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1 Chapter 1 : Medicine-induced Lung Disease Keywords: Lung, adverse drug reaction, drug-induced lung disease, mechanism of pulmonary toxicity, diagnosis, treatment, review. INTRODUCTION The lungs are a target for a variety of possible toxic substances because of their large contact surface. Received Dec 13; Accepted May This article has been cited by other articles in PMC. Abstract Drug-induced interstitial lung disease DILD is not uncommon and has many clinical patterns, ranging from benign infiltrates to life-threatening acute respiratory distress syndrome. There are two mechanisms involved in DILD, which are probably interdependent: Cytotoxic lung injury may result from direct injury to pneumocytes or the alveolar capillary endothelium. Drugs can induce all types of immunological reactions described by Gell and Coombs; however, most reactions in immune-mediated DILD may be T cell-mediated. DILD can be difficult to diagnose; diagnosis is often possible by exclusion alone. Identifying the causative drug that induces an allergy or cytotoxicity is essential for preventing secondary reactions. One method to confirm the diagnosis of a drug-induced disease is re-exposure or re-test of the drug. However, clinicians are reluctant to place patients at further risk of illness, particularly in cases with severe drug-induced diseases. Assessment of cell-mediated immunity has recently increased, because verifying the presence or absence of drug-sensitized lymphocytes can aid in confirmation of drug-induced disease. Using peripheral blood samples from drug-allergic patients, the drug-induced lymphocyte stimulation test DLST and the leukocyte migration test LMT can detect the presence of drug-sensitized T cells. However, these tests do not have a definite role in the diagnosis of DILD. This study explores the potential of these new tests and other similar tests in the diagnosis of DILD and provides a review of the relevant literature on this topic. The incidence of DILD for each individual drug is variable. DILD may be mild to progressive. In its more severe manifestation, DILD may result in respiratory failure and acute respiratory distress syndrome. DILD may develop within the first few days of treatment or may not until several years after treatment. The mechanisms involved in drug-induced lung injuries are unclear; therefore, DILD cannot be classified in terms of pathogenesis. Diagnosis of DILD generally depends on a definite temporal association between an exposure to the causative agent and the development of respiratory signs and symptoms. The most important for accurate diagnosis is the exclusion of other causes of lung damage. Specific markers, histological findings, and diagnostic clinical features are generally unremarkable in DILD [ 1, 2 ]. Difficulties arise when signs and symptoms develop after the drug is discontinued rather than during treatment or when no improvement follows discontinuation of the drug. Making a timely and accurate diagnosis of DILD is very important to ensure a favorable outcome [ 3 ]. Clinical manifestations and diagnosis of DILD Clinical manifestations Laboratory findings and clinical manifestations of DILD, such as cough, fever, dyspnea, and hypoxemia [ 1-4 ], are non-specific. Discontinuation of the drug is essential, and, in more severe cases, administration of corticosteroids may be of therapeutic value. Histology The histological findings of pulmonary drug reactions are often non-specific and mimic those of other conditions, such as idiopathic interstitial pneumonia and collagen vascular disease [ 5 ]. Almost, all histopathological subtypes of interstitial lung disease may be observed [ 3 ]: While some drugs, such as minocycline, methotrexate MTX, and nitrofurantoin, induce stereotypical reactions in the lungs EP, acute granulomatous interstitial lung disease, and the cellular type of non-specific pneumonia, respectively, other drugs, such as amiodarone and bleomycin, may be associated with more than one histological pattern [ 3 ]. HRCT may reveal abnormalities in patients with normal radiographs [ 8, 10, 11 ]. Thus, HRCT is limited in its ability to predict the histological patterns in drug-induced lung diseases [ 5 ]. HRCT can, however, be valuable in identifying findings that suggest an alternative diagnosis and in monitoring responses to treatments. Patchy ground-glass opacities with centrilobular opacities and interlobular septal lines were predominant radiographic findings in antibiotic agent-induced pneumonitis [ 12 ]. FDG uptake was detected at an extremely early stage when no symptoms or abnormal findings on HRCT were apparent [ 13, 14 ]. Serum Page 1

