- Email: [email protected]
Severe allergic reactions to oral artesunate: a report of two cases
182
MAYFONG
(1997). PuruSight@F test compared with the polymerase chain reaction and microscopy for the diagnosis of Pkzsmodium falciparum malaria in travelers. American Journal of Tropical Medicine and Hygiene, S&44-48. Jensen, J. B. (1979). Observations on gametocytogenesis in Pla.wwdium falciparum from continuous culture. 3ournal of Protozoology, 26,129-132. Karbwang, J. (1997). The PuruSightTM-F test for detecting treatment failure: a reply. Transactions of the Royal Society of Tropical Medicine and Hygiene, 91,49 1. Karbwang, J., Tasanor, O., Kanda, T., Wattanagoon, Y., Ibrahim, M., Na-BanFchang, K., Thanavibul, A. & Rooney, W. (1996). PamSight M-F test for the detection of treatment failure in multidrue resistant Plasmodium fulciaancm malaria. Transactions of the- Royal Society of Troiicai Medicine and Hygiene, 90,513-515. Kiliat+ A. H. D., Kabagambe, G., Byamukama, W., Langi, P., WeIs, P. & von Sonnenburg, F. (1999). Application of the ParuSightTM-F dipstick test for malaria diagnosis in a district control program. Aczu Tropica, 72,281-293. Laferl. H.. Kandel. K. & Pichler. H. (1997). False Dositive dipitick’test for malaria. New .??nglanh3oun?al of Medicine, 337,1635-1636. Mharakurwa, S. & Shiff, C. J. (1997). Post treatment sensitivity studies with the PamSight-F test for malaria diagnosis in Zimbabwe. Acra Tropicar66, 6 l-67. Mishra, B., Samantaray, J. C., Kumar, A. & Mirdha, B. R. (1999). Study of false positivity of two rapid antigen detection tests for diagnosis of PlasmodiumfaIciparum malaria. Journal of Clinical Microbiology, 37, 1233. Parra, M. E., Evans, C. B. & Taylor, D. W. (1991). Identification of Pkzmodium falciparum histidine-rich protein-2 in the olasma of humans with malaria. Youma of Clinical Microbiol&y, 29,1629-1634. Pieroni, P., Mills, C. D., Ohrt, C., Harrington, M. A. & Kain, K.
TRANSACTIONS
OF THE ROYAL
SOCIETY
OF TROPICAL
MEDICINE
Severe allergic reactions to oral artesunate: a report of two cases Elisabetta Leonardi”*, Gabriel Gilvary’, Nicholas J. White2y3 and Fraqois Nosten1S2~3 ‘Shoklo Malaria Research Unit, Mae Sod, Tak Province, Thailand; ‘Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; 3Centre for Tropical Medicine, Nufleld Depam?ent of Clinical Medicine, John RadclifJe Hospital, Headington, Oxford, UK
Keywords: malaria, chemotherapy, artesunate, artemisinin, adverse reactions, allergy, hypersensitivity, case reports, Thailand The artemisinin derivatives are being used increasingly for the treatment of multidrug-resistant falciparum malaria. They are highly effective, safe and well tolerated and, apart from very occasional haemoglobinuria
(‘blackwater’), no serious adverse events have been reported. We report here 2 cases of severe allergic reactions to oral artesunate. The most drug-resistant falciparum malaria parasites in the
world
are found
in north-western
Thailand. health
Multidrug-resistant malaria has been the major problem facing displaced persons of the Karen minority in camps located along the western Over the past 15 years a series of large prospective
ethnic border. studies
Author for correspondence: Professor N. J. White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd, Bangkok 10400, Thailand; fax +66 2 246 7795,
e-mail [email protected]
MAYXAY ETAL.
