Increased lymphotoxin in human malarial serum, and the ability of this cytokine to increase plasma interleukin-6 and cause hypoglycaemia in mice: implications for malarial pathology.

The origin of illness and pathology in malaria is now largely attributed to high levels of circulating tumour necrosis factor (TNF), released from cells of macrophage lineage after triggering by the products of malarial schizogony. The role of lymphocytes and their products in malarial pathology is not yet known. This paper reports the presence of a related cytokine, lymphotoxin, which is produced only by lymphocytes, in the serum of malarial patients. This is the first report of raised serum levels of lymphotoxin in a systemic disease state. When injected into mice, recombinant human lymphotoxin induced hypoglycaemia and increased serum levels of interleukin-6. These changes, which are seen in severe experimental and human malaria, were also provoked by TNF. Both of these cytokines acted synergistically with interleukin-1, which has also been reported to be raised in malaria, to produce these alterations. These observations imply that lymphotoxin, as well as TNF, may contribute to the hypoglycaemia and raised serum interleukin-6 observed in malaria. This reduces the likelihood of effectively blocking the pathology of this disease by the use of neutralizing antibody directed against just one member of this family of functionally overlapping mediators.     

Serum tumor necrosis factor associated with malaria in patients in the Solomon Islands

There is now significant evidence that tumor necrosis factor (TNF) is involved in the pathogenesis of malaria. We have tested sera from patients presenting with a febrile illness admitted to hospital in Honiara, Solomon Islands, for the presence of TNF, interferon-gamma, and interleukin-1 (IL-1). This study differs from previous reports as the subjects were mainly adults from a semi-immune population living in an endemic area. The results from 2 different commercially-available assays for TNF were compared, and one was found to be superior to the other. Serum TNF concentrations correlated with malarial parasite density and the patients' temperatures, but not with interferon or IL-1. The results are discussed in the context of the immunopathology of this disease.     

Correlation between susceptibility to malaria and babesia parasites and to endotoxicity

Adult (185g) rats are about twice as sensitive to the harmful effects of injected endotoxin as are younger (65g) rats. This relationship correlates with an earlier report on the densities of Plasmodium berghei at which deaths occur in rats of these two age groups. Similarly lizards, which withstand very high parasitaemias of malaria parasites, are refractory to very large doses of endotoxin. This correlation appears to hold for malaria and babesiosis in all host species for which information is available, with man, for instance, very sensitive to these infections and to injected endotoxin.It is now realized that endotoxicity is not caused by the direct effects of endotoxin, but is the consequence of the release of a range of harmful soluble mediators, mainly from macrophages. Since the susceptibility of a host species to endotoxicity and to malaria and babesiosis correlate, and the illness produced in each case is very similar, these harmful mediators which cause endotoxicity are likely candidates for the origins of much of the pathology of malaria and babesiosis. This concept may also explain the relationship between parasite density and illness in these infections in man.     

Role of biochemical mediators in clinical nutrition and surgical metabolism

Over the past several decades, research on the role of mediators in inflammation, immunity, repair processes, cell growth, and substrate metabolism have centered around the use of purified products of stimulated macrophages. With the current availability of recombinant mediators, the participation of individual monokines in cellular metabolism has been more clearly defined. Interactions among various mediators have been demonstrated, but their exact role in metabolism is currently under intense study. With the use of recombinant monokines, formal evidence for their participation in the acute phase response has been developed. Their use has also assisted in the reinterpretation of data gathered in older studies using purified preparations, which were almost certainly contaminated with several monokines. In this review we will try to give the reader insight into recent advances in the understanding of the role of cellular mediators in relation to nutrition and intermediary metabolism. With a clearer knowledge of the role of cellular mediators in the pathophysiology of disease, it may be possible to develop rationales for their therapeutic use as modulators of substrate metabolism during critical illness.     