2 markers KL-6 has been reported as a sensitive marker for interstitial lung diseases [ 4, 15 ]. Serum ADAM8 a disintegrin and a metalloproteinase 8 concentrations were significantly elevated in patients with drug-induced EP, and after a drug provocation test DPT, which demonstrated that ADAM8 induction paralleled drug-induced eosinophilic lung inflammation [ 18 ]. Bronchoscopy and bronchoalveolar lavage BAL Bronchoscopy can be helpful in determining the presence of pneumonitis and for the differential diagnosis of lymphangitic carcinomatosis, vasculitis, alveolar hemorrhage, or pneumonia from infectious agents. Both cytotoxic and immune mechanisms of action may be involved independently or in combination in the tissue expression of different forms of lung injury [ 22 ]. Cytotoxic pulmonary injury Multiple mechanisms may be responsible for cytotoxic pulmonary injury due to drugs, including reactive oxygen species ROS [ 21, ], reduction in deactivation of metabolites of the lung [ ], impairment of alveolar repair mechanisms [ ], and release of various cytokines [ 23 ]. Many agents may be toxic to the lungs. These include cytotoxic drugs, such as bleomycin, MTX, and cyclophosphamide, and non-cytotoxic drugs, such as nitrofurantoin, sulfasalazine, and amiodarone [ 32 ]. Chemotherapy lung is one representative example of cytotoxic lung injury. It is a severe type of pulmonary reaction that develops during or shortly after treatment with chemotherapeutic agents, such as antibiotics, alkylating agents, anti-metabolites, nitrosamines, rapamycin analogs, and podophyllotoxins [ 4 ]. Histologically, chemotherapy lung corresponds to DAD [ 1, 3 ]. Concurrent radiation or oxygen therapy increases the risk of developing chemotherapy lung. Moreover, chemotherapy lung can sometimes develop because of previously unresolved chemotherapy- or radiation-induced damage with additional chemotherapy [ 3 ]. Mechanisms of cytotoxic pulmonary injuries The pathogenesis of cytotoxic lung injury may include direct injury to pneumocytes or the alveolar capillary endothelium, with subsequent release of cytokines and recruitment of inflammatory cells. The systemic release of cytokines induced by chemotherapeutic agents e. Early events in lung injury induced by tricyclic antidepressants may be related to endothelial damage [ 21 ] because of impaired tight junctions mediated by amitriptyline-induced perturbations in intracellular calcium [ 21 ]. By impairing alveolar repair mechanisms, gefitinib may potentiate the effects of lung injury [ 29, 30 ]. The toxic mechanism of amiodarone leads to the disruption of the lysosomal membranes of molecules through protein C activation and the subsequent release of toxic oxygen radicals, which may induce activation of caspase pathways and lead to apoptosis of lung epithelial cells [ 24 ]. An additional mechanism reduces deactivation of toxic metabolites of the drug [ 26, 27 ]. Pulmonary toxicity may also be caused by the generation of free oxygen radicals by mitomycin C, nitrofurantoin, and bleomycin. In vivo and in vitro studies showed bleomycine, a cancer chemotherapeutic agent, to be the cause of pulmonary toxicity, which was mediated, at least partly, by a bleomycin-iron complex, generating toxic O2-derived species within the lung [ 25 ]. Particular susceptibility to bleomycin toxicity in the lung may depend on the fact that bleomycin is preferentially distributed in lung tissue and that the lung is relatively deficient in the hydrolase enzyme that detoxifies bleomycin [ 28 ]. Nitrofurantoin and bleomycin share the ability to generate O2 radicals and to cause lung damage. The reason that these drugs affect the lungs as their predominant site of toxicity remains unclear. One possibility is the rate of gas exchange and high oxygen load in the lungs, which enables damage due to these drugs [ 21 ]. Diagnosis of cytotoxic pulmonary injury Drug-induced pulmonary toxicity can be difficult to diagnose because cancer patients are usually administered multiple anti-neoplastic agents; thus, identifying the causative agent becomes difficult. Unfortunately, no single diagnostic test or tissue biopsy is currently available that can definitively confirm a diagnosis of chemotherapy-associated lung disease [ 33 ]. Currently, in vitro drug challenge is not a readily available or clinically validated diagnostic assay for cytotoxic lung injury. Reactive drug metabolites are believed to play a role in many drug reactions. Differences in the capacity of cells to detoxify the reactive metabolites of drugs are important determinants in drug toxicity reactions, and these differences could be used as the basis of a diagnostic assay. Microsomes are a source of oxidative enzymes, primarily cytochrome P CYP. Cell viability can be determined after incubating microsomes with PBMCs and the suspected drug in the presence or absence of a microsomal activating system. This assay has not been used for the diagnosis of Page 2

3 cytotoxic lung injury. However, this approach may enhance our understanding of selected drugs that cause DILD, paving the way for development of clinically useful assays [ 34, 35 ]. Immune-mediated pulmonary injuries General pathogenesis of drug allergies Exposure to a particular drug can induce immune reactions in a minority of individuals. Although most have not yet been identified, several factors may control this process: Drug hypersensitivity and other immune reactions are frequently categorized according to Gell and Coombs classification, which includes four categories that reflect distinct immune mechanisms. This variety explains the heterogeneous clinical presentations that can occur [ 37 ]. All these reactions are T cell-regulated, but the effector functions are primarily antibody-mediated factor functions I-III. In their native states, most drugs are not immunogenic. A hapten may directly bind to an immunogenic peptide presented by a major histocompatibility complex molecule. A drug that is not