention to it. So far, more than 100 kinds of drugs have been reported to cause lung diseases. Adverse reactions of drugs to the lungs are part of systemic adverse drug reactions, and their clinical manifestations vary. Some are acutely ill, the condition is serious, and some are subacute or chronic onset. The pathophysiological changes caused by some drugs are temporary and reversible. They can disappear after stopping the drug, and some can cause permanent damage to the lung tissue. In severe cases, even life-threatening, such drug-induced lung diseases are called drug sources. Drug-induced lungdiseases (DILD). basic knowledge The proportion of illness: 0.005% Susceptible people: no special people Mode of infection: non-infectious Complications: Asthma Respiratory failure Acute pulmonary edema Hemoptysis

Drug-induced causes of lung disease

(1) Causes of the disease

Drug-induced lung disease can be classified into different categories from different angles. According to clinical, pathological and X-ray findings, drug-induced lung diseases are classified as follows. Since the same drug can cause several different lung damages, drug-like There are many drugs involved in lung disease, and this section can only be discussed.

1. Interstitial changes in the lung

(1) pulmonary interstitial fibrosis: a large number of drugs that can cause pulmonary interstitial fibrosis, the most common of which are cytotoxic drugs. Since the first report of pulmonary fibrosis caused by busulfan in 1961, cytotoxic drugs caused lungs. Reports of toxic reactions are gradually increasing. The risk factors for the occurrence of diffuse fibrosis in the lungs are the frequency of drug use, the total dose of medication, combined medication, combined with radiotherapy, high-concentration oxygen therapy, original lung disease, and pulmonary function. Liver and kidney dysfunction and old age have a certain relationship.

(2) occlusive bronchiolitis with organizing pneumonia (BOOP).

(3) desquamative interstitial pneumonia and lymphocytic interstitial pneumonia: so far reported in the literature can cause desquamated interstitial pneumonia drugs such as busulfan, interferon alpha, sulfasalazine, nitrofurantoin Etc., drugs that can cause lymphocytic interstitial pneumonia are captopril, phenytoin and the like.

(4) Allergic pneumonia: Some drugs such as carbamazepine, docetaxel (DoeetaXel), gold salt, MTX, nitrofurantoin, procarbazine and the like can cause allergic pneumonia.

(5) Lung infiltration with eosinophilia: Many drugs can cause pulmonary infiltration with pulmonary eosinophilia, -lactams, sulfonamides, penicillins, fluoroquinoxanes, tetracyclines, macrocyclic Ester antibiotics, nitrofurantoin, methotrexate, p-aminosalicylic acid, procarbazine, isoniazid, chlorpropamide, aspirin, furazolidone, sodium cromoglycate, liquid paraffin, and the like.

(6) Diffuse pulmonary calcification: So far, there have been reports of long-term high doses of calcium or vitamin D leading to diffuse calcification of the lungs.

2. Pulmonary edema can cause a lot of drugs for drug-induced pulmonary edema.

3. Airway disease

(1) bronchospasm with or without laryngeal edema: drugs that can cause bronchospasm are shown in Table 5. The mechanism of bronchospasm caused by drugs is still not very clear, which may be summarized as three aspects: allergic reaction, pharmacological reaction and direct stimulation. Penicillin, immunoglobulin and lipiodol can cause bronchospasm through allergic reactions, while inhaled sodium cromolyn and polymyxin B are mostly caused by direct stimulation. Most other drugs such as -adrenergic receptor blockers, blood vessels are tight. Invertase inhibitors, non-corticosteroid anti-inflammatory drugs, prostaglandin E2 and aspirin, etc., through the pharmacological action in vivo, leading to bronchial smooth muscle contraction, as to why some anti-tumor drugs and antibiotics can cause bronchospasm, currently not clear.

(2) Cough: drugs that cause simple cough mainly include angiotensin-converting enzyme inhibitors, interleukin-2, methotrexate, streptokinase and hormones. The mechanism of action is still unclear, and may be slow-reacting with angiotensin. Substance, substance P and arachidonic acid are related to metabolism.

4. pleural lesions nitrofurantoin, metformin, bromocriptine, clomiphene, phenytoin, cyclophosphamide, procarbazine, methotrexate, propranolol and amine iodine that can cause lupus-like syndrome Ketone, carbamazepine, isoniazid, methyldopa, hydralazine, procainamide and oral contraceptives can cause different degrees of unilateral or bilateral non-specific pleural effusion, sometimes With pulmonary parenchymal infiltration, inappropriate use of anticoagulant warfarin can cause bloody pleural effusion, and other anti-tumor drugs such as bleomycin, BCNU and radiation therapy can cause pulmonary interstitial fibrosis, and pneumothorax occurs.

