Treatment of severe malaria in the United States with a continuous infusion of quinidine gluconate and exchange transfusion

During the past decade the incidence of Plasmodium falciparum malaria in the United States has increased 10-fold. Treatment may be delayed because the therapy recommended for severe or complicated disease, intravenous quinine dihydrochloride, is available only from the Centers for Disease Control. We studied 17 patients who were treated for severe or complicated P. falciparum malaria in the United States between 1985 and 1987. Five patients were treated with a continuous infusion of quinidine gluconate, 10 with an exchange transfusion in addition to the continuous infusion of quinidine gluconate, and 2 with intermittently administered intravenous quinine dihydrochloride and an exchange transfusion. All 16 patients with P. falciparum malaria (1 patient had P. vivax malaria) had hyperparasitemia at the time of diagnosis (6 to 54 percent of the erythrocytes infected; median, 13 percent). Three patients with marked hyperparasitemia (54, 38, and 30 percent) and multiple other indicators of a poor prognosis, including advanced age, died. The 13 patients who completed their courses of quinidine with or without exchange transfusion had a parasitemia level of 1.1 percent or less 28 to 72 hours (mean, 44.4 hours) after the start of therapy. Side effects of quinidine treatment were observed in only two patients, one of whom had a serum quinidine concentration above the toxic level. We conclude that the continuous infusion of quinidine gluconate is well tolerated alone and with exchange transfusion and is effective in the treatment of severe and complicated malaria.     

Experience with quinine in falciparum malaria

During a period of 1 year from July 95 to June 96, 60 patients with falciparum malaria were treated with quinine at Kasturba Medical College Hospital, Mangalore. Of these, 24 patients developed adverse effects to quinine. They were cinchonism (15) cardiotoxicity (10) hypoglycemia (9) hyperventilation (3) hypersensitivity reactions (3) and hypokalemia (1). Cardiotoxicity was noted in 4 of the 7 patients who received intravenous quinine and all four had renal and hepatic failure and prolonged Q-Tc on electrocardiogram. All 4 died of cardiac arrhythmias, 2 had broad QRS tachycardia and 2 had sinus bradycardia. We conclude that: 1. Quinine should be used cautiously in patients with impaired hepatic or renal function and in those with prolonged QTc as it can lead to cardiotoxicity in the form of I0 AV block, prolonged Q-Tc, broad QRS tachycardai or fatal bradyarrhythmia. Dosage reduction to 5 mg/kg body weight in the patients seem to be safer. 2. Hypoglycemia is a very frequent complication of quinine therapy and special care and frequent blood sugar estimations are required especially if the patient has vomiting. 3. Parenteral quinine is more likely to cause toxicity than oral quinine as earlier described.     

Pharmacology of absorption and distribution: optimal use of antimalarial drugs in the treatment of severe falciparum malaria in Kenya

Since 1989, a project at the KEMRI CRC Unit at Kilifi has focused on the design of appropriate and practicable regimens for the treatment of severe falciparum malaria. Initially, there was no data describing the absorption, distribution and elimination of quinine in Kenyan children, who constitute the great majority of patients. Pharmacokinetic studies were conducted to define these variables, which formed the basis for the design of appropriate and practicable treatment regimens. Even with optimal clinical management, the majority is high in cases of severe malaria treated with quinine at Kilifi. Alternative drugs have been studied in a search for a therapeutic regimen that will further reduce mortality.     

Management of severe and complicated malaria

Severe malaria is invariably caused by Plasmodium falciparum. In India, both adults and children are affected by severe malaria. However, children are more prone for developing anemia and convulsions as manifestations of severe malaria, while acute renal failure and jaundice are more common among adults. Pregnant women are vulnerable to hypoglycemia, anemia and pulmonary complications. The case-fatality rate due to severe malaria is 10-15% in spite of therapy but it increases in the presence of renal failure or respiratory distress (pulmonary edema or ARDS). Of late, multi-organ failure and high mortality figures are being reported increasingly from different parts of India. Early diagnosis and prompt treatment will reduce the mortality due to malaria. Cerebral malaria should always be suspected in a patient with altered sensorium in a malaria-endemic area. However, other causes of unconsciousness such as encephalitis, meningitis or hepatic coma should also be excluded. Parenteral quinine is the mainstay of therapy. A recent multi-centric study has demonstrated the efficacy of intravenous artesunate in reducing the mortality by 30%. The usefulness of adjunct therapy is still controversial.     

