Valproic acid-induced eosinophilic pleural effusion.
Abstract: Valproic acid is a carboxylic acid used for the treatment of both seizure and mood disorders. Its association with pleural fluid eosinophilia has been reported once in the English language literature. We present another case of valproic acid-induced pleural fluid eosinophilia associated with fever and peripheral blood eosinophilia. Extensive evaluation failed to reveal any other cause of eosinophilic eosinophilic /eo·sin·o·phil·ic/ (-fil´ik)
1. readily stainable with eosin.
2. pertaining to eosinophils.
3. pertaining to or characterized by eosinophilia. pleural effusion, and the effusion resolved with discontinuance of valproic acid. Rechallenge with valproic acid produced recurrent symptoms. Valproic acid should be considered a possible cause of eosinophilic pleural effusion.
* Eosinophilic pleural effusions can result from hemothorax or pneumothorax pneumothorax (nmōthôr`ăks), collapse of a lung with escape of air into the pleural cavity between the lung and the chest wall. The cause may be traumatic (e.g. but can also occur as a consequence of various medications.
* Valproic acid can be associated with the development of eosinophilic pleural effusions.
* Eosinophilic pleural effusions that develop in the setting of valproic acid use should first be treated by discontinuance of the medication before an extensive evaluation.
A 34-year-old white man with a history of schizophrenia and sickle cell trait sickle cell trait
A hereditary condition, usually harmless and without symptoms, in which an individual carries only one gene for sickle cell anemia. was admitted for evaluation of fever and nonproductive cough. His recent history included a prolonged hospitalization at an affiliated hospital for fever of unknown origin Fever of Unknown Origin Definition
Fever of unknown origin (FUO) refers to the presence of a documented fever for a specified time, for which a cause has not been found after a basic medical evaluation. . He had been admitted to an inpatient psychiatric ward 2 months earlier with an exacerbation of schizophrenia. Treatment included initiation of multiple medications, with a final regimen consisting of valproic acid (1,500 mg/d), clozapine, benztropine, haloperidol haloperidol /hal·o·peri·dol/ (hal?o-per´i-dol) an antipsychotic agent of the butyrophenone group with antiemetic, hypotensive, and hypothermic actions; used especially in the management of psychoses and to control vocal utterances and , olanzapine, and propranolol propranolol /pro·pran·o·lol/ (-pran´o-lol) a ß, used as the hydrochloride salt in the treatment and prophylaxis of certain cardiac disorders, the treatment of tremors and of inoperable pheochromocytoma, and the prophylaxis of migraine. .
One month before admission, the patient was transferred to the medical service of another hospital for evaluation of temperatures to 103.2[degrees]F with a declining mental status. At the time of the physical examination, his temperature was 100.4[degrees]F, pulse rate 122 beats/min, respiratory rate 32 breaths/min, and blood pressure 130/75 mm Hg. The patient was lethargic, and physical examination revealed an upper extremity nonblanching macular erythematous rash. Cardiopulmonary, abdominal, and extremity examinations were unremarkable. Chestxray showed bilateral pleural effusions. Laboratory tests revealed a leukocyte count of 12,600/[mm.sup.3] with 28% segmented neutrophils and 40% band forms and a valproic acid level of 113 [micro]g/ml.
The patient was treated with multiple antibiotics (including acyclovir, ceftriaxone, vancomycin, ampicillin, gentamicin, metronidazole, trimethoprim/sulfamethoxazole, azithromycin, and gatifloxacin) for possiblemeningitis and/or pneumonia throughout the hospitalization with little effect on the temperature curve. All antipsychotic agents were withheld throughout the hospitalization. On Day 7 of hospitalization on the medical service, the patient had a transient eosinophilia (cell counts to 3,800/ [mm.sup.3]), which resolved after 1 week.
Lumbar puncture showed four nucleated cells/[mm.sup.3], protein value 36 mg/dl, glucose value 83 mg/dl, negative culture, negative acid-fast stain, and negative Cryptococcus Cryptococcus /Cryp·to·coc·cus/ (-kok´us) a genus of yeastlike fungi, including C. neofor´mans, the cause of cryptococcosis in humans.cryptococ´cal
n. antigen. Results of human immunodeficiency virus human immunodeficiency virus
Human immunodeficiency virus (HIV)
A transmissible retrovirus that causes AIDS in humans. enzyme-linked immunosorbent assay enzyme-linked immunosorbent assay
Enzyme-linked immunosorbent assay (ELISA)
A diagnostic blood test used to screen patients for AIDS or other viruses. and polymerase chain reaction polymerase chain reaction (pŏl`ĭmərās') (PCR), laboratory process in which a particular DNA segment from a mixture of DNA chains is rapidly replicated, producing a large, readily analyzed sample of a piece of DNA; the process is were negative, and stool cultures were negative for Strongyloides species, ova, and parasites.