Cost analysis of malaria patients in Taikkyi Township Myanmar

A hospital and clinic-based study was conducted in one malaria endemic area, Taikkyi Township, Yangon Division, Myanmar, for analysis of cost incurred by different types of malaria cases and the factors influencing the cost of illness from July to October 1995. A total of 100 patients admitted to hospital and 100 patients receiving ambulatory care from malaria clinics were interviewed using a structured questionnaire. Total cost of one episode of malaria was estimated to be kyats 559 for ambulatory care, kyats 2582 for an uncomplicated admitted case, kyats 4056 for one episode of cerebral malaria, kyats 4568 for one episode of other severe and complicated malaria and kyats 4758 for one episode of malaria with other disease. This study showed that the cost of illness for patients attending outpatient malaria clinics who received early diagnosis and prompt treatment was four to seven times cheaper than the cost of illness for hospitalized malaria cases. Multivariate analysis revealed the factors that contributed to high cost of care. Duration of illness before getting any type of treatment was the key factor that contributed to high or low cost of care. Long duration of illness before getting any type of treatment can lead to high malaria parasite density, long duration of actual illness and high total attendance cost. Therefore, it is recommended that people from malaria endemic areas should be informed to seek early treatment from health staff, and primary health care services should be made accessible to people who live in malaria endemic areas. The information obtained from this study will be useful in planning future malaria control programs and influencing policy makers to focus on timely and effective treatment of non-severe cases, which can save a large amount of economic loss due to treatment of severe malaria.     

Critical illness polyneuropathy

Critical illness polyneuropathy is a syndrome of neuromuscular complications after artificial respiration. The authors present the data of their own 22 patients all suffering from severe flaccid tetraparesis, areflexia and muscle atrophy, after an average of two weeks on artificial respiration. The prognosis is relatively favourable. The multi-conditional causes are discussed with emphasis on the combination of polyneuropathy and myopathy. The role of plasma factors such as cachectin, which is identical to tumour necrosis factor (TNF), is described. Attention is drawn to this important illness which occurs especially in patients in the intensive care unit with problems in the weaning from artificial respiration.     

The effects of endometritis on the establishment of pregnancy in cattle

Endometritis is common in post partum dairy cows and is associated with impaired reproductive performance reflected in reduced first service conception, reduced hazard of pregnancy over the breeding period and increased risk of reproductive culling. The observed effects may be mediated directly by bacterial products, such as lipopolysaccharide (LPS, endotoxin), or indirectly by inflammatory mediators, such as cytokines, eicosanoids, nitric oxide and oxidative stress affecting sperm, ovarian, uterine and embryonic function. An inflammatory milieu in the uterus has been associated with changes in sperm motility and function as well as increased sperm phagocytosis. Zygotes resulting from fertilisation of oocytes with sperm subjected to oxidative stress are less likely to develop to the blastocyst stage. In addition, LPS and tumour necrosis factor-α (TNFα) impair follicular steroidogenesis, growth and ovulation. Oocytes exposed to LPS or prostaglandin (PG) F(2α) during maturation are less likely to develop to blastocyst stage after fertilisation. Embryos exposed to inflammatory mediators during development have fewer trophoectoderm cells. Nitric oxide impairs development of preimplantation embryos and TNFα increases blastomere apoptosis. Endometritis in women has been associated with higher rates of implantation failure. Extragenital inflammation (e.g. mastitis) is also associated with an increased rate of embryonic loss in cattle. These observations make it clear that direct and indirect effects of endometritis, and inflammation in general, can interrupt successful reproduction at several crucial stages.     

Treatment of rheumatoid arthritis by inhibition of tumor necrosis factor with infliximab or etanercept

The current pharmacotherapy of rheumatoid arthritis (RA) consists of non-steroidal anti inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) such as sulphasalazine, leflunomide and methotrexate. DMARDs can be given as monotherapy or in combination. However, not all patients show an adequate response due to toxicity or lack of efficacy. From animal studies and clinical studies in patients with RA, we know that tumour necrosis factor (TNF) is directly involved in the pathogenesis of RA. Two forms of TNF inhibition therapy have been extensively investigated in RA: anti-TNF monoclonal antibodies (infliximab) and TNF receptor-Fc fusion protein (etanercept). Both types of TNF inhibition induce a rapid improvement in multiple clinical measures of disease activity and patient functional status. Furthermore, a beneficial effect was demonstrated on radiographic progression of joint damage. Etanercept and the combination infliximab-methotrexate are generally well tolerated.     

