DRUG-INDUCED PLEURAL DISEASE

https://doi.org/10.1016/S0272-5231(05)70080-0Get rights and content

A large number of drugs are associated with the development of pleural inflammation.56, 67 Patients may be symptomatic, with evidence of pleural involvement, or remain asymptomatic, with the pleural effects of the drug noted as a corollary to the underlying lung disease. The effect of drugs on the pleura may be reflected in the development of pleural thickening, pleural fibrosis, or a pleural effusion. Although the onset of pleural disease has a temporal relationship to initiation of drug usage, the signs and symptoms may present much later in some cases, particularly if the drug effect is dose related.

Patients with drug-induced pleural disease often have dyspnea as the presenting symptom. The dyspnea may be secondary to the underlying lung parenchymal disease that is commonly associated with pleural disease or may be secondary to the presence of a rapidly increasing pleural effusion or fibrosis. Pulmonary parenchymal toxicity and its related symptoms often bring the patient to the attention of a physician. On radiologic examination, the patient may have parenchymal and pleural involvement secondary to drug-induced disease or, in some cases, the pleura may be involved exclusively.

A detailed history of drug intake is critical to making the diagnosis of drug-induced pleural pulmonary disease. As has been described with nitrofurantoin usage,36 a patient may not reveal the use of the drug for occasional urinary tract infections unless asked specifically. When chemotherapy for malignant disease is part of the history, the cause and effect is often readily obvious.78

The primary method of treatment involves discontinuation of the offending drug.12 The withdrawal of the drug is usually associated with partial or complete resolution of the underlying pleural inflammation.13 That may be more difficult to implement than it seems because drugs such as amiodarone, which may be critically important for the treatment of arrhythmia, may not be easily withdrawn without the development of other problems. The use of steroids to suppress inflammation may help in resolving the underlying disease. In some critically ill patients, several drugs that may cause pleural disease may be used, making it difficult to define the inducing agent. Considering the specific characteristics of different drugs and their toxicity may be helpful in reaching a logical conclusion. A significant number of data have now accumulated about the mechanisms of toxicity of different drugs. They may range from oxidant-induced mesothelial cell injury to the development of an acute hypersensitivity-type reaction. A direct dose-related toxic effect or a chemical-induced inflammation may also cause pleural inflammation. Although a general knowledge of the mechanisms of drug-induced toxicity exists, the details of cytokines, secondary messengers, and other factors that play a role in producing pleural changes remain unclear.

Section snippets

DRUG-INDUCED LUPUS PLEURITIS

Several drugs can cause a lupus erythematosis-like syndrome that is indistinguishable from patients who have native lupus.38 In fact, the administration of drugs known to cause lupus pleuritis to a patient with systemic lupus erythematosis (SLE) is contraindicated because there is a significant likelihood of aggravation of symptoms.1 The drugs that are associated with lupus pleuritis include procainamide, chlorpromazine, quinidine, isoniazid, phenytoin, and hydralazine. Antibiotic drugs such as

NITROFURANTOIN

Nitrofurantoin is an antibacterial agent that is chemically 1-5-Nitro-2-furanylmethyleneamino-2,4-imidazolidinedione.31 Nitrofurantoin is bactericidal in urine at therapeutic doses. Nitrofurantoin is reduced by bacterial flavoproteins to reactive intermediates that, in turn, inactivate or alter bacterial ribosomal proteins. It remains unclear whether that mechanism of nitrofurantoin action is involved in the acute hypersensitivity reaction that can occur in the lung parenchyma and the pleura.36

DANTROLENE

Dantrolene is a skeletal muscle relaxant that is similar to nitrofurantoin in structure. Dantrolene has been known to cause pleural effusions in patients using doses from 225 mg to 400 mg/day.60 Patients typically present with pleuritic chest pain, fever, and pleural effusions. The pleural effusion is usually unilateral, unlike nitrofurantoin-induced lung disease. It is not usually associated with pulmonary infiltrates as evaluated by routine radiograph. Pleural fluid, glucose, and amylase are

METHYSERGIDE

Methysergide maleate is a partially synthetic compound related to methylergonovine. The ergot alkaloids appear to have a common ability, both in vivo and in vitro, to block the effects of serotonin, a substance that may be involved in vascular headaches. Serotonin is a central neural humoral chemical mediator that acts directly or indirectly to lower the pain threshold. The use of methysergide for the treatment of cluster headaches or migraine has decreased somewhat but is still practiced in

