Abstract
Numerous drugs can cause pulmonary reactions in children. Chemotherapeutic agents are most frequently implicated, although toxic effects of other medications have been recognized. Reactions to chemotherapeutic agents may be dose-related; most reactions to noncytotoxic agents develop idiosyncratically. Clinical/pathologic syndromes described include diffuse interstitial pneumonitis and fibrosis, hypersensitivity pneumonitis, noncardiogenic pulmonary edema, pleural effusion, bronchiolitis obliterans, and alveolar hemorrhage. Presenting symptoms vary but often include fever, cough, and dyspnea, and radiologic studies demonstrate diffuse alveolar and/or interstitial abnormalities. Abnormalities in lung function may precede symptoms and radiographic changes. Patterns of abnormalities on chest CT, bronchoalveolar fluid analysis and cultures, and lung histopathology may be useful in categorizing and defining extent of disease but may be nonspecific. Other disorders, including infection, hemorrhage, lung disease related to underlying disease, and radiation damage, must be considered. Criteria for the diagnosis of drug-induced lung disease have been outlined. Although some drug-induced lung injury is reversible, persistent and even fatal dysfunction may occur. Survivors of childhood cancer require follow-up as lung disease may develop remotely from drug exposure and be progressive. More precise information about risk factors, including genetic predisposition and mechanisms of injury, along with more sensitive diagnostic and monitoring approaches are needed for development of improved therapeutic strategies, including early intervention.
Keywords
drug-induced lung disease, drug toxicity
Numerous drugs can cause pulmonary or pleural reactions in children. The most frequent offenders are chemotherapeutic agents used in the treatment of childhood neoplasms ( Table 59.1 ), although toxic effects of other agents are increasingly recognized ( Table 59.2 ). Diffuse interstitial pneumonitis and fibrosis constitutes the most frequent clinical syndrome. Hypersensitivity lung disease, noncardiogenic pulmonary edema, pleural effusion, bronchiolitis obliterans, and alveolar hemorrhage are also encountered.
| Incidence (%) | Mortality (%) | Clinical/Pathologic Syndromes | |
|---|---|---|---|
| Bleomycin | 2–40 | 1–10 | IP/PF, H, P Eff, EP |
| Cyclophosphamide | ≤1 | 40 | IP/PF, PE, B, AH |
| Chlorambucil | a | ≤50 | IP/PF |
| Busulfan | 2–43 | b | IP/PF, P Eff, AH |
| Melphalan | a | ≤60 | IP/PF |
| Carmustine (BCNU) | 10–30 | 15–90 | IP/PF |
| Methotrexate | 8 | 1 | IP/PF, H, PE, P Eff |
| 6-Mercaptopurine | a | b | IP/PF |
| Cytosine arabinoside | 13–28 | 50 | IP/PF, PE, BOOP, DMD |
| Gemcitabine | a | b | IP, B, PE, ARDS |
| Fludaribine | 9 | b | IP/PF |
| Procarbazine | a | b | H |
| Hydroxyurea | a | b | H |
| Paclitaxel | 4–9 | 0 | H |
| Docetaxel | 73 | 0 | H, IP, decreased DL CO |
| Gefitinib | 1 | 33 | IP |
| Imatinib | a | b | P Eff, PE |
| Cetuximab | 1 | b | IP |
| Interleukin-2 | >50 | 0 | PE, P Eff |
| ATRA | 5–27 | 5–29 | IP, P Eff, PE, AH |
| Recorded Cases or Incidence | Mortality | Clinical/Pathologic Syndromes | |
|---|---|---|---|
| Nitrofurantoin | >500 adult >10 pediatric | 8% (chronic exposure) | H, IP/PF, B, AH, P Eff, BOOP, GIP |
| Sulfasalazine | >50 adult | a | H, EP, IP/PF, BOOP, FA, B |
| Mesalazine | >40 adult 8 pediatric | a | H, EP, IP/PF,G |
| Diphenylhydantoin | >5 adult >5 pediatric | 0 | H, B, BOOP |
| Carbamazepine | >10 adult >10 pediatric | 0 | H, IP/EP, B, BOOP |
| Levetiracetam | 2 adult 1 pediatric | 0 | IP |
| Minocycline | >50 adult and adolescent | a | EP |
| Penicillamine | >40 adult 1 pediatric | 50% (AH, BO) | H, DA, BOOP, AH |
| Leflunomide | >40 adult | 20% | IP, DAD |
| Azathioprine | >15 adult 1 pediatric | 12% | H, AH, IP, DAD, BOOP |
| Amiodarone | 5% 4 pediatric | 10% 50% for ARDS | H, EP, IP/PF, BOOP,P Eff, AH, ARDS |
| HMG-CoA reductase inhibitors (statins) | >15 adult | 25% | H, IP/PF |
| Pegylated interferon | b | 7% | IP |
Although some drug-induced pulmonary damage is reversible, persistent and even fatal dysfunction may occur. Lung reactions occasionally are temporally remote from exposure to chemotherapeutic agents. Depending on the agent involved, the reaction may or may not be dose related. The mechanism of toxicity is thought to be direct injury to lung cells in most cases, but immunologic and central nervous system-mediated mechanisms seem to play a role in the toxicity of certain agents. Identified risk factors associated with cytotoxic drug therapy vary, but they include cumulative dose, age of patient, prior or concurrent radiation, oxygen therapy, and use of other toxic drugs. Most reactions to noncytotoxic drugs appear to develop idiosyncratically. When patients are treated with combinations of potentially toxic drugs or with a toxic drug plus irradiation to the chest or high concentrations of oxygen, as is common in the treatment of childhood cancers, specific offenders often cannot be identified. There is little if any evidence that children are more susceptible to drug-related pulmonary injury, and in fact, they may be less susceptible to some agents such as bleomycin.