C. (1998). Comparison of the PuraSightTM-F test and the ICT Malaria Pfr”’ test with the polymerase chain reaction for the diagnosis of Plasmodium fdciparum malaria in travellers. Transactions of Ihe Royal Society of Tropical Medicine and Hygiene, 92, 166-169.. Premii, Z., Minias, 1. N. & Shiff, C. 1. (1994). Laboratorv diagnosis of mala% by village he&h workers using the rapid manual PuruSightTM-F test. Transackonsofthe RoyalSociety of Tropical Medicine and Hygiene, 88,4 18. Shiff, C. J., Premji, Z. & Minjas, J. N. (1993). The rapid manual PuruSightTM-F test. A new diagnostic tool for Plasmodium falciparum infection. Transactions of the Royal Society of Tropical Medicine and Hygiene, 87, 646-648. Smalley, M. E. (1976). Plasmodium falciparum gametocytogenesis in vitro. Nature, 264, 271-272. Uguen, C., Rabodonirina, M., De Pina, J. J., Vigier, J. I’., Martet, G., Maret, M. & Peyron, F. (1995). PamSight-F rapid manual diagnostic test of Plasmodium fualciparum infection. Bulletin of the World Health Organization, 73, 643-649. Vakharia, S., Gopinathan, N. & Kshirsagar, N. A. (1997). The PamSight TM-F test for detecting treatment failure. Transactions of the Royal Society of Tropical Medicine and Hygiene, 91, 490-491. Van den Ende, J., Vervoort, T., van Gompel, A. & Lynen, L. (1998). Evaluation of two tests based on the detection of histidine-rich protein 2 for the diagnosis of imported Plusmodium falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 92,285-288. WHO (1990). Severe and complicated malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84, supplement 2. Received 11 July 2000; revised 22 August; publication 5 September 2000
AND HYGIENE
accepted for
(2001) 95182-183
of antimalarial treatment have been conducted in these camps to determine optimum treatment. These have led to the current recommended treatment of uncomplicated falciparum malaria in this area: a combination of mefloquine (25 mg base/kg) and artesunate (4 mg/kg daily for 3 days) (NOSTEN etal., 1994,200O). Artesunate is generally extremely well tolerated (HIEN & WHITE, 1993; GUO et al., 1994; NOSTEN et al., 1994, 2000; FUBEIRO & OuaRo, 1998; PRICE et al., 1999). We report 2 cases of potentially life-threatening allergic reactions to oral artesunate. Case 1 A 26-year-old previously well man presented to the Research Unit’s malaria clinic with acute uncomplicated falciparum malaria. Four years previously he had received artesunate-mefloquine (MAS3) antimalarial treatment without adverse reactions. About 15-20 min after receiving oral artesunate (Guilin Pharmaceutical Factory No. 1, Guangxi, PRC) 4 mg/kg, he developed generalized pruritus and a widespread urticarial rash. He was given chlorpheniramine (8 mg) orally. After 1 h he felt dizzy, and was found to be hypotensive (blood pressure, BP, 80/40 mmHg), but the chest was clear and other vital signs remained normal. After 2 h the hypotension, rash, and dizziness had resolved. Following the Unit’s previously satisfactory experience with rechallenge (PRICE et al., 1999), artesunate was given again the next day. The patient received chlorpheniramine orally 30 min before this second dose, as pretreatment. Mefloquine was not given. One hour later, he developed pruritus, periorbital, lip, and forearm swelling, tachycardia (140/min), hypotension (90/30 mmHg), a widespread urticarial rash and laboured breathing, although the chest remained clear. He was given dexamethasone, chlorpheniramine, and adrenaline twice and recovered rapidly. He was kept under observation for the afternoon and then discharged home. The third dose of artesunate
183
ALLERGIC REACTIONS TO ORAL ARTESUNATE
was withheld and he was given mefloquine supervision without further problems. Case
alone under
2
