Effects of pyrimethamine versus proguanil in malarial chemoprophylaxis in children with sickle cell disease: a randomized, placebo-controlled, open-label study

Abstract

Background: Malarial chemoprophylaxis is essential for patients with homozygous sickle cell disease (SCD) who live in areas where malaria is endemic. Endemic regions include most sub-Saharan African countries and Southeast Asia.

Objective: This study compared the efficacy and tolerability of pyrimethamine with that of proguanil and placebo in the prevention of malaria and the complications of Plasmodium falciparum infection (hepatomegaly, splenomegaly, bone pain crisis, hemolytic crisis) in children with SCD.

Methods: In this single-center, open-label study conducted in Nigeria, children aged 1 to 16 years with SCD were randomly assigned to receive tablets of pyrimethamine (0.5 mg/kg·wk), proguanil (1.5 mg/kg·d), or placebo (vitamin C, 7 mg/kg·d) for 9 months as prophylaxis from February to December (which includes the rainy season), the period of greatest malarial transmission. The clinical and laboratory features of malaria (presence of parasitemia, parasite count and density, hepatomegaly and/or splenomegaly, symptomatic malarial infection [fever, rigors], bone pain crises, and hemolytic crises) were assessed.

Results: A total of 97 patients completed the study (49 boys, 48 girls; mean [SD] age, 7.8 [4.3] years). The pyrimethamine group comprised 36 patients (mean [SD] age, 8.1 [4.3] years; range, 2-16 years); the proguanil group, 32 patients (mean [SD] age, 9.5 [3.7] years; range, 3-16 years); and the placebo group, 29 patients (mean age, 5.9 years; range, 1-14 years). The male:female ratio was 1.1:1 in the pyrimethamine group, 1:1.7 in the proguanil group, and 1.6:1 in the placebo group. Parasitemia was noted in 7 patients (19.4%) in the pyrimethamine group, 6 (18.8%) in the proguanil group, and 7 (24.1%) in the placebo group at the start of the study. P falciparum was the only isolate. The mean parasite density over the 9-month period was significantly lower with proguanil compared with pyrimethamine (P = 0.045) and placebo (P<0.05). The incidence of splenomegaly was least with pyrimethamine, but this group had the most patients clinically diagnosed with malaria. Hospitalizations and episodes of bone pain and hemolytic crisis occurred most frequently with placebo. One patient in the placebo group died of septicemia.

Conclusions: Proguanil and pyrimethamine both reduced parasitemia; however, proguanil significantly decreased mean parasite density more effectively than pyrimethamine. Pyrimethamine and proguanil may protect children with SCD from the complications of P falciparum infection despite persistent parasitemia. Proguanil may be more useful than pyrimethamine in the prevention of bone pain crises among patients with SCD.

Keywords: malarial chemoprophylaxis; proguanil; pyrimethamine; sickle cell disease.