The clinical presentation of drug-induced lung disease often includes fever, malaise, dyspnea, and nonproductive cough. Radiologic studies almost always demonstrate diffuse alveolar and/or interstitial involvement. Segmental or lobar disease, particularly if unilateral, should suggest another diagnosis. Abnormal pulmonary function, indicative of restrictive or obstructive disease, may be found before appearance of roentgenographic lesions. Chest computed tomography (CT) may also provide early evidence of parenchymal abnormalities, and hypoxemia is an early and clinically important functional consequence. Pathologic features do not distinguish between most drugs and most often consist of interstitial thickening with chronic inflammatory cell infiltrates in the interstitial or alveolar compartment, fibroblast proliferation, fibrosis, and hyperplasia of type II pneumocytes, which contain enlarged hyperchromatic nuclei. With hypersensitivity reactions, the interstitial infiltrate includes substantial numbers of eosinophils. Interstitial pneumonitis can be part of the multisystem syndrome known as “drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms” (DIHS/DRESS). Other diagnoses, such as infection, pulmonary hemorrhage, lung disease related to an underlying disorder, and radiation damage must be considered in patients with suspected drug-induced lung injury. Bronchoalveolar lavage (BAL) is increasingly utilized to provide microbiologic and cytologic information essential to differential diagnosis and as a tool to begin to identify disease markers and potential pathogenic mechanisms.
Practical criteria for diagnosing drug-induced lung disease have been suggested by Kubo and colleagues. These include (1) history of ingestion of a drug that is known to induce lung injury, (2) clinical manifestations have been reported to be induced by a drug, (3) other causes of clinical manifestations have been ruled out, (4) improvement of clinical manifestations after drug discontinuation, and (5) exacerbation of clinical manifestations after resuming drug administration.
Cytotoxic Drugs Used in Cancer Therapy
Survivors of childhood cancers have often been exposed to multiple cytotoxic agents with potential lung toxicity, in addition to radiation, and are thus at increased risk for long-term pulmonary complications from these agents. Compared to children without a cancer history, leukemia and lymphoma survivors are at increased risk for hospitalization for pulmonary-related reasons (relative risk [RR], 8.1; 95% confidence interval [CI], 3.9–16.8). A recent review by the Children’s Oncology Group Guideline Task Force on Pulmonary Complications recommended that health care providers following such children should receive a standardized cancer treatment summary from their oncologist to assess risk for pulmonary complications and that pediatric cancer survivors who received bleomycin, or who are subsequently undergoing general anesthesia for procedures, should have lung function monitored. A cohort of 5000 survivors of childhood cancers, using the Children’s Oncology Group Long-Term Follow-Up (COG-LTFU) Guidelines, underwent rigorous screening with pulmonary function tests (PFT), and abnormalities were present in 84%.
Bleomycin
Bleomycin is a mixture of peptide antibiotics obtained from Streptomyces verticillus. Its major use in children is in the treatment of Hodgkin disease and other lymphomas. Because of the high frequency of pulmonary reactions and the utility of bleomycin for generating animal models of lung fibrosis, this agent has been studied more thoroughly than others. Pulmonary damage develops in two distinct patterns, most commonly progressive fibrosis and uncommonly an acute hypersensitivity reaction.
Pulmonary disease secondary to bleomycin occurs in as many as 40% of patients receiving the drug, and a recent systematic review identified bleomycin exposure (along with alkylating agents) as a significant risk factor for long-term pulmonary toxicity. Forty-one percent of childhood cancer survivors treated with bleomycin had abnormal spirometry (obstructive changes) in a cross-sectional analysis, although only 9% were symptomatic. Multivariate analyses of follow-up data from the multicenter Childhood Cancer Survivor Study indicate that use of bleomycin is significantly associated with lung fibrosis (RR 1.7), bronchitis (RR 1.4), and chronic cough (RR 1.9) ≥5 years postdiagnosis. Bleomycin-induced pneumonitis may be diagnosed years after its use, as reported in a 15-year-old girl who had received bleomycin as an infant for yolk sac carcinoma. Significant lung damage rarely occurs in adults at cumulative doses less than 150 mg. When more than 283 mg/m 2 is administered, 50% of adult patients develop severe pneumonitis. Pulmonary damage is more severe in elderly than in young patients and in those with reduced glomerular filtration rate. Slow intravenous administration results in less lung disease than intramuscular injection or intravenous bolus. The combination of radiotherapy or high inspired oxygen concentrations and bleomycin produces more lung injury than either alone. Pulmonary toxicity associated with relatively small quantities of bleomycin has been reported during combination drug therapy, and pediatric sarcoma or Hodgkin disease patients receiving bleomycin have increased risk for radiation pneumonitis.
Pulmonary injury due to bleomycin occurs by direct injury to cells as well as by secondary immunologic reactions. Direct toxicity may be mediated by oxidant injury, either through the production of reactive oxygen metabolites or through inactivation of antioxidants. Data supporting this mechanism include the findings that pretreatment of rodents with antioxidants, or upregulation of the antioxidant gene transcription factor Nrf2, can reduce subsequent bleomycin-induced pulmonary fibrosis. Additionally, bleomycin may directly induce senescence or apoptosis of type II epithelial cells. Bleomycin also generates production of inflammatory mediators by lung cells, and inflammatory cells may participate in further oxidant and proteolytic damage to lung cells. Bleomycin promptly increases collagen synthesis by fibroblasts, an effect which may be mediated by transforming growth factor-β. Anti-inflammatory agents, antioxidants and, specifically, nebulized heparin or urokinase can inhibit bleomycin-induced lung damage in animal models. Gunther and colleagues have reported complete abrogation of bleomycin-induced pulmonary fibrosis in rabbits using nebulized heparin or urokinase.
