Effect of Brugia pahangi co-infection with Plasmodium berghei ANKA in gerbils (Meriones unguiculatus).

Malaria and lymphatic filariasis (LF) are two leading and common mosquito-borne parasitic diseases worldwide. These two diseases are co-endemic in many tropical and sub-tropical regions and are known to share vectors. The interactions between malaria and filarial parasites are poorly understood. Thus, this study aimed at establishing the interactions that occur between Brugia pahangi and Plasmodium berghei ANKA (PbA) co-infection in gerbils. Briefly, the gerbils were matched according to age, sex, and weight and grouped into filarial-only infection, PbA-only infection, co-infection, and control group. The parasitemia, survival and clinical assessment of the gerbils were monitored for a period of 30 days post Plasmodium infection. The immune responses of gerbils to both mono and co-infection were monitored. Findings show that co-infected gerbils have higher survival rate than PbA-infected gerbils. Food and water consumption were significantly reduced in both PbA-infected and co-infected gerbils, although loss of body weight, hypothermia, and anemia were less severe in co-infected gerbils. Plasmodium-infected gerbils also suffered hypoglycemia, which was not observed in co-infected gerbils. Furthermore, gerbil cytokine responses to co-infection were significantly higher than PbA-only-infected gerbils, which is being suggested as a factor for their increased longevity. Co-infected gerbils had significantly elicited interleukin-4, interferon-gamma, and tumor necrotic factor at early stage of infection than PbA-infected gerbils. Findings from this study suggest that B. pahangi infection protect against severe anemia and hypoglycemia, which are manifestations of PbA infection.

Inter-relationships of cardinal features and outcomes of symptomatic pediatric Plasmodium falciparum MALARIA in 1,933 children in Kampala, Uganda.

Malaria remains a challenging diagnosis with variable clinical presentation and a wide spectrum of disease severity. Using a structured case report form, we prospectively assessed 1,933 children at Mulago Hospital in Kampala, Uganda with acute Plasmodium falciparum malaria. Children with uncomplicated malaria significantly differed from those with severe disease for 17 features. Among 855 children with severe disease, the case-fatality rate increased as the number of severity features increased. Logistic regression identified five factors independently associated with death: cerebral malaria, hypoxia, severe thrombocytopenia, leukocytosis, and lactic acidosis. Cluster analysis identified two groups: one combining anemia, splenomegaly, and leukocytosis; and a second group centered on death, severe thrombocytopenia, and lactic acidosis, which included cerebral malaria, hypoxia, hypoglycemia, and hyper-parasitemia. Our report updates previous clinical descriptions of severe malaria, quantifies significant clinical and laboratory inter-relationships, and will assist clinicians treating malaria and those planning or assessing future research (NCT00707200) (www.clinicaltrials.gov).

Blood glucose and prognosis in children with presumed severe malaria: is there a threshold for 'hypoglycaemia'?

OBJECTIVES: Hypoglycaemia (glucose <2.2 mmol/l) is a defining feature of severe malaria, but the significance of other levels of blood glucose has not previously been studied in children with severe malaria. METHODS: A prospective study of 437 consecutive children with presumed severe malaria was conducted in Mali. We defined hypoglycaemia as <2.2 mmol/l, low glycaemia as 2.2-4.4 mmol/l and hyperglycaemia as >8.3 mmol/l. Associations between glycaemia and case fatality were analysed for 418 children using logistic regression models and a receiver operator curve (ROC). RESULTS: There was a significant difference between blood glucose levels in children who died (median 4.6 mmol/l) and survivors (median 7.6 mmol/l, P < 0.001). Case fatality declined from 61.5% of the hypoglycaemic children to 46.2% of those with low glycaemia, 13.4% of those with normal glycaemia and 7.6% of those with hyperglycaemia (P < 0.001). Logistic regression showed an adjusted odds ratio (AOR) of 0.75 (0.64-0.88) for case fatality per 1 mmol/l increase in baseline blood glucose. Compared to a normal blood glucose, hypoglycaemia and low glycaemia both significantly increased the odds of death (AOR 11.87, 2.10-67.00; and 5.21, 1.86-14.63, respectively), whereas hyperglycaemia reduced the odds of death (AOR 0.34, 0.13-0.91). The ROC [area under the curve at 0.753 (95% CI 0.684-0.820)] indicated that glycaemia had a moderate predictive value for death and identified an optimal threshold at glycaemia <6.1 mmol/l, (sensitivity 64.5% and specificity 75.1%). CONCLUSIONS: If there is a threshold of blood glucose which defines a worse prognosis, it is at a higher level than the current definition of 2.2 mmol/l.

Severe malaria: metabolic complications.

Metabolic complications of severe malaria are some of the most important and potentially treatable manifestations of this deadly disease. The commonest metabolic complications (lactic acidosis and hypoglycaemia) arise from increased host anaerobic metabolism probably due to a mismatch between tissue oxygen supply and requirement. Optimising treatments for these complications should be guided by detailed understanding of their underlying pathophysiology, and may help to reduce the intolerably high case fatality rate of severe malaria.