BROMOCRIPTINE

Bromocriptine is an ergot derivative with potent dopamine receptor agonist activity. The active ingredient is bromocriptine mesylate. Bromocriptine activates postsynaptic dopamine receptors. The dopaminergic neurons modulate the secretion of prolactin and significantly reduce prolactin levels. The inhibition of physiologic lactation does not affect the secretion of other tropic hormones from the anterior-pituitary gland. Bromocriptine is used in patients with acromegaly, in which it lowers

PRACTOLOL

Practolol is a β-blocker not marketed in the United States that has been noted to cause sclerosis of the pleura and peritoneum. It also causes development of pleural effusion, pleuropulmonary fibrosis, peritonitis, deafness, and nephrotic syndrome.19, 25, 34 It became popular because it has several advantages over other β-blockers, including a long half-life and good volume of distribution. Long-term usage of practolol has been associated with pleuropulmonary complications, including

AMIODARONE

Amiodarone is a class III antiarrhythmic drug that blocks sodium channels at rapid pacing frequencies and exerts a noncompetitive antisympathetic action. One of its main effects is to lengthen the cardiac action potential and block cardiac potassium channels, which contribute to slowing of conduction and prolongation of refractoriness. Administration of the drug prolongs intranodal conduction and refractoriness of the atrioventricular node, but has no effect on the sinus cycle. Amiodarone is

PROCARBAZINE

Procarbazine is a hydrazine derivative and an antineoplastic agent. It is indicated in combination with other anticancer drugs for the treatment of stage III and stage IV Hodgkin's disease. It is also used as part of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen.17, 50 Procarbazine is absorbed rapidly and completely. The mechanism of action is considered to be cessation of protein synthesis associated with inhibition of DNA and RNA synthesis. In addition,

METHOTREXATE

Methotrexate is an antimetabolite used in the treatment of neoplastic diseases, psoriasis, and rheumatoid arthritis. The mechanism of action includes inhibition of dihydrofolic acid reductase. Methotrexate interferes with DNA synthesis and cellular replication. Actively proliferating tissues such as malignant cells, mucosal cells, and cells of the urinary bladder are acutely sensitive to the effects of methotrexate. When used in the treatment of rheumatoid arthritis, it is hypothesized that

BLEOMYCIN

Bleomycin is a cytotoxic glycopeptide antibiotic isolated from Streptomyces verticillus. Bleomycin is known to inhibit synthesis of DNA, RNA, and protein. Bleomycin is typically used for the treatment of squamous cell carcinoma of the head and neck, lymphomas such as Hodgkin's disease and non-Hodgkin's lymphoma, and testicular carcinoma. Interestingly, bleomycin is also used as a sclerosing agent for the treatment of recurrent pleural effusions. Adverse pleuropulmonary reactions occur in

MITOMYCIN

Mitomycin is an antibiotic agent isolated from the broth of Streptomyces caespitosus. Mitomycin inhibits synthesis of DNA and protein. It is cleared rapidly from the serum after intravenous administration and up to 10% of the drug is excreted unchanged in the urine. Mitomycin is typically used in combination chemotherapy for the treatment of disseminated adenocarcinoma of the stomach or pancreas and with appropriate surgery or radiotherapy.

Toxic effects of mitomycin include the development of

MINOXIDIL

Minoxidil is an antihypertensive agent, the side effects of which include excessive body hair growth. It acts as a peripheral vasodilator and is used to control blood pressure in severely hypertensive patients. The drug has been associated with the development of fluid in both the pericardium and the pleural space.53 The effusions, particularly in the pericardium, have been associated with tamponade. Bilateral pleural effusions have been noticed following the initiation of minoxidil therapy.

References (81)

  • A.T. Skarin et al.

    The treatment of advanced non-Hodgkins lymphoma (NHL) with bleomycin, Adriamycin, cyclophosphamide, vincristine, and prednosine

    Blood

    (1977)
  • R. Utili et al.

    Dantrolene associated hepatic injury: Incidence and character

    Gastroenterology

    (1977)
  • R.B. Weiss et al.

