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Mefloquine-induced Stevens-Johnson syndrome
683
noradrenaline but produced no change. She had sinus tachycardia with left-axis deviation, anteroseptal Q waves, and a non-specific ST abnormality. A transoesophageal echocardiogram revealed severe depression of ventricular function (ejection fraction < 10%). An intra-aortic balloon pump achieved no improvement and amrinone 5 µg/kg per min was substituted for dopamine and dobutamine 35 h after the sting. Within an hour her heart rate was 176/min and stroke volume and cardiac index had improved to 21 ml per beat and 2.31/min per m2, respectively. The amrinone dose was increased to 12 µg/kg per min and 2 h later her heart rate was 150/min, stroke volume 33 ml per beat, cardiac output 6.22 1/min, and cardiac index 3-96 I/min per m2. 45 h after the sting her blood pressure was 100/50 mm Hg, heart rate 150/min, wedge pressure 15 mm Hg, cardiac output 6-291/min, cardiac index 4.01/min per m2, and stroke volume 42 ml per beat, with amrinone as the sole inotropic support. Her condition continued to improve and she was extubated and transferred from intensive care. 2 months after discharge from hospital findings on cardiac examination and on echocardiography were normal. Anaphylaxis results in excessive catecholamine production and mediators of anaphylaxis such as platelet-activating factor and leukotrienes have a direct cardiodepressant effect in animal models of anaphylaxis.2,3 In an isolated heart model’ and in human heart tissue5 antigen-mediated local histamine release is associated with a positive chronotropic and inotropic effect. Del Balzo et al6 have demonstrated in guineapigs the importance of complement activation and anaphylatoxins as amplifiers of cardiac anaphylaxis, and, in man, complement C3a has been implicated in the pathogenesis of hymenoptera-induced anaphylaxis, especially in those with cardiovascular involvement.7 A hypothetical mechanism implicates activation of complement in anaphylaxis-induced myocardial depression. The myocardium is rich in mast cells. Nonetheless, during systemic anaphylaxis, clinically apparent myocardial depression is not usual. When &bgr;-agonists and an intra-aortic balloon pump1 were unhelpful in our patient we tried amrinone, a phosphodiesterase inhibitor used in severe heart failure, and the impressive response to this drug could be explained by its positive inotropic effect via a non-&bgr;-receptor mechanism8,9 since constant catecholamine stimulation could have led to down regulation of &bgr;-receptors, myocardial c-AMP depletion, and further myocardial depression and thus decreased cAMP &bgr;-receptor coupling due to decreased levels of G-proteins. 10 Had colloid rather than crystalloid fluid replacement been used at the first hospital the persistent hypotension and anaphylactic insult to the heart might have been avoided. When myocardial depression is evident in anaphylaxis, invasive haemodynamic monitoring, the early use of colloids, and administration of non-catecholamine inotropic agents such as amrinone may prove
life-saving. Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA
ELIZABETH OTERO JOHN R. ONUFER CRAIG K. REISS PHILLIP E. KORENBLAT
Fisher MMD. Profound reversible myocardial depression after anaphylaxis. Lancet 1988, i: 386-88. Tosaki A, Koltai M, Braquet P, et al. Possible involvement of platelet activating factor in anaphylaxis of passively sensitised isolated guinea pig hearts. Cardiovas Res 1989;
1 Raper RF, 2
23: 715-22. 3. Burke JA, Levi R, Guo Z-G, et al. Leukotrienes C4, D4, and E4: effects on human and guinea pig cardiac preparations in vitro.J Pharmacol Exp Ther 1982; 221: 239. 4. Heller LJ, Regal JF. Relationship between alterations in atrial and ventricular histamine content and cardiac function during cardiac anaphylaxis of isolated guinea pig hearts. Int Arch Allergy Appl Immunol 1990; 91: 285-90. 5. Graver ML, Robertson DA, Levi R. IgE-mediated hypersensitivity in human heart tissue: histamine release and functional change. J Allergy Clin Immunol 1986; 77: 709-14. 6. Del Balzo U, Polley MJ, Levi R. Cardiac anaphylaxis complement activation as an amplification system. Circ Res 1989; 65: 847-57 7. Van der Linden PWG, Hack CE, Kerckhaert JAM, et al. Preliminary report: complement activation in wasp sting anaphylaxis Lancet 1990; 336: 904-06. 8 Silver PJ Biochemical aspects of inhibition ofcardiovascular low (Km) cyclic adenosine monophosphate phosphodiesterase. AmJ Cardiol 1989; 63: 2A-8A. 9 Evans DB Overview of cardiovascular physiologic and pharmacologic aspects of selective phosphodiesterase peak III inhibitors. Am J Cardiol 1989; 63: 9A-11A. 10. Editorial. G proteins and heart failure. Lancet 1990; 336: 1412-14.
