VOL 336
1201
MEDICAL SCIENCE
TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria
Plasma levels of tumour necrosis factor (TNF) were significantly higher in 178 Gambian children with uncomplicated malaria due to Plasmodium
falciparum than in 178 children with other illnesses. 110 children with cerebral malaria were studied shortly after admission to hospital; 28 subsequently died. Compared with the children with uncomplicated malaria, mean plasma TNF levels were twice as high in cerebral malaria survivors and ten times as high in the fatal cases. Although high TNF levels were associated with high parasitaemia and with hypoglycaemia, they predicted fatal outcome in cerebral malaria independently of parasitaemia and glucose concentrations. Concentrations of interleukin-1 alpha, but not interferon gamma, were also related to the severity of malaria. We conclude that increased TNF production is a normal host response to P falciparum infection, but that excessive levels of production may predispose to cerebral malaria and a fatal outcome.
Introduction
important cause of death in African population, repeated infections with Plasmodium falciparum are common and are usually selflimiting. Only a minority of infections (perhaps about 1 %) progress to cerebral malaria;l the mechanism is unknown. Cytokines, particularly tumour necrosis factor (TNF), may affect the outcome of malaria2 in either of two ways: (a) TNF promotes various host responses, including fever, that may suppress parasite growth;3-6 (b) TNF induces metabolic and inflammatory changes that could be involved in the pathogenesis of cerebral malaria. These observations Cerebral malaria is
an
children. In this
about TNF have led the
to
the idea that moderate
amounts
cytokine might be beneficial and excessive
of
amounts
harmful for the host, although the validity of this hypothesis has not been established. What is the normal TNF response to acute P falciparum infection in African children, and is there an abnormal response in those who get cerebral malaria? Two limited studies have addressed different aspects of this question. In a Malawian study of children with cerebral malaria, TNF concentrations were highest in fatal cases, but were not compared with concentrations in children with uncomplicated malaria.9 In a Gambian study, TNF concentrations were higher in children with malaria than in children with other infections, but there was no significant difference between cerebral and uncomplicated malaria.1o We have now measured plasma concentrations of TNF, interleukin-1alpha (IL-la), and interferon gamma (IFN-y) in a large sample of children with malaria of all grades of
severity. Patients and methods Patients The study was conducted at the Royal Victoria Hospital, Banjul, and the Medical Research Council (MRC) Laboratories, Fajara, between August and November, 1988, with the approval of the Gambia Government/MRC Joint Ethical Committee. Three clinical groups were defined. Mild malaria (MM)-febrile illness in a child with asexual P falciparum parasites on blood film, without other satisfactory explanation for the fever, and without cerebral malaria, severe anaemia (Hb < 5 g/dl), or other major complications of infection. ADDRESSES: MRC Laboratories, Fajara, The Gambia (D. Kwiatkowski, MRCP, I. Sambou, P. Twumasi, MD, B. M. Greenwood, FRCP); Institute of Molecular Medicine, Oxford University, UK (A.V.S. Hill, MRCP); Rockefeller University, New York, USA (K. R. Manogue, PhD, A. Cerami, PhD); Endogen Corporation, Boston, USA (J. Castracane); and Royal Victoria Hospital, Banjul, The Gambia (D. R. Brewster, FRACP). Correspondence to Dr D. Kwiatkowski, Institute of Molecular Medicine, John Radcliffe Hospital, Headirigton, Oxford OX3 9DU, UK
1202
TABLE I-CLINICAL DETAILS
Cerebral malaria (CM)--coma score of 2 or less (Molyneux and Taylor modification of the Glasgow scale") persisting for more than 30 min after any convulsions had ceased, in a child with P falciparum parasites on thick blood film and no evidence of
meningitis or any other cause of coma. with illnesses other than malaria Non-malaria {NM)-
1201
MEDICAL SCIENCE
TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria
Plasma levels of tumour necrosis factor (TNF) were significantly higher in 178 Gambian children with uncomplicated malaria due to Plasmodium
falciparum than in 178 children with other illnesses. 110 children with cerebral malaria were studied shortly after admission to hospital; 28 subsequently died. Compared with the children with uncomplicated malaria, mean plasma TNF levels were twice as high in cerebral malaria survivors and ten times as high in the fatal cases. Although high TNF levels were associated with high parasitaemia and with hypoglycaemia, they predicted fatal outcome in cerebral malaria independently of parasitaemia and glucose concentrations. Concentrations of interleukin-1 alpha, but not interferon gamma, were also related to the severity of malaria. We conclude that increased TNF production is a normal host response to P falciparum infection, but that excessive levels of production may predispose to cerebral malaria and a fatal outcome.
Introduction
important cause of death in African population, repeated infections with Plasmodium falciparum are common and are usually selflimiting. Only a minority of infections (perhaps about 1 %) progress to cerebral malaria;l the mechanism is unknown. Cytokines, particularly tumour necrosis factor (TNF), may affect the outcome of malaria2 in either of two ways: (a) TNF promotes various host responses, including fever, that may suppress parasite growth;3-6 (b) TNF induces metabolic and inflammatory changes that could be involved in the pathogenesis of cerebral malaria. These observations Cerebral malaria is
an
children. In this
about TNF have led the
to
the idea that moderate
amounts
cytokine might be beneficial and excessive
of
amounts
harmful for the host, although the validity of this hypothesis has not been established. What is the normal TNF response to acute P falciparum infection in African children, and is there an abnormal response in those who get cerebral malaria? Two limited studies have addressed different aspects of this question. In a Malawian study of children with cerebral malaria, TNF concentrations were highest in fatal cases, but were not compared with concentrations in children with uncomplicated malaria.9 In a Gambian study, TNF concentrations were higher in children with malaria than in children with other infections, but there was no significant difference between cerebral and uncomplicated malaria.1o We have now measured plasma concentrations of TNF, interleukin-1alpha (IL-la), and interferon gamma (IFN-y) in a large sample of children with malaria of all grades of
severity. Patients and methods Patients The study was conducted at the Royal Victoria Hospital, Banjul, and the Medical Research Council (MRC) Laboratories, Fajara, between August and November, 1988, with the approval of the Gambia Government/MRC Joint Ethical Committee. Three clinical groups were defined. Mild malaria (MM)-febrile illness in a child with asexual P falciparum parasites on blood film, without other satisfactory explanation for the fever, and without cerebral malaria, severe anaemia (Hb < 5 g/dl), or other major complications of infection. ADDRESSES: MRC Laboratories, Fajara, The Gambia (D. Kwiatkowski, MRCP, I. Sambou, P. Twumasi, MD, B. M. Greenwood, FRCP); Institute of Molecular Medicine, Oxford University, UK (A.V.S. Hill, MRCP); Rockefeller University, New York, USA (K. R. Manogue, PhD, A. Cerami, PhD); Endogen Corporation, Boston, USA (J. Castracane); and Royal Victoria Hospital, Banjul, The Gambia (D. R. Brewster, FRACP). Correspondence to Dr D. Kwiatkowski, Institute of Molecular Medicine, John Radcliffe Hospital, Headirigton, Oxford OX3 9DU, UK
1202
TABLE I-CLINICAL DETAILS
Cerebral malaria (CM)--coma score of 2 or less (Molyneux and Taylor modification of the Glasgow scale") persisting for more than 30 min after any convulsions had ceased, in a child with P falciparum parasites on thick blood film and no evidence of
meningitis or any other cause of coma. with illnesses other than malaria Non-malaria {NM)-
