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A 32-year-old man with tuberculosis, fever, and rash
Clinical allergy–immunology rounds
A 32-year-old man with tuberculosis, fever, and rash Rachel E. Story, MD, MPH, and Anne Marie Ditto, MD
CHIEF COMPLAINT Fever, malaise, and pruritic rash. HISTORY OF PRESENT ILLNESS A 32-year-old man recently diagnosed as having pulmonary tuberculosis presented to an outside emergency department complaining of fever, malaise, and pruritic rash. Four weeks before his presentation, the patient was diagnosed as having tuberculosis. A niece visiting from Mexico was diagnosed as having active tuberculosis while living in his home. The patient was asymptomatic, and his diagnosis was established from culture of bronchoalveolar lavage fluid. He was prescribed a 4-drug regimen of isoniazid, rifampin, ethambutol, and pyrazinamide. Liver function test results, prothrombin time, and partial prothrombin time were normal on initiation of treatment. Two weeks after starting treatment, the patient noted malaise, mild nasal congestion, and sore throat for which he took 2 doses of acetaminophen, 325 mg. He continued to have malaise, and 1 week later noted a low-grade fever (temperature, 38.1° C) and a diffuse, erythematous, pruritic rash starting on his chest and then spreading to involve his back, abdomen, arms, and legs. The patient presented to an outside emergency department and was instructed to discontinue use of isoniazid and given diphenhydramine. Four days later, he returned to the emergency department with temperatures to 39.4° C, increased rash, and generalized weakness. Laboratory data were collected, and the patient was transferred to our institution the following day.
daily; and pyridoxine, 25 mg by mouth once daily. He reported taking 2 doses of acetaminophen, 325 mg, 1 week before his presentation to the emergency department and denied any other over-the-counter medications or herbs. Past Medical History The patient was in excellent health and had no medical problems before his diagnosis of tuberculosis. He had no known drug allergies. Family History The patient’s parents were alive and well and living in Mexico. His niece, son, and wife were being treated for tuberculosis at the time of his presentation. There was no family history of atopy, asthma, or liver disease. Social History The patient was married with 1 son. The patient’s wife, son, and niece were also being treated for tuberculosis. The patient and his family moved to Chicago from Mexico 4 years before presentation. He worked in housekeeping at a nursing home. He denied tobacco, alcohol, or illicit drug use.
Current Medications The patient’s medications on presentation to the emergency department included isoniazid, 300 mg by mouth once daily; rifampin, 600 mg by mouth once daily; ethambutol, 800 mg by mouth once daily; pyrazinamide, 1,000 mg by mouth once
PHYSICAL EXAMINATION On admission the patient appeared comfortable and nontoxic. He had a temperature of 39.4° C with a pulse of 100/min, unlabored respirations at 18/min, blood pressure of 121/47 mm Hg, and oxygen saturation of 98% on room air. He had a diffuse morbilliform rash, sparing only his scalp, hands, and soles (Figs 1 and 2). There was no lymphadenopathy. He had no conjunctival injection, and his oropharynx appeared normal. Lung examination revealed good inspiratory and expiratory breath sounds, with no wheeze, rales, or rhonchi. Cardiac examination revealed normal Sl and S2 sounds with no murmurs. Abdominal examination revealed normoactive bowel sounds and was nontender, with no hepatosplenomegaly or masses. There was no cyanosis, clubbing, or pedal edema. His neurologic examination results were normal.
Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. This study was supported by the Ernest S. Bazley Grant to Northwestern Memorial Hospital and Northwestern University. Received for publication October 8, 2003. Accepted for publication in revised form November 4, 2003.
Laboratory Findings Complete cell blood count revealed the following levels: white blood cell count, 13,400/mL (reference range, 6,000 – 17,000/mL); hemoglobin, 13.7 g/dL (reference range, 11.3– 14.1 g/dL); and platelets, 168,000/mL (reference range, 140,000 – 400,000/mL). The differential was 66% neutrophils, 20% eosinophils, 8% lymphocytes, and 6% monocytes.
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Figure 1. Extensive morbilliform rash on the day of admission.
Liver function tests revealed the following values: alanine aminotransferase, 1,613 U/L (reference range, 0 – 48 U/L); aspartate aminotransferase, 1,079 U/L (reference range, 0 – 40 U/L); albumin, 2.4 g/dL (reference range, 3.5–5.0 g/dL); total bilirubin, 2.0 mg/dL (reference range, 0.0–1.3 g/dL); ␥-glutamyl-transferase, 206 U/L (reference range, 0–32 U/L); alkaline phosphatase, 143 U/L (reference range, 30–115 U/L); total protein, 7.2 g/dL (reference range, 6.0– 8.0 g/dL); prothrombin time, 22.3 seconds (reference range, 12–15 seconds); international normalized ratio, 2.0; and partial prothrombin time, 38.6 seconds (reference range, 25–35 seconds). Electrolyte levels and renal function were normal. Hepatitis A, B, and C, toxoplasmosis, cytomegalovirus, and Epstein-Barr virus serologic test results were negative. Antinuclear antibody, anti–smooth muscle antibodies, and antimitochondrial antibodies were negative. The human immunodeficiency virus test result was nonreactive. Chest radiography revealed a density in the apex of the right lung but was otherwise clear. Hospital Course The patient was admitted to our institution with acute liver failure and coagulopathy in stable condition for liver transplantation evaluation. The use of rifampin, pyrazinamide, and ethambutol was discontinued on admission, and the allergy-immunology, hepatology, and infectious disease services were consulted. Liver and skin biopsy specimens were obtained.
