- Email: [email protected]
Allergic reactions to long-term benzathine penicillin prophylaxis for rheumatic fever
1308
the incidence of the disease. The sustained administration of DFO may provide a valuable treatment for carefully selected patients with early AD. We recommend a multicentre trial to confirm the present findings. Caution should be exercised with DFO in future studies and side-effects must be evaluated promptly. We thank Mr R. Duff, Ms M. Henry, and Mr R. Major for their assistance. This work was supported by the Extramural Program, National Health and Welfare Canada, and the Ministry of Universities and Colleges of the Province of Ontario. Desferrioxamine was supplied by Ciba-Geigy, Canada.
REFERENCES Krishnan SS, Dalton AJ, DeBoni U, Intranuclear aluminium content in Alzheimer’s disease, dialysis encephalopathy, and experimental aluminium encephalopathy. Acta Neuropathol 1980; 50: 19-24. 2. Edwardson JA, Candy JM. Aluminium and the pathogenesis of senile plaques in Alzheimer’s disease, Down’s syndrome and chronic renal dialysis. Ann Med 1989; 21: 95-97. 3. Martyn CN, Barker DJP, Osmond C, Harris EC, Edwardson JA, Lacey RF. Geographical relation between Alzheimer’s disease and drinking water. Lancet 1989; i: 59-62. 4. Chang TMS, Barre P. Effect of desferrioxamine on removal of aluminium and iron by coated charcoal haemoperfusion and haemodialysis. Lancet 1983; ii: 1051-53. 5. Propper R, Cooper B, Rufo B, et al. Continuous subcutaneous administration of desferoxamine in patients with iron overload. N Engl J Med 1977; 297: 418-23. 6. Olivieri NF, Bunic JR, Chew E, et al. Visual and auditory neurotoxicity in patients receiving subcutaneous desferoxamine infusions. N Engl J Med 1986; 314: 869-73. 7. Pengloan J, Dantal J, Rossazza C, Abazza M, Nivet H. Ocular toxicity after a single intravenous dose of desferrioxamine in two hemodialyzed patient. Nephron 1987; 46: 211-12. 8. Piga A, Lazzatto L, Capalbo P, Gambotto S, Tricta F, Gabutti V. High dose desferrioxamine as a cause of growth failure in thalassemic patients. Eur J Hematol 1988; 40: 380-81. 9. Kruck TPA, Kalow W, Crapper McLachlan D. Determination of desferoxamine and a major metabolite by high performance liquid
1. Crapper DR, Quittkat S,
chromatography: Applications to the treatment of aluminium related disorders. J Chromatogr 1985; 34: 123-29. 10. Kruck TPA, Teichert-Kuliszewska K, Fisher E, Kalow W, McLachlan DR. High performance liquid chromotographic analysis of desferrioxamine: Pharmacokenetic and metabolic studies. J Chromatogr 1988; 433: 207-16. 11. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939-44. 12. Hachinski VC, Iliff LD, Zilhka E, et al. Cerebral blood flow in dementia. Arch neurol 1975; 32: 632-37. 13. Wechsler D. Manual for the Wechsler Adult Intelligence Scale-Revised. New York: The Psychological Corp, 1981. 14. Wechsler D, Stone CP. Wechsler Memory Scale. New York: The Psychological Corp, 1945. 15. Kertesz A. Western Aphasia Battery. New York: Greene and Stratton Inc, 1982. 16. Kazdin AE. Behavior Modification in Applied Settings, 4th ed. California: Brooks Cole Publishing Co, 1984: 71. 17. Kruck TPA, Fisher EA, McLachlan DRC. Suppression of deferoxamine mesylate treatment-induced side effects by coadministration of isoniaziud in a patient with Alzheimer’s disease subject to aluminium removal by ionspecific chelation. Clin Pharmacol Ther 1990; 48: 439-46. 18. Senator GB, Muirden KD. Iron in the synovial membrane in rheumatoid arthritis and other joint diseases. Ann Rheum Dis 1968; 27: 38-47. 19. Blake DR, Hall ND, Bacon PA, Dieppe PA, Halliwell B, Gutteridge JMC. Effect of a specific iron chelating agent on animal models of inflammation. Ann Rheum Dis 1983; 42: 89-93. 20. Sedgwick AD, Blake DR, Winwood P, Moore AR, Al-Duaij AY, Willoughby DA. Studies into the effects of the iron chelator desferrioxamine on the inflammatory process. Eur J Rheumatol Inflamm 1984; 7: 87-94. 21. Hirschelmann R, Bekemeier H. Influence of the iron-chelating agent desferrioxamine on two rat inflammatory models. Free Radical Res Commun 1986; 2: 125-27. 22. Morgan A, McDonald-Gibson RG, Slater TF. Stimulation of rat uterine prostacyclin production and inhibition of hydroxyeicosatetraenoic acid production by dsferrioxamine in vitro. ICRS Med Sci 1986; 14: 399-400.