HIV--Leishmania infantum co-infection: humoral and cellular immune responses to the parasite after chemotherapy

Specific serum antibodies, peripheral blood T-cell subsets, cellular response in vitro to soluble Leishmania antigens, phenotype of stimulated cells, and serum levels of tumour necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta 1 were studied in Spain in 17 patients co-infected with HIV and Leishmania infantum who had been previously treated with pentavalent antimony. Both humoral and cellular responses to Leishmania sp. appeared diminished, 8 out of 17 patients were positive by indirect immunofluorescence, and immunoblotting detected heterogeneous antibody-binding pattern in 11 out of 13 subjects. A blastogenesis test was positive in 4 cases; 2 of them presented proliferation of CD4+ cells while CD8+ cells proliferated in the other 2 patients. Serum levels of TNF-alpha were similar to those observed in patients infected with HIV only, while serum levels of TGF-beta 1 were significantly lower in the co-infected patients. The inability of antibody response to control the parasite and the absence of specific T-cell immunity to Leishmania sp. would explain the high frequency of relapses reported in these patients. The decreased levels of TGF-beta 1 could have an important role in the interaction between the 2 pathogens.     

Metabolic responses to tumour disease and progression: tumour-host interaction

The progressive nutritional deterioration frequently found in cancer patients, is often referred to as cancer cachexia. In contrast to starvation, where it is possible to reverse the body composition changes by the provision of extra calories, in cancer cachexia this reversal is not observed, suggesting that anorexia alone is unlikely to be responsible for this wasting syndrome. Over the past decades a number of studies have focused on the possible mediators which may be responsible for metabolic abnormalities observed in cancer patients. Pro-inflammatory cytokines have been strongly implicated, but evidence supporting such a direct role is lacking. Recently, exciting work regarding molecules produced by tumour cells, and which may induce lipolysis and proteolysis, has been published. There is also evidence that increased metabolism of host resources may provide substrates which might promote tumour growth. A number of studies have demonstrated that polyunsaturated fatty acids, such as linoleic and arachidonic acid, are able to promote tumour cell growth either by directly stimulating mitosis or by inhibiting apoptosis. Even more interesting is the discovery of antagonists of these catabolic factors such as eicosapentanoic acid for the lipolytic factor, which may play a role in the treatment of these patients in the near future.     

Metabolic responses to tumour disease and progression: tumour–host interaction

The progressive nutritional deterioration frequently found in cancer patients, is often referred to as cancer cachexia. In contrast to starvation, where it is possible to reverse the body composition changes by the provision of extra calories, in cancer cachexia this reversal is not observed, suggesting that anorexia alone is unlikely to be responsible for this wasting syndrome. Over the past decades a number of studies have focused on the possible mediators which may be responsible for metabolic abnormalities observed in cancer patients. Pro-inflammatory cytokines have been strongly implicated, but evidence supporting such a direct role is lacking. Recently, exciting work regarding molecules produced by tumour cells, and which may induce lipolysis and proteolysis, has been published. There is also evidence that increased metabolism of host resources may provide substrates which might promote tumour growth. A number of studies have demonstrated that polyunsaturated fatty acids, such as linoleic and arachidonic acid, are able to promote tumour cell growth either by directly stimulating mitosis or by inhibiting apoptosis. Even more interesting is the discovery of antagonists of these catabolic factors such as eicosapentanoic acid for the lipolytic factor, which may play a role in the treatment of these patients in the near future.     

Unstable malaria in Sudan: the influence of the dry season. Clone multiplicity of Plasmodium falciparum infections in individuals exposed to variable levels of disease transmission.