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Figure 2. Morbilliform rash on the day of admission.
QUESTIONS 1. What is the differential diagnosis? A. Hypersensitivity syndrome (HSS) B. Isoniazid toxicity and drug eruption C. Stevens-Johnson syndrome (SJS) Additional Laboratory Data A skin biopsy specimen (Fig 3) revealed perivascular dermatitis with lymphocytes and eosinophils. A liver biopsy specimen (Fig 4) revealed liver tissue with centrilobular necrosis, portal inflammation, and lobular inflammation consisting of activated lymphocytes and eosinophils. There was 30% necrosis. 2. With which diagnosis is the patient’s presentation and laboratory data consistent? Hypersensitivity syndrome is a severe idiosyncratic systemic reaction to a drug characterized by fever, rash, and internal organ involvement, including lymphadenopathy, eosinophilia, and hepatitis. The syndrome, previously know as the anticonvulsant HSS, was initially described with phenytoin and later with the other aromatic antiepileptic agents, carbamazepine and phenobarbital.1 Many additional drugs are now known to cause HSS, including sulfonamides, allopurinol, dapsone, minocycline, lamotrigine, valproic acid, diltiazem, mexiletine, terbinafine, sorbinil, and zalcitabine.2 It has
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Figure 3. Dense lymphocytic infiltration of the papillary dermis with occasional eosinophils.
Figure 4. Liver biopsy specimen taken on the day of admission showing periportal and lobular infiltrate of lymphocytes and eosinophils.
been suggested that the syndrome be renamed DRESS or drug rash with eosinophilia and systemic symptoms.3 Most patients present with fever and rash within 2 to 6 weeks of starting a medication. The patient’s course was typical, since he developed symptoms 2 to 3 weeks after starting antituberculosis therapy. The fever often precedes the rash by several days, with temperatures usually ranging from 38° to 40° C.4 Many types of rashes have been reported, but most are diffuse morbilliform rashes that become indurated and infiltrated, with some patients developing facial swelling, exfoliative dermatitis, and bullae and purpura.5 Patients may develop mucosal lesions, but they are not as prominent a feature as in SJS and toxic epidermal necrolysis (TEN).6 The rash often reoccurs when steroids are weaned, requiring a slow taper over several months. Internal organ involvement varies between patients and includes lymphadenopathy, hepatitis, hematologic abnormal-
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ities, interstitial nephritis, and less commonly cardiac, gastrointestinal, pulmonary, thyroid, and central nervous system involvement. Lymphadenopathy occurs in 75% of cases and can be localized or general but was not seen in our patient. Biopsy specimens generally show benign lymphoid hyperplasia; however, sometimes atypical hyperplasia or pseudolymphoma is seen. Subsequent biopsy specimens after termination of the drug use typically show normal lymph node architecture, but there are case reports of progression to lymphoma in a few patients who developed HSS to phenytoin.7 Because lymphadenopathy is often a prominent feature of the syndrome, it is sometimes referred to as drug-induced pseudolymphoma. Hepatitis is seen in more than half the patients with HSS, and acute liver failure is the most common cause of death.5 Although the overall mortality is estimated at l0% in all cases of HSS, it is between 18% and 40% in patients with hepatic involvement.1 The severity of hepatitis is related to the duration of time the offending agent is continued after symptoms begin. Thus, early diagnosis and discontinuation of drug use are essential. Hematologic abnormalities are present in most patients with eosinophilia, and mononucleosis-like atypical lymphocytes are seen most commonly. Eosinophilia often reoccurs with rapid tapering of steroids, and often a slow taper over many weeks is required. In contrast to SJS and TEN, symptoms of HSS tend to occur later in treatment (after 2 to 6 weeks rather than 1 to 3 weeks), most patients develop fever, there are rarely mucosal lesions, and most patients have significant eosinophilia and hepatitis. Patients with SJS/TEN have prominent mucosal involvement, and visceral involvement is usually restricted to the epithelia of the pulmonary and gastrointestinal tract. Severe involvement of the liver with acute liver failure is not seen, although liver function levels may be elevated.5 In addition, SJS is a lymphocytic process and eosinophilia is not typically present. Isoniazid hepatotoxicity is a toxic and idiosyncratic reaction. Severe hepatic necrosis can occur in up to 1% of patients and presents clinically like viral hepatitis, with biopsy specimens showing bridging hepatic necrosis.8 It is unusual for patients to have fever, rash, or eosinophilia. Patients with slow acetylation produce more of the toxic metabolite acetylhydrazine that is known to be hepatotoxic. Mortality is 10% in patients with severe disease.9 The combination of isoniazid with pyrazinamide or rifampin is more hepatotoxic than any of the drugs alone.10,11 There is one case report of HSS to isoniazid that occurred in a 34-year-old woman treated with isoniazid, rifampin, and pyrazinamide.12 After 2 months of therapy, she developed fever, rash, lymphadenopathy, eosinophilia, and hepatitis. The patient was treated with methylprednisolone, and her hepatic function and eosinophilia normalized within 15 days, although the rash persisted for several months. The patient underwent epicutaneous tests to rifampin, pyrazinamide, and