Bleomycin-induced lung disease can begin insidiously, and asymptomatic patients may have decreases in arterial oxygen saturation and carbon monoxide diffusing capacity (DL CO ). As the illness progresses, there is a decline in vital capacity and total lung capacity, which is characteristic of restrictive lung disease. In both interstitial pneumonitis and hypersensitivity lung reactions, patients typically present with a dry hacking cough and dyspnea; these signs occur only on exertion in mild cases, but profound respiratory distress accompanies advanced illness. Fever suggests a hypersensitivity reaction. Physical examination reveals tachypnea and fine crackles. Chest radiographs in symptomatic patients most commonly demonstrate diffuse linear densities. A widespread reticulonodular or alveolar pattern may also be seen. Chest CT is more sensitive for detection of early interstitial disease, and in animal models, chest CT findings correlate well with pathologic changes. Biopsy specimens usually reveal interstitial pneumonitis, fibrosis, and extensive alveolar damage with hyperplasia of type II cells, which are most prominently in subpleural and basilar regions.
Patients receiving bleomycin should be monitored by serial determinations of DL CO . Chest CT may also be useful for monitoring progression of disease, although the radiation exposure from this source cannot be ignored. Therapy of bleomycin-induced pneumonitis consists largely of supportive measures. Withdrawal of the drug at the onset of toxicity must be considered. Careful monitoring of oxygen therapy to avoid excessive exposure is imperative. Although the inflammatory cell element resolves substantially with therapy, much of the fibrotic damage is irreversible. Treatment with bleomycin is a significant predictor of long-term respiratory symptomatology and pulmonary function decrements in survivors of Hodgkin disease. Use of steroids is controversial, but reversal of severe toxicity has been documented in some patients after use of high-dose steroids. In the few patients exhibiting hypersensitivity reactions or eosinophilic pneumonitis with bleomycin, corticosteroids have a definite role.
Alkylating Agents
Cyclophosphamide
Cyclophosphamide is widely used in the treatment of leukemias, lymphomas, and nonmalignant illnesses. Although pulmonary toxicity is uncommon, it does produce severe and even fatal lung damage. Data from the Childhood Cancer Survivor Study indicate a significantly increased long-term risk for supplemental oxygen requirement, recurrent pneumonia, chronic cough, dyspnea on exertion, and bronchitis. Frankovich and colleagues reported a series of 34 children who underwent autologous bone marrow transplant for relapsing Hodgkin disease and were treated with cyclophosphamide in combination with etoposide and either carmustine, chloroethylcyclohexylnitrosourea, or irradiation. Fifteen of these patients developed lung injury syndromes including interstitial pneumonitis, acute alveolitis, diffuse alveolar hemorrhage, acute respiratory distress syndrome (ARDS), and bronchiolitis obliterans. Four of the patients died of pulmonary complications. In this series, a history of atopy was associated with pulmonary complications.
Cyclophosphamide appeared to result in greater pulmonary toxicity than fludarabine in one pediatric series when either agent was combined with busulfan for prehematopoietic cell transplantation conditioning. Experiments in rodents indicate that, as for bleomycin, both oxidant and inflammatory or immune mechanisms are involved in cyclophosphamide lung toxicity. Acute IgE-mediated systemic reactions have been reported, including angioedema and bronchospasm. Cyclophosphamide also may predispose to toxicity when medications such as bleomycin, azathioprine, and carmustine are used subsequently.
Little is known regarding the relationship of dose, duration, and frequency of administration to the appearance of parenchymal disease in humans, although cytotoxicity appears to be dose-related in rats. Pulmonary reactions have occurred following total doses between 0.15 and 50 g. Pulmonary disease may begin during cyclophosphamide therapy or weeks to years after. A striking feature in pediatric cases has been chest wall deformity secondary to failure of lung growth during the adolescent growth spurt. Subacute dry cough and dyspnea herald the onset of pulmonary toxicity; and then malaise, anorexia, and weight loss follow. Physical examination reveals tachypnea and diffusely diminished breath sounds. Chest roentgenograms may show diffuse bilateral infiltrates, sometimes with pleural thickening, and pulmonary function testing reveals hypoxemia and restrictive lung disease. Biopsy and postmortem specimens show interstitial fibrosis, alveolar exudates, and atypical alveolar epithelial cells. Withdrawal of the drug, supportive therapy, and corticosteroids are recommended treatment.
Chlorambucil
Chlorambucil is used in the treatment of leukemias, some lymphomas, nephrosis, and inflammatory conditions such as sarcoidosis. Several reports indicate that the drug produces pulmonary toxicity, albeit rarely. Little is known concerning the dose or duration of therapy necessary to produce lung damage. Patients develop cough, dyspnea, fatigue, and weight loss that appear 6 months to 3 years after initiation of therapy and progressively worsen. Physical examination reveals tachypnea and fine bibasilar crackles. Chest roentgenograms demonstrate diffuse interstitial infiltrate, and pulmonary function tests indicate restrictive lung disease accompanied by a defect in DL CO . Histopathologic findings are similar to those associated with busulfan and cyclophosphamide therapy. Although improvement with discontinuation of the drug and corticosteroid therapy has been reported, progression of disease may occur.
Other Alkylating Agents
Busulfan (Myleran) is used to treat chronic myelogenous leukemia, which occurs occasionally in childhood, and in some preparative regimens for bone marrow transplantation. Four percent of adult patients undergoing long-term treatment with this drug develop interstitial pneumonitis and fibrosis. Mertens and colleagues reported increased long-term risk for supplemental oxygen requirement and pleurisy after busulfan treatment. As with chlorambucil, pulmonary injury is usually not evident for many months after initiation of treatment, and radiation and previous cytotoxic therapy are risk factors. The clinical syndrome is similar to that produced by the other alkylating agents, and the treatment consists of discontinuation of busulfan. Efficacy of corticosteroids is unproven, but a carefully monitored trial is indicated because of the poor prognosis.
An increase in incidence of alveolar hemorrhage has been reported when etoposide (VP-16) was added to a regimen of busulfan and cyclophosphamide for bone marrow transplantation; toxicity in this study was largely confined to patients who had been given prior chest radiotherapy. However, Quigley and colleagues found that in children, preparative regimens for bone marrow transplantation that included busulfan were associated with preservation of pulmonary function compared to regimens using other combination high-dose chemotherapeutic regimens or total body irradiation.