5. Pulmonary hemorrhage can be caused by long-term and improper use of anticoagulants and their analogues, such as warfarin, aspirin, fibrinolytic agent, streptokinase, urokinase, and other drugs such as lipiodol, mitomycin, card It is caused by mazepine, cyclosporine, nitrofurantoin, phenytoin, etc. In addition, penicillamine can cause lung and kidney bleeding through type III allergy.

6. Pulmonary opportunistic infection with chemotherapy drugs, corticosteroids, antibiotics for a long time after application, secondary lung infection may occur.

7. Pulmonary vascular changes There are many drugs that can cause changes in pulmonary blood vessels, such as oral contraceptives, cyclosporine, mitomycin, interleukin-2, propranolol can cause pulmonary hypertension; corticosteroids, estrogens, Plu Cainamide and other diseases easily cause pulmonary embolism; bleomycin, BCNU, CCNU, oral contraceptives and radiation can cause occlusion of the pulmonary veins, and many drugs can cause pulmonary vasculitis.

8. Mediastinal changes of phenytoin, carbamazepine, minocycline, aspirin, etc. can cause unilateral or bilateral hilar and/or mediastinal lymphadenopathy, long-term use of corticosteroids can cause mediastinal fat deposition, resulting in increased mediastinum Wide, interferon alpha and interferon beta can cause sarcoidosis-like manifestations, while interferon gamma can cause thymus enlargement.

9. Neuromuscular lesions can cause alveolar hypoventilation and respiratory failure are mainly anesthetics, sedatives, hypnotics and muscle relaxants. There are many drugs in this category, which will not be repeated here.

10. Pulmonary granuloma-like reaction drugs can be used as a foreign body to stimulate lung tissue reaction, or as an organic antigen to cause allergic reactions in the body, such as oil inhalation into the lungs can cause lipid pneumonia; liquid paraffin inhalation into the lungs, can be limited Granuloma, bronchography, iodized oil can sometimes cause pulmonary granuloma formation, and even develop into interstitial fibrosis, in addition to amiodarone, bleomycin, carbamazepine, phenytoin, vinblastine, minnow Magnesium and the like can also cause multiple nodular changes in the lungs.

11. Lupus-like changes So far more than 40 drugs have caused lupus-like changes, and lupus-like changes in the lungs are part of systemic lupus erythematosus.

12. Some other drugs can cause chest pain, such as bleomycin, bumetanide, etoposide, mesalazine, methotrexate, methyldopa, minocycline, nigralin (brain pass) And nitrofurantoin, etc.; salbutamol (sulphate) can cause metabolic acidosis and dyspnea.

(two) pathogenesis

The pathogenesis of drug-induced lung disease is still not fully understood. The possible mechanisms are as follows: 1 oxygen free radical damage, direct toxic effects of 2 cytotoxic drugs on alveolar capillary endothelial cells, 3 phospholipids deposited in cells, 4 immunization System-mediated damage, in addition, the lungs not only have respiratory function, but also have metabolic functions. It is known that the lungs are involved in some important vasoactive substances such as prostaglandins, angiotensin, serotonin and bradykinin. Metabolism, but it is unclear whether the lungs are involved in the metabolism of the drug.

Oxygen free radical damage is considered to be one of the important damage pathways. Especially in acute lung injury caused by drugs, oxygen free radical damage may play an important role. For the anti-infective drug nitrofuranto, in vitro tests prove that nitrofurantoin It can cause excessive amounts of hydrogen peroxide (H202), hydroxide ions (·OH), superoxide anion (O2-), and monoatomic oxygen (1O2) in the lung cells, which can produce important cell functions. Damage, leading to diffuse alveolar damage, increased alveolar epithelial permeability, cellulose-like exudate in the alveoli, formation of transparent membrane, hemorrhage, edema, subsequent fibroblast proliferation, formation of pulmonary interstitial fibrosis, chemotherapy The lung damage caused by the drug is mainly through direct damage to the lung. The pulmonary interstitial fibrosis caused by the anti-tumor drug bleomycin is typical. Although the exact mechanism of bleomycin-induced pulmonary fibrosis is still unclear. However, there is evidence that the levels of enzymes that specifically inactivate bleomycin in lung and skin epithelial cells are lower than those in other organs, so bleomycin is susceptible to epithelial cells in the lungs and skin. In the middle of aggregation, bleomycin enters the nucleus through the nuclear membrane, causing damage to the DNA fragment. The damage of lung damage caused by bleomycin is dose- and age-dependent. The damage of amiodarone on the lung is mainly caused by alveolar macrophages. Phospholipid deposition in cells and alveolar type II epithelial cells. More than 20 drugs have been identified to cause phospholipid deposition in cells, especially in lung cells. Phospholipid deposition by these drugs has been reported to be due to intracellular phospholipid catabolic disorders. Caused by this, but this effect is reversible, phospholipid metabolism can return to normal after stopping the drug, and the body's damage caused by immune-mediated diseases such as drug-induced systemic lupus erythematosus (SLE) is another pathogenesis of drug-induced lung disease. It is known that at least 20 drugs can cause SLE, which can be divided into two groups. The first group can cause anti-nuclear antibody production, but only a few patients have SLE symptoms; the other group rarely produces anti-nuclear antibodies, but almost all SLE occurs, because these drugs do not have an immune source, so some scholars believe that these drugs may act as adjuvants or immunostimulants after entering the body, so that The body produces autoantibodies.

