Abstract
Purpose of Review
To provide an updated summary of the pleurotoxic drugs and their manifestations.
Recent Findings
Novel antineoplastic agents for the treatment of hematologic and non-hematologic malignancies have been associated with the induction of pleural disorders. Moreover, the list of agents that have been associated with drug-induced lupus pleuritis is steadily increasing.
Summary
Pleurotoxic medications are agents that may cause pleural disorders, most commonly pleural effusions. Connecting a pleural disorder to a specific drug requires the exclusion of other potential causes combined with resolution of the disorder after drug discontinuation while previous literature reports on similar cases may be of assistance. The incorporation of new therapies into clinical practice over the last few years has exposed medical professionals to areas devoid of a historic evidence base. Thus, drug-induced pleurotoxicity should be always included in the diagnostic approach to the patient with a pleural effusion.
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Introduction
Pleurotoxic medications are agents which, at therapeutic dose, result in pleural disease. Such adverse events arise through a variety of mechanisms including hypersensitivity reactions, direct toxic effects on mesothelial cells, chemical inflammation of the pleura, or fluid retention [1,2,3]. Although pleural fibrosis and pneumothorax may occasionally occur, pleural effusion represents the most common manifestation of drug pleurotoxicity. Effusions can appear as an isolated disorder, in combination with parenchymal disease, in the context of systemic drug reaction or in the setting of specific syndromes, such as drug-induced lupus pleuritis (DILP: typically bilateral exudative pleural effusion combined with high serum antinuclear antibody (ANA) titers with/without pulmonary infiltrates, pericarditis, and joint symptoms) and the ovarian hyperstimulation syndrome (OHSS: extravasation of protein-rich fluid into the peritoneal and pleural cavities following administration of follicular stimulating agents) [1,2,3]. In clinical practice, connecting a pleural disorder to a specific drug is rarely a straightforward procedure and typically requires the exclusion of other potential causes combined with resolution of the disorder following drug discontinuation. Previous literature reports on similar cases may be of assistance [3]. A definite connection between the culprit drug and pleural disease may be established with a positive re-challenge test (i.e., recurrence of disorder with drug re-administration); however, this is rarely advisable.
The aim of our review is to provide the reader with an updated summary of pleurotoxic drugs and their manifestations.
Anticoagulants and Thrombolytics
Therapeutic doses of these agents rarely induce hemothorax. This develops usually soon after treatment initiation [4]. Although most cases reported involve unfractionated heparin or warfarin, low molecular weight heparins (LMWH) and rt-PA have also been implicated [4, 5]. Warfarin was also implicated in the induction of pleural effusion and concomitant peripheral eosinophilia in a post-CABG (i.e., coronary artery bypass grafting) patient while ticlopidine has been associated with DILP [6, 7].
Antiglycemic Agents
Pleural effusions due to fluid retention have been reported with glitazones (i.e., rosiglitazone, pioglitazone) and neutral protamine Hagedorn (NPH) insulin [8,9,10].
Gliclazide has been associated with drug-induced eosinophilic pleural effusion (DIEPE, i.e., effusion containing at least 10% eosinophils) while troglitazone was connected to the induction of small bilateral pleural effusions after 1–2 weeks of treatment in two patients [11, 12].
Antimicrobials
Isoniazid and minocycline can cause drug-induced lupus pleuritis (i.e., ANA-positive exudative pleural effusion with/without pulmonary infiltrates and/or pericarditis in the absence of other causes of pleural effusion, DILP) while nitrofurantoin is a common source of drug-induced eosinophilic pleural effusions [3, 13,14,15,16].
Prophylactic treatment with aerosolized pentamidine has been reported to cause spontaneous pneumothorax in HIV patients. However, such a connection has not been definitely established since additional risk factors (i.e., asthma, emphysema, cystic lung disease and active Pneumocystis jiroveci infection) for the occurrence of pneumothorax were also present in several of the reported patients [17, 18]. Steroid-responding acute respiratory distress syndrome (ARDS) with small bilateral pleural effusions was attributed to a combination of medication to treat a patient with hepatitis C (i.e., ritonavir/paritaprevir/ombitasvir/dasabuvir or VIEKIRA PAK) while nevirapine was associated with pleuropericarditis in a patient with HIV. This developed in the context of DRESS syndrome (i.e., drug rash with eosinophilia and systemic symptoms), presumably due to eosinophilic infiltration of the pleura and the pericardium [19,20,21].