Hypoglycemia during diarrhea in childhood. Prevalence, pathophysiology, and outcome

To determine the frequency and outcome of hypoglycemia during diarrhea in childhood, we screened 2003 consecutive patients less than 15 years of age who were admitted to a diarrhea treatment center in Dhaka, Bangladesh. Hypoglycemia, defined as a blood glucose concentration less than 2.2 mmol per liter, was found in 91 patients (4.5 percent), 39 (42.9 percent) of whom died. We also measured the plasma concentrations of glucoregulatory hormones and gluconeogenetic substrates in 46 of the patients with hypoglycemia who were 2 to 15 years old and in 25 normoglycemic patients matched with them for age and weight. The patients with hypoglycemia had had diarrhea for less time than the normoglycemic patients (median, 12 vs. 72 hours; P less than 0.05), and their last feeding had been 18 hours before admission, as compared with 9 hours for the normoglycemic patients (P less than 0.05). The groups were similar in terms of nutritional status, the proportion of patients who had fever, and the types of pathogens recovered from stool samples. The plasma C-peptide concentrations were low (less than 0.30 nmol per liter) in all the hypoglycemic patients. As compared with the normoglycemic patients, the patients with hypoglycemia had elevated median plasma concentrations of glucagon (44 vs. 11 pmol per liter; P = 0.001), epinephrine (3400 vs. 1500 pmol per liter; P = 0.012), norepinephrine (7500 vs. 2900 pmol per liter; P = 0.002), and lactate (3.5 vs. 2.1 mmol per liter; P = 0.020) and similar alanine and beta-hydroxybutyrate concentrations. Eighteen hypoglycemic patients with severe malnutrition had been ill longer than 26 better-nourished patients with hypoglycemia (median duration of illness, 18 vs. 10 hours; P = 0.023) and had lower median plasma concentrations of lactate (1.9 vs. 3.9 mmol per liter; P = 0.021) and alanine (173 vs. 293 micromol per liter; P = 0.040). We conclude that hypoglycemia is a major cause of death in association with diarrhea. Because the glucose counterregulatory hormones were appropriately elevated in the children with diarrhea and hypoglycemia, whereas the gluconeogenetic substrates were inappropriately low, we further conclude that the hypoglycemia observed in such patients is most often due to the failure of gluconeogenesis.     

Intravenous quinidine for the treatment of severe falciparum malaria. Clinical and pharmacokinetic studies

Quinidine has proved more effective than quinine against chloroquine-resistant Plasmodium falciparum both in vitro and in patients with uncomplicated disease. To examine the effectiveness and pharmacokinetics of quinidine for this use, we treated 14 patients who had severe falciparum malaria with intravenous quinidine gluconate; a loading dose of 15 mg of the base per kilogram of body weight was followed by 7.5 mg per kilogram every eight hours. Two of the five patients with cerebral malaria died, but parasitemia was eliminated in the 12 survivors. Two patients had recurrent parasitemia on Days 25 and 28. Times required for parasite clearance and elimination of fever (49.4 +/- 17.8 and 69.5 +/- 18.7 hours, respectively) were comparable to those in earlier studies with a loading dose of quinine. Quinidine appears to have a larger volume of distribution than quinine. The elimination half-life was 12.8 hours, the volume of distribution was 1.68 liters per kilogram, total clearance was 1.75 ml per kilogram per minute, and urinary clearance was 0.62 ml per kilogram per minute. Electrocardiographic changes were common but there were no dysrhythmias. In two patients, blood pressure fell during the initial infusion of quinidine. Quinidine gluconate is more widely available than quinine in many countries, and our findings show that it is effective in severe falciparum malaria.     

