bronchopleural fistulas in the mechanically ventilated patient.Chest 1990; 97:721–728

8 Otani T, Tatsuka T, Knamaru K, et al. Intramural injection ofethanol under direct vision for the treatment of protuberantstomach. Gastroenterol 1975; 69:123–129

9 Asaki S, Nishimura S, Iwai H, et al. Tissue solidification incoping with digestive tract bleeding: hemostatic effect of localinjection of 99.5% ethanol. Tohoku J Exp Med 1981; 134:223–227

10 Roukema JA, Verpalen MC, Lobach HJ, et al. Bronchopleuralfistula: the use of tissue glue. J Thorac Cardiovasc Surg 1992;103:167

11 Fujisawa T, Yamaguchi Y, Hongo H, et al. Intratumoral ethanolinjection for malignant tracheobronchial lesions: a new broncho-fiberscopic procedure. Endoscopy 1986; 18:188–191

12 Jessen C, Sharma P. Use of fibrin glue in thoracic surgery.Ann Thorac Surg 1985; 39:521–524

13 York LE, Lewall BD, Hirij M, et al. Endoscopic diagnosis andtreatment of post operative bronchopleural fistula. Chest1990; 97:1390–1393

14 Regal G, Sturm JA, Neumann C, et al. Occlusion of broncho-pleural fistula after lung injury: a new treatment by bronchos-copy. J Trauma 1989; 29:223–226

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16 Jones DP, David I. Gelform occlusion of peripheral broncho-pleural fistulas. Ann Thorac Surg 1989; 42:223–226

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Severe Erythroderma as aComplication of ContinuousEpoprostenol Therapy*

Gregory S. Ahearn, MD; M. Angelica Selim, MD; andVictor F. Tapson, MD, FCCP

Epoprostenol is a vasodilator that is produced byvascular endothelial cells and is currently the “goldstandard” therapy for patients with severe primarypulmonary hypertension or pulmonary hypertensionsecondary to collagen vascular disease. Hypersensi-

tivity to the drug has not been reported. We report acase of a patient with pulmonary hypertension andundifferentiated connective tissue disease who, after2 months of treatment with epoprostenol, presentedwith rapidly progressive erythema, scaling, nauseaand vomiting, and fever. Test results from a skinbiopsy specimen were consistent with a drug reac-tion. The patient’ condition improved after rapidtapering of her epoprostenol and administration ofcorticosteroids. Epoprostenol may be associatedrarely with severe erythroderma.

(CHEST 2002; 122:378–380)

Key words: allergic reaction; connective tissue disease; drugreaction; epoprostenol; erythroderma; pulmonary hypertension;skin biopsy

A llergic drug reactions occur most commonly withthe administration of sulfonamides, anticonvulsants,

allopurinol, and nonsteroidal anti-inflammatory drugs,but may occur following the administration of almostany drug. Dermatologic manifestations are a continuumranging from diffuse erythema to fulminant toxic epi-dermal necrolysis. Such reactions occur in all humanpopulations and all age ranges. Continuous IV epopro-stenol is the drug of choice for severe primary pulmo-nary hypertension or pulmonary arterial hypertensiondue to the scleroderma spectrum of diseases.1,2 Patientsreceiving epoprostenol therapy often develop mild-to-moderate erythema. We present the first reportedcase of severe erythroderma associated with the initia-tion of therapy with this drug, a previously unreportedcomplication.

Case ReportA 56-year-old white woman presented to her local medical

doctor with increasing dyspnea over several months, which wasassociated with occasional substernal chest pain and a nonpro-ductive cough. Her medical history was significant for undiffer-entiated connective tissue disease, gastroesophageal reflux dis-ease, and morbid obesity. Her evaluation was consistent withpulmonary arterial hypertension secondary to undifferentiatedconnective tissue disease. She underwent cardiac catheterization,which revealed a right atrial pressure of 13 mm Hg, a rightventricular pressure of 80/8 mm Hg, a pulmonary artery pressureof 90/40 mm Hg, and a pulmonary capillary wedge pressure of14 mm Hg. The cardiac output was 5.1 L/min with a cardiacindex of 2.5 L/min/m2. The pulmonary vascular resistance was6.32 Wood units.

She was referred to Duke University Medical Center forfurther evaluation and treatment of primary pulmonary hyper-tension. Because of the severity of her symptoms, she wasadmitted to the hospital and was started on a regimen of IV

*From the Department of Medicine (Drs. Ahearn and Tapson),Division of Pulmonary and Critical Care Medicine, and theDepartment of Pathology (Dr. Selim), Duke University MedicalCenter, Durham, NC.Manuscript received September 17, 2001; revision acceptedMarch 26, 2002.Correspondence to: Victor F. Tapson, MD, FCCP, AssociateProfessor of Medicine, Division of Pulmonary and Critical Care,Duke University Medical Center, Box 31175, Durham, NC27710; e-mail: tapso001@mc.duke.edu

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epoprostenol, which she tolerated well. A central venous catheteralso was placed in the patient for long-term access withoutcomplication. At 2 months of follow-up, she was continuing totolerate epoprostenol therapy well. Her dose was titrated up to11.5 ng/kg/min. She experienced mild jaw pain and flushing,which are common side effects of epoprostenol.

Two weeks later, the patient was admitted to the medical ICUfor management of worsening erythroderma. She reported that10 days before she had developed diffuse erythema, pruritus, andscaling. These symptoms were associated with chills, nauseaand vomiting, and diarrhea. These symptoms were progressive,and she presented to an outside emergency department, whereshe was found to have a temperature of 100.7 F and an oxygensaturation of 96% while receiving 4 L oxygen administered witha nasal cannula. She was transferred to the medical ICU at DukeMedical Center for further management of her condition. Hermedications included warfarin, furosemide, spironolactone, fexo-fenadine, epoprostenol, and oxygen. Epoprostenol was the mostrecently added medication.