Perihilar pulmonary infiltrates and left-sided pleural effusion were reported in a patient with fever and hemoptysis after 3 days of acyclovir; these resolved with drug cessation [22].
Praziquantel therapy has been associated with a polyserositis (i.e., right-sided DIEPE, pericardial effusion, and ascites) as part of a systemic reaction (i.e., generalized rash, myalgia, fever, abdominal pain, diarrhea, and severe chest pain); these appeared within 4 h of drug administration and resolved on discontinuation [23].
Antiinflammatory and analgesic agents
Anti-TNF agents
Infliximab and etanercept may cause drug-induced lupus pleuritis in 0.22% and 0.18% of patients after 3–16 and 2–5 months of treatment, respectively [24,25,26]. Drug discontinuation alone leads to resolution of the syndrome within 3 weeks to 6 months in the majority of patients while corticosteroids or additional immunosuppressant drugs (e.g., azathioprine, cyclophosphamide, leflunomide, methotrexate or mycophenolate) are required in 40% and 12% of the patients, respectively [27].
Adalimumab has been associated with pleuropericardial effusions and an isolated pleural effusion, which resolved with drug withdrawal and ibuprofen or corticosteroids, respectively [28, 29].
Cyclophosphamide and methotrexate
Pleuroparenchymal fibroelastosis presenting as progressive steroid-unresponsive pleural thickening combined with late-onset pneumonitis, often years after first exposure to the drug, represents the main pleurotoxic manifestation of cyclophosphamide. Patients may develop breathlessness of gradual onset or cough. A patient with bilateral transudative pleural effusions following the administration of high cyclophosphamide doses and two patients with spontaneous pneumothorax (presumably due to tumor lysis and rupture to the pleural cavity) within days after the administration of cyclophosphamide-containing chemotherapy regimens have also been reported [30,31,32,33,34,35,36]. In 4–8% of patients, high dose (8–12 g/m2) methotrexate can cause pleuritis with pleuritic chest pain typically developing 2–5 days after drug initiation; resolution is seen 3–5 days post discontinuation. Within this cohort, pleural effusion and secondary pleural thickening developed in 20–30% and a small minority respectively [37,38,39]. Bilateral lymphocytic pleural effusions, widespread lymphadenopathy, and two bone masses, all attributed to a methotrexate-induced lymphoproliferative disorder that responded to drug discontinuation, have been reported in a patient with rheumatoid arthritis [40].
Other Antiinflammatory and Analgesic Drugs
Mesalazine may cause pulmonary infiltrates accompanied by small pleural effusions and occasionally by pleural thickening weeks or even years after treatment initiation [41,42,43,44,45]. Case reports of resultant pleuropericarditis, drug-induced lupus pleuritis and drug-induced eosinophilic pleural effusion have also been reported with this agent [43, 46]. Characteristically, the effusions respond to drug discontinuation, whereas pleural thickening persists despite corticosteroid treatment [41,42,43,44].
D-penicillamine usually causes drug-induced lupus pleuritis; however, a unilateral exudative ANA-negative pleural effusion has also been described [3, 47].
Capillary leak syndrome presenting with pleural effusion, pulmonary infiltrates and renal dysfunction after 2 months of treatment was definitely attributed to acitretin following repeated exposure [48].
Bilateral exudative pleural effusions have been reported in a patient receiving etoricoxib for 2 weeks, while tizanidine was connected to a large right-sided DIEPE after 6 weeks of treatment—the effusion resolved on stopping the treatment [49, 50].
Antithyroid Agents
Propylthiouracil has been associated with the induction of pleuropericarditis in the context of drug-induced p-ANCA-positive vasculitis in two patients (only one had his effusion aspirated revealing a lymphocytic exudate) and with a small DIEPE in another [51,52,53].