The relevance of malaria pathophysiology to strategies of clinical management.

PURPOSE OF REVIEW: Malaria claims 1-2 million lives a year, mostly children in sub-Saharan Africa. The majority of hospital deaths occur within 24 h of admission despite adequate treatment with antimalarial chemotherapy. Understanding the pathophysiological disturbances of malaria should allow the development of supportive therapy to "buy time" for antimalarial chemotherapy to clear the infection. It is sobering, however, that despite many trials over the last quarter of a century all large trials of adjunctive therapy so far have resulted in either increased morbidity or mortality, or both. RECENT FINDINGS: Severe malaria may be divided broadly into neurological and metabolic complications. We review recent findings about the pathophysiology of these complications and the implications for future adjunctive therapy of malaria, including the proposed importance of fluid volume depletion and sequestration of parasitized red cells in severe malaria. We also consider other anaemia, hyperparasitaemia and renal failure, which also require urgent treatment in severe malaria. SUMMARY: We review the important pathophysiological features of severe malaria and promising adjunctive therapies such as dichloroacetate that warrant further larger trials to determine whether they improve the so-far intractable death rate of severe malaria.

Trichinella spiralis: activity of the cerebral pyruvate recycling pathway of the host (mouse) in hypoglycemia induced by the infection.

The activity of the cerebral pyruvate recycling pathway and energy metabolism in mice infected with Trichinella spiralis were investigated using (13)C-NMR and in vivo (31)P-NMR spectroscopy, respectively. The (13)C-NMR analysis, using [1,2-(13)C(2)] acetate as a substrate, of whole-brain extracts demonstrated that activity of the pathway increased when T. spiralis infection induced hypoglycemia in the host. The in vivo (31)P-NMR observation showed that the cerebral ATP in normal level sustained throughout this experiment. These findings indicate that the pyruvate recycling pathway plays a role in the energy supply to the host in hypoglycemia induced by T. spiralis infection.

Plasma glucose and tumour necrosis factor-alpha in adult patients with severe falciparum malaria.

Plasma glucose was assessed in 81 patients with severe falciparum malaria at the time of presentation along with tumour necrosis factor-alpha (TNF-alpha). The lowest plasma glucose value was 3.38 mmol/l and none of the patients had hypoglycaemia at admission. Plasma glucose values were not significantly lower in those with multiple organ dysfunction (MOD) than in patients with single organ dysfunction (cerebral malaria only) and in those who died compared with patients who survived. Conversely, TNF-alpha showed a good correlation with depth of coma and was significantly higher in patients who had MOD and those who died. There was no correlation between plasma glucose and TNF-alpha values.

Hyponatraemia in severe falciparum malaria: a clinical study of nineteen comatose African children.

In a prospective study, hyponatraemia was observed in 52.6% of 19 children with cerebral malaria on admission, the plasma sodium ranging from 117 to 129 mumol/l. In addition, a further 10% developed hyponatraemia between 48 and 96 hrs after admission; in half of these, there was continuing urinary sodium loss. The clinical presentation of hypo- and normonatraemic children was similar except for vomiting and hypoglycaemia which were commoner in the normonatraemic and irritability and signs of lower respiratory tract infection which were commoner in the hyponatraemic groups. In hyponatraemic and normonatraemic children, there was a negative correlation between hyponatraemia and parasite density (r = -0.503, P < 0.05) and (r = -0.14, P < 0.05 respectively) and between parasite density and urinary sodium concentration during the first 24 hours of admission (r = -0.034; P < 0.05 and r = -0.045, P > 0.05 respectively). Irrespective of group, a relative increase in plasma sodium in the first 24 hours of admission (positive delta Na 24 h) was associated with a reduction in seizure frequency during this period as compared to the reported 24 hour of pre-admission seizure frequency, and, vice-versa. It is concluded that hyponatraemia is not uncommon in childhood cerebral malaria; urinary sodium loss may be contributory to the hyponatraemia seen in this condition.

Phospholipid-containing toxic malaria antigens induce hypoglycaemia.

Hypoglycaemia is associated with severe malaria and is an important prognostic indicator. Molecules liberated during overnight incubation of erythrocytes infected with Plasmodium yoelii induce marked hypoglycaemia in normal mice, with a delayed time course compared with insulin; some, though weaker, activity could also be obtained by overnight incubation of uninfected erythrocytes. The active component shares many properties with the phospholipid-containing molecules which we have previously shown to be toxic and to induce the release of tumour necrosis factor (TNF) from macrophages. However a MoAb which neutralizes the cytotoxicity of tumour necrosis factor in vitro did not prevent this induction of hypoglycaemia, whereas antiserum against the toxic antigens did, as did immunization of normal (but not the immunoglobulin-deficient SCID) mice with the same material. Furthermore, normal mice injected with the antigens after immunization with phosphatidyl inositol or inositol monophosphate did not develop hypoglycaemia; the latter compound was also inhibitory when mixed with the antigens before injection. These compounds were previously shown to block the induction of TNF by the antigens and to induce the production of inhibitory antibodies. The role of these molecules in the etiology of the hypoglycaemia of malaria is discussed.