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isoniazid, with a positive reaction to isoniazid after 48 and 96 hours. Ten healthy controls had negative epicutaneous test results to isoniazid. 3. What is the role of tissue biopsy in distinguishing HSS from isoniazid hepatotoxicity? In HSS, liver biopsy specimens typically show a prominent inflammatory infiltrate of eosinophils and activated lymphocytes in the portal and centrilobular areas.13 Liver biopsy specimens in patients experiencing isoniazid toxic effects show hepatic necrosis similar to viral hepatitis, with bridging necrosis in severe cases. The liver biopsy specimen of our patent showed features of both HSS and isoniazid toxicity, with activated lymphocytes and eosinophils in the portal areas typical of HSS. Necrosis without inflammatory cells is more often seen in isoniazid toxicity and was seen in the centrilobular area of our patient’s liver biopsy specimen. Skin biopsy specimens in HSS typically show dense infiltrate of the papillary dermis with lymphocytes and occasionally eosinophils.5 Our patient’s biopsy specimen showed these changes. Diagnosis Our diagnosis was HSS related to antituberculosis therapy with features of isoniazid toxicity. Given the clinical and histopathologic evidence of HSS, the patient was given methylprednisolone at a dose of 60 mg intravenously every 6 hours within 18 hours of admission and within 6 hours of allergy-immunology consultation. The patient’s eosinophil count and liver function improved significantly after more than 48 hours undergoing high-dose steroid therapy (Figs 5 and 6), and steroids were then weaned every 3 to 4 days. On hospital day 11, after weaning prednisone from 60 to 40 mg/d, the eosinophil count increased (Fig 5). The 60-mg dose was reinstituted, and within 1 week the eosinophil count
Figure 5. Absolute eosinophilia vs time. Note the significant decrease in absolute eosinophils within 48 hours of starting steroids. On hospital day 11, the absolute eosinophil count increased to 1,900/mL after prednisone was tapered from 60 to 40 mg/d. The 60-mg dose was resumed and the absolute eosinophil count was normal within 1 week.
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Figure 6. Alanine aminotransferase (ALT) levels vs time. The ALT level decreased steadily from the administration of steroids on admission and was within normal limits at last follow-up.
returned to normal. The rash resolved during the next 2 weeks and never reoccurred. Prednisone was tapered during a 10week period, and on completion of the taper the patient had no eosinophils in his complete blood cell count and his liver function test results were normal. The patient was seen in our clinic for follow-up 30 days after discharge and was doing well. The remainder of his follow-up was at the county tuberculosis clinic. Complete blood cell count with differential and liver function tests were followed every 2 weeks for several weeks after completion of the steroid taper and remained normal. Five months after discharge, the staff of the tuberculosis clinic reported that the patient was doing well and that his laboratory test results were normal. As previously mentioned, on admission antituberculosis treatment was discontinued and the patient was prescribed high-dose steroids. The infectious disease service followed the patient closely, because there was concern about prescribing high-dose steroids and discontinuing all antituberculosis therapy in a patient with active tuberculosis. On the second day of admission, the patient began taking levofloxacin and amikacin. Ethambutol and pyrazinamide were later reintroduced without adverse effect, and the patient’s final regimen included levofloxacin, ethambutol, pyrazinamide, and streptomycin under directly observed therapy. He had no adverse reactions. 4. What is the pathogenesis of HSS? The pathogenesis of HSS is not known, but an immune mechanism is suspected. As in patients with allergic sensitization, patients with HSS require an induction period after initial exposure to an offending agent to develop symptoms. With reexposure to even small amounts of the offending agent, rapid development of severe hepatic and cutaneous manifestations of HSS occurs. In addition, studies suggest that massive release of interleukin 5 from activated lymphocytes contributes to the eosinophilia of HSS.14