Carbimazole caused a large, painful left-sided exudative pleural effusion in a patient after 3 months of treatment. Symptoms resolved on drug discontinuation [54].
Antineoplastic Agents
Tyrosine Kinase Inhibitors
Imatinib, Nilotinib, Bosutinib, and Dasatinib
Imatinib is the standard first-line therapy for chronic myelogenous leukemia (CML) while dasatinib, nilotinib, and bosutinib are reserved for imatinib-resistant disease [55,56,57].
Up to 1% of imatinib-treated patients develop pleural effusion that is usually due to fluid retention and responds to diuretics [58,59,60,61]. However, an exudative effusion and effusions requiring combined diuretic and corticosteroid treatment have been reported [62].
Nilotinib can rarely (< 1%) cause lymphocytic exudative pleural effusions that resolve with steroids and may not relapse with drug re-administration for reasons that are still unknown [59, 63, 64].
Bosutinib may cause pleural effusions in up to 8% of patients. This appears to be an age-dependent phenomenon affecting 3 to 14% of patients < 65 and > 65 years old, respectively [57, 65, 66•].
Contrary to the rarity of pleural effusion with the aforementioned tyrosine kinase inhibitors (TKIs), dasatinib is a common cause of pleural effusion. Data from the FDA Adverse Event Reporting System (FAERS) suggests a strong association of dasatinib with occurrence of pleural effusion and chylothorax [67••]. Although the methodology of this study does not allow for incidence evaluation, other studies indicate that pleural effusion may appear in up to 55% of patients. Supporting evidence from a trial comparing dasatinib with imatinib in patients with newly diagnosed CML (the DASISION trial) reports a heightened incidence of pleural effusion in the dasatinib-arm (n = 258) at 14% (1% grade 3/4, i.e., severe or life-threatening pleural effusion requiring hospitalization or immediate intervention) [55, 68,69,70]. The risk of pleural effusion increases with increasing dose, a continuous instead of intermittent regimen, increasing patient age, detection of numerous large granular lymphocytes on blood smears, presence of co-morbidities (e.g., heart disease and hypertension), and the use of dasatinib in the accelerated phase of CML [58, 68, 69••, 70,71,72,73]. The pathogenesis of dasatinib-induced effusions has not been fully elucidated, although dysfunction of normal T cells and off-target inhibition of angio-/lymphangio-genesis promoting receptors are thought to contribute [55]. Patients typically develop bilateral pleural effusion (80%) accompanied by a pericardial effusion in 30% of cases [55, 62, 74]. Thoracentesis usually reveals a lymphocytic exudate; chylothoraces and transudative effusions have been observed [55, 62, 75]. Drug discontinuation usually ensures resolution of the effusions; however, drainage and corticosteroid treatment may be required in symptomatic patients [55]. Although dasatinib re-administration at lower doses and in a single-dose regimen is feasible, definitive discontinuation is advisable in case of relapse post re-exposure [55].
Erlotinib, Gefitinib, and Crizotinib
These oral TKIs are increasingly used as targeted therapy for selected patients with non-small cell lung cancer [76].
Erlotinib targets the epidermal growth factor receptor (EGFR) and has been implicated in the induction of unilateral pleural effusion in two patients presenting with fever and dyspnea 11–12 days after treatment initiation [77, 78]. In addition to drug withdrawal, the effusion was managed with pleurodesis in one case and oral corticosteroid in the other; both patients restarted erlotinib with no relapse of the effusion. This phenomenon has been attributed to an immune response following acute lysis of cancer cells by the drug [77]. Tumor lysis was also responsible for development of a spontaneous pneumothorax in three patients with multiple lung metastases, some abutting the pleural surface, which cavitated and ruptured towards the pleural space as a result of their response to erlotinib, gefitinib, and crizotinib, respectively [79,80,81].
Pazopanib
This multi-targeted antiangiogenesis TKI has been associated with spontaneous pneumothorax in 10–14% of the patients receiving the agent for sarcoma [82]. Patients with large (> 3 cm in diameter) cavitary or pleura-based lung metastases, and those with a history of previous pneumothorax appear most at risk [83,84,85].
