Intravenous immunoglobulin in the treatment of paediatric cerebral malaria

Abstract

SUMMARYHyperimmune globulin can inhibit and reverse the cytoadherence between Piasmodium falciparuminfected erythrocytes and melanoma cells in vitro. Cytoadherence is believed to mediate disease in cerebral malaria. Therefore we studied the efficacy of i.v. immunoglobulin, purified from the plasma of local semi-immune blood donors, as an adjunct to standard treatment for cerebral malaria in Malawian children.The immunoglobulin preparation (IFAT antimalarial antibody titre 1:5120) recognized erythrocyte-associated antigens ofeach of 22 Malawian P.falciparum isolates studied, and reversed binding of Malawian isolates to melanoma cells. Immunoglobulin did not reverse binding to human monocytes or to cells of the human hystiocytic lymphoma cell line U937.Thirty-one children with P.falciparum parasitaemia and unrousable coma were enrolled. All were treated with i.v. quinine dihydrochloride; in addition patients were randomized to receive either immunoglobulin (400 mg/kg by i.v. infusion over 3 h) or placebo (albumen and sucrose by similar infusion) in a double blind trial with sequential analysis. Of 16 patients receiving immunoglobulin, five (31%) died and five survivors had neurological sequelae. Of 15 patients receiving placebo, one (7%) died and two had sequelae. Parasite clearance, fever clearance and coma resolution times in survivors were similar in the two groups.Although the difference in outcome between the two groups was not significant, the trial was stopped because immunoglobulin was demonstrated not to be superior to placebo.

Management of severe paediatric malaria in resource-limited settings

“…infusion over 15-mins (other randomization: im artemether vs quinine)1 0 mortality in hospital and residual neurologic sequelae (NS) (6 months).1 0 Death Mab (60/302; 19.9%) vs (64/308; 20.8%) P  = 0.9, NS at 6 month 6.8% (15/221) vs 2.2 (5/225) P  = 0.04Faster fever clearance on Mab arm. After adjustment for severity features and antimalarial strategy there was no significant survival benefit in children treated with Mab but significantly increased NS rate at 6 month in survivors (15/221 (6.8%) in the Mab arm compared with 5/225 (2.2%) 3.35 (1.08 to 10.4) P  = 0.022 0 parasite and fever clearance rates, coma recovery time, neurologic sequelae (NS) at discharge and 1 month2 0 NS at discharge 24.4% (59/242) and 22.1% (54/244); P  = 0 .6 and NS at 1 month 11% (25/228) vs 6.4% (15/234) P  = 0.1Taylor et al [123]Blantyre, Malawi1 to 12 yearsCerebral malaria (BCS < = 1) n = 31Placebo controlled trial i.v. immune globulin (IVIG) (pooled from local blood donations) during the first 3 hours treatment plus quinine1 0 Composite of mortality or neurological sequelae16 received IVIG; 15 placeboTrial was stopped (based on preplanned stopping rules) – no benefit of IVIG.…”

Sequential design with boundaries approach in pediatric intervention research reduces sample size

“…The estimation of the expected or minimal clinically important effect is always arbitrary, and may turn out to be too optimistic during the trial. The sequential design enables stopping a trial early for futility [48], as is shown by several examples in this review [18,28,31,35,40,44]. This way unnecessary experimenting with vulnerable patients is avoided as much as possible.…”

“…Eight of the nine studies for which a fixed sample size could be calculated, had been ended because one of the boundaries was crossed, either indicating rejection of H 0 [17,23,24,33], or no rejection of H 0 [28,31,40,44]. The median reduction in included sample size in these eight trials compared with the fixed sample size calculation was 52 subjects (range: À22 to 229), a reduction of 35% (range: À42% to 90%) of the fixed sample size.…”

“…The methodological items concerning intention-to-treat analysis, co-interventions, and blinding (of patients/parents, doctors, nurses, therapists, and of outcome assessors) were the least reported. One study was stopped because new treatments were introduced, without having reached a boundary [45], 15 were stopped after the boundary indicating rejection of H 0 had been reached [17,20e27,30,32,33,36,38,39,42], and eight trials ended with the crossing of the boundary indicating no rejection of H 0 [18,28,29,31,34,35,40,44]. Although the items concerning description of statistical methods were well reported, in several cases (5 of 24), the information about the assumptions was insufficient to calculate a fixed sample size.…”

Plasmodium falciparum Line-Dependent Association of In Vitro Growth-Inhibitory Activity and Risk of Malaria

“…Enzyme-linked immunosorbent assays (ELISAs) against P. falciparum schizont extract prepared from the cultures of the three P. falciparum lines were performed according to a previously described protocol (40). A significant modification to this protocol was that serial dilutions of purified malaria immunoglobulin (prepared by cold ethanol fractionation as previously described [47]) were run on each ELISA plate to allow for standardization of plate-to-plate variations and to allow for the conversion of optical densities to antibody concentrations.…”