The typical pathological changes in pulmonary vascular changes are central inflammation and necrosis of the blood vessels, possibly due to type III or type IV allergies.

5 to 40% of patients with bleomycin have pulmonary lesions, and 1% to 7% of them can die. The pathogenesis may be related to bleomycin directly causing DNA breaks in the lung cells, which leads to The incidence of pulmonary lesions is related to the cumulative dose of bleomycin, age, inhaled oxygen concentration, radiotherapy and combination with other anti-tumor drugs. When the total dose exceeds 450 U or is older than 70 years, bleomycin causes lungs. The incidence of lesions is significantly increased. When inhaling high concentrations of oxygen (>25%), patients can easily develop ARDS within 18 to 48 hours.

The first case of mitomycin-induced lung injury was reported in 1971, and its exact pathogenesis is still unclear.

The incidence of lung injury caused by methotrexate is about 7%, and its pathogenesis remains unclear. The toxicity of methotrexate to the lung is not related to the dose, but it is related to the frequency of administration. Studies have shown that it is administered once a day or once a week. The incidence of pulmonary toxicity is higher than that administered once every 2 to 3 weeks.

The lung damage caused by cytarabine is related to the total dose of the drug and whether other antitumor drugs are used in combination, and the incidence varies from 5% to 44%.

Azathioprine causes a lower incidence of lung damage. Because this drug is often used in combination with other drugs that cause pulmonary fibrosis, it is difficult to conclude that lung damage must be related to azathioprine, but so far there have been at least four Interstitial lung damage in 27 patients was associated with azathioprine.

The incidence of lung toxicity is 1.5% to 20% and is related to the drug dose. The literature reports that when the total dose reaches 1500mg/m2, the incidence of pulmonary toxicity can reach 50%.

Amiodarone is an antiarrhythmic drug that causes a lung toxicity rate of about 5%, resulting in a mortality rate of 10% to 20%. The mechanism of amiodarone-induced lung injury is still unclear. It may be related to amiodarone leading to metabolic disorders of cellular phospholipids. On the other hand, it may be related to the cellular immune response caused by amiodarone.

Drug-induced lung disease prevention

The most important thing to prevent drug-induced lung disease is to improve the understanding of the duality of drugs. All drugs should be familiar with their pharmacological effects, strictly control the indications, dosage and course of treatment. Doctors should always maintain adverse reactions to drugs in clinical work. Vigilance, should always analyze the role of the drug used by the patient in both positive and negative aspects, to avoid the application of unnecessary drugs, especially for patients with physical allergies should try to simplify the type and dosage of drugs, to achieve a truly rational use of drugs.

Drug-induced complications of lung disease Complications asthmatic respiratory failure acute pulmonary edema hemoptysis

Drug-induced lung disease often occurs in asthma, respiratory failure, acute pulmonary edema, ARDS, hemoptysis, etc.

Drug-induced symptoms of lung disease Common symptoms Chest pain Low fever Fever fatigue Joint pain Hypoxemia Dyspnea Lung infection Pulmonary fibrosis Atelectasis

1. Interstitial changes in the lung

(1) The clinical manifestations of pulmonary interstitial fibrosis are very similar to idiopathic pulmonary interstitial fibrosis. The main symptoms of patients are cough and progressive dyspnea. Physical examination usually smells inspiratory and snoring. Sometimes you can see it.

(2) occlusive bronchiolitis with organizing pneumonia (BOOP) and infection, connective tissue disease and BOOP caused by bone marrow, organ transplantation, etc., clinical cough, difficulty breathing, low fever and increased ESR, physical examination It is usually audible and inhaled.