Immune Checkpoint Inhibitors
Nivolumab has been implicated in development of pleuropericardial effusions, within the first 7–9 weeks of treatment, in two lung cancer patients [86•]. In one patient, the effusions resolved after eight consecutive thoracenteses despite ongoing nivolumab use, while drug withdrawal, repeated pleural aspiration, and corticosteroid therapy were required in the second patient.
Ipilimumab works by blocking cytotoxic T lymphocyte antigen-4 to increase patients’ antitumor T cell response. Ipilimumab-induced pleural effusion occurred in 11% of adolescents receiving high (10 mg/kg) dose therapy for advanced solid organ tumors. Large, bilateral transudative pleural effusions with pericarditis and hypothyroidism have also been reported in a patient with melanoma after four cycles of treatment [87, 88].
Other Chemotherapeutics
Azacitidine can cause severe pleuritic chest pain during and up to 24 h after the drug infusion [89, 90].
Pleuropericarditis with a lymphocytic exudative pleural effusion was observed in a neutropenic patient following receipt of the third cycle of decitabine treatment. This resolved within 14 weeks of drug discontinuation [91].
Pleural effusion develops in a minority of patients with bleomycin-induced pneumonitis, a side effect which occurs in up to 10% of patients receiving the drug, especially those with concurrent exposure to oxygen, radiation or other chemotherapeutics [92]. Acute pleuritic chest pain and pneumothorax have also been reported with bleomycin [93,94,95,96].
A steroid-responsive diffuse lung infiltrate with pleuropericarditis was observed in a lymphoma patient a month after stem cell collection with cyclophosphamide and subsequent BCNU, etoposide, ARA-C, and melphalan (BEAM) treatment [97].
Kido et al report a patient with pancreatic cancer who developed bilateral transudative pleural effusions due to pericarditis-induced cardiac tamponade following gemcitabine therapy [33].
Hypersensitivity reactions with fever, cough, dyspnea, and pleural effusions, together with positive re-challenge testing, have been described in two lymphoma patients receiving procarbazine [98, 99].
Biologic Agents
Bortezomib and Ruxolitinib
Single case reports have described development of ARDS, with bilateral pleural effusion or pleuropericarditis in patients receiving bortezomib (a proteasome inhibitor) and ruxolitinib (a JAK1 and JAK2 inhibitor) for myeloma and myelofibrosis respectively [100, 101].
In the patient receiving ruxolitinib, the symptoms appeared 1 day after drug initiation and responded partially to drug withdrawal and steroids. Ruxolitinib was re-started at a lower dosage due to fear of cytokine-rebound phenomenon and the effusion relapsed. Complete resolution of the effusion was seen only after permanent discontinuation of the drug.
Interferons
Pleural effusions accompanying interstitial pneumonitis have been described in two patients with chronic hepatitis C following 33–44 weeks of treatment with IFN-alpha [102, 103]. The effusions resolved with drug withdrawal in one patient; adjunctive corticosteroids were given to the second [102, 103].
Serous pleuropericardial effusions were also reported in a melanoma patient who died from ARDS and multi-organ failure 6 h after the third infusion of IFN-alpha-2b and had no evidence of infection, melanoma metastases, or significant atherosclerotic heart disease on autopsy [104].
Interleukins
Up to 50% of patients treated with interleukin-2 develop pleural effusion and pulmonary edema due to increased capillary permeability, especially if bolus intravenous therapy is used [105]. More than 80% of the effusions resolve within a month of drug discontinuation.
Interleukin-11 can cause pleural effusion due to severe fluid retention while a patient with pleural effusion secondary to capillary leak syndrome has also been reported [106, 107]. Although the pathogenesis of capillary leak syndrome due to interleukin-11 has not been fully elucidated yet, cytokine-induced VEGF production and increased NO synthesis have been reported to play a role.
Sirolimus
Immunosuppression with sirolimus results in pleural effusion in approximately 8% of treated liver transplant patients. In addition, patients with steroid-resistant bilateral pleural effusion, in the context of generalized edema and polyserositis post renal and lung transplant respectively, have been described [108,109,110].
