We estimated the frequency of clinically diagnosed Stevens-Johnson syndrome and toxic epidermal necrolysis associated with sulfadoxine-pyrimethamine (SP) and trimethoprim-sulfamethoxazole (CTX) in Blantyre District, Malawi. Cases were detected by passive surveillance at 22 health centers from March 2001 through September 2002. Denominators were estimated from the Malawi national census for Blantyre District and the frequency of SP and CTX use reported in five household surveys. Crude rates of adverse reactions were estimated to be 1.2 per 100,000 exposures for SP and 1.5 per 100,000 exposures for CTX. Rates were higher in adults (1.7 cases per 100,000 SP exposures and 2.6 cases per 100,000 CTX exposures) and in persons positive for human immunodeficiency virus (4.9 cases per 100,000 SP exposures and 8.4 cases per 100,000 CTX exposures). Infrequent treatment doses with SP are associated with a low risk of an adverse cutaneous reaction, and SP can be recommended for treatment of malaria in areas where P. falciparum is susceptible.
Sulfadoxine-pyrimethamine (SP), alone or in combination with other drugs, has replaced chloroquine as first-line therapy for uncomplicated Plasmodium falciparum malaria in many African countries because of increasing chloroquine resistance.1 Trimethroprim-sulfamethoxazole (cotrimoxazole or CTX) is used for the treatment of urinary tract or lower respiratory infections and is increasingly being advocated for prophylaxis against opportunistic infections in persons infected with human immunodeficiency virus (HIV).2,3 Sulfonamide drugs, including SP and CTX, cause a variety of adverse reactions including the skin conditions erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).4–7 Although there is substantial variability in the use of the terms EM, SJS, and TEN among medical practitioners, distinct clinical patterns permit a more reliable classification of these mucocutaneous disorders. The classification we used in this study was proposed in 1993 and subsequently validated in a large case control study supports EM as a condition that differs in both clinical presentation and etiology from SJS and TEN.8–11 Erythema multiforme is the least serious of these conditions. In addition to mucosal blistering or ulcers, typical target or raised atypical target lesions acrally distributed are seen. The extent of blisters or epidermal detachment is usually low and almost always less than 10%. Erythema multiforme is most associated with infection, with drugs an infrequent cause.12,13
SJS, TEN, and SJS/TEN overlap represent a severity spectrum of a single condition that is usually drug induced. SJS is characterized by typical or atypical targets on the trunk and face that are often confluent. Although > 10% of the body surface is affected, skin detachment usually occurs on less than 10% of the body surface. Extensive, often confluent, lesions are observed in TEN cases. The outer layer of the epidermis readily separates from the basal layer with lateral pressure and bullae/skin detachment occurs over more than 30% of the body surface. Cases with 10–30% skin detachment have often been described as SJS/TEN overlap. Mucosal erosions have been reported in more than 90% of cases with SJS or TEN. Typically, cases with SJS/TEN are febrile. Lesions of the respiratory and gastrointestinal tracts may occur.8–11 Case fatality rates as high as 30% have been observed in TEN patients in North American health facilities.9,10 Resistance to the adoption and implementation of SP for malaria treatment because of concerns about adverse reactions has been reported among both policy-makers14 and the general public.15
Estimates of the frequency of adverse cutaneous reactions in travelers using SP for malaria chemoprophylaxis have ranged from 0.01 to 20.4 adverse events per 100,000 exposures.16–18 It has been estimated that persons taking regular, repeated doses of SP for prophylaxis have a 40-fold higher risk compared with those using it for single-dose treatment.16 However, the frequency of adverse events from treatment may have been underestimated and there is concern that, in disease-endemic areas, repeated treatment doses might lead to sensitization and an increased occurrence of side effects, even in persons receiving only a single treatment dose each time.
Another concern is the effect of HIV infection. It has been shown for several different drugs, including CTX, that HIV-infected persons experience higher rates of adverse reactions relative to HIV-negative persons.19–21 With a high prevalence in many parts of sub-Saharan Africa, HIV may contribute to higher rates of the adverse reactions to numerous drugs, including SP.
In 1993, Malawi became the first country in sub-Saharan Africa to implement SP nationally as first-line treatment for uncomplicated Plasmodium falciparum malaria. Since its implementation, there have been anecdotal reports of severe cutaneous reactions but the frequency of these adverse events has never been estimated. We therefore set up a surveillance system in Blantyre District, Malawi to estimate the incidence of SJS and TEN to SP and CTX.