Studies of infection and immunity to malaria often take little account of the fact that the amount of infectious challenge individuals receive is very variable. Classic studies in areas of holoendemic transmission showed that clinical immunity develops quite rapidly during childhood, although the processes through which increasing levels of resistance to infection are acquired are still not understood. However, holoendemic transmission is one end of the spectrum of malaria epidemiology and the development of clinical immunity is also affected by factors such as the infection rate and the local parasite species composition. An exceptionally simple type of malaria transmission occurs during the short, autumnal malaria outbreaks of the Sudanese sahel-savannah belt, where a sparse 200-500 mm of rain falls in 2-3 summer months, Plasmodium falciparum causes > 95% of malaria cases in most areas, and the entomological inoculation rate (EIR) is very low by African standards; thus the population dynamics of malaria parasites are less affected by super-infection. A comparison of certain features of parasite genetic diversity, particularly the average number of parasite clones present in infections in the Sudanese sahel and in malaria study sites with different levels of transmission, is presented. It is proposed that increasing EIRs are associated with progressively smaller increases in the average number of malaria parasite clones per host and the implications of this relationship for studies on malaria infection and immunity are discussed.     

Late relapse of Plasmodium ovale malaria--Philadelphia, Pennsylvania, November 2004

Approximately 1,300 cases of malaria are reported each year in the United States; nearly all of these cases occur in travelers, many of whom fail to receive or adhere to prescribed chemoprophylaxis or do not follow recommendations for prevention of mosquito bites. Malaria can persist if not treated or if treated incorrectly (e.g., with an ineffective drug or an incorrect dosage of an effective drug). Early treatment is required to avoid severe illness or death. Although malaria typically becomes clinically apparent within 1 month of infection, cases can occur years after the last presumed exposure. In November 2004, CDC received a report of a late relapse of malaria in a Nigerian man aged 23 years in Philadelphia, Pennsylvania. His malaria was determined to have been caused by Plasmodium ovale, one of the four species of Plasmodium parasite that are transmitted by mosquitoes and cause malaria. The patient had been treated for malaria in Nigeria on multiple occasions, most recently 6 years before onset of his illness in the United States. This report describes the Philadelphia case, which underscores the importance of taking a detailed travel and immigration history when evaluating unexplained fever and considering malaria in the differential diagnosis.     

The pituitary-thyroid axis in severe falciparum malaria: evidence for depressed thyrotroph and thyroid gland function

Abnormal thyroid function is strongly associated with mortality in severe non-thyroidal illness. We have assessed the pituitary-thyroid axis serially in 18 Thai adults with severe falciparum malaria and in 18 matched controls. The admission total serum thyroxine (T4) concentrations of the patients (median [range]: 64 nmol/litre [less than 30-91]) were significantly lower than those of controls (81 nmol/litre [61-133]; 2P less than 0.01), and remained depressed until after fever and parasite clearance. Two patients who died in hospital had admission serum T4 concentrations less than 35 nmol/litre. The admission basal serum thyrotropin (TSH) levels of the patients (0.9 mU/litre [less than 0.2-3.1]) were similar to those of controls (1.3 mU/litre [less than 0.2-3.7], 2P greater than 0.1) and remained normal throughout fever and parasitaemia. Thirty-minute TSH increments during a thyrotropin-releasing hormone test on admission were reduced in 13 patients with severe malaria (4.1 mU/litre [0.7-8.1]) relative to those in convalescence (7.1 mU/litre [1.7-14.4], n = 10, 2P less than 0.01) and controls (5.6 mU/litre [3.3-12.9], n = 9, 2P less than 0.05). These findings suggest that thyrotroph and thyroid gland function are depressed during acute, severe malaria. As these changes may be an adaptation to accelerated catabolism, the role of thyroid replacement in such patients is uncertain.     

Functional and ultrastructural changes of platelets in malarial infection

This paper describes changes in the circulating platelets of 25 patients with acute malaria within 2 to 6 days of onset of illness. Thrombocytopenia was observed in 10 out of 15 patients with Plasmodium falciparum infection, and in 4 out of 9 patients with P. vivax infection. One patient with a mixed infection of both species had a disseminated intravascular coagulation. Platelet antibody was detected in the sera of 8 out of 11 cases by the complement lysis inhibition technique and indirect immunofluorescence. The mean platelet antibody concentrations in the sera of 11 patients and 53 control subjects were 122.70 +/- 80.25 ng/10(7) platelets and 36.69 +/- 18.72 ng/10(7) platelets, respectively. An inverse relationship between the platelet count and platelet antibody levels in serum supported the view that thrombocytopenia in malaria may be partly immune-mediated. Platelet aggregation responses to agonists such as ADP, adrenaline, collagen and ristocetin revealed hyperactivity. Ultrastructural study of unstimulated platelets from patients revealed several changes such as centralization of dense granules, glycogen depletion, and formation of pseudopods and microaggregates, indicating in vivo activation of the platelets, which may also lead to thrombocytopenia.     

