708
Rouby JJ, Fusciardi J, Bourgain JL, Viars P. High frequency jet ventilation in postoperative respiratory failure: determinants of oxygenation. Anesthesiol 1983; 59: 281-87. 19. Chakrabarti MK, Sykes MK. Cardiorespiratory effects of highfrequency intermittent positive pressure ventilation in the dog. Br J
18.
Anaesth 1980; 52: 475-82. 20.
Bourgain JL, Desruennes E, Cossett MF, Mamelle G, Belaiche S, Truffa-Bachi J. Measurement of end expiratory pressure during transtracheal high frequency jet ventilation for laryngoscopy. Br J
Anaesth 1990; 65: 373-4326. 21. Young JD, Sykes MK. A method for measuring tidal volume during high frequency ventilation. Br J Anaesth 1988; 61: 601-05. 22. Lin ES, Jones MJ, Mottram SD, Smith BE, Smith G. Relationship between resonance and gas exchange during high frequency jet ventilation. Br J Anaesth 1990; 64: 453-59.
Tumour necrosis factor and malaria How is it that tissues
not
invaded
by
the
damaged during malaria? plasmodium parasite Earlier notions that the parasites competed for nutrients or released a toxin that had a direct effect on the host have been discarded, and it now seems that damage is caused by proteins released by the host in response to infection. Tumour necrosis factor alpha (TNF-a) has been the focus of special attention in this context. This cytokine is released by are
monocytes/macrophages
and T
lymphocytes
in
inflammation and infection. Increased response concentrations of TNF-oc have been found in various infectious diseases,l including malaria,in which it is probably released in response to schizont ruptures3 TNF-a is an essential part of the host’s immune response because it modulates the effects of macrophages, neutrophils, lymphocytes, and endothelial cells and thereby mediates destruction of invading organisms. However, excessive amounts of TNF-a seem to be harmful. Injection of mice with recombinant TNF-a to
produces
the
same
changes
as
are
seen
in
terminal Plasmodium vinckei malaria, including hypoglycaemia.4 The effects of TNF-a treatment of tumours in man resemble the features of malaria—eg,
vomiting, fever, rigor, headache, myalgia, hypotension, thrombocytopenia, and neurological changes.s Since TNF-a was detected in the serum of patients with malaria,2interest has tended to focus on the relation of this cytokine to severe and cerebral disease. Kwiatkowski and colleagues reported significantly higher plasma concentrations in Gambian children with P falciparum malaria than in those with other illnesses.6They also found that plasma concentrations of TNF-a were much greater in cerebral malaria than in uncomplicated malaria-twice as high in those with cerebral malaria who survived and ten times as high in fatal cases. Previously, the same group had found that nausea,
raised concentrations were associated with acute P falciparum infection but did not correlate with disease severity or outcome.3Grau and colleagues,’ in a study of Malawian children with severe falciparum increased TNF-a malaria, reported that concentrations were associated with fatal outcome,
cerebral malaria, and hypoglycaemia; the association between high concentrations and complicated malaria was also found in European adults.8 The relation between raised TNF-a concentrations and severe malaria has been confirmed in children in Zaire,l but there was no particular association with cerebral malaria. That increased concentrations of circulating TNF-a are related to the illness of malaria is now beyond doubt; but does this association represent cause and effect? TNF-a might lead to cerebral involvement in malaria by increasing expression of parasite receptors on the endothelium of cerebral blood vessels, or by inducing hypoglycaemia, lactic acidosis, and other metabolic changes.So how can one explain the low concentrations of circulating TNF-a in some comatose patients and the high concentrations in some healthy individuals?9 Although TNF -cx has a short half-life in human serum (about 20 min), the effects persist; thus, the circulating concentration should correlate more closelv with time since schizogony than with the patient’s illness.3 High concentrations in a patient without severe malaria can be explained-provided they occur late rather than early during the disease-in terms of acquired tolerance to TNF-cx.5 TNF-a is only one of a family of cytokines with overlapping functions. Concentrations of lymphotoxin (TNF-&bgr;),lO interleukin-lcx,6 and interleukin-68 are all increased in malaria and correlate with disease severity. These cytokines may induce another family of mediators-eg, platelet-activated factor, prostaglandin E2-that actually cause the tissue damaged5 Treatment of malaria with neutralising antibody to TNF-a now seems a distinct possibility, but antibodies directed against other cytokines will probably be required as well.