    Cytotoxic drug-induced pulmonary disease. Update 1980

    Am J Med

    (1980)
  • D.L. Wood et al.

    Amiodarone pulmonary toxicity: Report of two cases associated with rapidly progressive fatal adult respiratory distress syndrome after pulmonary angiography

    Mayo Clin Proc

    (1985)
  • D. Alarcon-Segovia

    Drug induced lupus

    Mayo Clin Proc

    (1969)
  • L.A. Anderson et al.

    A study of the distribution of methotrexate in human tissues and tumors

    Cancer Res

    (1970)
  • O. Back et al.

    Adverse reactions to nitrofurantoin in relation to cellular and humoral mechanisms

    Clin Exp Immunol

    (1977)
  • R.P. Bays

    Pleuropulmonary fibrosis following therapy with methysergide maleate: Two case reports

    J La State Med Soc

    (1968)
  • R.J. Boucek et al.

    Increase in survival of subcultured fibroblasts mediated by serotonin

    Nature

    (1971)
  • M.R. Boyd et al.

    Acute pulmonary injury in rats by nitrofurantoin and modification by vitamin E, dietary fat, and oxygen

    American Review of Respiratory Disease

    (1979)
  • H.A. Cameron et al.

    The lupus syndrome induced by hydralazine: A common complication with low dose treatment

    BMJ

    (1984)
  • S.B. Chyatte et al.

    Dantrolene sodium: Long-term effects in severe spasticity

    Arch Phys Med Rehabil

    (1973)
  • A.M. Clarysse et al.

    Pulmonary disease complicating intermittent therapy with methotrexate

    JAMA

    (1969)
  • J.A. Cooper et al.

    Drug-induced pulmonary disease. Part I: Cytotoxic drugs

    American Review of Respiratory Disease

    (1986)
  • J.A. Cooper et al.

    Drug-induced pulmonary disease. Part II: Non-cytotoxic drugs

    American Review of Respiratory Disease

    (1986)
  • D.J. D'Amico et al.

    Amiodarone keratopathy: Drug-induced lipid storage disease

    Arch Ophthalmol

    (1981)
  • M. Dan et al.

    Amiodarone and pneumonitis

    Ann Intern Med

    (1983)
  • R.B. David et al.

    Nitrofurantoin sensitivity: Report of a child with chronic inflammatory lung disease

    American Journal of Diseases of Children

    (1968)
  • N.H. Dyer et al.

    Practol induced pleurisy and constrictive pericarditis

    BMJ

    (1975)
  • M.D. Ecker et al.

    Procarbazine lung

    AJR

    (1978)
  • T.M. Erwteman et al.

    Interstitial pulmonary fibrosis: A new side effect of practolol

    BMJ

    (1977)
  • C.S. Everts et al.

    Methotrexate therapy and pulmonary disease

    Radiology

    (1973)
  • R.J. Farney et al.

    Diffuse pulmonary disease after therapy with nitrogen mustard, vincristine, procarbazine, and prednisone

    American Review of Respiratory Disease

    (1977)
  • D.J. Filip et al.

    Pulmonary and hepatic complications of methotrexate therapy of psoriasis

    JAMA

    (1971)
  • W.B. Gefter et al.

    Pleural thickening caused by Sansert and ergotrate in the treatment of migraine

    AJR

    (1980)
  • P.L. Goldiner et al.

    Factors influencing postoperative morbidity in patients treated with bleomycin

    BMJ

    (1978)
  • G.C. Goldman et al.

    Severe pneumonitis occurring during methotrexate therapy. Report of two cases

    Arch Dermatol

    (1971)
  • C.R. Goodman et al.

    Death associated with dantrolene sodium

    NY State J Med

    (1977)
  • J.R. Graham

    Cardiac and pulmonary fibrosis during methysergide therapy for headache

    Am J Med Sci

    (1967)
  • Cited by (0)

    Address reprint requests to Veena B. Antony, MD, Chief, Pulmonary and Critical Care Medicine, RL Roudebush VA Medical Center, 1481 W. 10th Street, Indianapolis, IN 46202

    *

    Division of Pulmonary, Critical Care and Occupational Medicine, Department of Medicine, Indiana University School of Medicine; and Pulmonary and Critical Care Medicine, RL Roudebush VA Medical Center, Indianapolis, Indiana

    View full text