On arrival in the ICU, the patient was diffusely erythema-tous and was having rigors. Her temperature was 37.4°C, pulsewas 97 beats/min, respiratory rate was 12 breaths/min, and BPwas 106/51 mm Hg. Her skin was diffusely erythematous withexcoriations and large areas of exfoliation. The patient did nothave any mucosal lesions. The results of the cardiac examina-tion were consistent with pulmonary hypertension, the resultsof the abdominal examination were benign, and there was 3�symmetric lower extremity edema. The result of her stool testwas guaiac negative. The WBC count was 10.9 � 106 cells/Lwith 22% band forms and 2% eosinophils. Serum chemistrylevels were normal except for a BUN level of 22 mg/dL and analbumin level of 2.2 g/dL.

Parenteral dexamethasone therapy was initiated at 20 mg every6 h, and the patient was started on a regimen of cefazolin,triamcinalone 0.1% ointment, and a lubricant (petroleum jelly).She underwent a skin biopsy (Fig 1), the results of which werethought to be consistent with a drug reaction, based on thepresence of eosinophils in the dermal infiltrate. Epoprostenolwas believed to be the most likely cause as it was the mostrecently added drug. Epoprostenol dosage was tapered off at arate of 1 ng/kg/min/d. After 48 h of receiving high-dose paren-teral and topical steroids, the erythema was improved, however,the patient continued to desquamate in many areas, especiallythe palms and soles. She remained hemodynamically stable whilethe epoprostenol was tapered off. The parenteral steroid therapywas changed to therapy with oral prednisone, which was slowlytapered. She had no further complications and was dischargedfrom the hospital on hospital day 18 in stable condition.

DiscussionAllergic drug reactions can present as a continuum of

conditions from urticaria and exanthema to the moresevere Stevens-Johnson syndrome and toxic epidermalnecrolysis. The incidence of adverse cutaneous reactionsto drugs is high (estimated at 2 to 3% of hospitalizedpatients3), and it is difficult to predict which patients willprogress from minor skin eruptions to severe life-threat-ening reactions, emphasizing the importance of stoppingthe offending drug immediately.

When a patient’s presentation is suspicious for a drugreaction, it is often difficult to determine which drug isresponsible. Generally, it is attributed to the drug mostrecently added. Further support of causation is providedwhen the patient improves after administration of thesuspicious drug is stopped. In this case, the patient had

been following a stable medical regimen prior to receivingepoprostenol and improved after administration of thedrug was tapered off.

The immunologic mechanisms underlying allergic drugreactions are poorly understood.3 Most immediate allergicdrug reactions are IgE-mediated, however, delayed reac-tions seem to have more complex underlying pathologicmechanisms that involve T lymphocytes.3 Most allergicskin reactions occur in response to low-molecular-weightcompounds. It has been proposed4 that small molecules,once bound to peptide structures, can become immuno-genic and can stimulate T lymphocytes. Some molecules,such as �-lactam antibiotics, lidocaine, and sulfamethox-azole, can bind directly to peptides and stimulate Tlymphocytes. It is thought, however, that most drugs areimmunologically inert and gain immunogenicity throughtheir metabolites.5

It is interesting to speculate on the role that immunedysfunction associated with undifferentiated connectivetissue disease might play in this case. Patients with HIVhave a higher incidence of adverse drug reactions com-pared with the general population,6,7 suggesting the im-portance of immune dysregulation. There is some evi-dence that the altered immune function associated withcollagen vascular disease may increase the risk.8

At physiologic pH, epoprostenol is rapidly hydrolyzedboth spontaneously and enzymatically, resulting in a short

Figure 1. Epidermal acanthosis with neutrophilic exocytosis isshown. Papillary dermis with perivascular mononuclear infiltrateand scattered eosinophils may be noted.

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half-life of about 2.7 min. The two major metabolites are6-keto-PGF1́ (the result of spontaneous degradation) and6,15-diketo-13,14-dihydro-PGF1́. Fourteen other minormetabolites are formed, indicating that epoprostenol isextensively metabolized. The immunogenic potential ofthe parent compound and its metabolites is difficult toassess because of the short half-life of the drug and thelack of sufficiently sensitive assays.

This patient’s clinical presentation was severe in thatshe developed diffuse erythroderma associated withexfoliation. Interestingly, her biopsy results did notdemonstrate extensive necrosis, which would be ex-pected in such a situation. This may have been due to abiopsy sampling error.

Epoprostenol therapy is associated with flushing andpatchy areas of erythema, which are thought to be related tothe vasodilator properties of the drug. While there has beenno reported pathologic investigation of these phenomena,they seem less likely to be inflammatory, as they are oftenintermittent and may respond to a lowering of the drug dose.There are no reported cases of such severe allergic reactionsto epoprostenol or other prostaglandin derivatives. Whileapparently rare, this case suggests that severe allergic reac-tions may occur after epoprostenol therapy has begun.

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3 Gonzalez FJ, Leyva L, Posadas S, et al. Participation of Tlymphocytes in cutaneous allergic reactions to drugs. ClinExp Allergy 1998; 28(suppl):3–6

4 Merk HF, Baron J, Kawakubo Y, et al. Metabolites and allergicdrug reactions. Clin Exp Allergy 1998; 28(suppl):21–24

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