A 33-year-old man presented with acute uncomplicated falciparum malaria. Eleven hours after receiving artesunate 4 mg/kg, he was admitted to the inpatient department with agitation, generalized pruritus, leftsided chest pain, and dyspnoea. He was apyrexial with pulse 96/min, BP 150/l 10 mmHg, wheezes over both lung fields, and a widespread urticarial rash over the limbs and abdomen. Parenteral chlorpheniramine and dexamethasone were given. He improved over 2 h; the vital signs returned to normal, the rash faded, and chest auscultation revealed only a few wheezes, but then the rash reappeared suddenly and the patient became clammy and sweaty and collapsed to the floor, unconscious with impalpable pulses. Adrenaline and dexamethasone were given. He regained consciousness after l-2 min, vomited, and became extremely agitated. The following morning he was well with only a fading urticarial rash. Antimalarial treatment was completed with quinine and doxycycline. On questioning further, he remembered that 2 years previously he had been treated for malaria with MAS3, and had been admitted to hosoital because of a generalized rash. Unfortunately his records were untraceable. He denied previous allergic reactions or asthma. Both patients were well at 1 week follow-up, and were warned not to take artemisinin derivatives again. I
Discussion
Of some 17 000 patients treated with artemisinin derivatives in our research unit since 1991, only 6 had allergic reactions witnessed: 2 children (PRICE al., 1999), 1 pregnant woman and 1 man, whose cases were not documented fully, and the 2 cases described above (i.e., a risk of 1 in 2833, 95% confidence interval 1 in 1362 to 6944). Each developed an urticarial rash, but only in the 2 cases described here was the allergic picture more severe, requiring administration of adrenaline, high-dose antihistamines, and steroids. The mechanism underlying this dangerous immediate hypersensitivity reaction is not known. Although manufacturing impurities cannot be excluded with certainty, this product is generally of good quality, and the reactions occurred with different batches of drug. This suggests that the reactions et
were to artesunate or dihydroartemisinin-the principal biologically active metabolite. Artemisinin derivatives should not be given to treat uncomplicated falciparum malaria if there is a previous history of allergic reaction after their consumption, or an urticarial rash develops during treatment. All patients who develop an allergic reaction to artemisinin derivatives should be counselled against taking them again. Acknowledgements We are mat&l to the staff of the Shoklo Malaria Research Unit, and-the Dean of the Faculty of Tropical Medicine, Professor Somchai Looareesuwan, for their support. These observations were made during studies which wei; part of the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme supported by the Wellcome Trust of Great Britain. References Guo, X. B., Fu, L. C., Jian, H. X., Li, G. Q. & Wang, W. H. (1994). Clinical trials of artemisinin and its derivatives in the treatment of malaria in China. Trunsaczions of rhe Royal Society of Tropical Medicine and Hygiene, 88, supplement 1, 5-6. Hien, T. T. & White, N. J. (1993). Qinghaosu. Lancer, 341, 1044- 1049. Nosten, F., Luxemburger, C., ter Kuile, F., Woodrow, C., Pa Eh, J., Chongsuphajaisiddhi, T. & White, N. J. (1994). Treatment of multidrue resistant Plasmodium fulcibarum malaria with a 3 day a;esunate-mefloquine co&b&ation. Journal of Infectious Diseases, 170,97 l-977. Nosten, F., van Vugt, M., Price, R., Luxemburger, C., Brockman. A.. McGreadv, R.. ter Kuile. F.. Looareesuwan. S. & While, fi. J. (2000j.-Effects of art&&ate-mefloquiie’combination on the incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thaiian& a prospective study. Lancet, 356, 297-302. Price, R., van Vugt, M., Phaipun, L., Luxemburger, C., Simpson, J., McGready, R., ter Kuile, F., Kham, A., Chongsuphajaisiddhi, T., White, N. J. & Nosten, F. (1999). Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. American Journal of Tropical Medicine and Hygiene, 60,547-555. Ribeiro, I. R. & Olliaro. P. (19981. Safetv of artemisinin and its derivatives. A review of published anh unpublished clinical trials. Mbdecine Tropicale, 58, 5OS-53s. Received 22 August October 2000