Melphalan is used primarily in the treatment of multiple myelomas and hence is employed infrequently in pediatrics. Although overt toxicity is unusual, frequency of epithelial changes and fibrosis at autopsy may be as high as 50%. Bronchial epithelial cell proliferation has been an unusual finding. Otherwise, the pathologic changes are typical for alkylating agents and may be reversible with discontinuation of the drug.
Nitrosoureas
Carmustine
Carmustine, also called bis-chloroethylnitrosurea (BCNU), is a synthetic antineoplastic compound, and its major use is in the therapy of lymphomas and gliomas. The incidence of BCNU pulmonary toxicity is quite variable; 20%–30% of treated patients develop some lung disease. The total dose administered, duration of therapy, and preexistence of lung disease are the most accurate predictors of pulmonary toxicity. Most patients with symptomatic respiratory disease have received large cumulative doses (>777 mg/m 2 ). When the cumulative dose exceeds 1500 mg/m 2 , there is a 50% probability of lung disease. Patients with toxicity also appear to have received the drug over a shorter period, irrespective of the total dose given. The onset of pulmonary symptoms has been noted between 30 and 371 days after institution of therapy, sometimes after BCNU has been discontinued. Young patients are reportedly at greater risk, but this may be the result of relatively higher doses and increased numbers of therapy cycles because of greater general tolerance. Mertens and colleagues reported a significant risk for supplemental oxygen requirement among children ≥5 years status post BCNU or lomustine (CCNU) treatment. A study of 73 children with high-grade glioma treated with the combination of BCNU, cisplatin, and vincristine reported that seven children developed interstitial pneumonitis, which was fatal in six children. Radiation therapy may be synergistic. In adult patients, female gender and combination with cyclophosphamide have been identified as risk factors for pulmonary complications.
Patients with BCNU pulmonary toxicity exhibit much the same clinical picture as that described for bleomycin. Histologic findings are also similar. In a study of eight patients who underwent lung biopsy 12–17 years after treatment with BCNU, there was electron microscopic evidence of ongoing endothelial and epithelial damage, suggesting long-term toxic effects of the drug. One of these patients died with pulmonary hypertension due to interstitial fibrosis. The disease is fatal in approximately 15% of those affected.
Therapy is essentially supportive. Corticosteroids are often administered concomitantly with BCNU for brain tumors and afford no protection from subsequent pulmonary toxicity. However, corticosteroids may offer some benefit in the treatment of early stages of acute disease. Thymidine has been used as a biomodulator to protect from BCNU pulmonary toxicity in patients with malignant melanoma and may act via modulation of DNA repair enzymes in normal tissue. In a rat model, metallothionein attenuated BCNU toxicity via antioxidant effects.
Antimetabolites
Methotrexate
Methotrexate (4-aminopteroylglutamic acid) is a folic acid antagonist used in the treatment of several childhood malignancies, notably leukemias and osteogenic sarcoma as well as nonmalignant conditions such as rheumatoid arthritis and psoriasis. The lung inflammation induced by methotrexate appears to be linked to activation of the p38 mitogen-activated protein (MAP) kinase signaling pathway with subsequent cytokine activation. Prevalence rates of 0.3%–11.6% have been reported for pulmonary toxicity due to methotrexate, but ascertainment of its effects is complicated by the frequent use of combination therapy and the tendency of underlying diseases such as rheumatoid arthritis to also cause lung disease. No correlation has been found between lung toxicity and dose of methotrexate, and pneumonitis may occur remotely.
The clinical features of methotrexate lung toxicity are consistent with a hypersensitivity pneumonitis. Disease usually begins with a prodrome of headache and malaise and is then followed by dyspnea and dry cough. Pleuritic pain is rare, and fever may also occur. Physical examination reveals tachypnea, diffuse crackles, cyanosis, and occasionally skin eruptions. Hypoxemia is observed in 90%–95% of patients, and mild eosinophilia has been reported in 41%. Few reports have documented pulmonary function changes but decreased DL CO may occur. Lung function testing in a series of children with juvenile rheumatoid arthritis who received methotrexate showed a similar incidence of abnormal function, including DL CO , to a control population not receiving methotrexate. The most common abnormalities on chest radiographs are bilateral interstitial infiltrates or mixed interstitial and alveolar infiltrates. Lung biopsy in adults reveals interstitial pneumonitis with lymphocytic and sometimes eosinophilic infiltrates, bronchiolitis, and granuloma formation consistent with a hypersensitivity reaction, although type II alveolar cell hyperplasia typical of cytotoxicity has also been found. BAL fluids typically show lymphocytosis with variable CD4/CD8 ratios and moderate neutrophilia.
Diagnosis of methotrexate-induced pneumonitis is difficult because this condition may mimic other diseases. Pulmonary infection must be excluded, particularly if high-dose methotrexate is used or if the underlying disease is associated with immunosuppression. Therapy consists of withdrawal of the drug and administration of corticosteroids, but the latter has not been analyzed in controlled trials. Treatment with folinic acid (leucovorin rescue) does not prevent methotrexate lung toxicity, and the outcome is usually favorable with clinical improvement preceding radiographic and pulmonary function improvement. However, two fatal outcomes in arthritis patients with a history of lung toxicity suggest that retreatment should be avoided after recovery from methotrexate lung injury.