Shaffer N, Grau GE, Hedberg K, et al. Tumor necrosis factor and severe malaria. J Infect Dis 1991; 163: 96-101. 2. Scuderi P, Lam KS, Ryan KJ, et al. Raised serum levels of tumour necrosis factor in parasitic infections. Lancet 1986; i: 1364-65. 3. Kwiatkowski D, Cannon JG, Manogue KR, Cerami A, Dinarello CA. Tumour necrosis factor production in falciparum malaria and its association with schizont rupture. Clin Exp Immunol 1989; 77: 361-66. 4. Clark IA, Cowden WB, Butcher GA, Hunt NH. Possible roles of tumor necrosis factor in the pathology of malaria. Am J Pathol 1987; 129: 1.
192-99. 5. Clark IA, Chaudhri G, Cowden WB. Roles of tumour necrosis factor in the illness and pathology of malaria. Trans R Soc Trop Med Hyg 1989; 83: 436-40.
6. Kwiatkowski D, Hill AVS, Sambou I, et al. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet 1990; 336: 1201-04. 7. Grau GE, Taylor TE, Molyneux ME, et al. Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med 1989; 320: 1586-91. 8. Kern P, Hemmer CJ, Van Damme J, Gruss HJ, Dietrich M. Elevated tumor necrosis factor alpha and interleukin-6 serum levels as markers for complicated Plasmodium falciparum malaria. Am J Med 1989; 87: 139-43.
9.
Phillips RE, Solomon T. Cerebral malaria in children. Lancet 1990; 336: 1355-60.
10. Clark IA, Rockett KA, Cowden WB. Role of TNF in cerebral malana Lancet 1991; 337: 302-03.
Rouby JJ, Fusciardi J, Bourgain JL, Viars P. High frequency jet ventilation in postoperative respiratory failure: determinants of oxygenation. Anesthesiol 1983; 59: 281-87. 19. Chakrabarti MK, Sykes MK. Cardiorespiratory effects of highfrequency intermittent positive pressure ventilation in the dog. Br J
18.
Anaesth 1980; 52: 475-82. 20.
Bourgain JL, Desruennes E, Cossett MF, Mamelle G, Belaiche S, Truffa-Bachi J. Measurement of end expiratory pressure during transtracheal high frequency jet ventilation for laryngoscopy. Br J
Anaesth 1990; 65: 373-4326. 21. Young JD, Sykes MK. A method for measuring tidal volume during high frequency ventilation. Br J Anaesth 1988; 61: 601-05. 22. Lin ES, Jones MJ, Mottram SD, Smith BE, Smith G. Relationship between resonance and gas exchange during high frequency jet ventilation. Br J Anaesth 1990; 64: 453-59.