(3) The clinical manifestations of desquamative interstitial pneumonia (DIP) and lymphocytic interstitial pneumonia (LIP) are similar to idiopathic pulmonary interstitial fibrosis, and the diagnosis depends mainly on pathological examination.

(4) allergic pneumonia often acute onset (a few days), clinical manifestations of cough, fever, difficulty breathing, accompanied by general malaise, muscle soreness and joint pain, etc., about 40% of patients may have varying degrees Peripheral blood eosinophilia.

(5) Lung infiltration with eosinophilia The clinical features of this disease are subacute or gradual onset, shortness of breath, cough, with or without fever and rash, eosinophilia in the surrounding blood, eosinophilic in the alveoli Granulocyte and macrophage infiltration, its clinical manifestations are similar to Loeffler syndrome.

2. Pulmonary edema: Drug-induced pulmonary edema can occur several hours after administration, the main clinical manifestations of dyspnea and hypoxemia.

3. pleural lesions: can cause different degrees of unilateral or bilateral non-specific pleural effusion, sometimes accompanied by pulmonary parenchymal infiltration, some patients may have antinuclear antibody positive and / or pleural effusion in the pleural fluid The granulocytes are increased, but the amount of pleural effusion is generally below medium. Usually, after 1 to 2 weeks of withdrawal, the effusion can be gradually absorbed. The inappropriate use of the anticoagulant warfarin can cause bloody pleural effusion, and some other antibiotics. Oncology drugs such as bleomycin, BCNU and radiation therapy can cause pulmonary interstitial fibrosis, and pneumothorax occurs.

4. Pulmonary hemorrhage: Pulmonary hemorrhage caused by drugs is often diffuse alveolar hemorrhage. In addition, penicillamine can cause lung and kidney bleeding through type III allergy, similar to Goodpasture syndrome.

5. Pulmonary vascular changes: Its clinical manifestations may include fever, weight loss, joint pain, muscle pain, and even pulmonary hemorrhage, gastrointestinal bleeding and renal failure.

6. Lupus-like changes: 40% to 80% of cases have pulmonary manifestations, including pleurisy, pleural effusion, atelectasis and diffuse interstitial pneumonia, drug-induced lupus syndrome similar to systemic lupus, There are multiple joint pains, fatigue, fever, skin and lung lesions, but central nervous system and kidney involvement are rare.

7. Common pulmonary interstitial fibrosis drugs

(1) Busulfan (Maliland) is the first choice for anti-myeloproliferative drugs. Due to the needs of the disease, patients often need to take a long time. Although the dose of Busulfan has not been determined, its accumulation in the body has long been recognized. Note that about 6% (2.5% to 43%) of patients taking busulfan can have different degrees of pulmonary interstitial fibrosis, but most patients have no clinical symptoms, and the onset of the patient is more insidious, usually after treatment. It occurs in months or years, with an average of 3.5 years (from 8 months to 10 years), but there are also cases that can occur 6 weeks after administration. The main symptoms include cough, fever, fatigue, weight loss and progressive dyspnea.

(2) The onset of pulmonary toxicity caused by cyclophosphamide is usually hidden. The main symptoms are cough, progressive dyspnea and fever. The time from drug use to pulmonary toxicity varies greatly from 2 weeks to 13 years. Some patients even appeared after a few months of withdrawal, but most patients occurred shortly after administration, and there was no significant dose-related pulmonary toxicity caused by cyclophosphamide.

Other alkylating agents, such as melphalan, phenylbutyrate, and ifosfamide, have been reported to cause pulmonary fibrosis, but the overall incidence is relatively small, with clinical manifestations and pathological changes and other The alkylating agent is similar to the antitumor drug.

(3) Bleomycin can cause many changes, including not only pulmonary interstitial fibrosis but also allergic pneumonia and occlusive pneumonia with organizing pneumonia (BOOP), BOOP caused by bleomycin and other types of BOOP Unlike it, it tends to have nodular changes similar to metastatic lung cancer.

(4) Lung injury caused by mitomycin includes pulmonary fibrosis, acute interstitial pneumonia, bronchospasm, etc. It has been reported that mitomycin can cause microvascular hemolytic anemia syndrome leading to acute renal failure, ARDS and alveoli Hemorrhage, when the combination of mitomycin and vinblastine drugs, the incidence of lung injury increased significantly, from 3% to 8% of mitomycin alone to about 39%, mitomycin-induced lung The injury usually occurs 2 to 12 months after treatment, and its clinical manifestations are similar to those of other cytotoxic drugs.