The patient defervesced (Fig. 1) and was discharged to an inpatient psychiatric ward 13 days later for further management. Discharge medications included haloperidol and lorazepam lorazepam /lor·a·ze·pam/ (lor-az´e-pam) a benzodiazepine used as an antianxiety agent, sedative-hypnotic, preanesthetic medication, and anticonvulsant.
n. . During this second inpatient psychiatric stay, he was treated with valproic acid (1,500 mg/ d), haloperidol, and diphenhydramine diphenhydramine /di·phen·hy·dra·mine/ (di?fen-hi´drah-men) a potent antihistamine, used as the hydrochloride salt in the treatment of allergic symptoms and for its anticholinergic, antitussive, antiemetic, antivertigo, and antidyskinetic .
[FIGURE 1 OMITTED]
The patient came to our institution 2 weeks after admission to the psychiatric ward because of recurrent fevers, pleuritic pleu·rit·ic
Of or relating to pleurisy.
pertaining to or emanating from pleurisy. See also pleural.
pleuritic ridge chest pain, and a nonproductive cough. He denied any rash, shortness of breath Shortness of Breath Definition
Shortness of breath, or dyspnea, is a feeling of difficult or labored breathing that is out of proportion to the patient's level of physical activity. , headache, myalgias, abdominal pain, or diarrhea.
At physical examination, his temperature was 100.1[degrees]F, pulse rate 122 beats/min, respiratory rate 26 breaths/min, oxygen saturation on room air 94%, and blood pressure 158/76 mm Hg. Cardiopulmonary examination revealed diminished breath sounds bilaterally in the lower half of the lung fields, with associated dullness to percussion, and decreased fremitus fremitus /frem·i·tus/ (frem´it-us) a vibration felt on palpation.
friction fremitus rub.
hydatid fremitus see under thrill. . Abdominal and extremity examinations were unremarkable and there was no lymphadenopathy, and no skin lesions were present. Neurologic examination was within normal limits.
Laboratory examination revealed a leukocyte count of 9,900/[mm.sup.3], an eosinophil eosinophil /eo·sin·o·phil/ (e?o-sin´o-fil) a granular leukocyte having a nucleus with two lobes connected by a thread of chromatin, and cytoplasm containing coarse, round granules of uniform size. count of 1,500/[mm.sup.3], and a valproic acid level of 114.7 [micro]g/ml. A chest x-ray revealed bilateral pleural effusions (Fig. 2). Diagnostic thoracentesis yielded 45 ml of an exudative exudative
of or pertaining to a process of exudation.
a disease of young pigs and chickens caused by a nutritional deficiency of vitamin E. Characterized by severe edema of the subcutaneous tissues. yellow fluid with a leukocyte count of 3,900/[mm.sup.3] (40% eosinophils Eosinophils
A leukocyte with coarse, round granules present.
Mentioned in: Histiocytosis X
eosinophils ), a lactate dehydrogenase value of 674 U/L (serum value 221 U/L), protein value 4.8 g/dl (serum value 6.5 g/dl), glucose value 105 mg/dl, and a pH of 7.56. Gram stain revealed no organisms; bacterial and mycobacterial cultures were negative and acid-fast stain was negative. Computed tomography of the chest revealed bilateral pleural effusions without infiltrates, masses, or lymphadenopathy.
[FIGURE 2 OMITTED]
The patient was treated with vancomycin and ceftazidime for possible pneumonia, and the valproic acid was discontinued. The patient defervesced, and the eosinophilia resolved (Fig. 1). Laboratory tests were negative for serum Coccidioides and Toxocara Toxocara /Tox·o·ca·ra/ (tok?so-kar´ah) a genus of nematode parasites found in the dog (T. ca´nis) and cat (T. ca´ti); both species are sometimes found in humans. antibodies and moderately positive for Aspergillus. Immunoglobulin E (IgE) was at 2.9 kU/L. Morning cortisol level was 26.3 [micro]g/dl. A PPD tuberculin skin test Tuberculin Skin Test Definition
Tuberculosis (TB) is an airborne infectious disease caused by the bacteria Mycobacterium tuberculosis. Besides culturing in the laboratory, the two most common types of tests to screen for exposure to this disease revealed no in-duration with a reactive anergy anergy /an·er·gy/ (an´er-je)
1. extreme lack of energy.