Tumour necrosis factor and malaria How is it that tissues
not
invaded
by
the
damaged during malaria? plasmodium parasite Earlier notions that the parasites competed for nutrients or released a toxin that had a direct effect on the host have been discarded, and it now seems that damage is caused by proteins released by the host in response to infection. Tumour necrosis factor alpha (TNF-a) has been the focus of special attention in this context. This cytokine is released by are
monocytes/macrophages
and T
lymphocytes
in
inflammation and infection. Increased response concentrations of TNF-oc have been found in various infectious diseases,l including malaria,in which it is probably released in response to schizont ruptures3 TNF-a is an essential part of the host’s immune response because it modulates the effects of macrophages, neutrophils, lymphocytes, and endothelial cells and thereby mediates destruction of invading organisms. However, excessive amounts of TNF-a seem to be harmful. Injection of mice with recombinant TNF-a to
produces
the
same
changes
as
are
seen
in
terminal Plasmodium vinckei malaria, including hypoglycaemia.4 The effects of TNF-a treatment of tumours in man resemble the features of malaria—eg,
vomiting, fever, rigor, headache, myalgia, hypotension, thrombocytopenia, and neurological changes.s Since TNF-a was detected in the serum of patients with malaria,2interest has tended to focus on the relation of this cytokine to severe and cerebral disease. Kwiatkowski and colleagues reported significantly higher plasma concentrations in Gambian children with P falciparum malaria than in those with other illnesses.6They also found that plasma concentrations of TNF-a were much greater in cerebral malaria than in uncomplicated malaria-twice as high in those with cerebral malaria who survived and ten times as high in fatal cases. Previously, the same group had found that nausea,
raised concentrations were associated with acute P falciparum infection but did not correlate with disease severity or outcome.3Grau and colleagues,’ in a study of Malawian children with severe falciparum increased TNF-a malaria, reported that concentrations were associated with fatal outcome,
cerebral malaria, and hypoglycaemia; the association between high concentrations and complicated malaria was also found in European adults.8 The relation between raised TNF-a concentrations and severe malaria has been confirmed in children in Zaire,l but there was no particular association with cerebral malaria. That increased concentrations of circulating TNF-a are related to the illness of malaria is now beyond doubt; but does this association represent cause and effect? TNF-a might lead to cerebral involvement in malaria by increasing expression of parasite receptors on the endothelium of cerebral blood vessels, or by inducing hypoglycaemia, lactic acidosis, and other metabolic changes.So how can one explain the low concentrations of circulating TNF-a in some comatose patients and the high concentrations in some healthy individuals?9 Although TNF -cx has a short half-life in human serum (about 20 min), the effects persist; thus, the circulating concentration should correlate more closelv with time since schizogony than with the patient’s illness.3 High concentrations in a patient without severe malaria can be explained-provided they occur late rather than early during the disease-in terms of acquired tolerance to TNF-cx.5 TNF-a is only one of a family of cytokines with overlapping functions. Concentrations of lymphotoxin (TNF-&bgr;),lO interleukin-lcx,6 and interleukin-68 are all increased in malaria and correlate with disease severity. These cytokines may induce another family of mediators-eg, platelet-activated factor, prostaglandin E2-that actually cause the tissue damaged5 Treatment of malaria with neutralising antibody to TNF-a now seems a distinct possibility, but antibodies directed against other cytokines will probably be required as well.
Shaffer N, Grau GE, Hedberg K, et al. Tumor necrosis factor and severe malaria. J Infect Dis 1991; 163: 96-101. 2. Scuderi P, Lam KS, Ryan KJ, et al. Raised serum levels of tumour necrosis factor in parasitic infections. Lancet 1986; i: 1364-65. 3. Kwiatkowski D, Cannon JG, Manogue KR, Cerami A, Dinarello CA. Tumour necrosis factor production in falciparum malaria and its association with schizont rupture. Clin Exp Immunol 1989; 77: 361-66. 4. Clark IA, Cowden WB, Butcher GA, Hunt NH. Possible roles of tumor necrosis factor in the pathology of malaria. Am J Pathol 1987; 129: 1.
192-99. 5. Clark IA, Chaudhri G, Cowden WB. Roles of tumour necrosis factor in the illness and pathology of malaria. Trans R Soc Trop Med Hyg 1989; 83: 436-40.
6. Kwiatkowski D, Hill AVS, Sambou I, et al. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet 1990; 336: 1201-04. 7. Grau GE, Taylor TE, Molyneux ME, et al. Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med 1989; 320: 1586-91. 8. Kern P, Hemmer CJ, Van Damme J, Gruss HJ, Dietrich M. Elevated tumor necrosis factor alpha and interleukin-6 serum levels as markers for complicated Plasmodium falciparum malaria. Am J Med 1989; 87: 139-43.
9.
Phillips RE, Solomon T. Cerebral malaria in children. Lancet 1990; 336: 1355-60.
10. Clark IA, Rockett KA, Cowden WB. Role of TNF in cerebral malana Lancet 1991; 337: 302-03.