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Certain populations may be at increased risk of developing HSS secondary to a genetic defect in drug metabolism. The aromatic antiepileptic agents (phenytoin, carbamazepine, and phenobarbital) are metabolized by the cytochrome P-450 system to a toxic arene oxide metabolite. Patients who develop HSS have absent or abnormal epoxide hydrolase, the enzyme responsible for detoxification of the arene oxide metabolite.15 Although it is not commercially available, there is an in vitro lymphocyte toxicity assay that can help diagnose HSS and potentially identify patients at high risk for the syndrome before being prescribed an aromatic antiepileptic agent.15 Similarly, patients who display slow N-acetylation of sulfonamide, resulting in increased toxic hydroxylamine metabolites, have an increased susceptibility to HSS. However, most people who have slow N-acetylation of sulfonamides do not develop HSS. Treatment If HSS is suspected, use of the offending agent must be stopped immediately. If a patient develops HSS during treatment with an aromatic antiepileptic agent, other agents in that class should not be used, since cross-reactivity is well described. Although there have been no controlled trials of steroid use in this syndrome, they are thought to be life saving in severe cases, and many case reports describe the rapid resolution of eosinophilia, hepatitis, and other internal organ involvement in HSS with institution of systemic steroids. In our patient, we believe steroids were life saving, because he had severe acute liver failure on presentation. Steroid tapers often last many months, since the skin eruption, eosinophilia, and hepatitis of HSS tend to last weeks and frequently relapse when steroids are tapered. Prognosis Most patients recover completely from HSS. Overall mortality is 10% and primarily from hepatitis, nephritis, and carditis. Care should be taken to label the patient allergic to the offending agent and any cross-reacting drugs, because reexposure could be fatal. CONCLUSION The patient presented with the classic features of HSS and had histologic evidence suggestive of isoniazid toxicity as well. He developed fever, a morbilliform eruption, severe hepatitis, and eosinophilia 4 weeks after antituberculosis treatment with isoniazid, rifampin, pyrazinamide, and ethambutol was initiated. Skin and liver biopsy specimens were consistent with HSS and isoniazid hepatotoxicity. The patient had significant resolution of his fevers, rash, hepatitis, and eosinophilia with high-dose steroid therapy and did not relapse after steroids were tapered. Pyrazinamide and ethambutol were not the culprits, because he had no reoccurrence of symptoms on rechallenge. Rechallenge with isoniazid and
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rifampin is not planned, because life-threatening hepatitis could develop. REFERENCES 1. Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med. 1995;155:2285–2290. 2. Carroll MC, Yueng-Yue KA, Esterly NB, Drolet BA. Druginduced hypersensitivity syndrome in pediatric patients. Pediatrics. 2001;108:485– 492. 3. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms-DRESS). Semin Cutan Med Surg. 1996;15:250 –257. 4. Silverman AK, Fairley J, Wong RC. Cutaneous and immunologic reactions to phenytoin. J Am Acad Dermatol. 1988;18: 721–741. 5. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. 1994;331:1272–1284. 6. Revuz J. New advances in severe adverse drug reactions. Dermatol Clin. 2001;19:697–709. 7. Rosenthal CJ, Noguera CA, Coppola A, Kapelner SN. Pseudolymphoma with mycosis fungoides manifestations, hyperresponsiveness to diphenylhydantoin, and lymphocyte dysregulation. Cancer. 1982;49:2305–2314. 8. Black M, Mitchell JR, Zimmerman HJ, Ishak KG, Epter GR. Isoniazid-associated hepatitis in 114 patients. Gastroenterology. 1975;69:289 –302. 9. Lewis JH. Drug-induced liver disease. Med Clin North Am. 2000;84:1275–1311. 10. Durand F, Bernuau L, Pessayre D, et al. Deleterious influence of pyrazinamide on the outcome of patients with fulminant or subfulminant liver failure during antituberculosis treatment including isoniazid. Hepatology. 1995;21:929 –932. 11. Pessayre D, Bentata M, Degott C, et al. Isoniazid-rifampin fulminant hepatitis: a possible consequence of the enhancement of isoniazid hepatotoxicity by enzyme induction. Gastroenterology. 1997;72:284 –289. 12. Rubira N, Baltasar MA, Marti E. Hypersensitivity syndrome from isoniazid. Allergy. 1999;54:1011–1012. 13. Ramkumar D, LaBrecque DR. Drug induced liver disease and environmental toxins. In: Boyer TD, editor. Hepatology. Philadelphia, PA: Sanders; 2003:792–793. 14. Choquet-Kastylevsky G, Intrator L, Chenal C, Bocquet H, Revuz J, Roujeau JC. Increased levels of interleukin 5 are associated with the generation of eosinophilia in drug-induced hypersensitivity syndrome. Br J Dermatol. 1998;139: 1026 –1032. 15. Shear NH, Speilberg SP. Anticonvulsant hypersensitivity syndrome: in vitro assessment of risk. J Clin Invest. 1988;82: 1826 –1832. Requests for reprints should be addressed to: Anne M. Ditto, MD Division of Allergy-Immunology 676 N St Clair #14108 Chicago, IL 60611 E-mail: [email protected]
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A 32-year-old man with tuberculosis, fever, and rash Rachel E. Story, MD, MPH, and Anne Marie Ditto, MD