2000;
accepted for
publication
10
MAYFONG
(1997). PuruSight@F test compared with the polymerase chain reaction and microscopy for the diagnosis of Pkzsmodium falciparum malaria in travelers. American Journal of Tropical Medicine and Hygiene, S&44-48. Jensen, J. B. (1979). Observations on gametocytogenesis in Pla.wwdium falciparum from continuous culture. 3ournal of Protozoology, 26,129-132. Karbwang, J. (1997). The PuruSightTM-F test for detecting treatment failure: a reply. Transactions of the Royal Society of Tropical Medicine and Hygiene, 91,49 1. Karbwang, J., Tasanor, O., Kanda, T., Wattanagoon, Y., Ibrahim, M., Na-BanFchang, K., Thanavibul, A. & Rooney, W. (1996). PamSight M-F test for the detection of treatment failure in multidrue resistant Plasmodium fulciaancm malaria. Transactions of the- Royal Society of Troiicai Medicine and Hygiene, 90,513-515. Kiliat+ A. H. D., Kabagambe, G., Byamukama, W., Langi, P., WeIs, P. & von Sonnenburg, F. (1999). Application of the ParuSightTM-F dipstick test for malaria diagnosis in a district control program. Aczu Tropica, 72,281-293. Laferl. H.. Kandel. K. & Pichler. H. (1997). False Dositive dipitick’test for malaria. New .??nglanh3oun?al of Medicine, 337,1635-1636. Mharakurwa, S. & Shiff, C. J. (1997). Post treatment sensitivity studies with the PamSight-F test for malaria diagnosis in Zimbabwe. Acra Tropicar66, 6 l-67. Mishra, B., Samantaray, J. C., Kumar, A. & Mirdha, B. R. (1999). Study of false positivity of two rapid antigen detection tests for diagnosis of PlasmodiumfaIciparum malaria. Journal of Clinical Microbiology, 37, 1233. Parra, M. E., Evans, C. B. & Taylor, D. W. (1991). Identification of Pkzmodium falciparum histidine-rich protein-2 in the olasma of humans with malaria. Youma of Clinical Microbiol&y, 29,1629-1634. Pieroni, P., Mills, C. D., Ohrt, C., Harrington, M. A. & Kain, K.
TRANSACTIONS
OF THE ROYAL
SOCIETY
OF TROPICAL
MEDICINE
Severe allergic reactions to oral artesunate: a report of two cases Elisabetta Leonardi”*, Gabriel Gilvary’, Nicholas J. White2y3 and Fraqois Nosten1S2~3 ‘Shoklo Malaria Research Unit, Mae Sod, Tak Province, Thailand; ‘Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; 3Centre for Tropical Medicine, Nufleld Depam?ent of Clinical Medicine, John RadclifJe Hospital, Headington, Oxford, UK
Keywords: malaria, chemotherapy, artesunate, artemisinin, adverse reactions, allergy, hypersensitivity, case reports, Thailand The artemisinin derivatives are being used increasingly for the treatment of multidrug-resistant falciparum malaria. They are highly effective, safe and well tolerated and, apart from very occasional haemoglobinuria
(‘blackwater’), no serious adverse events have been reported. We report here 2 cases of severe allergic reactions to oral artesunate. The most drug-resistant falciparum malaria parasites in the
world
are found
in north-western
Thailand. health
Multidrug-resistant malaria has been the major problem facing displaced persons of the Karen minority in camps located along the western Over the past 15 years a series of large prospective
ethnic border. studies
Author for correspondence: Professor N. J. White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Rd, Bangkok 10400, Thailand; fax +66 2 246 7795,
e-mail [email protected]
MAYXAY ETAL.