(5) Common clinical symptoms of methotrexate are dyspnea, fever, cough, general malaise and myalgia. These symptoms usually occur within a few weeks after treatment.

(6) The main clinical manifestation of cytarabine is acute pulmonary edema. Hupt et al reported that a group of 42 patients who died of cytarabine treatment showed that there were 28 cases of pulmonary edema without other causes, considering possible with arabinose. Cytidine is involved.

(7) The lung damage caused by the card nitrogen is mostly occurring within 6 months to 3 years after administration. The clinical symptoms are similar to those caused by bleomycin and CTX, but some cases may occur several years after the end of chemotherapy. ODriscoll et al performed 17 years of follow-up in 17 patients, and 12 patients (71%) developed fibrosis in the upper lobe. Other nitrosourea drugs, including lomustine (CCNU) and methyl The lung toxicity caused by CCNU has also been reported in the literature.

(8) The clinical manifestations of lung damage caused by amiodarone are various, from pulmonary infiltration, allergic pneumonia to pulmonary fibrosis, clinical manifestations can be acute or chronic, chronic onset is more common, accounting for 2/3, manifested as gradual cough, dyspnea and weight loss, and about 1/3 of patients may show acute onset, the main symptoms are fever, chest pain, difficulty breathing, and its clinical manifestations and lung infections are very Similarly, amiodarone can also cause non-cardiogenic pulmonary edema.

Drug-induced lung disease examination

The majority of patients with lupus erythematosus-like changes are anti-nuclear antibodies positive, but anti-dsDNA negative, serum complement determination can be normal or abnormal, Coombs test is about 1/3 positive, methotrexate has about 17% and 40% of patients There may be rash and peripheral blood eosinophils, amiodarone about 1/3 of patients may show acute onset, laboratory tests may have increased white blood cells and increased erythrocyte sedimentation rate, but blood eosinophilia is not much see.

1. Interstitial changes in the lung

(1) Chest X-ray examination of pulmonary interstitial fibrosis: It can be found that the density of the nucleus and nodular density of the double lungs is increased. When the lesion is severe, the bilateral lungs may be involved. In a few cases, the chest radiograph can be normal, and the pulmonary function test can be performed. Restricted ventilatory dysfunction and diffuse function were reduced to varying degrees. Pathological examination of lung tissue revealed atypical type II alveolar epithelial cell hyperplasia, alveolitis or interstitial inflammation, and varying degrees of pulmonary interstitial fibrosis.

(2) Obstructive bronchiolitis with organizing pneumonia (BOOP) chest X-ray examination can be found in multiple lung patchy infiltrates, pulmonary function tests can be restrictive ventilation dysfunction or obstructive ventilation function The disorder, corticosteroid treatment responded well.

(3) The diagnosis of desquamative interstitial pneumonia (DIP) and lymphocytic interstitial pneumonia (LIP) mainly depends on pathological examination.

(4) Allergic pneumonia can be seen in the chest X-ray of the acinar nodules and the lesions are located in the periphery of the lungs. The lung function tests have different degrees of restrictive ventilatory dysfunction and hypoxemia. The lung biopsy shows how much in the alveolar cavity. Renal leukocytes or eosinophils and monocytes infiltrate, and pulmonary interstitial fibrosis is rare.

(5) Lung infiltration with eosinophilic chest X-ray film showed patchy lung infiltration, often migratory.

2. Pulmonary edema The chest X-ray showed diffuse acinar nodular invasive changes and the heart size and morphology were normal. Lung edema was observed in lung biopsy but there was little inflammatory reaction.

Diagnosis and differentiation of lung diseases caused by drugs

The diagnosis of drug-induced lung disease is difficult because of the non-specific lung changes and the lack of specific examination methods. Some auxiliary examinations such as immunological examination, histological examination and pulmonary function examination may be helpful, but not specific. Sex, and because of the limitations of patients and hospitals, not all patients can perform the above tests. The most important thing is to have a vigilant and reliable detailed history of drug-induced lung disease. Therefore, clinicians should respond to various drugs. The pharmacological effects, indications, dosage, route of administration and side effects are well understood. If an adverse reaction is found during the course of administration, a comprehensive and in-depth analysis should be combined with the clinical process to exclude other diseases of the lungs and make correct Diagnosis, the disappearance of symptoms after suspicious cases in time to help the diagnosis, but the histological changes in advanced cases are often irreversible, so the symptoms continue after stopping the drug can not rule out the possibility of drug-induced lung disease.

It should be differentiated from pneumonia, acute cardiogenic pulmonary edema, lung tumor, and idiopathic pulmonary interstitial fibrosis.

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