6-Mercaptopurine, Cytosine Arabinoside, and Gemcitabine
Scattered case reports have linked pulmonary dysfunction to 6-mercaptopurine and cytosine arabinoside (also known as Ara-C ). In addition, an autopsy study of patients who had leukemia and who received cytosine arabinoside within 30 days of death demonstrated significant pulmonary edema for which there was no obvious other explanation in most instances. An adult patient receiving low-dose cytosine arabinoside (20 mg/m 2 per day) and recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) developed ARDS on day 12 and died 40 days after initiation of therapy. It has recently been reported that 5 of 22 pediatric patients receiving Ara-C (1.0–1.5 g/m 2 per day) for treatment of acute myelogenous leukemia developed pulmonary insufficiency secondary to noncardiogenic pulmonary edema. The outcome was fatal in 3 of 5 patients. Bronchiolitis obliterans organizing pneumonia (BOOP) developed in an adult patient with chronic myelogenous leukemia after treatment with Ara-C in combination with interferon alpha, and the condition resolved after discontinuation of these agents. Chagnon and colleagues described a series of six young adults with acute myelogenous leukemia who developed fever and diffuse micronodular lung disease associated with high-dose Ara-C. Gemcitabine, a similar drug in structure and metabolism to Ara-C, has been associated with ARDS in three patients. These authors reported that corticosteroids and diuretics were helpful, but two of the three patients died. Gemcitabine has also been associated with dyspnea, bronchoconstriction, and nonspecific pneumonitis, particularly in Hodgkin disease patients also treated with bleomycin. The nucleoside analog fludaribine, used in treatment of lymphoma and chronic lymphocytic leukemia, is associated with steroid-responsive interstitial disease in 9% of cases.
Other Cytotoxic Agents
Procarbazine, VM-26, and vinca alkaloids (vinblastine and vindesine) have been associated with pulmonary injury, but in all cases, other agents may have contributed. Three of five young adults treated with a regimen of vinblastine, doxorubicin, bleomycin, and dacarbazine for Hodgkin disease, and granulocyte colony stimulating factor (G-CSF) to increase neutrophil counts developed pulmonary toxicity in one report. G-CSF may thus potentiate the lung toxicity of these agents. Reactions to procarbazine have been of the hypersensitivity type. Hydroxyurea has been reported to induce severe, corticosteroid-responsive, hypersensitivity pneumonitis. Paclitaxel is a plant-derived taxane agent that has been used against a broad range of tumors, including breast, ovarian, lung, head, and neck cancers; and it has been associated with a high frequency of hypersensitivity pneumonitis reactions. Lung biopsy has shown interstitial pneumonitis, and BAL fluid has shown eosinophilia and lymphocytosis with a depressed CD4/CD8 ratio. In a 5-year review of a series of cancer patients who received monthly paclitaxel infusions, the incidence of hypersensitivity reactions was 4%, and pretreatment with dexamethasone, diphenhydramine, and H 2 -blockers was effective in preventing recurrence. Interstitial pneumonitis is more common when paclitaxel is combined with radiation therapy and has been reported in association with a paclitaxel-eluting coronary artery stent. Docetaxel, a semisynthetic taxane, has been proposed as a safer alternative but has also occasionally been associated with severe hypersensitivity reactions or corticosteroid-responsive interstitial pneumonitis. For example, a series of asymptomatic adult cancer patients who received docetaxel monotherapy for nonlung cancers had a small but significant drop in lung function post treatment. Oxaliplatin appeared to cause cryptogenic organizing pneumonitis in a 30-year-old being treated for colorectal cancer and has been associated with fatal diffuse alveolar damage in adults.
Epidermal Growth Factor Receptor/Tyrosine Kinase Inhibitors
Gefitinib is an inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR), and it inhibits the growth of human cancer cell lines expressing EGFR in preclinical studies. In an irradiated rat model, gefitinib treatment augmented lung inflammation but attenuated fibrotic lung remodeling due to the inhibition of lung fibroblast proliferation. In clinical trials in patients with nonsmall cell lung cancer, gefitinib was associated with development of interstitial lung disease in about 1% of patients, and about one third of cases of gefitinib-associated interstitial lung disease have been fatal. Patients presented with acute dyspnea with or without cough or fever at a median of 24–42 days after starting treatment. Another tyrosine kinase inhibitor, imatinib, is used in treatment of chronic myelogenous leukemia and has been associated with pleural effusion and pulmonary edema in a small number of cases. Cetuximab is a monoclonal antibody that specifically binds to EGFR and inhibits its downstream signaling. In a series of 2006 patients with colorectal cancer in a prospective multicenter registry, ranging in age from 18 to 80 years, 1.2% developed diffuse interstitial pneumonitis due to cetuximab. Such drugs targeting specific molecular pathways are likely to be increasingly used in cancer treatment, as well as pulmonary fibrosis, in the future.
Interleukin-2 (IL-2) has been used as an antitumor factor that stimulates lymphokine-activated killer (LAK) cell and natural killer cell activity, and it is sometimes given in combination with LAK cells. Although a number of systemic side effects such as fever and hypotension are seen, its major toxicity appears to be a vascular leak syndrome characterized by fluid retention, peripheral edema, ascites, pleural effusion, and pulmonary edema. This syndrome has been described in children with acute lymphocytic leukemia (ALL) treated with IL-2. Infusion of IL-2 in cancer patients has resulted in increased alveolar-arterial oxygen gradients and decreased forced vital capacity (FVC), forced expiratory volume in 1 second (FEV 1 ), and DL CO . A retrospective review of chest radiographic abnormalities in 54 patients with metastatic cancer receiving IL-2 revealed that 52% developed pleural effusions, 41% developed pulmonary edema, and 22% developed focal infiltrates. While most changes resolved by 4 weeks after therapy, residual pleural effusion was sometimes seen, primarily in patients receiving IL-2 by intravenous bolus rather than by continuous infusion. Lung histopathology in rodents that received high doses of IL-2 showed widespread mononuclear and eosinophilic infiltration of parenchyma, increased lung weight, and endothelial damage. Mechanisms implicated are increased generation of oxygen free radicals, activation of complement by IL-2, and injury mediated by tumor necrosis factor (TNF)-α. Rapid recovery from toxic effects of IL-2 followed withholding of treatment in most cases.