Mefloquine-induced Stevens-Johnson syndrome SIR,-Chloroquine-resistant Plasmodium falciparum continues spread. At present, there is no completely effective and safe method for the prevention of falciparum malaria. Travellers on short visits (less than 3 months) to chloroquine-resistant endemic 1 areas are advised to take mefloquine as chemoprophylaxis. Side-effects of mefloquine include dizziness, nausea, erythema, and neurological disturbance.2,3 We report a case of erythema multiforma major (Stevens-Johnson syndrome) associated with mefloquine prophylaxis. A 66-year-old healthy Belgian woman travelled to South-East Asia. She had never had any allergic reaction. Mefloquine 250 mg weekly was started on Oct 28, 1990, 7 days before departure. She was not taking any other drug and had not taken mefloquine before. Three days later a sore lower lip developed, which started blistering. During the next few days, erythematous lesions appeared on both lips, oral mucosa, and arms. The lesions spread rapidly and started to ulcerate, affecting oral and nasal mucosae, arms, legs, and back. There were no eye complaints, nor genital or anal discomfort. She was treated in Asia with antihistamine and oral steroids. Mefloquine was stopped. After 3 weeks the patient returned to Belgium. She still had widespread mucosal ulceration of the mouth and nose, with bleeding and crust formation. Several circular crusted lesions (7-25 mm diameter) were present on both arms, legs, and back. There were no ocular, genital, or anal lesions. Skin biopsy was not done because the lesions seemed to be healing. Viral cultures for herpes simplex (lip) and Coxsackie A (wound, throat, and stool) were negative. Eosinophils were 0-08 x 109/1 (normal). Serological tests for mycoplasma pneumonia were negaive. There was gradual healing over 2 weeks. The history of this patient strongly suggests that mefloquine can cause a Stevens-Johnson syndrome. The lack of conjunctival and genital involvement is compatible with this diagnosis.4 To confirm the diagnosis a rechallenge with mefloquine would be needed but this would have been unacceptable. Severe cutaneous reactions with the antimalarial sulfadoxine/pyrimethamine (’Fansidar’) have been described, but as far as we are aware no previous case of Stevens-Johnson syndrome secondary to mefloquine has been reported. Mefloquine is now widely used for prophylaxis and treatment of chloroquine-resistant falciparum malaria. A good surveillance system for side-effects of this drug is certainly needed.5 to
Institute for Tropical Medicine, B-2000 Antwerp,
ERWIN VAN DEN ENDEN ALFONS VAN GOMPEL ROBERT COLEBUNDERS
Belgium
JEF VAN DEN ENDE
Organisation. International travel and health: vaccination certificate requirements and health advice, 1990. Geneva: WHO, 1990. 2. Steffen R, Heusser R, Machler R, et al. Malaria chemoprophylaxis in European tourists visiting tropical Africa: use, adverse drug reactions, and efficacy. Bull 1. World Health
WHO 1990; 68: 313-22. 3. Lobel HO, Phillips-Howard PA, Brandling-Bennett AD, et al. Malaria incidence and prevention among European and North American travellers to Kenya. Bull WHO 1990; 68: 209-15. 4. Champion RH. Disorders affecting small blood vessels: erythema and telangiectasia. In: Rook A, Wilkinson DS, Ebling FJG, Champion RH, Burton JL, eds. Textbook of dermatology, 4th ed, vol 2. Oxford: Blackwell Scientific Publications, 1986. 1086. 5. Phillips-Howard PA, Bjorkman AB. Ascertainment ofrisk ofserious adverse reactions associated with chemoprophylactic antimalarial drugs. Bull WHO 1990; 68: 493-504.