Allergic reactions to long-term benzathine penicillin prophylaxis for rheumatic fever INTERNATIONAL RHEUMATIC FEVER STUDY GROUP*
1790 patients from 11 countries were enrolled in a prospective international study to determine the incidence of allergic reactions to monthly intramuscular benzathine penicillin (penicillin G benzathine) injections to prevent recurrences of rheumatic fever. After 32 430 injections during 2736 patient years of observation, 57 of the 1790 patients (3·2%) had an allergic reaction. 4 had anaphylaxis, an incidence of 0·2% (1&mid ot; 2/10 000 injections), all in patients over 12 years of age, and 1 patient died, a fatality incidence of 0·05% (0·31/10 000 injections). These rates are similar to those described for patients without rheumatic fever who receive short-term treatment with parenteral penicillin. Rheumatic fever recurred in 8 of 1790 patients (0·45%) who received benzathine penicillin prophylaxis compared with 11 of 96 (11 ·5%) who did not comply with treatment. Life-threatening allergic reactions are rare in patients on long-term parenteral benzathine penicillin to prevent recurrences of rheumatic fever; the long-term benefits of such prophylaxis by far outweigh the risk of a serious allergic reaction.
Introduction Rheumatic fever causes 25-40% of all cardiovascular disease in developing countries; disability and death from rheumatic heart disease are mainly caused by recurrent attacks.2 The efficacy of antibiotic prophylaxis to prevent recurrences of rheumatic fever has been known for over 50 years3,4-amajor advance that has strikingly reduced the morbidity and mortality from rheumatic fever. 5-8 Because of the impact of this disease on public health, and the proven efficacy of antibiotic prophylaxis, the World Health Organisation has helped to establish programmes for prevention of rheumatic fever in developing countries.9 A single intramuscular injection of 1-2 million units of benzathine penicillin every 4 weeks is the most widely used method for antibiotic prophylaxis.9,10 Penicillins can cause
*M. Markowitz and E. Kaplan (USA); R. Cuttica (Argentina); X. Berrios (Chile); Z. Huang and X. Rao (People’s Republic of China); P. L Wahi and H. K. Bali (India); D. Millard (Jamaica); J. Y. Choi and C. Y. Hong (Korea); H. A. Majeed (Kuwait); P. Clarkson and J. Neutze (New Zealand), H. C. Lue (Taiwan); C. Vongprateep and C. Phornphutkul (Thailand), and S.
Munoz (Venezuela). Correspondence to Prof M. Markowitz, Room AG 062, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
1309
and even fatal allergic reactions," which led to when a long-acting depot penicillin became available in 1951, but the initial studies of benzathine severe
concern
for rheumatic fever prophylaxis reported only mild allergic reactions in a few patients. 12 Since then, benzathine penicillin has been used extensively, with few well-documented reports of serious allergic reactions in patients with rheumatic feverP,14 However, anecdotal accounts of fatal allergic reactions are common in some developing countries and the fears generated by such reports have deterred both physicians and patients from continuing this effective method of prevention. 15 Are such fears warranted? To determine the true incidence of allergic reactions to long-term prophylaxis with benzathine penicillin in patients with past rheumatic fever, we organised a prospective international study, and now describe the incidence of allergic reactions in 1790 such
penicillin
who received benzathine penicillin prophylaxis 4 weeks for 2736 patient-years of follow-up. every
patients
Patients and methods Patients with a history of rheumatic fever who received benzathine penicillin prophylaxis were recruited in 1988-1990 from 11 geographically widespread countries in which rheumatic fever remains an important public health problem. Study sites selected all had an established prevention programme for rheumatic fever and used 12 million units of benzathine penicillin administered intramuscularly every 4 weeks as the principal treatment to prevent recurrent attacks. Injections were given by health personnel, usually nurses, who had been trained to administer this drug, and each site had an emergency medicine kit available for prompt treatment should a life-threatening reaction occur. All patients enrolled in the study fulfilled the Jones criteria for diagnosis of rheumatic fever and none had a history of an allergic reaction to penicillin. Age, injection schedule, duration of previous prophylaxis, and manufacturer of the penicillin used were recorded for all patients. After entry to the study the date of each benzathine penicillin injection and any subsequent signs and symptoms of a possible allergic reaction (hypotension, dyspnoea, pruritus, urticaria, angioneurotic oedema, arthralgia, and maculopapular rash) were recorded. Any allergic reaction was classified according to its time of onset: immediate, or within 1 h of administration; accelerated, after 1-72 h; and late, after more than 72 h.16 A record was also kept of rheumatic fever recurrences among patients who received benzathine penicillin prophylaxis and among those who did not comply with treatment. 1107 patients who had had rheumatic fever and who received benzathine penicillin prophylaxis were enrolled at the start of the study in 1988 and another 683 were added during the 2-year study period, a total of 1790 patients. The duration of prophylaxis before entry to the study ranged from 1 month to 12 years, with a mean of 3-8 years. Patients were followed prospectively for 6-24 months for a total of 2736 patient-years on prophylaxis. Their ages ranged from 5-28 years; 33% were 12 years or younger. Benzathine penicillin from 12 different manufacturers was used, with 32 430 injections given during the observation period.
Results 57
(32%)
of the 1790
patients had
an
allergic reaction.
Immediate anaphylactic reactions occurred in 4, 3 of whom had anaphylactic shock within minutes of injection of
benzathine penicillin, and the other had dyspnoea and
hypotension
30 min
subsequently.