CHIEF COMPLAINT Fever, malaise, and pruritic rash. HISTORY OF PRESENT ILLNESS A 32-year-old man recently diagnosed as having pulmonary tuberculosis presented to an outside emergency department complaining of fever, malaise, and pruritic rash. Four weeks before his presentation, the patient was diagnosed as having tuberculosis. A niece visiting from Mexico was diagnosed as having active tuberculosis while living in his home. The patient was asymptomatic, and his diagnosis was established from culture of bronchoalveolar lavage fluid. He was prescribed a 4-drug regimen of isoniazid, rifampin, ethambutol, and pyrazinamide. Liver function test results, prothrombin time, and partial prothrombin time were normal on initiation of treatment. Two weeks after starting treatment, the patient noted malaise, mild nasal congestion, and sore throat for which he took 2 doses of acetaminophen, 325 mg. He continued to have malaise, and 1 week later noted a low-grade fever (temperature, 38.1° C) and a diffuse, erythematous, pruritic rash starting on his chest and then spreading to involve his back, abdomen, arms, and legs. The patient presented to an outside emergency department and was instructed to discontinue use of isoniazid and given diphenhydramine. Four days later, he returned to the emergency department with temperatures to 39.4° C, increased rash, and generalized weakness. Laboratory data were collected, and the patient was transferred to our institution the following day.
daily; and pyridoxine, 25 mg by mouth once daily. He reported taking 2 doses of acetaminophen, 325 mg, 1 week before his presentation to the emergency department and denied any other over-the-counter medications or herbs. Past Medical History The patient was in excellent health and had no medical problems before his diagnosis of tuberculosis. He had no known drug allergies. Family History The patient’s parents were alive and well and living in Mexico. His niece, son, and wife were being treated for tuberculosis at the time of his presentation. There was no family history of atopy, asthma, or liver disease. Social History The patient was married with 1 son. The patient’s wife, son, and niece were also being treated for tuberculosis. The patient and his family moved to Chicago from Mexico 4 years before presentation. He worked in housekeeping at a nursing home. He denied tobacco, alcohol, or illicit drug use.
Current Medications The patient’s medications on presentation to the emergency department included isoniazid, 300 mg by mouth once daily; rifampin, 600 mg by mouth once daily; ethambutol, 800 mg by mouth once daily; pyrazinamide, 1,000 mg by mouth once
PHYSICAL EXAMINATION On admission the patient appeared comfortable and nontoxic. He had a temperature of 39.4° C with a pulse of 100/min, unlabored respirations at 18/min, blood pressure of 121/47 mm Hg, and oxygen saturation of 98% on room air. He had a diffuse morbilliform rash, sparing only his scalp, hands, and soles (Figs 1 and 2). There was no lymphadenopathy. He had no conjunctival injection, and his oropharynx appeared normal. Lung examination revealed good inspiratory and expiratory breath sounds, with no wheeze, rales, or rhonchi. Cardiac examination revealed normal Sl and S2 sounds with no murmurs. Abdominal examination revealed normoactive bowel sounds and was nontender, with no hepatosplenomegaly or masses. There was no cyanosis, clubbing, or pedal edema. His neurologic examination results were normal.
Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. This study was supported by the Ernest S. Bazley Grant to Northwestern Memorial Hospital and Northwestern University. Received for publication October 8, 2003. Accepted for publication in revised form November 4, 2003.
Laboratory Findings Complete cell blood count revealed the following levels: white blood cell count, 13,400/mL (reference range, 6,000 – 17,000/mL); hemoglobin, 13.7 g/dL (reference range, 11.3– 14.1 g/dL); and platelets, 168,000/mL (reference range, 140,000 – 400,000/mL). The differential was 66% neutrophils, 20% eosinophils, 8% lymphocytes, and 6% monocytes.
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Figure 1. Extensive morbilliform rash on the day of admission.
Liver function tests revealed the following values: alanine aminotransferase, 1,613 U/L (reference range, 0 – 48 U/L); aspartate aminotransferase, 1,079 U/L (reference range, 0 – 40 U/L); albumin, 2.4 g/dL (reference range, 3.5–5.0 g/dL); total bilirubin, 2.0 mg/dL (reference range, 0.0–1.3 g/dL); ␥-glutamyl-transferase, 206 U/L (reference range, 0–32 U/L); alkaline phosphatase, 143 U/L (reference range, 30–115 U/L); total protein, 7.2 g/dL (reference range, 6.0– 8.0 g/dL); prothrombin time, 22.3 seconds (reference range, 12–15 seconds); international normalized ratio, 2.0; and partial prothrombin time, 38.6 seconds (reference range, 25–35 seconds). Electrolyte levels and renal function were normal. Hepatitis A, B, and C, toxoplasmosis, cytomegalovirus, and Epstein-Barr virus serologic test results were negative. Antinuclear antibody, anti–smooth muscle antibodies, and antimitochondrial antibodies were negative. The human immunodeficiency virus test result was nonreactive. Chest radiography revealed a density in the apex of the right lung but was otherwise clear. Hospital Course The patient was admitted to our institution with acute liver failure and coagulopathy in stable condition for liver transplantation evaluation. The use of rifampin, pyrazinamide, and ethambutol was discontinued on admission, and the allergy-immunology, hepatology, and infectious disease services were consulted. Liver and skin biopsy specimens were obtained.