L-arginine-induced hypotension to our report of L-arginine-induced it was suggested that histamine release may be responsible for hypotensionand that our suggestion that Larginine-induced hypotension resulted from nitric oxide (NO) release was merely speculative.3 To clarify these points, we completed further studies in the same 5 subjects who were examined in our previous report. To test the histamine hypothesis, subjects took 1-2 mg/kg d-chlorpheniramine maleate orally (sufficient to antagonise H1 receptor-mediated hypotension) 2 h before L-arginine infusion. Chlorpheniramine
SIR,-In
response
hypotension,l
noradrenaline but produced no change. She had sinus tachycardia with left-axis deviation, anteroseptal Q waves, and a non-specific ST abnormality. A transoesophageal echocardiogram revealed severe depression of ventricular function (ejection fraction < 10%). An intra-aortic balloon pump achieved no improvement and amrinone 5 µg/kg per min was substituted for dopamine and dobutamine 35 h after the sting. Within an hour her heart rate was 176/min and stroke volume and cardiac index had improved to 21 ml per beat and 2.31/min per m2, respectively. The amrinone dose was increased to 12 µg/kg per min and 2 h later her heart rate was 150/min, stroke volume 33 ml per beat, cardiac output 6.22 1/min, and cardiac index 3-96 I/min per m2. 45 h after the sting her blood pressure was 100/50 mm Hg, heart rate 150/min, wedge pressure 15 mm Hg, cardiac output 6-291/min, cardiac index 4.01/min per m2, and stroke volume 42 ml per beat, with amrinone as the sole inotropic support. Her condition continued to improve and she was extubated and transferred from intensive care. 2 months after discharge from hospital findings on cardiac examination and on echocardiography were normal. Anaphylaxis results in excessive catecholamine production and mediators of anaphylaxis such as platelet-activating factor and leukotrienes have a direct cardiodepressant effect in animal models of anaphylaxis.2,3 In an isolated heart model’ and in human heart tissue5 antigen-mediated local histamine release is associated with a positive chronotropic and inotropic effect. Del Balzo et al6 have demonstrated in guineapigs the importance of complement activation and anaphylatoxins as amplifiers of cardiac anaphylaxis, and, in man, complement C3a has been implicated in the pathogenesis of hymenoptera-induced anaphylaxis, especially in those with cardiovascular involvement.7 A hypothetical mechanism implicates activation of complement in anaphylaxis-induced myocardial depression. The myocardium is rich in mast cells. Nonetheless, during systemic anaphylaxis, clinically apparent myocardial depression is not usual. When &bgr;-agonists and an intra-aortic balloon pump1 were unhelpful in our patient we tried amrinone, a phosphodiesterase inhibitor used in severe heart failure, and the impressive response to this drug could be explained by its positive inotropic effect via a non-&bgr;-receptor mechanism8,9 since constant catecholamine stimulation could have led to down regulation of &bgr;-receptors, myocardial c-AMP depletion, and further myocardial depression and thus decreased cAMP &bgr;-receptor coupling due to decreased levels of G-proteins. 10 Had colloid rather than crystalloid fluid replacement been used at the first hospital the persistent hypotension and anaphylactic insult to the heart might have been avoided. When myocardial depression is evident in anaphylaxis, invasive haemodynamic monitoring, the early use of colloids, and administration of non-catecholamine inotropic agents such as amrinone may prove
life-saving. Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA
ELIZABETH OTERO JOHN R. ONUFER CRAIG K. REISS PHILLIP E. KORENBLAT
Fisher MMD. Profound reversible myocardial depression after anaphylaxis. Lancet 1988, i: 386-88. Tosaki A, Koltai M, Braquet P, et al. Possible involvement of platelet activating factor in anaphylaxis of passively sensitised isolated guinea pig hearts. Cardiovas Res 1989;
1 Raper RF, 2
23: 715-22. 3. Burke JA, Levi R, Guo Z-G, et al. Leukotrienes C4, D4, and E4: effects on human and guinea pig cardiac preparations in vitro.J Pharmacol Exp Ther 1982; 221: 239. 4. Heller LJ, Regal JF. Relationship between alterations in atrial and ventricular histamine content and cardiac function during cardiac anaphylaxis of isolated guinea pig hearts. Int Arch Allergy Appl Immunol 1990; 91: 285-90. 5. Graver ML, Robertson DA, Levi R. IgE-mediated hypersensitivity in human heart tissue: histamine release and functional change. J Allergy Clin Immunol 1986; 77: 709-14. 6. Del Balzo U, Polley MJ, Levi R. Cardiac anaphylaxis complement activation as an amplification system. Circ Res 1989; 65: 847-57 7. Van der Linden PWG, Hack CE, Kerckhaert JAM, et al. Preliminary report: complement activation in wasp sting anaphylaxis Lancet 1990; 336: 904-06. 8 Silver PJ Biochemical aspects of inhibition ofcardiovascular low (Km) cyclic adenosine monophosphate phosphodiesterase. AmJ Cardiol 1989; 63: 2A-8A. 9 Evans DB Overview of cardiovascular physiologic and pharmacologic aspects of selective phosphodiesterase peak III inhibitors. Am J Cardiol 1989; 63: 9A-11A. 10. Editorial. G proteins and heart failure. Lancet 1990; 336: 1412-14.