chemically reactive per se may become reactive on metabolism [ 39 ]. The ability to form immunogenic complexes and mount an immune response to these complexes differs among individuals [ 39 ]. They found that chemically inert drugs, which could not covalently bind to peptides or proteins, could directly activate certain T cells if they happened to bear T cell receptors that could interact with the drug. In contrast, encounter with non-self or foreign proteins leads to an immune response. Matzinger proposed an alternative explanation, labeled the Danger Model, of the generation of immune responses [ 40 ]. According to Matzinger, the activation of dendritic cells can be induced by endogenous danger signals, such as - release by tissues undergoing stress, damage, or abnormal death, and by exogenous danger signals elaborated by pathogens. Certain drugs may cause cell injury and act as immunologic triggers. Page 3

4 Chapter 2 : Drug-Induced Lung Disease - Cancer Therapy Advisor Iatrogenic Lung Diseases: Drug-Induced Lung Disease and Radiation Pneumonitis W. Richard Webb DRUG-INDUCED LUNG DISEASE Many drugs, both therapeutic and illicit, can be associated with lung disease. However, drug-induced lung disease is manifested in a limited number of ways. Pharmacological agents responsible for pulmonary toxicity Cytotoxic drugs A. Vinca alkaloids Non cytotoxic drugs A. Acetylsalicylic acid aspirin 2. 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. 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. 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. 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. 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 years of therapy and is characterized by acute onset of hemoptysis, Page 4

5 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. 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. 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. Specific Treatment Discontinuation of potential offending medications is critical in treating cases Page 5

6 of suspected medication-induced lung disease. 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. 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. 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. Page 6

7 Chapter 3 : Drug-induced interstitial lung disease: mechanisms and best diagnostic approaches Drug-induced Lung Disease. Also known as. Drug-induced pneumonitis/fibrosis. Drug-induced non-cardiogenic pulmonary edema. Bronchiolitis Obliterans and Organizing Pneumonia. Bronchioles and alveoli in the lungs Bronchioles and alveoli in the lungs Within your lungs, the main airways bronchi branch off into smaller and smaller passageways, the smallest of which are called bronchioles. At the end of the bronchioles are tiny air sacs alveoli. Pneumonitis occurs when an irritating substance causes the tiny air sacs alveoli in your lungs to become inflamed. This inflammation makes it difficult for oxygen to pass through the alveoli into the bloodstream. Many irritants, ranging from airborne molds to chemotherapy drugs, have been linked to pneumonitis. But for most people, the specific substance causing the inflammation is never identified. Pneumonitis causes may include: A variety of drugs can cause pneumonitis, including some antibiotics, several types of chemotherapy drugs and medications that keep your heartbeat regular. An overdose of aspirin can cause pneumonitis. Repeated exposure to some molds and bacteria can cause the lungs to become inflamed. Exposure to feathers or bird excrement is a common cause of pneumonitis. Some people who undergo radiation therapy to the chest, such as for breast or lung cancer, may develop pneumonitis. Pneumonitis also can occur after whole-body radiation therapy, which is needed to prepare a person for a bone marrow transplant. Risk factors Occupations or hobbies Some occupations and hobbies carry higher risks of pneumonitis, including: Many types of farming operations expose workers to aerosolized mists and pesticides. Inhaling airborne particles from moldy hay is one of the most common causes of occupational pneumonitis. Mold particles also can be inhaled during harvests of grain and hay. Poultry workers and people who breed or keep pigeons are often exposed to droppings, feathers and other materials that can cause pneumonitis. Hot tubs and humidifiers. Moldy conditions in hot tubs can trigger pneumonitis because the bubbling action makes a mist that can be inhaled. Home humidifiers are another common reservoir for mold. Cancer treatment Some chemotherapy drugs can cause pneumonitis, as can radiation therapy to the lungs. The combination of the two increases the risk of irreversible lung disease. Complications Pneumonitis that goes unnoticed or untreated can cause irreversible lung damage. In normal lungs, the air sacs stretch and relax with each breath. Chronic inflammation of the thin tissue lining each air sac causes scarring and makes the sacs less flexible. They become stiff like a dried sponge. This is called pulmonary fibrosis. In severe cases, pulmonary fibrosis can cause right heart failure, respiratory failure and death. Page 7