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Figure 2. Morbilliform rash on the day of admission.
QUESTIONS 1. What is the differential diagnosis? A. Hypersensitivity syndrome (HSS) B. Isoniazid toxicity and drug eruption C. Stevens-Johnson syndrome (SJS) Additional Laboratory Data A skin biopsy specimen (Fig 3) revealed perivascular dermatitis with lymphocytes and eosinophils. A liver biopsy specimen (Fig 4) revealed liver tissue with centrilobular necrosis, portal inflammation, and lobular inflammation consisting of activated lymphocytes and eosinophils. There was 30% necrosis. 2. With which diagnosis is the patient’s presentation and laboratory data consistent? Hypersensitivity syndrome is a severe idiosyncratic systemic reaction to a drug characterized by fever, rash, and internal organ involvement, including lymphadenopathy, eosinophilia, and hepatitis. The syndrome, previously know as the anticonvulsant HSS, was initially described with phenytoin and later with the other aromatic antiepileptic agents, carbamazepine and phenobarbital.1 Many additional drugs are now known to cause HSS, including sulfonamides, allopurinol, dapsone, minocycline, lamotrigine, valproic acid, diltiazem, mexiletine, terbinafine, sorbinil, and zalcitabine.2 It has
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Figure 3. Dense lymphocytic infiltration of the papillary dermis with occasional eosinophils.
Figure 4. Liver biopsy specimen taken on the day of admission showing periportal and lobular infiltrate of lymphocytes and eosinophils.
been suggested that the syndrome be renamed DRESS or drug rash with eosinophilia and systemic symptoms.3 Most patients present with fever and rash within 2 to 6 weeks of starting a medication. The patient’s course was typical, since he developed symptoms 2 to 3 weeks after starting antituberculosis therapy. The fever often precedes the rash by several days, with temperatures usually ranging from 38° to 40° C.4 Many types of rashes have been reported, but most are diffuse morbilliform rashes that become indurated and infiltrated, with some patients developing facial swelling, exfoliative dermatitis, and bullae and purpura.5 Patients may develop mucosal lesions, but they are not as prominent a feature as in SJS and toxic epidermal necrolysis (TEN).6 The rash often reoccurs when steroids are weaned, requiring a slow taper over several months. Internal organ involvement varies between patients and includes lymphadenopathy, hepatitis, hematologic abnormal-
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ities, interstitial nephritis, and less commonly cardiac, gastrointestinal, pulmonary, thyroid, and central nervous system involvement. Lymphadenopathy occurs in 75% of cases and can be localized or general but was not seen in our patient. Biopsy specimens generally show benign lymphoid hyperplasia; however, sometimes atypical hyperplasia or pseudolymphoma is seen. Subsequent biopsy specimens after termination of the drug use typically show normal lymph node architecture, but there are case reports of progression to lymphoma in a few patients who developed HSS to phenytoin.7 Because lymphadenopathy is often a prominent feature of the syndrome, it is sometimes referred to as drug-induced pseudolymphoma. Hepatitis is seen in more than half the patients with HSS, and acute liver failure is the most common cause of death.5 Although the overall mortality is estimated at l0% in all cases of HSS, it is between 18% and 40% in patients with hepatic involvement.1 The severity of hepatitis is related to the duration of time the offending agent is continued after symptoms begin. Thus, early diagnosis and discontinuation of drug use are essential. Hematologic abnormalities are present in most patients with eosinophilia, and mononucleosis-like atypical lymphocytes are seen most commonly. Eosinophilia often reoccurs with rapid tapering of steroids, and often a slow taper over many weeks is required. In contrast to SJS and TEN, symptoms of HSS tend to occur later in treatment (after 2 to 6 weeks rather than 1 to 3 weeks), most patients develop fever, there are rarely mucosal lesions, and most patients have significant eosinophilia and hepatitis. Patients with SJS/TEN have prominent mucosal involvement, and visceral involvement is usually restricted to the epithelia of the pulmonary and gastrointestinal tract. Severe involvement of the liver with acute liver failure is not seen, although liver function levels may be elevated.5 In addition, SJS is a lymphocytic process and eosinophilia is not typically present. Isoniazid hepatotoxicity is a toxic and idiosyncratic reaction. Severe hepatic necrosis can occur in up to 1% of patients and presents clinically like viral hepatitis, with biopsy specimens showing bridging hepatic necrosis.8 It is unusual for patients to have fever, rash, or eosinophilia. Patients with slow acetylation produce more of the toxic metabolite acetylhydrazine that is known to be hepatotoxic. Mortality is 10% in patients with severe disease.9 The combination of isoniazid with pyrazinamide or rifampin is more hepatotoxic than any of the drugs alone.10,11 There is one case report of HSS to isoniazid that occurred in a 34-year-old woman treated with isoniazid, rifampin, and pyrazinamide.12 After 2 months of therapy, she developed fever, rash, lymphadenopathy, eosinophilia, and hepatitis. The patient was treated with methylprednisolone, and her hepatic function and eosinophilia normalized within 15 days, although the rash persisted for several months. The patient underwent epicutaneous tests to rifampin, pyrazinamide, and