C. (1998). Comparison of the PuraSightTM-F test and the ICT Malaria Pfr”’ test with the polymerase chain reaction for the diagnosis of Plasmodium fdciparum malaria in travellers. Transactions of Ihe Royal Society of Tropical Medicine and Hygiene, 92, 166-169.. Premii, Z., Minias, 1. N. & Shiff, C. 1. (1994). Laboratorv diagnosis of mala% by village he&h workers using the rapid manual PuruSightTM-F test. Transackonsofthe RoyalSociety of Tropical Medicine and Hygiene, 88,4 18. Shiff, C. J., Premji, Z. & Minjas, J. N. (1993). The rapid manual PuruSightTM-F test. A new diagnostic tool for Plasmodium falciparum infection. Transactions of the Royal Society of Tropical Medicine and Hygiene, 87, 646-648. Smalley, M. E. (1976). Plasmodium falciparum gametocytogenesis in vitro. Nature, 264, 271-272. Uguen, C., Rabodonirina, M., De Pina, J. J., Vigier, J. I’., Martet, G., Maret, M. & Peyron, F. (1995). PamSight-F rapid manual diagnostic test of Plasmodium fualciparum infection. Bulletin of the World Health Organization, 73, 643-649. Vakharia, S., Gopinathan, N. & Kshirsagar, N. A. (1997). The PamSight TM-F test for detecting treatment failure. Transactions of the Royal Society of Tropical Medicine and Hygiene, 91, 490-491. Van den Ende, J., Vervoort, T., van Gompel, A. & Lynen, L. (1998). Evaluation of two tests based on the detection of histidine-rich protein 2 for the diagnosis of imported Plusmodium falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 92,285-288. WHO (1990). Severe and complicated malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84, supplement 2. Received 11 July 2000; revised 22 August; publication 5 September 2000
AND HYGIENE
accepted for
(2001) 95182-183
of antimalarial treatment have been conducted in these camps to determine optimum treatment. These have led to the current recommended treatment of uncomplicated falciparum malaria in this area: a combination of mefloquine (25 mg base/kg) and artesunate (4 mg/kg daily for 3 days) (NOSTEN etal., 1994,200O). Artesunate is generally extremely well tolerated (HIEN & WHITE, 1993; GUO et al., 1994; NOSTEN et al., 1994, 2000; FUBEIRO & OuaRo, 1998; PRICE et al., 1999). We report 2 cases of potentially life-threatening allergic reactions to oral artesunate. Case 1 A 26-year-old previously well man presented to the Research Unit’s malaria clinic with acute uncomplicated falciparum malaria. Four years previously he had received artesunate-mefloquine (MAS3) antimalarial treatment without adverse reactions. About 15-20 min after receiving oral artesunate (Guilin Pharmaceutical Factory No. 1, Guangxi, PRC) 4 mg/kg, he developed generalized pruritus and a widespread urticarial rash. He was given chlorpheniramine (8 mg) orally. After 1 h he felt dizzy, and was found to be hypotensive (blood pressure, BP, 80/40 mmHg), but the chest was clear and other vital signs remained normal. After 2 h the hypotension, rash, and dizziness had resolved. Following the Unit’s previously satisfactory experience with rechallenge (PRICE et al., 1999), artesunate was given again the next day. The patient received chlorpheniramine orally 30 min before this second dose, as pretreatment. Mefloquine was not given. One hour later, he developed pruritus, periorbital, lip, and forearm swelling, tachycardia (140/min), hypotension (90/30 mmHg), a widespread urticarial rash and laboured breathing, although the chest remained clear. He was given dexamethasone, chlorpheniramine, and adrenaline twice and recovered rapidly. He was kept under observation for the afternoon and then discharged home. The third dose of artesunate
183
ALLERGIC REACTIONS TO ORAL ARTESUNATE
was withheld and he was given mefloquine supervision without further problems. Case
alone under
2