G-CSF
Unilateral pleural effusion and capillary leak syndrome with bilateral pleural effusions have been described 10 days and immediately after G-CSF administration in two neutropenic patients and a healthy leukocyte donor, respectively [111,112,113].
Cardiovascular Agents
ACE Inhibitors, Beta-Blockers, and Diltiazem
Imidapril and diltiazem have been implicated in case reports as the trigger for patients’ developing unilateral or bilateral DIEPE with peripheral eosinophilia respectively; cilazapril has been linked to occurrence of a lymphocytic (95% lymphocytes) pleural effusion [114,115,116].
Steroid-resistant pleural and pulmonary fibrosis has been described with practolol and oxprenolol, whereas captopril, lisinopril, ramipril, acebutolol, betaxolol, and pindolol have been associated with DILP [107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127].
Amiodarone
The pneumotoxic effects of amiodarone are well described with an estimated incidence of pulmonary infiltrate and/or pleural thickening in 5–10% of patients [128, 129].
Pleural effusions are rare and, if present, usually accompany parenchymal disease [123]. In cases of isolated pleural effusion, effusions are typically bilateral and appear 2 months to 6 years after drug initiation [130,131,132,133]. Pleural fluid is usually a lymphocytic exudate with or without foamy cells (i.e., macrophages containing large phagolysosomes with phospholipidic material organized in lamellar structures, which are indicative of amiodarone exposure) [128]. Three patients with neutrophilic exudative loculated pleural effusions have also been described [128, 129, 131,132,133]. Resolution of the effusions is usually seen within 1–3 months of drug cessation; adjunctive corticosteroids may be required in patients with severe symptoms.
Hydralazine and Procainamide
These agents are common causes of drug related lupus pleuritis (DILP), which appears approximately 1 month to 12 years after drug exposure in 0.6–6% and at least 15% of hydralazine- and procainamide-treated patients, respectively [3, 134,135,136,137]. Not all patients develop pleural effusion, but this is seen in over half of patients who develop DILP with hydralazine and up to a third with hydralazine-induced DILP.
Quinidine, Methyldopa, and Minoxidil
Quinidine has been associated with DILP in 30 patients with concomitant skin rash and arthritis; there is one case report of a patient who developed a 3-week history of fever, chills, malaise, and chest pain after starting methyldopa [13, 138].
Minoxidil has been linked to exudative pleuropericarditis and relapsing migratory exudative pleural effusion in two cases, while a hemodialysis-unresponsive unilateral pleural transudate in a patient with end-stage renal disease resolved only after minoxidil discontinuation similarly intimating a causal link [139,140,141].
Prostaglandins and Sildenafil
Exudative pleuropericarditis during prostaglandin-E1 treatment has been described while sildenafil has been reported to cause pleural effusion in 6.7% of pediatric patients with pulmonary hypertension [142, 143].
Statins
Simvastatin has been associated with DIEPE after 6 months and 13 years of exposure in two patients and pravastatin triggered bilateral lymphocytic, exudative effusions after 12 months of treatment [144,145,146,147]. The effusions resolved within 2 months of drug discontinuation; however, corticosteroids were required in one patient receiving simvastatin. Unilateral DIEPE in the setting of simvastatin-induced lupus syndrome has also been reported [146].
Neuropsychiatric Agents
Anticonvulsants
Valproic acid has been associated with DIEPE (> 40% eosinophils) in several case reports with a peripheral eosinophilia secondary to an induced hypersensitivity drug reaction [148,149,150,151,152,153,154,155]. The drug has also been connected to a development of a temporally related lymphocytic exudative and a unilateral transudative pleural effusion [156, 157].
Carbamazepine has been associated with the development of DILP in two adult patients after 8–12 months of treatment while in a retrospective study assessing the incidence of anticonvulsant drug-induced lupus in children, ethosuximide was implicated in the development of DILP in two (11%) of the 18 children receiving the drug [158,159,160]. A recent review of 26 carbamazepine-induced lupus erythematosus cases demonstrated that pleuritis was among the common manifestations of the syndrome, antihistone and anti-dsDNA antibodies were respectively less and more frequent compared to the classic drug-induced lupus erythematosus and that ANA remained positive despite carbamazepine discontinuation in more than 60% of the patients [161].