8 Chapter 4 : Radiation-induced lung disease Radiology Reference Article blog.quintoapp.com Drug-induced lung diseases are an increasingly frequent cause of morbidity. Over drugs are now recognized as being implicated in drug-induced lung diseases. Early diagnosis is critical. A rapid course may mimic noncardiogenic pulmonary edema, while a more subacute course presents insidiously over weeks or months. Progressive pneumonitis may result in pulmonary fibrosis developing over months or years after cessation of drug use; in some cases, respiratory failure may develop. In one study of long-term survivors of childhood and adolescent malignancies, pulmonary fibrosis developed many years after exposure to some chemotherapeutic agents, particularly the nitrosoureas carmustine and lomustine, bleomycin, cyclophosphamide, and busulfan. Chest radiographs show reticular infiltrates, which reflect irreversible fibrosis in severe cases; traction bronchiectasis may be seen. Pulmonary function tests demonstrate abnormalities in DLCO and a restrictive ventilatory defect. Lung biopsies characteristically demonstrate proliferation of atypical type II pneumocytes; organizing pneumonia may be seen, a finding which may not enable differentiation between drug-induced pneumonitis and infection. Noncardiogenic Pulmonary Edema Noncardiogenic pulmonary edema usually presents abruptly with rapidly progressive respiratory distress developing over hours. Diffuse crackles are noted on exam, and arterial blood gas reveals hypoxemia. Chest radiograph demonstrates diffuse alveolar or reticular infiltrates without cardiomegaly or pleural effusions. BAL findings are nonspecific. In severe cases, diffuse alveolar damage DAD may be seen on lung biopsy; however, DAD is a nonspecific finding and may also be seen with infection, shock, transfusion reactions, and tumor lysis syndrome. Withdrawal of the offending drug and supportive care are usually associated with a good prognosis. Hypersensitivity Pneumonitis Pulmonary eosinophilic syndromes typically occur acutely after the patient is exposed to a drug. Several syndromes that are likely pathophysiologically distinct tend to be included in the hypersensitivity category, all of which result in cough and dyspnea; some are accompanied by fever and fatigue, and less commonly, myalgias, arthralgias, or skin eruption. Symptoms are usually mild, and chest radiographs demonstrate patchy pulmonary infiltrates that may be migratory; peripheral eosinophilia is typically seen. Symptoms usually resolve with withdrawal of the drug, and re-challenge will result in relapse. Chronic eosinophilic pneumonia associated with drug toxicity follows a subacute course over weeks to months and is often accompanied by systemic symptoms, peripheral eosinophilia, and radiographic infiltrates that may be migratory. Patients usually respond well to corticosteroids, as do patients with idiopathic chronic eosinophilic pneumonia; however, unlike in patients with idiopathic chronic eosinophilic pneumonia, relapse is rare as long as the patient is not re-challenged with the drug. True hypersensitivity pneumonitis due to a cell-mediated type IV delayed reaction also appears to occur in some cases of drug toxicity, with symptoms and radiographic changes occurring within hours to days after drug exposure; it may be difficult to distinguish from acute noncardiogenic pulmonary edema. Pulmonary Vascular Disease Pulmonary hypertension can occur by several mechanisms including pre-capillary due to dasatinib, post-capillary pulmonary veno-occlusive disease due to mitomycin-c, and cardiac toxicities such as from trastuzumab. Pulmonary veno-occlusive disease PVOD, characterized by fibrotic occlusion of pulmonary veins and eventual development of pulmonary hypertension, is an uncommon complication of chemotherapy. The usual symptom is progressive dyspnea. PVOD may be associated with interstitial abnormalities; pleural effusions are commonly seen, which is unusual in patients with pre-capillary pulmonary hypertension. Evaluation for PVOD may be difficult; a definitive diagnosis requires a surgical lung biopsy. Hepatic sinusoidal obstruction syndrome previously called veno-occlusive disease in the context of treatment for hematopoietic malignancies is more common than PVOD and is thought to result from injury to hepatic venules from toxic drug metabolites. Pleural Disease Pleural disease related to drug toxicity usually occurs in conjunction with pulmonary parenchymal toxicity. An isolated pleural effusion or pleuritis without parenchymal lung disease has been described with methotrexate, docetaxel, dasatinib and others. In contrast to non-chemotherapeutic agents, drug-induced lupus Page 8

9 has not been described with cancer therapies. Carmustine and pazopinib are associated with pneumothorax. The reactions usually occur during or within a few hours of termination of the infusion. Pulmonary symptoms may be as mild as dyspnea or chest tightness, or as severe as anaphylaxis or hypoxemia. Systemic symptoms include pruritus, tachycardia, fever, chills, gastrointestinal complaints, and skin rash. In general, the severity of infusion reactions may be mitigated by premedication with steroids or by slowing the infusion rate. The exception to this rule is anaphylaxis, the most severe and most dangerous form of infusion reaction. In cancer treatment, anaphylaxis is most commonly observed with platinum drugs and taxanes, although it has the potential to occur with any drug. Radiation Sensitization Many