Accelerated reactions
(1-72 h) occurred in 37 patients: 30 had pruritus or urticaria, 6 had
arthralgia,
and 1 started
to
wheeze. Late reactions
included 2 patients with arthralgia, 3 with urticaria, and 11I with maculopapular rashes. There was no preponderance of allergic reactions at any one site, nor were they associated
with a particular manufacturer of benzathine penicillin. Another patient had an unexplained, brief seizure after an injection, but did not become hypotensive and did not appear to have a true allergic reaction. Several patients had transient febrile reactions or brief syncopal episodes, which were also not considered true allergic reactions. The 4 episodes of anaphylaxis represent a case incidence of 0-2% and an injection frequency of 0-012% (1-2 reactions/10 000 injections). All 4 patients were over 12 years of age (15, 16, 17, and 18) and had been treated with benzathine penicillin for 2 months to 7 years before anaphylaxis occurred. All 4 had rheumatic valvular heart disease and 3 required treatment for congestive heart failure. 1 of these 4 patients died, a case fatality incidence of 0-05% and an injection frequency of 0-0031% (0-31/10 000 injections). The patient who died was a 15-year-old girl with severe mitral valve disease and chronic congestive cardiac failure who had received 24 earlier injections of benzathine penicillin without incident. 30-60 seconds after the last injection she developed respiratory stridor and cardiac arrest, and died after initial resuscitation and mechanical ventilation for 6 days. 8 of the 1790 patients (0-45%) had recurrent rheumatic fever while on benzathine penicillin prophylaxis. 290 patients dropped out of the study, either because they
moved, stopped prophylactic treatment for medical reasons other than allergy, or did not comply with treatment. Among 96 patients who did not comply with prophylaxis and who could be traced, 11 (11-5%) had recurrent rheumatic fever.
Discussion The 3-2% incidence of allergic reaction observed among patients with a history of rheumatic fever on continuous prophylaxis with benzathine penicillin does not differ significantly from the 2-24% reported in patients who received short-term treatment with benzathine penicillin for sexually transmitted disease." Thus we found no evidence that the duration of previous treatment with benzathine penicillin increased the risk of an allergic reaction. Stollerman et al,12 in an early study of benzathine penicillin prophylaxis for rheumatic fever, also found no increase in allergic reactions over time. Preliminary results from skin tests for penicillin allergy indicate that repeated exposure to benzathine penicillin does not unduly increase the occurrence of positive skin tests: 4 of 76 patients (5-2%) on long-term benzathine penicillin prophylaxis for rheumatic fever were positive for major and minor determinants of penicillin, well within the 2-7% range found in subjects with no history of rheumatic fever or of penicillin allergy." Anaphylaxis is the most worrying potential allergic reaction to penicillin. The reported incidence of serious reactions among patients without a history of rheumatic fever or of penicillin allergy ranges from 1-4/10 000 treatment courses. 17,111 The 4 episodes of anaphylaxis that we encountered in 1790 patients with a history of rheumatic fever who received 32 430 injections of benzathine penicillin represent a frequency of 1-23/10 000 injections, no greater than that in patients given one course of parenteral penicillin. The risk of a serious reaction is usually less in children under 12 years of age;19,zO of approximately 600 such patients in our study, none had anaphylaxis. Death from an allergic reaction to penicillin occurs at an incidence of about 1 per 50 000 treatment courses of parenteral penicillin in the general population.18 We observed 1 death after 32 430 injections of benzathine penicillin in patients
1310
who had had rheumatic fever. Reported deaths in patients with a history of rheumatic fever treated with benzathine penicillin prophylaxis have all been in adults with advanced rheumatic heart disease.13.14 Death during or after an anaphylactic reaction may be more likely in patients with a history of rheumatic fever than in normal controls because of their increased prevalence of heart disease, and because pre-existing heart disease, or treatment for such disease, may exacerbate the cardiovascular effects of anaphylaxis or hinder attempts at resuscitation .22-25 Although skin tests for penicillin allergy are not recommended for patients without a history of such allergic reactions, it is possible that selective skin tests with major and minor determinants of penicillin 16-27 might further reduce the already low risk of a fatal reaction in patients with severe heart disease; patients with a positive skin test could receive an alternative prophylactic drug such as sulphadiazine. This study also enabled comparison of the incidence of recurrent attacks of rheumatic fever in patients while on continuous benzathine penicillin prophylaxis with recurrence in patients who did not comply with prophylaxis. Rheumatic fever recurred in 8 (0-45%) of 1790 patients while on regular prophylaxis compared with 11 (11-5%) of 96 who were not. This striking difference is further evidence of the efficacy of four-weekly intramuscular injection of 1.2 million units of benzathine penicillin to prevent recurrent attacks of rheumatic fever. The prognosis is greatly improved in patients on regular prophylaxis, as shown by Lue and colleagues,8 who found an 8-year mortality rate of 3% among patients with a history of rheumatic fever who received regular prophylaxis, compared to 28% among similar patients who did not. In conclusion, life-threatening allergic reactions to penicillin in patients with a history of rheumatic fever and who receive continuous prophylaxis with benzamine penicillin are rare, and are no more frequent than in patients without rheumatic fever who receive one course of parenteral penicillin for other indications. It is essential to look out for untoward reactions to penicillin and to have resuscitation facilities available when patients are injected, and extra vigilance may be necessary in patients with severe heart disease and a history of cardiac decompensation. However, the long-term benefits of benzathine penicillin prophylaxis to prevent recurrent rheumatic fever far outweigh the risk of a serious allergic reaction to penicillin. We thank
Strasser T, Dondog N, El Kholy AM, Gharagozloo R. Report of a WHO international cooperative project. Bull WHO 1981; 59: 285-94. 10. Wood HF, Feinstein AR, Taranta A, et al. Rheumatic fever in children and adolescents, III. Comparative effectiveness of three prophylactic regimens in preventing streptococcal infections and rheumatic recurrences. Ann Intern Med 1964; 60 (suppl 5): 31-46. 11. Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18: 515-40. 12. Stollerman GH, Rusoff JH, Hirschfeld I. Prophylaxis against group A streptococci in rheumatic fever. N Engl J Med 1955; 252: 787-92. 13. Hsu I, Evans JM. Untoward reactions to benzathine penicillin G in study of rheumatic fever prophylaxis m adults. N Engl J Med 1958; 259: 9.