Antidepressants and Antipsychotics
In their case series, Alagha et al. implicated fluoxetine and olanzapine in the induction of DIEPE (with or without peripheral eosinophilia) in two patients respectively; pleural biopsies yielded a non-specific pleuritis with eosinophilic infiltration without granulomas. The effusions were resolved within 4–6 weeks of drug discontinuation [162, 163].
Clozapine, a second-generation antipsychotic often reserved for treatment of resistant schizophrenia, may cause polyserositis with typically bilateral pleural effusions arising 7 days to 13 months after treatment initiation [164,165,166,167,168,169,170,171]. The fluid is usually a monocyte or neutrophil predominant exudate; however, transudative effusions have been described. Drug discontinuation or dose reduction is generally followed by resolution of the effusions while corticosteroids may be required in severe disease. Positive re-challenge testing has been reported in two patients [3].
Dantrolene
Dantrolene has been associated with DIEPE in small case series. The effusion is classically unilateral with normal glucose levels. Its occurrence has been reported in patients treated for between 2 months and up to 12 years [162, 172,173,174]. Symptoms often include pleuritic chest pain and fever; peripheral eosinophilia and co-existent pericarditis are not uncommon.
Ergot Derivatives
Ergot alkaloid derivatives are used in the prophylaxis of migraine and cluster headaches (e.g., methysergide, ergotamine) and treatment of Parkinson’s disease (e.g., bromocriptine, dihydroergotamine, nicergoline, pergolide, lisuride, cabergoline).
Pleuropneumotoxicity arises after long term treatment, typically 6 months to 30 years after treatment commences. Pleural fibrosis with or without an associated effusion is the main feature. The precise pathophysiology is unclear but is thought to be related to the increased serotonin activity invoked by these agents with promoted fibroblast proliferation and collagen synthesis/deposition.
Clinically, insidious dyspnea, pleuritic chest pain, and cough may develop with systemic upset, i.e., malaise and fever. In the case of pleural effusion, analysis of fluid frequently reveals a lymphocytic or eosinophilic exudate.
Most patients’ symptoms and pleural effusion resolve with drug curtailment although this may take months or years and complete resolution of the changes is uncommon with residual pleural thickening evident. Adjuvant corticosteroid therapy has been tried although does not appear to alter the outcome, and evidence base to support their use is lacking.
Ovarian Hyperstimulation Syndrome: Follicular Stimulating Agents
Follicular stimulating medications, such as clomiphene, gonadotropin, and gonadotropin-releasing hormone, are fertility agents used to stimulate ovulation. Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening iatrogenic complication of the treatments. Pleural effusions may arise in the setting of severe OHSS [175]. The exact pathophysiology is unknown although increased vascular permeability possibly related to ovarian release of vasoactive substances has been implicated, with third spacing precipitating ascites and pleural and/or pericardial effusion. Pleural fluid analysis often shows an exudate but transudates have been observed.
Patients usually report dyspnea, cough, and chest pain. In severe cases, hepatorenal failure, thromboembolic phenomena, ARDS, and multi-organ failure may occur.
Overall, the prognosis is good. Symptoms typically resolve approximately a week after their onset when pregnancy does not ensue; resolution takes up to 20 days if the patient is successful in her fertility attempt. .
Conclusion
The incorporation of a significant number of new therapies into clinical practice over the last few years has exposed medical professionals, and their patients, to areas devoid of a historic evidence base. In particular, the use of novel antineoplastic treatments (targeted therapy, immunotherapy, etc.) has been increasing steadily along with its inherent, ever-evolving, and unheralded adverse event spectrum.
Drug-induced pleurotoxicity should be always included in the diagnostic approach to the patient with a pleural effusion, especially if other, common, etiologies have been excluded.
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Skouras, V.S., Kalomenidis, I. Pleurotoxic Drugs—an Update: Someone Else to Blame?. Curr Pulmonol Rep 8, 50–59 (2019). https://doi.org/10.1007/s13665-019-0225-8
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DOI: https://doi.org/10.1007/s13665-019-0225-8