chemotherapeutic agents increase the risk of radiation injury to the lung; particularly noteworthy are bleomycin, actinomycin-d, mitomycin, taxanes, and gemcitabine. Pulmonary toxicity should be of particular concern in patients treated with combined chemotherapy and thoracic radiation, such as in patients with lung cancer, breast cancer, or mediastinal tumors, including lymphoma. A broad differential is warranted and chemotherapy induced toxicity is typically a diagnosis of exclusion. Which individuals are at greatest risk for developing chemotherapy-related drug-induced lung injury? Risk factors depend on the particular cancer and chemotherapy. The diagnosis of pulmonary toxicity related to drug exposure is a diagnosis of exclusion. No laboratory tests are diagnostic, though the presence of peripheral eosinophilia can be suggestive of certain toxicities. Laboratory evaluation should be performed primarily to exclude other causes of progressive pulmonary symptoms and abnormal imaging, including infection, volume overload, or progressive malignancy. Often, the first evidence of a new pulmonary process may be an abnormal chest radiograph, with or without pulmonary symptoms. In many cases, chest CT will better characterize the pattern and extent of the abnormality. As with routine laboratory studies, radiographic findings are nonspecific. Radiographic patterns that may be useful in determining the basis for clinical findings include that of radiation pneumonitis, which typically follows the distribution of the thoracic radiation portal, or the discovery of mediastinal or hilar adenopathy, findings which would be uncommon with drug toxicity and more suggestive of progressive malignancy. What imaging studies will be helpful in making or excluding the diagnosis of chemotherapy-related drug-induced lung injury? See discussion of individual agents. What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of chemotherapy-related drug-induced lung injury? Pulmonary function tests PFTs provide an objective measurement of physiologic lung function at the time of initial concern about drug toxicity and may be useful in patient follow-up. The use of PFTs in evaluating patients with various drug toxicities has been widely reported for nearly all drugs known to cause lung injury; however, as with laboratory and radiographic evaluation, PFT abnormalities are nonspecific. PFTs performed to evaluate patients with suspected or known drug toxicity should include measurements of DLCO and lung volumes; DLCO impairment and a restrictive pattern are the most common abnormalities observed. Spirometry may be influenced by a multitude of factors, including muscular weakness, general fatigue, and pain. Anemia impacts the DLCO. Currently, there are no strong recommendations for routine performance of PFTs before, during, or after chemotherapeutic regimens. What diagnostic procedures will be helpful in making or excluding the diagnosis of chemotherapy-related drug-induced lung injury? Bronchoscopic findings are not diagnostic for drug toxicity. BAL and transbronchial biopsies are performed primarily to identify or exclude recurrent malignancy or infection. Performed in sequential fashion, BAL may be useful in identifying patients with alveolar hemorrhage syndrome, which may occur as an uncommon manifestation of drug-induced pulmonary injury. BAL fluid analysis usually demonstrates a nonspecific elevation in cell counts in patients with drug toxicity, although an elevation in eosinophils may suggest hypersensitivity reactions. Surgical lung biopsy, including video-assisted thoracoscopic surgery VATS and open thoracotomy, are more invasive procedures that allow for larger portions of lung tissue to be sampled compared to transbronchial biopsies. Reliable pathologic recognition of patterns of interstitial pneumonitis, organizing pneumonia, hypersensitivity reactions, diffuse alveolar damage, and other potential manifestations of drug toxicity is much more likely with surgical than bronchoscopic lung biopsy. While the findings may not definitively establish a diagnosis of Page 9

10 drug toxicity, the exclusion of malignancy and infection, along with consistent histopathologic findings, supports the diagnosis. Cytologic studies and tissue biopsies obtained from bronchoscopy or surgical lung biopsy may be useful in distinguishing drug toxicity from underlying tumor. If you decide the patient has chemotherapy-related drug-induced lung injury, how should the patient be managed? The cardinal rule of management in patients suspected of having pulmonary disease related to drug toxicity is drug withdrawal; few situations e. Since the impact of discontinuing a chemotherapeutic agent beneficial to cancer treatment may be great, the decision should be made only if other causes of the findings--most importantly, infection or cancer progression--are reasonably excluded. Withdrawal of a drug may be adequate to reverse toxicity, particularly in the case of infusion reactions. Patients with acute or subacute interstitial pneumonitis or hypersensitivity syndromes should be considered for glucocorticoid treatment e. Patients who are unlikely to respond to glucocorticoids include those with chronic pulmonary fibrosis that presents months or years after treatment, noncardiogenic pulmonary edema, or pulmonary vascular disease. All patients should receive supportive care, including alleviation of dyspnea, supplemental oxygen if indicated, and adequate pain management. What is the prognosis for patients managed in the recommended ways? See discussion under individual agents. What other considerations exist for patients with chemotherapy-related drug-induced lung injury? No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. Page 10