All- trans retinoic acid (ATRA), a vitamin A derivative with multiple regulatory activities in the lung, is effective as induction and maintenance chemotherapy for acute promyelocytic leukemia (APL). Its major toxicity is a syndrome including fever, weight gain and peripheral edema, respiratory distress, interstitial infiltrates, pleural and pericardial effusions, hyperleukocytosis, intermittent hypotension, and acute renal failure. Chest CT shows small, irregular parenchymal lung nodules and pleural effusions. The incidence of ATRA syndrome was 26% in a large series of APL patients followed prospectively, and among patients developing ATRA syndrome, mortality was 2% including a 4-year-old child. Mean duration of therapy before the syndrome appeared was 11 days with a range of 2–47 days. Nicolls and colleagues reported an 18-year-old with APL who developed diffuse alveolar hemorrhage 15 days after starting ATRA. Lung histology in patients who died of ATRA syndrome showed differentiation of APL cells, endothelial cell damage, and leukocyte infiltration. ATRA may upregulate TNF receptors on lung cell lines. In a murine model of APL, ATRA increased lung and heart expression of chemokines macrophage inflammatory protein 2 (MIP-2) and keratinocyte-derived cytokine (KC), suggesting that proinflammatory cytokines play a role. Treatment for ATRA syndrome consists of prompt initiation of corticosteroids. Tallman and colleagues used dexamethasone 10 mg/day and found that the syndrome resolved rapidly in most patients, even if ATRA was continued. In addition, these authors suggested that ATRA may be safely restarted in most patients once the syndrome has resolved. The cis-retinoic acids used for the treatment of neuroblastoma have not been associated with lung toxicities.
Noncytotoxic and Other Drugs
Nitrofurantoin
Nitrofurantoin is an antimicrobial agent used for prophylaxis of urinary tract infections. Significant pulmonary reactions are relatively common, and more than 500 cases have been reported, including children (see Table 59.2 ). Pulmonary reactions occur in two distinct clinical patterns. In the more common acute presentation, patients report abrupt onset of fever, cough, and dyspnea within hours to 2 weeks after initiation of therapy. Alveolar hemorrhage has been described in two patients. Rash and flu-like symptoms may occur. Diffuse fine crackles and, rarely, wheezes are noted. Bilateral interstitial or alveolar infiltrates with or without pleural effusions are characteristically present, although chest radiographs may be normal. Physiologic abnormalities include hypoxemia, evidence of a restrictive ventilatory defect, and a reduced DL CO . Eosinophilia, leukocytosis, and an elevated sedimentation rate may accompany the reaction. Symptoms and chest radiographic abnormalities usually resolve within several days after withdrawal of the drug. Pulmonary histopathology of the acute syndrome has not been well defined, as patients improve rapidly, making biopsy unnecessary.
In the less common chronic presentation, patients develop insidious onset of cough, dyspnea, and chest pain after months to years of nitrofurantoin therapy. Fever may be present, and a lupus-like syndrome has also been reported. Crackles are heard, and diffuse interstitial infiltrates are present on chest radiographs. Pleural effusion is less common than in the acute reaction. Physiologic abnormalities are similar to those found in the acute reaction but are often more severe. Eosinophilia, positive reactions for antinuclear antibodies, and elevated gamma globulin and hepatic enzymes are often found, and significant concurrent hepatic toxicity has been reported. Pulmonary histopathology typically reveals interstitial pneumonitis with variable fibrosis, and chest CT findings vary but may show ground glass opacities. Desquamative interstitial pneumonia, BOOP, and giant cell interstitial pneumonia have also been reported on long-term nitrofurantoin therapy. Treatment includes withdrawal of the drug and supportive measures. Corticosteroids have been used with apparent benefit; however, controlled studies to evaluate efficacy are not available. Resolution of symptoms, physiologic dysfunction, and radiographic abnormalities require weeks to months and may be incomplete. Approximately 8% of adult cases with the chronic syndrome are fatal.
The findings of eosinophilia, elevation of sedimentation rate, and positive antinuclear antibodies support a role for immunologic mechanisms of injury. The drug may also damage the lungs by promoting production of toxic oxygen species.
Sulfasalazine and Mesalazine
Sulfasalazine, a combination of 5-aminosalicylic acid and sulfapyridine, is used primarily in the treatment of inflammatory bowel disease. Adverse reactions occur in approximately 20% of recipients, but pulmonary reactions are uncommon; 50 cases were identified in the most comprehensive review. Diagnosis can be challenging, because inflammatory bowel disease is at times associated with lung disorders including bronchitis, BOOP, bronchiectasis, nonspecific interstitial pneumonitis, and granulomatous lung disease. Patients experiencing drug-related illness report acute onset of fever, cough, dyspnea, and chest pain 1 month to several years into therapy; and fine crackles are usually present. Hypoxemia, eosinophilia, obstructive and occasionally restrictive pulmonary function patterns, and bilateral alveolar densities have been noted. Cytology from BAL fluid has no consistent pattern of cell predominance. Histopathologic lesions include interstitial pneumonitis with or without fibrosis, eosinophilic pneumonia, fibrosing alveolitis, and bronchiolitis obliterans with or without a component of organizing pneumonia. Discontinuation of the drug usually results in resolution of symptoms and radiographic abnormalities in several weeks to months. Corticosteroids may accelerate improvement, although effectiveness is not well established. At least five fatalities have been reported. The mechanism of toxicity is unknown.
Therapy with mesalazine or 5-aminosalicylic acid, an alternative for inflammatory bowel disease that is related chemically to sulfasalazine, has also been associated with pulmonary toxicity; more than 40 cases have been described, including children. Symptoms typically include fever, cough, dyspnea, and chest pain recognized 1–6 months into therapy. Eosinophilia is often present peripherally and may be present in BAL fluid. Bilateral densities are present on chest radiographs, and CT scans may show patchy infiltrates, ground glass opacities, or lung nodules. Eosinophilic pneumonia, interstitial pneumonitis, and nonnecrotizing granulomas have been observed on lung biopsy. Symptoms and radiographic changes usually resolve when therapy is discontinued. Consideration of corticosteroid therapy has been suggested in patients with severe disease and those not responding to discontinuation of the medication.