581-83.
Steigmann F, Suker JR. Fatal reactions to benzathine penicillin G. JAMA 1962; 179: 288-90. 15. Lue HC, Chen HC, Wei HY. Some problems in long term prevention of streptococcal infections among children with rheumatic heart disease in Taiwan. Jpn Heart J 1976; 17: 550-59. 16. Levine BB. Immunologic mechanisms of penicillin allergy. A haptene model system for the study of allergic diseases of man. N Engl J Med 14.
1966; 275: 1115-25. 17. Enffmeyer JE. Penicillin allergy. Clin Rev Allergy 1986; 4: 171-86. 18. Idsoe O, Guthe T, Willcox RR, deWeck AL. Nature and extent of
19.
penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull WHO 1968; 38: 159-88. Sullivan TJ. Pathogenesis and management of allergic reactions to penicillin and other beta-lactam antibiotics. Pediatr Infect Dis 1982; 1: 344-50.
20.
21.
Graff-Lounevig V, Hedlin G, Lindfors A. Penicillin allergy—a rare pediatric condition? Arch Dis Child 1988; 63: 1342-46. Chandra RG, Joglehar SA, Tomas E. Penicillin allergy: anti-penicillin IgE antibodies and immediate hypersensitivity skin reactions employing major and minor determinants of penicillin. Arch Dis Child
1980; 55: 857-60. AA, Kotler MN. EKG changes associated with penicillin anaphylaxis. Chest 1973; 64: 66-69. 23. Jacobs RL, Rake GW, Fournier DC, Chilton RJ. Potentiated
22. Petsas
anaphylaxis in patients with drug-induced beta-adrenergic blockade. J Allergy Clin Immunol 1981; 68: 125-27. 24. Berkelman RL, Finton RJ, Elsea WR. Beta adrenergic antagonists and fatal anaphylaxis reactions to oral penicillin. Ann Intern Med 1968; 104: 134. 25. Sullivan TJ. Cardiac disorders in penicillin-induced anaphylaxis. JAMA 1982; 248: 2161-62. 26. Adkinson NF, Spence M, Wheeler B. Randomized clinical trial of routine penicillin skin testing. J Allergy Clin Immunol 1984; 73 (suppl): 163
(abstr). 27. Sue MA, Noritake DT, Klaustermeyer WB. Penicillin anaphylaxis: fatality in elderly patients without a history of penicillin allergy. Am J Emerg Med 1988; 6: 456-58.
From The Lancet
Wyeth-Ayerst International for support of this study. Medical
protection
REFERENCES
Agarwal BL. Rheumatic fever and rheumatic heart disease in developing countries. A monograph. New Delhi: Arnold Publishers, 1988. 2. Taranta A, Markowitz M. Rheumatic fever. A monograph. 2nd ed. London: Kluwer, 1989. 3. Thomas CB, France R. A preliminary report of the prophylactic use of sulfonamide in patients susceptible to rheumatic fever. Bull Johns Hopkins Hosp 1939; 64: 67-77. 4. Coburn AF, Moore LV. The prophylactic use of sulfonamide in streptococcal respiratory infections with special reference to rheumatic fever. J Clin Invest 1939; 18: 147-55. 5. Tompkins DG, Boxerbaum B, Liebman J. Long term prognosis of rheumatic fever patients receiving intramuscular benzathine penicillin. 1.
Circulation 1972; 45: 543-51. of the initial attack of rheumatic fever in children in North India. Circulation 1982; 65: 375-79. 7. Majeed HA, Yousof AM, Khuffash FA. The natural history of acute rheumatic fever in Kuwait: a prospective six year follow-up report. J Chronic Dis 1986; 39: 361. 8. Lue HC, Tseng WP, Lin GJ, et al. Clinical and epidemiologic features of rheumatic fever and rheumatic heart disease in Taiwan and the Far East. Indian Heart J 1983; 35: 139-46. 6.
Sanyal SK, Barry AM, Duggal S. Sequelae
If medicine be
a
necessary of life, is
a
civilised nation-with
an
enlightened Government at its head-to take no means to test the qualifications of its professors? Are the lives of the people to be the sport of impostors? Is quackery to be allowed to blow its brazen trumpet through the length and breadth of the land? Are poisons to be patented? Are the articles of the materia medica to be adulterated with impunity? Is a class of tradesmen-respectable when they restrict themselves to weighing and selling drugs-to be encouraged and permitted to pretend to the healing art, without any knowledge either of the structure of the body, or of the laws of health and disease? Is this to be countenanced in the name of free trade; and are medical men to be denied protection, when the poor are deprived of foreign sugar-and com-to protect the landholders, and the late slaveholders, of the country? We are confident that these topics will not be forgotten by our medical brethren at the ensuing elections. The Medical Associations should be up and stirring. If the House of Commons be dissolved, medical election committees should be formed in every district, to impress more strongly upon candidates the claims of the medical profession, and of the public health ...