High mobility group box 1 (HMGB1) protein: possible amplification signal in the pathogenesis of falciparum malaria

High mobility group box 1 (HMGB1) protein, a DNA-binding protein that can also act as a pro-inflammatory cytokine if released from cells, is an important amplification signal in various forms of inflammation. The concentration of HMGB1 in serum taken at admission was increased in falciparum malaria in sixteen African children, more so in fatal cases than in those who subsequently recovered (P<0.001). Serum from both non-fatal (P=0.0048) and fatal (P<0.001) cases contained significantly more circulating HMGB1 than did serum from healthy Caucasian adults. These data provide an additional argument that malaria is fundamentally a systemic inflammatory state. In keeping with its developing role in sepsis, HMGB1 may enhance and prolong the inflammatory processes, and thus illness, in malaria.     

Parasitological profile of the surveyed population for malaria in an endemic area in Faiyoum Governorate, Egypt

Egypt represents the only focus in the Mediterranean region where Plasmodium falciparum transmission still occurs. A longitudinal parasitological study has been implemented (September 1995 to December 1996) in Faiyoum, Egypt. A total of 9065 blood slides for malaria parasites were taken from all people in the study area as mass blood examination (MBE); those attending the malaria unit as passive case detection (PCD) as well as from neighborhood of the detected cases (NOD). They were stained by Giemsa stain and examined under standard conditions for positivity, parasite species and parasite density. Our results show that MBE detected 61.5% of malaria cases while 23.1% and 15.4% of the confirmed cases were detected through PCD and NOD respectively. The overall parasite rate was 5.7/1000 examined population. P. falciparum was the most predominant species (96.1%), followed by P. vivax (3.9%). The epidemiological factors causing the persistence of malaria transmission in the study area are discussed.     

Immune response to Plasmodium falciparum liver stage antigen-1: geographical variations within Central Africa and their relationship with protection from clinical malaria

Two populations of schoolchildren from Gabon and Cameroon were tested in 1995 for their immunological reactivity to synthetic peptides (LSA-Rep, LSA-J and LSA-CTL) from Plasmodium falciparum liver stage antigen-1 (LSA-1). The prevalence and levels of both cellular (lymphocyte proliferation, tumour necrosis factor alpha (TNF alpha), interferon gamma (IFN gamma), and interleukin-10 (IL-10)) and humoral (immunoglobulin G) responses were determined. Protection from clinical malaria, determined after a prospective 1 year study in both sites, was associated with elevated proliferative responses to LSA-Rep and LSA-CTL in the Gabonese children, as well as with higher antibody levels to both schizont extract and LSA-Rep. The prevalence of peptide-stimulated TNF-alpha secretion was higher in the Cameroonian group, but higher levels of antibodies to LSA-Rep and LSA-J were found in the Gabonese children. The immunological differences observed between children in the 2 study sites are discussed in the context of both epidemiological and individual host factors.     

Immune activation during cerebellar dysfunction following Plasmodium falciparum malaria.

Evidence for immune activation was investigated in 12 patients with a rare syndrome of self-limiting, delayed onset cerebellar dysfunction following an attack of falciparum malaria which occurred 18-26 d previously. Concentrations of tumour necrosis factor, interleukin 6 and interleukin 2 were all significantly higher in serum samples of patients during cerebellar ataxia than in recovery sera and in the sera of 8 patients who did not develop delayed cerebellar dysfunction following an attack of falciparum malaria. Cytokine concentrations in the cerebrospinal fluid were also significantly higher in ataxic patients than in controls. These findings suggest that immunological mechanisms may play a role in delayed cerebellar dysfunction following falciparum malaria.