Diphenylhydantoin, Carbamazepine, and Levetiracetam
The anticonvulsant agents diphenylhydantoin, carbamazepine, and levetiracetam have been associated rarely with acute pulmonary disease as part of a generalized hypersensitivity reaction, including the syndrome of drug reaction with eosinophilia and systemic symptoms (DRESS). Clinical manifestations include fever, cough, dyspnea, and rash occurring typically 2–8 weeks after initiation of therapy. Facial swelling and lymphadenopathy may be prominent. Crackles and, rarely, wheezes are heard; bilateral interstitial or alveolar infiltrates, sometimes with hilar adenopathy, are seen on chest radiographs. Associated findings include eosinophilia, elevated liver enzymes, hypoxemia with a restrictive pattern of lung function, and reduced DL CO . Cell counts from BAL fluid reveal lymphocyte predominance, and lung biopsy typically shows interstitial pneumonitis, possibly with mild fibrosis, and rarely BOOP. Ventilatory failure has been described. Rapid improvement occurs over days to weeks, following discontinuation of the drug, although manifestations may linger with multisystem involvement. Resolution may be hastened by corticosteroid administration. Carbamazepine hypersensitivity has been associated with transient pan-hypogammaglobulinemia and has been implicated in the occurrence of interstitial pneumonitis/eosinophilic pneumonia in an adolescent with cystic fibrosis (CF) on immunosuppressive therapy following lung transplant. Levetiracetam has been associated with biopsy demonstrated diffuse interstitial lung disease in a child.
Minocycline
Multisystem hypersensitivity with a prominent component of skin rash has been associated with minocycline, often in a pattern consistent with DRESS. More than 50 cases have involved the lung, often in adolescents and young adults treated for acne. Eosinophilic pneumonia has been suggested by the finding of excess eosinophils in blood and BAL fluid or on lung biopsy. Minocycline-associated lupus has been well described. Infrequently, significant organ dysfunction with or without lung involvement has been reported including hyperthyroidism or hypothyroidism, renal failure, hepatitis, sometimes in an autoimmune pattern, and, rarely, myocarditis. Withdrawal of the drug typically prompts improvement, although resolution may require months. Corticosteroids may accelerate improvement and have been used in combination with immunosuppression for autoimmune hepatitis. Hypersensitivity to doxycycline has been implicated in a single case involving respiratory failure.
Penicillamine
Penicillamine, a chelating agent, is commonly used to treat Wilson disease, cystinuria, and lead poisoning and, occasionally, rheumatoid arthritis and primary biliary cirrhosis. A conclusive association of this agent with lung disease is problematic, because similar lung disorders occur in underlying diseases. More than 40 cases of penicillamine-associated lung disease are reported, and these cases are primarily in patients with rheumatoid arthritis. Several patterns have been described: diffuse alveolitis, hypersensitivity pneumonitis, alveolar hemorrhage with or without associated acute glomerulonephritis (similar to antiglomerular basement membrane disease [Goodpasture syndrome]), and obstructive airway disease characterized pathologically as bronchiolitis obliterans. Duration of therapy before onset of symptoms tends to be short in patients with hypersensitivity reactions (<2 months), intermediate with diffuse alveolitis and bronchiolitis obliterans (3–19 months), and prolonged with alveolar hemorrhage (7 months to 20 years, but typically 2–7 years). Cough and dyspnea develop progressively over several weeks but may begin abruptly in hypersensitivity reactions with hemoptysis. Crackles and, occasionally, wheezes are present. Elevation of erythrocyte sedimentation rate, increased serum IgE, and eosinophilia may be noted. Chest films show diffuse alveolar or interstitial infiltrate, hyperinflation alone, or no changes. Hypoxemia and severe obstructive lung disease are usually identified in patients with bronchiolitis obliterans or restrictive disease in those with alveolitis or hypersensitivity disease. Discontinuation of the drug and corticosteroid therapy is warranted in most cases. Diffuse alveolitis and hypersensitivity pneumonitis generally improve using this approach, although some patients have residual lung disease. Response to corticosteroids alone has been disappointing in most cases of bronchiolitis obliterans and alveolar hemorrhage. Addition of azathioprine or cyclophosphamide in combination with plasmapheresis has been beneficial in several patients with Goodpasture-like syndrome and in a single patient with bronchiolitis obliterans.
Leflunomide
Leflunomide, an immunomodulatory drug that inhibits pyrimidine synthesis in activated lymphocytes that is used in treatment of rheumatoid arthritis and other autoimmune disorders, has been associated rarely with significant lung injury. Injury appears to be more likely in those with underlying interstitial lung disease. Presentation typically includes acute onset of cough and dyspnea 12–20 weeks after its introduction (occasionally after its discontinuation) with crackles on exam and bilateral patchy densities on chest radiograph. Ground glass and reticular/interstitial densities are identified on chest CT. The most common histologic abnormalities are diffuse alveolar injury and interstitial pneumonia. Leflunomide should be stopped when injury related to the drug is suspected. Because of its long half-life, some have advocated treatment with cholestyramine, although the benefit of cholestyramine is uncertain. Steroid therapy has been recommended; however, effectiveness is unclear. Mortality of nearly 20% has been described.
Azathioprine
Azathioprine, an immunosuppressive agent used in a variety of conditions including inflammatory bowel disease, autoimmune disorders, and following solid organ transplant, has been implicated rarely in lung injury. Fever, cough, shortness of breath, and hypoxemia typically develop within weeks to months of onset of therapy in association with infiltrates on chest imaging. Hemoptysis and a clinical pattern of ARDS have been described and restrictive lung disease and reduced DL CO observed. Histologic patterns identified in the lung have been consistent with hypersensitivity, interstitial pneumonitis, diffuse alveolar damage, and BOOP. Treatment consists of discontinuation of the drug with or without corticosteroids. Most improve relatively quickly, but progressive deterioration and death have occurred in about 12%.