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isoniazid, with a positive reaction to isoniazid after 48 and 96 hours. Ten healthy controls had negative epicutaneous test results to isoniazid. 3. What is the role of tissue biopsy in distinguishing HSS from isoniazid hepatotoxicity? In HSS, liver biopsy specimens typically show a prominent inflammatory infiltrate of eosinophils and activated lymphocytes in the portal and centrilobular areas.13 Liver biopsy specimens in patients experiencing isoniazid toxic effects show hepatic necrosis similar to viral hepatitis, with bridging necrosis in severe cases. The liver biopsy specimen of our patent showed features of both HSS and isoniazid toxicity, with activated lymphocytes and eosinophils in the portal areas typical of HSS. Necrosis without inflammatory cells is more often seen in isoniazid toxicity and was seen in the centrilobular area of our patient’s liver biopsy specimen. Skin biopsy specimens in HSS typically show dense infiltrate of the papillary dermis with lymphocytes and occasionally eosinophils.5 Our patient’s biopsy specimen showed these changes. Diagnosis Our diagnosis was HSS related to antituberculosis therapy with features of isoniazid toxicity. Given the clinical and histopathologic evidence of HSS, the patient was given methylprednisolone at a dose of 60 mg intravenously every 6 hours within 18 hours of admission and within 6 hours of allergy-immunology consultation. The patient’s eosinophil count and liver function improved significantly after more than 48 hours undergoing high-dose steroid therapy (Figs 5 and 6), and steroids were then weaned every 3 to 4 days. On hospital day 11, after weaning prednisone from 60 to 40 mg/d, the eosinophil count increased (Fig 5). The 60-mg dose was reinstituted, and within 1 week the eosinophil count
Figure 5. Absolute eosinophilia vs time. Note the significant decrease in absolute eosinophils within 48 hours of starting steroids. On hospital day 11, the absolute eosinophil count increased to 1,900/mL after prednisone was tapered from 60 to 40 mg/d. The 60-mg dose was resumed and the absolute eosinophil count was normal within 1 week.
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Figure 6. Alanine aminotransferase (ALT) levels vs time. The ALT level decreased steadily from the administration of steroids on admission and was within normal limits at last follow-up.
returned to normal. The rash resolved during the next 2 weeks and never reoccurred. Prednisone was tapered during a 10week period, and on completion of the taper the patient had no eosinophils in his complete blood cell count and his liver function test results were normal. The patient was seen in our clinic for follow-up 30 days after discharge and was doing well. The remainder of his follow-up was at the county tuberculosis clinic. Complete blood cell count with differential and liver function tests were followed every 2 weeks for several weeks after completion of the steroid taper and remained normal. Five months after discharge, the staff of the tuberculosis clinic reported that the patient was doing well and that his laboratory test results were normal. As previously mentioned, on admission antituberculosis treatment was discontinued and the patient was prescribed high-dose steroids. The infectious disease service followed the patient closely, because there was concern about prescribing high-dose steroids and discontinuing all antituberculosis therapy in a patient with active tuberculosis. On the second day of admission, the patient began taking levofloxacin and amikacin. Ethambutol and pyrazinamide were later reintroduced without adverse effect, and the patient’s final regimen included levofloxacin, ethambutol, pyrazinamide, and streptomycin under directly observed therapy. He had no adverse reactions. 4. What is the pathogenesis of HSS? The pathogenesis of HSS is not known, but an immune mechanism is suspected. As in patients with allergic sensitization, patients with HSS require an induction period after initial exposure to an offending agent to develop symptoms. With reexposure to even small amounts of the offending agent, rapid development of severe hepatic and cutaneous manifestations of HSS occurs. In addition, studies suggest that massive release of interleukin 5 from activated lymphocytes contributes to the eosinophilia of HSS.14