A 33-year-old man presented with acute uncomplicated falciparum malaria. Eleven hours after receiving artesunate 4 mg/kg, he was admitted to the inpatient department with agitation, generalized pruritus, leftsided chest pain, and dyspnoea. He was apyrexial with pulse 96/min, BP 150/l 10 mmHg, wheezes over both lung fields, and a widespread urticarial rash over the limbs and abdomen. Parenteral chlorpheniramine and dexamethasone were given. He improved over 2 h; the vital signs returned to normal, the rash faded, and chest auscultation revealed only a few wheezes, but then the rash reappeared suddenly and the patient became clammy and sweaty and collapsed to the floor, unconscious with impalpable pulses. Adrenaline and dexamethasone were given. He regained consciousness after l-2 min, vomited, and became extremely agitated. The following morning he was well with only a fading urticarial rash. Antimalarial treatment was completed with quinine and doxycycline. On questioning further, he remembered that 2 years previously he had been treated for malaria with MAS3, and had been admitted to hosoital because of a generalized rash. Unfortunately his records were untraceable. He denied previous allergic reactions or asthma. Both patients were well at 1 week follow-up, and were warned not to take artemisinin derivatives again. I
Discussion
Of some 17 000 patients treated with artemisinin derivatives in our research unit since 1991, only 6 had allergic reactions witnessed: 2 children (PRICE al., 1999), 1 pregnant woman and 1 man, whose cases were not documented fully, and the 2 cases described above (i.e., a risk of 1 in 2833, 95% confidence interval 1 in 1362 to 6944). Each developed an urticarial rash, but only in the 2 cases described here was the allergic picture more severe, requiring administration of adrenaline, high-dose antihistamines, and steroids. The mechanism underlying this dangerous immediate hypersensitivity reaction is not known. Although manufacturing impurities cannot be excluded with certainty, this product is generally of good quality, and the reactions occurred with different batches of drug. This suggests that the reactions et
were to artesunate or dihydroartemisinin-the principal biologically active metabolite. Artemisinin derivatives should not be given to treat uncomplicated falciparum malaria if there is a previous history of allergic reaction after their consumption, or an urticarial rash develops during treatment. All patients who develop an allergic reaction to artemisinin derivatives should be counselled against taking them again. Acknowledgements We are mat&l to the staff of the Shoklo Malaria Research Unit, and-the Dean of the Faculty of Tropical Medicine, Professor Somchai Looareesuwan, for their support. These observations were made during studies which wei; part of the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme supported by the Wellcome Trust of Great Britain. References Guo, X. B., Fu, L. C., Jian, H. X., Li, G. Q. & Wang, W. H. (1994). Clinical trials of artemisinin and its derivatives in the treatment of malaria in China. Trunsaczions of rhe Royal Society of Tropical Medicine and Hygiene, 88, supplement 1, 5-6. Hien, T. T. & White, N. J. (1993). Qinghaosu. Lancer, 341, 1044- 1049. Nosten, F., Luxemburger, C., ter Kuile, F., Woodrow, C., Pa Eh, J., Chongsuphajaisiddhi, T. & White, N. J. (1994). Treatment of multidrue resistant Plasmodium fulcibarum malaria with a 3 day a;esunate-mefloquine co&b&ation. Journal of Infectious Diseases, 170,97 l-977. Nosten, F., van Vugt, M., Price, R., Luxemburger, C., Brockman. A.. McGreadv, R.. ter Kuile. F.. Looareesuwan. S. & While, fi. J. (2000j.-Effects of art&&ate-mefloquiie’combination on the incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thaiian& a prospective study. Lancet, 356, 297-302. Price, R., van Vugt, M., Phaipun, L., Luxemburger, C., Simpson, J., McGready, R., ter Kuile, F., Kham, A., Chongsuphajaisiddhi, T., White, N. J. & Nosten, F. (1999). Adverse effects in patients with acute falciparum malaria treated with artemisinin derivatives. American Journal of Tropical Medicine and Hygiene, 60,547-555. Ribeiro, I. R. & Olliaro. P. (19981. Safetv of artemisinin and its derivatives. A review of published anh unpublished clinical trials. Mbdecine Tropicale, 58, 5OS-53s. Received 22 August October 2000
2000;
accepted for
publication
10