11 Chapter 5 : Drug-induced lung disease Radiology Reference Article blog.quintoapp.com Drug-induced lung disease is a common iatrogenic illness. Different drugs can cause similar pulmonary syndromes/presentations. The most common presentation is an abnormality on the chest X-ray in an asymptomatic patient or a symptom-sign complex. Azathioprine, beta-blockers, fluoxetine, gefitinib, nitrofurantoin Eosinophilic pneumonia Amiodarone, aspirin, azathioprine, carbamazepine, clarithromycin, contrast media, diclofenac, G-CSF, gold, levofloxacin, methotrexate, minocycline, naproxen, paracetamol, penicillamine, penicillins, phenytoin, simvastatin Other non-medicine causes of DLI include talc and cocaine 6. Risk Factors The likelihood of developing adverse pulmonary effects secondary to medicines remains largely unpredictable and idiosyncratic 1. However, possible risk factors include: Mechanisms The mechanisms of DLI are unknown, but may include: Management The primary goal of treatment is to suppress the inflammatory response and prevent the deposition of fibrotic tissue. Failure to appreciate the relationship between the medicine and lung injury may lead to significant morbidity or death 1. Therefore, any medicine that is suspected of causing a DLI should be discontinued immediately, unless the benefits clearly outweigh the risks of DLI. Discontinuation in mild cases can be followed by spontaneous improvement and no further management is required 1. Patients with moderate to severe DLI should also receive steroids and supportive treatment 4. If the patient requires continued treatment, it is recommended to switch to a medicine less likely to cause lung injury, if possible 4. Prognosis If DLI is diagnosed early, the patient may make a full recovery. Delayed diagnosis can lead to significant morbidity or death. This is related to the degree of fibrosis and comorbidity rather than severity of the initial clinical presentation. These reports involved suspected medicines as more than one suspected medicine was described in some reports. The most frequently reported medicines are shown in Figure 1. The average age of the patients experiencing a DLI was 67 years. The youngest patient was 16 years and the oldest was 97 years. Time to onset was reported for of the suspected medicines. For eight of the suspected medicines, the onset was reported to have occurred within one day of treatment initiation. For of the suspected medicines, the onset was longer than one year. In 95 of the cases, the patient was reported to have fully recovered, while 38 cases reported a fatal outcome. Drug induced interstitial lung disease. The Open Respiratory Medicine Journal 6: Zibrak JD, Price D. Consensus statement for the diagnosis and treatment of drug-induced lung injuries. The diagnosis and management of interstitial lung diseases. Amiodarone Pulmonary Toxicity â early recognition is vital. Prescriber Update 34 4: Page 11

12 Chapter 6 : Drug-Induced Pulmonary Disease - Pulmonary Disorders - MSD Manual Professional Edition ABSTRACT: Drug-induced lung disease (DILD) can be caused by a variety of agents, including chemotherapeutic drugs, antiarrhythmic agents, antibiotics, and blog.quintoapp.com clinical syndromes associated with DILD include alveolar hypoventilation, acute bronchospasm, organizing pneumonia, and hypersensitivity reactions. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License http: This article has been cited by other articles in PMC. Abstract With an increasing number of therapeutic drugs, the list of drugs that is responsible for severe pulmonary disease also grows. Many drugs have been associated with pulmonary complications of various types, including interstitial inflammation and fibrosis, bronchospasm, pulmonary edema, and pleural effusions. Drug-induced interstitial lung disease DILD can be caused by chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents. There are no distinct physiologic, radiographic or pathologic patterns of DILD, and the diagnosis is usually made when a patient with interstitial lung disease ILD is exposed to a medication known to result in lung disease. Other causes of ILD must be excluded. Treatment is avoidance of further exposure and systemic corticosteroids in patients with progressive or disabling disease. Lung, adverse drug reaction, drug-induced lung disease, mechanism of pulmonary toxicity, diagnosis, treatment, review. They can also act as a metabolism site for certain substances. Drugs can induce specific respiratory reactions or the lungs may be affected as part of a generalized response. More than medications are known to cause drug-induced respiratory diseases, the true frequency is unknown [ 1, 2 ]. The number of drugs, that cause lung disease, will undoubtedly continue to increase as new agents are developed. To minimize the potential morbidity and mortality from drug-induced respiratory diseases, all health care providers