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Certain populations may be at increased risk of developing HSS secondary to a genetic defect in drug metabolism. The aromatic antiepileptic agents (phenytoin, carbamazepine, and phenobarbital) are metabolized by the cytochrome P-450 system to a toxic arene oxide metabolite. Patients who develop HSS have absent or abnormal epoxide hydrolase, the enzyme responsible for detoxification of the arene oxide metabolite.15 Although it is not commercially available, there is an in vitro lymphocyte toxicity assay that can help diagnose HSS and potentially identify patients at high risk for the syndrome before being prescribed an aromatic antiepileptic agent.15 Similarly, patients who display slow N-acetylation of sulfonamide, resulting in increased toxic hydroxylamine metabolites, have an increased susceptibility to HSS. However, most people who have slow N-acetylation of sulfonamides do not develop HSS. Treatment If HSS is suspected, use of the offending agent must be stopped immediately. If a patient develops HSS during treatment with an aromatic antiepileptic agent, other agents in that class should not be used, since cross-reactivity is well described. Although there have been no controlled trials of steroid use in this syndrome, they are thought to be life saving in severe cases, and many case reports describe the rapid resolution of eosinophilia, hepatitis, and other internal organ involvement in HSS with institution of systemic steroids. In our patient, we believe steroids were life saving, because he had severe acute liver failure on presentation. Steroid tapers often last many months, since the skin eruption, eosinophilia, and hepatitis of HSS tend to last weeks and frequently relapse when steroids are tapered. Prognosis Most patients recover completely from HSS. Overall mortality is 10% and primarily from hepatitis, nephritis, and carditis. Care should be taken to label the patient allergic to the offending agent and any cross-reacting drugs, because reexposure could be fatal. CONCLUSION The patient presented with the classic features of HSS and had histologic evidence suggestive of isoniazid toxicity as well. He developed fever, a morbilliform eruption, severe hepatitis, and eosinophilia 4 weeks after antituberculosis treatment with isoniazid, rifampin, pyrazinamide, and ethambutol was initiated. Skin and liver biopsy specimens were consistent with HSS and isoniazid hepatotoxicity. The patient had significant resolution of his fevers, rash, hepatitis, and eosinophilia with high-dose steroid therapy and did not relapse after steroids were tapered. Pyrazinamide and ethambutol were not the culprits, because he had no reoccurrence of symptoms on rechallenge. Rechallenge with isoniazid and
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rifampin is not planned, because life-threatening hepatitis could develop. REFERENCES 1. Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med. 1995;155:2285–2290. 2. Carroll MC, Yueng-Yue KA, Esterly NB, Drolet BA. Druginduced hypersensitivity syndrome in pediatric patients. Pediatrics. 2001;108:485– 492. 3. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms-DRESS). Semin Cutan Med Surg. 1996;15:250 –257. 4. Silverman AK, Fairley J, Wong RC. Cutaneous and immunologic reactions to phenytoin. J Am Acad Dermatol. 1988;18: 721–741. 5. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. 1994;331:1272–1284. 6. Revuz J. New advances in severe adverse drug reactions. Dermatol Clin. 2001;19:697–709. 7. Rosenthal CJ, Noguera CA, Coppola A, Kapelner SN. Pseudolymphoma with mycosis fungoides manifestations, hyperresponsiveness to diphenylhydantoin, and lymphocyte dysregulation. Cancer. 1982;49:2305–2314. 8. Black M, Mitchell JR, Zimmerman HJ, Ishak KG, Epter GR. Isoniazid-associated hepatitis in 114 patients. Gastroenterology. 1975;69:289 –302. 9. Lewis JH. Drug-induced liver disease. Med Clin North Am. 2000;84:1275–1311. 10. Durand F, Bernuau L, Pessayre D, et al. Deleterious influence of pyrazinamide on the outcome of patients with fulminant or subfulminant liver failure during antituberculosis treatment including isoniazid. Hepatology. 1995;21:929 –932. 11. Pessayre D, Bentata M, Degott C, et al. Isoniazid-rifampin fulminant hepatitis: a possible consequence of the enhancement of isoniazid hepatotoxicity by enzyme induction. Gastroenterology. 1997;72:284 –289. 12. Rubira N, Baltasar MA, Marti E. Hypersensitivity syndrome from isoniazid. Allergy. 1999;54:1011–1012. 13. Ramkumar D, LaBrecque DR. Drug induced liver disease and environmental toxins. In: Boyer TD, editor. Hepatology. Philadelphia, PA: Sanders; 2003:792–793. 14. Choquet-Kastylevsky G, Intrator L, Chenal C, Bocquet H, Revuz J, Roujeau JC. Increased levels of interleukin 5 are associated with the generation of eosinophilia in drug-induced hypersensitivity syndrome. Br J Dermatol. 1998;139: 1026 –1032. 15. Shear NH, Speilberg SP. Anticonvulsant hypersensitivity syndrome: in vitro assessment of risk. J Clin Invest. 1988;82: 1826 –1832. Requests for reprints should be addressed to: Anne M. Ditto, MD Division of Allergy-Immunology 676 N St Clair #14108 Chicago, IL 60611 E-mail: [email protected]
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