The Effect of a Monoclonal Antibody to Tumor Necrosis Factor on Survival from Childhood Cerebral Malaria

Abstract

Tumor necrosis factor (TNF) is thought to playa key role in the pathogenesis of cerebral malaria. A double-blind, placebo-controlled trial of an anti-TNF monoclonal antibody (B-C7) comprised 610 Gambian children with cerebral malaria, with mortality and residual neurologic sequelae as primary study end points. Sixty (19.9%) of 302 children who received B-C7 died compared with 64 (20.8%) of 308 children who received placebo (adjusted odds ratio [OR], 0.90; 95% confidence interval [CI], 0.57-1.42). Residual neurologic sequelae were detected in 15 (6.8%) of 221 survivors from the B-C7 group and in 5 (2.2%) of 225 survivors of the placebo group (adjusted OR, 3.35; 95% CI, 1.08-10.4). The monoclonal antibody used in this study did not improve survival in cerebral malaria and was associated with a significant increase in neurologic sequelae. A possible explanation of the latter observation is that the antibody acts to retain TNF within the circulation and thereby prolongs its effects on vascular endothelium. Cerebral malaria in children has a case fatality rate of 10%-30% despite effective antimalarial treatment [1, 2]. Deaths in cases of cerebral malaria occur frequently in the first hours after admission, before antimalarial therapy has become effective. Recently, it has been shown that a fast-acting antimalarial agent, artemether, did not change this pattern, nor did it improve outcome [3]. Thus, there is a need to develop new forms of therapy for cerebral malaria. These should have antidisease properties and a fast onset of action and be given in conjunction with conventional antimalarial treatment. Recent studies strongly suggest that tumor necrosis factor (TNF) plays a key role in the pathogenesis of cerebral malaria. In clinical studies, an association has been found between plasma TNF levels and disease severity and outcome [4, 5], and it has been shown that children homozygous for the TNF2 allele, which has been associated with high TNF production, are more likely to develop cerebral malaria and die as a conse

Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria.

“…A later trial in 302 Gambian children with cerebral malaria compared the use of 5mg/kg of a similar monoclonal anti-TNF-␣ antibody with a control group. 7 This study confirmed the anti-pyretic effect but case fatality was not reduced and there was a significantly increased incidence of neurologic sequelae in the antibody-treated children.…”

“…The variation in a small study is large and the effect on parasite clearance time needs to be carefully evaluated in a larger study. Whereas temperature in the Gambian children with cerebral malaria gradually decreased during the first 12 hr after treatment, 7 all patients in this study had transient, repeated temperature peaks during the first few days, which may reflect differences in the clinical manifestations of childhood and adult malaria. The three highest doses of the antibody lowered the FCT compared with the control group and a similar anti-pyretic effect was previously demonstrated by a monoclonal antibody against TNF-␣ in cerebral malaria.…”

Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development

“…To date, no adjuvant treatment has proved effective in severe malaria; all have been ineffective or harmful. [88][89][90] …”

Febrile temperatures induce cytoadherence of ring-stage Plasmodium falciparum -infected erythrocytes

“…These proinflammatory cytokines are pyrogenic. TNF plays a central role in causing fever (16). Fluctuating fever is the essential clinical feature of symptomatic human malaria.…”