should be familiar with the possible adverse effects of the medications they prescribe. The person-to-person variability of a drug response is a major problem in clinical practice and in drug development. The variability in drug response among patients is multifactorial, including extrinsic factors like environmental aspects and also genetic and intrinsic factors that affect the disposition of a certain drug. The most common form of drug-induced lung toxicity is drug-induced interstitial lung disease DILD. Oral and parenteral routes of drug administration are most frequently cited as causing DILD; however, nebulized and intrathecal administration have been also been implicated. Pulmonary drug toxicity may result from a direct or indirect drug effect. Direct effects may be either idiosyncratic or due to a toxic reaction of the drug or one of its metabolites. Recognition of drug-induced lung disease, however, is difficult because the clinical, radiological, and histological findings are nonspecific. The connection with drug use and the development of related inflammatory damage or idiosyncratic toxicities is hard to recognize and objectify, especially in those cases using multiple drugs [ 3 ]. A Swedish study has implicated adverse drug reactions as 7th most common cause of death [ 8 ]. A large prospective study of adverse drug reaction in UK hospital in-patients suggests that at least 1 in 7 in-patient episodes is complicated by an adverse drug reaction and the incidence of Over the period between and the annual number of adverse drug reactions increased by An estimated calculation in the Netherlands showed that about million euros could be saved each year when side effects are reduced [ 6 ]. In the United States, an estimated 0. Exact frequency of drug-induced pulmonary toxicity is unknown. Several studies suggest that drug-induced pulmonary toxicity is underdiagnosed worldwide. Global incidence of interstitial lung disease ILD is not clearly known but 2. The list and frequency of toxicity of all drugs implicated in lung injury can be found elsewhere [ 14 ]. Patients likely to develop DILD are those receiving chemotherapy, those with inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease, and those receiving concurrent multiple toxic agents. Some of the known risk factors are as follows: Age In general, both extremes of age i. The elderly patient is more prone to develop severe side effects, partly because of the fact that the excretory function of the kidney is lower, the liver blood perfusion is diminished and the overall metabolic function is changed. For instance, Simpson et al. Sex In long-term nitrofurantoin prophylaxis, a chronic form of pulmonary reactions has been reported to occur after 8 Page 12

13 months to 16 years of treatment [ 16 ]. Most of those affected have been elderly and most have been females. However at yet, there is no scientific evidence in the literature that the gender influences the risk of DILD. In Japan, cases of lung diseases presumably induced by gefitinib have provided important findings, including evidence about racial differences in the DILD and pathological variety of the lung diseases [ 17 ]. However, it is difficult to determine the relative incidence of DILD during the drug-development phase, because the events are too rare and the sample sizes are too small to make reliable estimates from the results of clinical studies. Acute and organizing diffuse alveolar damage associated with Bortezomib were also first reported in Japan and subsequently in African American patients with severe pneumonitis [ 18, 19 ]. Ethnic influences could be also observed by leflunomide and tacrolimus [ 20, 21 ]. Genetic polymorphisms may help explain why some groups of patients have the expected response to pharmacotherapy whereas others experience toxicity or therapeutic failure [ ]. Dose In several cases, such as therapies with amiodarone, bleomycin or BCNU, the dose has been found to be a risk factor for a drug to cause ILD [ 1, ]. Although this affirmation is not universal, physicians should keep in mind this possibility and monitor a drug dose according to the published information. Oxygen Lung tissue is vulnerable to the toxic effects of oxygen and oxygen damage readily occurs. The lungs are normally equipped with an extensive antioxidant network to protect against tissue damage by reactive oxygen species. This network may be insufficient and this situation of inadequate protection is called oxidative stress. It is striking that numerous conditions that lead to ILD may cause reactive oxygen species and result in oxidative stress [ 32 ]. Amiodarone is damaging to the lungs via transfer of electrons to O2. Drug Interaction The role of drugs taken concomitantly may be important. Drugs in the same therapeutic class can often induce similar pulmonary toxicity pattern [ 34 ]. Hazardous associations have been reported with the coadministration of cisplatin and bleomycin, which can increase the risk of bleomycin-induced interstitial lung disease. The combination therapy of gemcitabine and bleomycin is very toxic too. Radiation DNA damage and repair proteins are involved in many types of lung injury and repair. Radiation can be injure the lung by this mechanisms and radiation therapy in combination with chemotherapy may be synergistic [ 1 ]; for instance, conjoint radiation therapy is associated with high rates of lung toxicity by bleomycin. Underlying Lung Disease Preexisting lung disease as an important risk factor is controversial. By logistic regression analysis, the following risk factors were identified to be most commonly associated with a poor prognosis: The hitherto existing literature states the prevalence of methotrexate pneumonitis to be 3. Sathi N et al. The possible link between leflunomide and ILD has evoked increasing concern. On the other hand, Suissa et al. The increase in the risk of ILD associated with leflunomide is restricted to the subgroup of patients with a history of methotrexate use or existing ILD relative risk 2. Page 13