(May 15, 1841)
the incidence of the disease. The sustained administration of DFO may provide a valuable treatment for carefully selected patients with early AD. We recommend a multicentre trial to confirm the present findings. Caution should be exercised with DFO in future studies and side-effects must be evaluated promptly. We thank Mr R. Duff, Ms M. Henry, and Mr R. Major for their assistance. This work was supported by the Extramural Program, National Health and Welfare Canada, and the Ministry of Universities and Colleges of the Province of Ontario. Desferrioxamine was supplied by Ciba-Geigy, Canada.
REFERENCES Krishnan SS, Dalton AJ, DeBoni U, Intranuclear aluminium content in Alzheimer’s disease, dialysis encephalopathy, and experimental aluminium encephalopathy. Acta Neuropathol 1980; 50: 19-24. 2. Edwardson JA, Candy JM. Aluminium and the pathogenesis of senile plaques in Alzheimer’s disease, Down’s syndrome and chronic renal dialysis. Ann Med 1989; 21: 95-97. 3. Martyn CN, Barker DJP, Osmond C, Harris EC, Edwardson JA, Lacey RF. Geographical relation between Alzheimer’s disease and drinking water. Lancet 1989; i: 59-62. 4. Chang TMS, Barre P. Effect of desferrioxamine on removal of aluminium and iron by coated charcoal haemoperfusion and haemodialysis. Lancet 1983; ii: 1051-53. 5. Propper R, Cooper B, Rufo B, et al. Continuous subcutaneous administration of desferoxamine in patients with iron overload. N Engl J Med 1977; 297: 418-23. 6. Olivieri NF, Bunic JR, Chew E, et al. Visual and auditory neurotoxicity in patients receiving subcutaneous desferoxamine infusions. N Engl J Med 1986; 314: 869-73. 7. Pengloan J, Dantal J, Rossazza C, Abazza M, Nivet H. Ocular toxicity after a single intravenous dose of desferrioxamine in two hemodialyzed patient. Nephron 1987; 46: 211-12. 8. Piga A, Lazzatto L, Capalbo P, Gambotto S, Tricta F, Gabutti V. High dose desferrioxamine as a cause of growth failure in thalassemic patients. Eur J Hematol 1988; 40: 380-81. 9. Kruck TPA, Kalow W, Crapper McLachlan D. Determination of desferoxamine and a major metabolite by high performance liquid
1. Crapper DR, Quittkat S,
chromatography: Applications to the treatment of aluminium related disorders. J Chromatogr 1985; 34: 123-29. 10. Kruck TPA, Teichert-Kuliszewska K, Fisher E, Kalow W, McLachlan DR. High performance liquid chromotographic analysis of desferrioxamine: Pharmacokenetic and metabolic studies. J Chromatogr 1988; 433: 207-16. 11. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939-44. 12. Hachinski VC, Iliff LD, Zilhka E, et al. Cerebral blood flow in dementia. Arch neurol 1975; 32: 632-37. 13. Wechsler D. Manual for the Wechsler Adult Intelligence Scale-Revised. New York: The Psychological Corp, 1981. 14. Wechsler D, Stone CP. Wechsler Memory Scale. New York: The Psychological Corp, 1945. 15. Kertesz A. Western Aphasia Battery. New York: Greene and Stratton Inc, 1982. 16. Kazdin AE. Behavior Modification in Applied Settings, 4th ed. California: Brooks Cole Publishing Co, 1984: 71. 17. Kruck TPA, Fisher EA, McLachlan DRC. Suppression of deferoxamine mesylate treatment-induced side effects by coadministration of isoniaziud in a patient with Alzheimer’s disease subject to aluminium removal by ionspecific chelation. Clin Pharmacol Ther 1990; 48: 439-46. 18. Senator GB, Muirden KD. Iron in the synovial membrane in rheumatoid arthritis and other joint diseases. Ann Rheum Dis 1968; 27: 38-47. 19. Blake DR, Hall ND, Bacon PA, Dieppe PA, Halliwell B, Gutteridge JMC. Effect of a specific iron chelating agent on animal models of inflammation. Ann Rheum Dis 1983; 42: 89-93. 20. Sedgwick AD, Blake DR, Winwood P, Moore AR, Al-Duaij AY, Willoughby DA. Studies into the effects of the iron chelator desferrioxamine on the inflammatory process. Eur J Rheumatol Inflamm 1984; 7: 87-94. 21. Hirschelmann R, Bekemeier H. Influence of the iron-chelating agent desferrioxamine on two rat inflammatory models. Free Radical Res Commun 1986; 2: 125-27. 22. Morgan A, McDonald-Gibson RG, Slater TF. Stimulation of rat uterine prostacyclin production and inhibition of hydroxyeicosatetraenoic acid production by dsferrioxamine in vitro. ICRS Med Sci 1986; 14: 399-400.