2. diminished reactivity to one or more specific antigens.aner´gic
The patient's condition continued to improve after completion of antibiotic therapy, and he was transferred to inpatient psychiatric care after 13 days. Treatment with valproic acid has not been restarted, and the patient has not had recurrent fevers. A follow-up chest x-ray obtained 1 month after admission to our hospital showed significant improvement (Fig. 3).
[FIGURE 3 OMITTED]
Eosinophilic pleural effusions, defined as effusions with eosinophil counts greater than 10% of the total fluid nucleated cell count, account for 5 to 8% of exudative pleural effusions. (1) The presence of eosinophils confers a more benign prognosis in comparison with other exudative effusions, with average survival more than twice as long. (1) Pleural fluid eosinophilia most commonly arises from hemothorax or pneumothorax (2) but can also result from asbestosis asbestosis
Lung disease caused by long-term inhalation of asbestos fibres. A pneumoconiosis found primarily in asbestos workers, asbestosis is also seen in people living near asbestos industries. , (3) pulmonary infarction, (4) parapneumonic effusion, (1,4) tuberculosis, (4) parasitic infections including toxocariasis toxocariasis /tox·o·car·i·a·sis/ (-kah-ri´ah-sis) infection by worms of the genus Toxocara.
Infection with nematodes of the genus Toxocara. , (5) and strongyloidiasis strongyloidiasis /stron·gy·loi·di·a·sis/ (stron?ji-loi-di´ah-sis) infection with Strongyloides stercoralis. In the small intestine it causes mucosal ulceration and diarrhea. In the lungs it causes hemorrhaging. , (6,7) eosinophilic pneumonia, (8) malignancy, (1) and medications. (2) Valproic acid has been reported to be the cause of pleural fluid eosinophilia in two previous cases. (2,9) We report another case of pleural fluid eosinophilia attributable to the use of valproic acid.
Although pleural fluid eosinophilia can result from blood or air in the pleural space, other possibilities, including reactions to medications, must be considered, as 25% of eosinophilic pleural effusions are idiopathic. (1) Medications associated with pleural fluid eosinophilia include dantrolene, (10) mesalamine, (11) fluoxetine, (12) gliclazide, (13) and isotretinoin isotretinoin /iso·tret·i·noin/ (i?so-tret´in-o-in) a synthetic form of retinoic acid, used orally to clear cystic and conglobate acne.
n. . (14,15) Our search of the English-language literature yielded only one case report of valproic acid leading to the development of eosinophitic pleural effusion. (2)
Our patient's recurrent bilateral eosinophilic pleural effusions, accompanied by systemic eosinophilia and fever, were associated with the use of valproic acid. Our case is unique because there was an inadvertent rechallenge with valproic acid and the patient's symptoms recurred, therefore lending more evidence to the association. Furthermore, an extensive evaluation did not reveal any of the other known causes of eosinophilic pleural effusion. Specifically, there was no evidence of pneumothorax, hemothorax, pulmonary infiltrates, lymphadenopathy, or mycobacterial, fungal, or parasitic infection. Finally, the two medications common to both hospitalizations were valproic acid and haloperidol; the latter has not been associated with the development of pleural effusions. In addition, haloperidol was given to our patient at a later date, without the development of recurrent symptoms.
Valproic acid is a carboxylic acid used in the treatment of seizure disorders and has more recently been used as a mood stabilizer for selected patients with psychiatric disease. As the use of this agent increases, physicians should increase their awareness that it may cause eosinophilic pleural effusion. If a patient taking valproic acid presents with eosinophilic pleural effusion, we recommend prompt discontinuance of the drug and careful observation. If improvement is noted, the patient can forego an extensive evaluation for other causes and should not be rechallenged with this medication.
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From the Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, and the VA Connecticut Health Care System, West Haven, CT.
Reprint requests to Jeffrey D. Kravetz, MD, 278 W. Elm Street, New Haven, CT 06515. Email: firstname.lastname@example.org
Accepted February 28, 2002.