Other Immunomodulatory Agents
Drugs targeting or modifying immune pathways are increasingly used for a variety of chronic inflammatory diseases and after transplantation. Most information on pulmonary toxicities of these agents is from adult literature. Rituximab, a monoclonal antibody against CD20 expressed on B lymphocytes has been associated with interstitial pneumonitis, including a fatal case in a 10 year old status-post renal transplant. Rituximab-associated lung injury (RALI: ground-glass lesions on CT, negative bronchoscopy with BAL and deficit in DL CO ) was described in two adolescents with nephrotic syndrome, 14 and 40 days following a single rituximab infusion. Infusion of alemtuzumab (Campath), a humanized monoclonal antibody against CD52 expressed on all lymphocytes, as well as some natural killer (NK) cells and monocytes, was associated with severe bronchospasm responsive to steroids in an adult with chronic lymphocytic leukemia. Cetuximab, an anti-EGFR monoclonal antibody, caused dyspnea with infusion in 13% of adult colorectal cancer patients. Trastuzumab, a humanized monoclonal antibody against the EGFR, has become standard treatment of HER2-expressing breast cancer. Acute interstitial pneumonitis developed after its infusion in a 56-year-old. Infliximab (Remicade) is a TNF-α inhibitor used in treatment of rheumatic and inflammatory bowel disease at all ages. Acute interstitial pneumonitis and respiratory failure has been reported in association with infliximab. The calcineurin inhibitor tacrolimus has been associated with interstitial lung disease in adult rheumatologic patients, where it is often seen in the setting of preexisting chronic lung disease and has a high mortality. Chronic use of sirolimus (rapamycin), an immunosuppressive agent used as an alternative to calcineurin inhibitors, has been associated with interstitial pneumonitis or BOOP in adults after renal transplant and children following hematopoietic stem cell transplant. Standard treatment for hepatitis C in children and adults is a combination of pegylated interferon and ribavirin. Interstitial pneumonitis with 7% mortality was reported in adult patients treated with peg interferon α-2β for hepatitis C.
Amiodarone
Amiodarone, a benzofurane derivative with Class III antiarrhythmic activity, is used in the treatment of serious ventricular and supraventricular tachyarrhythmias. Pulmonary toxicity is one of the most significant complications of therapy and develops in about 5% of patients. Most affected patients have been adults; however, lung toxicity has been reported in at least four children. The risk of lung toxicity appears to be dose related; for example, approximately 5%–15% of patients who take ≥500 mg/day and 0.1%–0.5% of those who take up to 200 mg/day develop drug-related lung disease. Onset of symptoms is often insidious, but symptoms can be acute and rapidly progressive with alveolar hemorrhage or the development of ARDS. Risk for ARDS may be increased by exposure to high concentrations of inspired oxygen, cardiothoracic surgery, or iodinated contrast media.
In the more common subacute presentation, patients insidiously develop nonproductive cough, dyspnea on exertion, weight loss, weakness, and in some instances, pleuritic chest pain and fever, usually during the first year of therapy. Approximately one-third of the patients have an acute onset of symptoms more consistent with hypersensitivity pneumonitis. Chest examination reveals tachypnea, crackles and, occasionally, a pleural friction rub. Physiologic abnormalities include hypoxemia, restrictive lung disease, and impaired diffusion. Predominance of cell type on cytology of bronchoalveolar fluid is variable. Diffuse or asymmetrical interstitial or alveolar infiltrates are typically present on chest x-rays. Chest CT shows bilateral involvement with ground-glass or reticular opacities often in the upper lobes or periphery of the lung bases, wedge-shaped consolidations, or nodules and may show pleural effusion or thickening.
Amiodarone interferes with movement of phospholipid across intracellular membranes and reduces phospholipid catabolism by inhibition of lysosomal phospholipase. The drug accumulates in structures such as macrophage lysosomes, leading to the recovery of ‘foamy’ macrophages in BAL fluid that are indicative of “amiodarone effect” (not toxicity) and may accumulate in type II pneumocytes and interstitial cells, interfering with gas exchange and causing a reduction in diffusing capacity that may be asymptomatic in patients with otherwise healthy lungs. Among those manifesting subacute symptoms, patterns of abnormalities identified on lung biopsy include eosinophilic pneumonia, nonspecific interstitial pneumonitis with or without fibrosis, chronic organizing pneumonia (BOOP), and rarely nodular lung disease.
Discontinuation of the drug results in gradual symptomatic improvement in most patients and resolution of physiologic and radiographic abnormalities over several months. Clinical evidence supports corticosteroid treatment, particularly for more advanced disease. Recurrence of symptoms was observed in some patients as steroid doses were tapered, potentially related to extended storage of drug in the lung. Alternative approaches for patients who must remain on amiodarone because of life-threatening refractory dysrhythmias are limited. Reinstitution of amiodarone therapy at lower doses after resolution of pulmonary disease, alone or in combination with low-dose corticosteroid therapy, has been successful in a few patients.
Mechanisms that may contribute to lung injury include direct cytotoxic effects on type II pneumocytes and other lung parenchymal cells, immune mediated injury, and injury related to activation of the angiotensin enzyme system leading to apoptosis of alveolar epithelial cells.
Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors
Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins, widely used in the treatment of hypercholesterolemia, have been rarely associated with lung disease heralded by onset of dry cough, dyspnea and bilateral infiltrates, often with ground glass changes on chest CT, after months to years of treatment. When measured, lung function has shown a restrictive pattern with reduction in DL CO . In a few cases, BAL fluid or tissue from lung biopsy has been demonstrated to contain “foamy” alveolar macrophages reminiscent of those in the BAL fluid of patients on amiodarone, which is considered indicative of so-called phospholipidosis. Discontinuation of the drug and, in some cases, use of corticosteroids have been associated with resolution of symptoms, although mortality of about 25% is described.
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