Allergic reactions to long-term benzathine penicillin prophylaxis for rheumatic fever INTERNATIONAL RHEUMATIC FEVER STUDY GROUP*
1790 patients from 11 countries were enrolled in a prospective international study to determine the incidence of allergic reactions to monthly intramuscular benzathine penicillin (penicillin G benzathine) injections to prevent recurrences of rheumatic fever. After 32 430 injections during 2736 patient years of observation, 57 of the 1790 patients (3·2%) had an allergic reaction. 4 had anaphylaxis, an incidence of 0·2% (1&mid ot; 2/10 000 injections), all in patients over 12 years of age, and 1 patient died, a fatality incidence of 0·05% (0·31/10 000 injections). These rates are similar to those described for patients without rheumatic fever who receive short-term treatment with parenteral penicillin. Rheumatic fever recurred in 8 of 1790 patients (0·45%) who received benzathine penicillin prophylaxis compared with 11 of 96 (11 ·5%) who did not comply with treatment. Life-threatening allergic reactions are rare in patients on long-term parenteral benzathine penicillin to prevent recurrences of rheumatic fever; the long-term benefits of such prophylaxis by far outweigh the risk of a serious allergic reaction.
Introduction Rheumatic fever causes 25-40% of all cardiovascular disease in developing countries; disability and death from rheumatic heart disease are mainly caused by recurrent attacks.2 The efficacy of antibiotic prophylaxis to prevent recurrences of rheumatic fever has been known for over 50 years3,4-amajor advance that has strikingly reduced the morbidity and mortality from rheumatic fever. 5-8 Because of the impact of this disease on public health, and the proven efficacy of antibiotic prophylaxis, the World Health Organisation has helped to establish programmes for prevention of rheumatic fever in developing countries.9 A single intramuscular injection of 1-2 million units of benzathine penicillin every 4 weeks is the most widely used method for antibiotic prophylaxis.9,10 Penicillins can cause
*M. Markowitz and E. Kaplan (USA); R. Cuttica (Argentina); X. Berrios (Chile); Z. Huang and X. Rao (People’s Republic of China); P. L Wahi and H. K. Bali (India); D. Millard (Jamaica); J. Y. Choi and C. Y. Hong (Korea); H. A. Majeed (Kuwait); P. Clarkson and J. Neutze (New Zealand), H. C. Lue (Taiwan); C. Vongprateep and C. Phornphutkul (Thailand), and S.
Munoz (Venezuela). Correspondence to Prof M. Markowitz, Room AG 062, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
1309
and even fatal allergic reactions," which led to when a long-acting depot penicillin became available in 1951, but the initial studies of benzathine severe
concern
for rheumatic fever prophylaxis reported only mild allergic reactions in a few patients. 12 Since then, benzathine penicillin has been used extensively, with few well-documented reports of serious allergic reactions in patients with rheumatic feverP,14 However, anecdotal accounts of fatal allergic reactions are common in some developing countries and the fears generated by such reports have deterred both physicians and patients from continuing this effective method of prevention. 15 Are such fears warranted? To determine the true incidence of allergic reactions to long-term prophylaxis with benzathine penicillin in patients with past rheumatic fever, we organised a prospective international study, and now describe the incidence of allergic reactions in 1790 such
penicillin
who received benzathine penicillin prophylaxis 4 weeks for 2736 patient-years of follow-up. every
patients
Patients and methods Patients with a history of rheumatic fever who received benzathine penicillin prophylaxis were recruited in 1988-1990 from 11 geographically widespread countries in which rheumatic fever remains an important public health problem. Study sites selected all had an established prevention programme for rheumatic fever and used 12 million units of benzathine penicillin administered intramuscularly every 4 weeks as the principal treatment to prevent recurrent attacks. Injections were given by health personnel, usually nurses, who had been trained to administer this drug, and each site had an emergency medicine kit available for prompt treatment should a life-threatening reaction occur. All patients enrolled in the study fulfilled the Jones criteria for diagnosis of rheumatic fever and none had a history of an allergic reaction to penicillin. Age, injection schedule, duration of previous prophylaxis, and manufacturer of the penicillin used were recorded for all patients. After entry to the study the date of each benzathine penicillin injection and any subsequent signs and symptoms of a possible allergic reaction (hypotension, dyspnoea, pruritus, urticaria, angioneurotic oedema, arthralgia, and maculopapular rash) were recorded. Any allergic reaction was classified according to its time of onset: immediate, or within 1 h of administration; accelerated, after 1-72 h; and late, after more than 72 h.16 A record was also kept of rheumatic fever recurrences among patients who received benzathine penicillin prophylaxis and among those who did not comply with treatment. 1107 patients who had had rheumatic fever and who received benzathine penicillin prophylaxis were enrolled at the start of the study in 1988 and another 683 were added during the 2-year study period, a total of 1790 patients. The duration of prophylaxis before entry to the study ranged from 1 month to 12 years, with a mean of 3-8 years. Patients were followed prospectively for 6-24 months for a total of 2736 patient-years on prophylaxis. Their ages ranged from 5-28 years; 33% were 12 years or younger. Benzathine penicillin from 12 different manufacturers was used, with 32 430 injections given during the observation period.
Results 57
(32%)
of the 1790
patients had
an
allergic reaction.
Immediate anaphylactic reactions occurred in 4, 3 of whom had anaphylactic shock within minutes of injection of
benzathine penicillin, and the other had dyspnoea and
hypotension
30 min
subsequently.