14 Chapter 7 : Drug- and radiation-induced lung disease Radiology Key Interstitial Lung Disease Induced by Drugs and The diagnosis of drug-induced lung disorders rests on radiation therapy is used concomitantly. Accordingly, DI-. Drug-induced disease of any system in the body is associated with a high degree of morbidity or mortality; however, when it affects the pulmonary system, the risks grow substantially. Over medications can adversely affect the lungs. Adverse drug reactions include asthmatic exacerbations, cough, interstitial pneumonitis, and pleural effusions. Medications implicated in life-threatening pulmonary reactions include cardiovascular drugs, cytotoxic agents, and antimicrobials, as well as smoking and alcohol use. It is imperative that clinicians obtain an accurate, detailed, and current medication history, including alternative medicines to enable accurate differentiation between drug-induced pulmonary disorders and other pulmonary diseases. Adverse drug reactions ADRs have been estimated to be the third leading cause of death in the United States, following heart disease and cancer. Although the liver is the primary drug-metabolizing organ of the body, the lungs are also capable of drug metabolism. Japanese and Korean patients have experienced much higher incidence and mortality rates when using tumor necrosis factor TNF and methotrexate. Prevention Prospective patients should be screened for preexisting lung disease and renal, hepatic, and cardiac function. A thorough risk-benefit analysis should be undertaken, and therapy with high-risk DIPD drugs should be initiated at lowest effective therapeutic doses with pulmonary, renal, and hepatic function monitoring. Dose-dependent symptoms of pneumonitis and fibrosis, including dyspnea, cough, and pulmonary crackles, were reported with many medications, most notably, amiodarone. Drug hypersensitivity presents as an immediate reaction with urticaria, angioedema, rhinitis, conjunctivitis, dyspnea, and bronchospasm. Patients who present with drug-induced pulmonary edema experience persistent cough, tachypnea, dyspnea, tachycardia, and hypoxemia. Drug-induced bronchospasm can be sudden and severe, causing asphyxia and irreversible brain damage. The list includes hydralazine, isoniazid, phenytoin, procainamide, and sulfonamides. Chest x-rays and CT scans are helpful in establishing the diagnosis. Common adverse pulmonary effects are allergic reactions, which can affect breathing. COPD exacerbation is common in illicit drug smokers. Preventive Services Task Force currently recommends an annual cancer screening for smokers. Alcohol Alcohol is excreted into the airways as evidenced by its presence in the breath test i. The most significant pulmonary effects are an increased risk for bacterial infection. Improved awareness of medications that can cause pulmonary disease can expedite diagnosis and treatment of patients and facilitate harm reduction to prevent future complications. Additionally, knowledge of drugs and other substances that may induce pulmonary disease can represent a prime opportunity for patient counseling. Before starting any medication, pharmacists should counsel patients about potential adverse effects. A detailed medication history including prescription drugs, OTC products, herbals, tobacco, alcohol to identify underlying risk and causative factors for DIPD is essential. Smoking cessation through patient counseling and OTC product selection is helpful. Through patient counseling and OTC product selection i. Every patient at each pharmacy visit should be asked if he or she smokes and is interested in quitting. Conclusion Pulmonary diseases can result from a number of agents and can have myriad presentations. DIPDs are common, although underreported. An analysis of the risks and benefits of administration of medication with documented pulmonary ADRs should be undertaken. DIPD should be considered in the differential diagnosis of many respiratory conditions. Is US health really the best in the world? Incidence of adverse drug reactions in hospitalized patients. A meta-analysis of prospective studies. Mechanisms in pulmonary toxicity. Drug-induced inflammatory responses to the lungs. Accessed March 14, Therapeutic update on drug-induced pulmonary disorders. Okuno SH, Frytak S. Acute and chronic phases. Am J Clin Oncol. Bronchiolitis obliterans organising pneumonia associated with the use of nitrofurantoin. Incidence, prevention and management. Churg-Strauss syndrome in patients treated with omalizumab. Interstitial lung disease and gefitinib. N Engl J Med. Pleural disease during treatment with Page 14