Mefloquine-induced Stevens-Johnson syndrome SIR,-Chloroquine-resistant Plasmodium falciparum continues spread. At present, there is no completely effective and safe method for the prevention of falciparum malaria. Travellers on short visits (less than 3 months) to chloroquine-resistant endemic 1 areas are advised to take mefloquine as chemoprophylaxis. Side-effects of mefloquine include dizziness, nausea, erythema, and neurological disturbance.2,3 We report a case of erythema multiforma major (Stevens-Johnson syndrome) associated with mefloquine prophylaxis. A 66-year-old healthy Belgian woman travelled to South-East Asia. She had never had any allergic reaction. Mefloquine 250 mg weekly was started on Oct 28, 1990, 7 days before departure. She was not taking any other drug and had not taken mefloquine before. Three days later a sore lower lip developed, which started blistering. During the next few days, erythematous lesions appeared on both lips, oral mucosa, and arms. The lesions spread rapidly and started to ulcerate, affecting oral and nasal mucosae, arms, legs, and back. There were no eye complaints, nor genital or anal discomfort. She was treated in Asia with antihistamine and oral steroids. Mefloquine was stopped. After 3 weeks the patient returned to Belgium. She still had widespread mucosal ulceration of the mouth and nose, with bleeding and crust formation. Several circular crusted lesions (7-25 mm diameter) were present on both arms, legs, and back. There were no ocular, genital, or anal lesions. Skin biopsy was not done because the lesions seemed to be healing. Viral cultures for herpes simplex (lip) and Coxsackie A (wound, throat, and stool) were negative. Eosinophils were 0-08 x 109/1 (normal). Serological tests for mycoplasma pneumonia were negaive. There was gradual healing over 2 weeks. The history of this patient strongly suggests that mefloquine can cause a Stevens-Johnson syndrome. The lack of conjunctival and genital involvement is compatible with this diagnosis.4 To confirm the diagnosis a rechallenge with mefloquine would be needed but this would have been unacceptable. Severe cutaneous reactions with the antimalarial sulfadoxine/pyrimethamine (’Fansidar’) have been described, but as far as we are aware no previous case of Stevens-Johnson syndrome secondary to mefloquine has been reported. Mefloquine is now widely used for prophylaxis and treatment of chloroquine-resistant falciparum malaria. A good surveillance system for side-effects of this drug is certainly needed.5 to
Institute for Tropical Medicine, B-2000 Antwerp,
ERWIN VAN DEN ENDEN ALFONS VAN GOMPEL ROBERT COLEBUNDERS
Belgium
JEF VAN DEN ENDE
Organisation. International travel and health: vaccination certificate requirements and health advice, 1990. Geneva: WHO, 1990. 2. Steffen R, Heusser R, Machler R, et al. Malaria chemoprophylaxis in European tourists visiting tropical Africa: use, adverse drug reactions, and efficacy. Bull 1. World Health
WHO 1990; 68: 313-22. 3. Lobel HO, Phillips-Howard PA, Brandling-Bennett AD, et al. Malaria incidence and prevention among European and North American travellers to Kenya. Bull WHO 1990; 68: 209-15. 4. Champion RH. Disorders affecting small blood vessels: erythema and telangiectasia. In: Rook A, Wilkinson DS, Ebling FJG, Champion RH, Burton JL, eds. Textbook of dermatology, 4th ed, vol 2. Oxford: Blackwell Scientific Publications, 1986. 1086. 5. Phillips-Howard PA, Bjorkman AB. Ascertainment ofrisk ofserious adverse reactions associated with chemoprophylactic antimalarial drugs. Bull WHO 1990; 68: 493-504.
L-arginine-induced hypotension to our report of L-arginine-induced it was suggested that histamine release may be responsible for hypotensionand that our suggestion that Larginine-induced hypotension resulted from nitric oxide (NO) release was merely speculative.3 To clarify these points, we completed further studies in the same 5 subjects who were examined in our previous report. To test the histamine hypothesis, subjects took 1-2 mg/kg d-chlorpheniramine maleate orally (sufficient to antagonise H1 receptor-mediated hypotension) 2 h before L-arginine infusion. Chlorpheniramine
SIR,-In
response
hypotension,l