Accelerated reactions
(1-72 h) occurred in 37 patients: 30 had pruritus or urticaria, 6 had
arthralgia,
and 1 started
to
wheeze. Late reactions
included 2 patients with arthralgia, 3 with urticaria, and 11I with maculopapular rashes. There was no preponderance of allergic reactions at any one site, nor were they associated
with a particular manufacturer of benzathine penicillin. Another patient had an unexplained, brief seizure after an injection, but did not become hypotensive and did not appear to have a true allergic reaction. Several patients had transient febrile reactions or brief syncopal episodes, which were also not considered true allergic reactions. The 4 episodes of anaphylaxis represent a case incidence of 0-2% and an injection frequency of 0-012% (1-2 reactions/10 000 injections). All 4 patients were over 12 years of age (15, 16, 17, and 18) and had been treated with benzathine penicillin for 2 months to 7 years before anaphylaxis occurred. All 4 had rheumatic valvular heart disease and 3 required treatment for congestive heart failure. 1 of these 4 patients died, a case fatality incidence of 0-05% and an injection frequency of 0-0031% (0-31/10 000 injections). The patient who died was a 15-year-old girl with severe mitral valve disease and chronic congestive cardiac failure who had received 24 earlier injections of benzathine penicillin without incident. 30-60 seconds after the last injection she developed respiratory stridor and cardiac arrest, and died after initial resuscitation and mechanical ventilation for 6 days. 8 of the 1790 patients (0-45%) had recurrent rheumatic fever while on benzathine penicillin prophylaxis. 290 patients dropped out of the study, either because they
moved, stopped prophylactic treatment for medical reasons other than allergy, or did not comply with treatment. Among 96 patients who did not comply with prophylaxis and who could be traced, 11 (11-5%) had recurrent rheumatic fever.
Discussion The 3-2% incidence of allergic reaction observed among patients with a history of rheumatic fever on continuous prophylaxis with benzathine penicillin does not differ significantly from the 2-24% reported in patients who received short-term treatment with benzathine penicillin for sexually transmitted disease." Thus we found no evidence that the duration of previous treatment with benzathine penicillin increased the risk of an allergic reaction. Stollerman et al,12 in an early study of benzathine penicillin prophylaxis for rheumatic fever, also found no increase in allergic reactions over time. Preliminary results from skin tests for penicillin allergy indicate that repeated exposure to benzathine penicillin does not unduly increase the occurrence of positive skin tests: 4 of 76 patients (5-2%) on long-term benzathine penicillin prophylaxis for rheumatic fever were positive for major and minor determinants of penicillin, well within the 2-7% range found in subjects with no history of rheumatic fever or of penicillin allergy." Anaphylaxis is the most worrying potential allergic reaction to penicillin. The reported incidence of serious reactions among patients without a history of rheumatic fever or of penicillin allergy ranges from 1-4/10 000 treatment courses. 17,111 The 4 episodes of anaphylaxis that we encountered in 1790 patients with a history of rheumatic fever who received 32 430 injections of benzathine penicillin represent a frequency of 1-23/10 000 injections, no greater than that in patients given one course of parenteral penicillin. The risk of a serious reaction is usually less in children under 12 years of age;19,zO of approximately 600 such patients in our study, none had anaphylaxis. Death from an allergic reaction to penicillin occurs at an incidence of about 1 per 50 000 treatment courses of parenteral penicillin in the general population.18 We observed 1 death after 32 430 injections of benzathine penicillin in patients
1310
who had had rheumatic fever. Reported deaths in patients with a history of rheumatic fever treated with benzathine penicillin prophylaxis have all been in adults with advanced rheumatic heart disease.13.14 Death during or after an anaphylactic reaction may be more likely in patients with a history of rheumatic fever than in normal controls because of their increased prevalence of heart disease, and because pre-existing heart disease, or treatment for such disease, may exacerbate the cardiovascular effects of anaphylaxis or hinder attempts at resuscitation .22-25 Although skin tests for penicillin allergy are not recommended for patients without a history of such allergic reactions, it is possible that selective skin tests with major and minor determinants of penicillin 16-27 might further reduce the already low risk of a fatal reaction in patients with severe heart disease; patients with a positive skin test could receive an alternative prophylactic drug such as sulphadiazine. This study also enabled comparison of the incidence of recurrent attacks of rheumatic fever in patients while on continuous benzathine penicillin prophylaxis with recurrence in patients who did not comply with prophylaxis. Rheumatic fever recurred in 8 (0-45%) of 1790 patients while on regular prophylaxis compared with 11 (11-5%) of 96 who were not. This striking difference is further evidence of the efficacy of four-weekly intramuscular injection of 1.2 million units of benzathine penicillin to prevent recurrent attacks of rheumatic fever. The prognosis is greatly improved in patients on regular prophylaxis, as shown by Lue and colleagues,8 who found an 8-year mortality rate of 3% among patients with a history of rheumatic fever who received regular prophylaxis, compared to 28% among similar patients who did not. In conclusion, life-threatening allergic reactions to penicillin in patients with a history of rheumatic fever and who receive continuous prophylaxis with benzamine penicillin are rare, and are no more frequent than in patients without rheumatic fever who receive one course of parenteral penicillin for other indications. It is essential to look out for untoward reactions to penicillin and to have resuscitation facilities available when patients are injected, and extra vigilance may be necessary in patients with severe heart disease and a history of cardiac decompensation. However, the long-term benefits of benzathine penicillin prophylaxis to prevent recurrent rheumatic fever far outweigh the risk of a serious allergic reaction to penicillin. We thank
Strasser T, Dondog N, El Kholy AM, Gharagozloo R. Report of a WHO international cooperative project. Bull WHO 1981; 59: 285-94. 10. Wood HF, Feinstein AR, Taranta A, et al. Rheumatic fever in children and adolescents, III. Comparative effectiveness of three prophylactic regimens in preventing streptococcal infections and rheumatic recurrences. Ann Intern Med 1964; 60 (suppl 5): 31-46. 11. Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18: 515-40. 12. Stollerman GH, Rusoff JH, Hirschfeld I. Prophylaxis against group A streptococci in rheumatic fever. N Engl J Med 1955; 252: 787-92. 13. Hsu I, Evans JM. Untoward reactions to benzathine penicillin G in study of rheumatic fever prophylaxis m adults. N Engl J Med 1958; 259: 9.
581-83.
Steigmann F, Suker JR. Fatal reactions to benzathine penicillin G. JAMA 1962; 179: 288-90. 15. Lue HC, Chen HC, Wei HY. Some problems in long term prevention of streptococcal infections among children with rheumatic heart disease in Taiwan. Jpn Heart J 1976; 17: 550-59. 16. Levine BB. Immunologic mechanisms of penicillin allergy. A haptene model system for the study of allergic diseases of man. N Engl J Med 14.
1966; 275: 1115-25. 17. Enffmeyer JE. Penicillin allergy. Clin Rev Allergy 1986; 4: 171-86. 18. Idsoe O, Guthe T, Willcox RR, deWeck AL. Nature and extent of
19.
penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bull WHO 1968; 38: 159-88. Sullivan TJ. Pathogenesis and management of allergic reactions to penicillin and other beta-lactam antibiotics. Pediatr Infect Dis 1982; 1: 344-50.
20.
21.
Graff-Lounevig V, Hedlin G, Lindfors A. Penicillin allergy—a rare pediatric condition? Arch Dis Child 1988; 63: 1342-46. Chandra RG, Joglehar SA, Tomas E. Penicillin allergy: anti-penicillin IgE antibodies and immediate hypersensitivity skin reactions employing major and minor determinants of penicillin. Arch Dis Child
1980; 55: 857-60. AA, Kotler MN. EKG changes associated with penicillin anaphylaxis. Chest 1973; 64: 66-69. 23. Jacobs RL, Rake GW, Fournier DC, Chilton RJ. Potentiated
22. Petsas
anaphylaxis in patients with drug-induced beta-adrenergic blockade. J Allergy Clin Immunol 1981; 68: 125-27. 24. Berkelman RL, Finton RJ, Elsea WR. Beta adrenergic antagonists and fatal anaphylaxis reactions to oral penicillin. Ann Intern Med 1968; 104: 134. 25. Sullivan TJ. Cardiac disorders in penicillin-induced anaphylaxis. JAMA 1982; 248: 2161-62. 26. Adkinson NF, Spence M, Wheeler B. Randomized clinical trial of routine penicillin skin testing. J Allergy Clin Immunol 1984; 73 (suppl): 163
(abstr). 27. Sue MA, Noritake DT, Klaustermeyer WB. Penicillin anaphylaxis: fatality in elderly patients without a history of penicillin allergy. Am J Emerg Med 1988; 6: 456-58.
From The Lancet
Wyeth-Ayerst International for support of this study. Medical
protection
REFERENCES
Agarwal BL. Rheumatic fever and rheumatic heart disease in developing countries. A monograph. New Delhi: Arnold Publishers, 1988. 2. Taranta A, Markowitz M. Rheumatic fever. A monograph. 2nd ed. London: Kluwer, 1989. 3. Thomas CB, France R. A preliminary report of the prophylactic use of sulfonamide in patients susceptible to rheumatic fever. Bull Johns Hopkins Hosp 1939; 64: 67-77. 4. Coburn AF, Moore LV. The prophylactic use of sulfonamide in streptococcal respiratory infections with special reference to rheumatic fever. J Clin Invest 1939; 18: 147-55. 5. Tompkins DG, Boxerbaum B, Liebman J. Long term prognosis of rheumatic fever patients receiving intramuscular benzathine penicillin. 1.
Circulation 1972; 45: 543-51. of the initial attack of rheumatic fever in children in North India. Circulation 1982; 65: 375-79. 7. Majeed HA, Yousof AM, Khuffash FA. The natural history of acute rheumatic fever in Kuwait: a prospective six year follow-up report. J Chronic Dis 1986; 39: 361. 8. Lue HC, Tseng WP, Lin GJ, et al. Clinical and epidemiologic features of rheumatic fever and rheumatic heart disease in Taiwan and the Far East. Indian Heart J 1983; 35: 139-46. 6.
Sanyal SK, Barry AM, Duggal S. Sequelae
If medicine be
a
necessary of life, is
a
civilised nation-with
an
enlightened Government at its head-to take no means to test the qualifications of its professors? Are the lives of the people to be the sport of impostors? Is quackery to be allowed to blow its brazen trumpet through the length and breadth of the land? Are poisons to be patented? Are the articles of the materia medica to be adulterated with impunity? Is a class of tradesmen-respectable when they restrict themselves to weighing and selling drugs-to be encouraged and permitted to pretend to the healing art, without any knowledge either of the structure of the body, or of the laws of health and disease? Is this to be countenanced in the name of free trade; and are medical men to be denied protection, when the poor are deprived of foreign sugar-and com-to protect the landholders, and the late slaveholders, of the country? We are confident that these topics will not be forgotten by our medical brethren at the ensuing elections. The Medical Associations should be up and stirring. If the House of Commons be dissolved, medical election committees should be formed in every district, to impress more strongly upon candidates the claims of the medical profession, and of the public health ...
(May 15, 1841)