Tolerance and efficacy of mefloquine as the first line treatment of uncomplicated P. falciparum malaria in children

INTRODUCTION: Given the national therapeutic guidelines in France, halofantrine represents the first line treatment of uncomplicated Plasmodium falciparum (P. falciparum) malaria in children. But several disadvantages exist using halofantrine in paediatrics. OBJECTIVES: The primary objective of this study is to evaluate the tolerance and the efficacy of mefloquine as the first line treatment of uncomplicated P. falciparum malaria in a paediatric emergency department. The secondary objective of the study is to evaluate whether symptomatic measures may improve the gastrointestinal tolerance of mefloquine. PATIENTS AND METHODS: This retrospective observational cohort study includes all the patients who have been treated for acute uncomplicated P. falciparum malaria in the paediatric emergency department of the Hospital Trousseau (Paris, France) in 2003. RESULTS: First line treatment was mefloquine in 35 children. Early vomiting occurred in 22 (63%) cases. All children responded to mefloquine therapy except two children who had persistent vomiting early after mefloquine therapy and required intravenous quinine. Those two children had initial vomiting. Light meal and metopimazine prophylaxis did not precede mefloquine intake in those two children. CONCLUSION: This study suggests that mefloquine treatment of uncomplicated P. falciparum malaria is effective and well tolerated in children. Furthermore, a light meal and metopimazine prophylaxis preceding mefloquine intake may improve its gastrointestinal tolerance.     

Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria.

BACKGROUND. Cerebral malaria is a severe complication of Plasmodium falciparum infection in children, with a mortality rate of 15 to 50 percent despite antimalarial therapy. METHODS. To determine whether combining iron chelation with quinine therapy speeds the recovery of consciousness, we conducted a randomized, double-blind, placebo-controlled trial of the iron chelator deferoxamine in 83 Zambian children with cerebral malaria. To be enrolled, patients had to be less than six years old, have P. falciparum parasitemia, have normal cerebrospinal fluid without evidence of bacterial infection, and be in a coma from which they could not be aroused. Deferoxamine (100 mg per kilogram of body weight per day, infused intravenously for 72 hours) or placebo was added to standard therapy with quinine and sulfadoxine-pyrimethamine. The time to the recovery of full consciousness, time to parasite clearance, and mortality were examined with Cox proportional-hazards regression analysis. RESULTS. The rate of recovery of full consciousness among the 42 patients given deferoxamine was 1.3 times that among the 41 given placebo (95 percent confidence interval, 0.7 to 2.3); the median time to recovery was 20.2 hours in the deferoxamine group and 43.1 hours in the placebo group (P = 0.38). Among 50 patients with deep coma, the rate of recovery of full consciousness was increased 2.2-fold with deferoxamine (95 percent confidence interval, 1.1 to 4.7), decreasing the median recovery time from 68.2 to 24.1 hours (P = 0.03). Among 69 patients for whom data on parasite clearance were available, the rate of clearance with deferoxamine was 2.0 times that with placebo (95 percent confidence interval, 1.2 to 3.6). Among all 83 patients, mortality was 17 percent in the deferoxamine group and 22 percent in the placebo group (P = 0.52). CONCLUSIONS. Iron chelation therapy may hasten the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria.     

Ventricular fibrillation in a 5-year-old child on therapeutic dose of quinine dihydrochloride infusion for acute malaria

Malaria is no doubt a disease of public health significance in the tropics. Plasmodium falciparum, resistant to the majority of the first-line antimalarial drugs, now causes most of the infections treated in sub-Saharan Africa. Although there is increasing use of artemisinin-based combination therapy in many African nations, quinine still remains a commonly used drug for severe and chloroquine-resistant malaria. Cardiotoxicity associated with quinine has been largely reported. However, this was often more common with toxic doses. This case report is on a 5-year-old African Nigerian who was undergoing treatment for uncomplicated malaria with quinine dihydrochloride infusion. All the laboratory investigations done were within normal limits except for positive blood films for malarial parasites. However, pretreatment electrocardiographic evaluation of the patient was not carried out. She developed ventricular fibrillation and died < 1.5 hours into the quinine infusion.     

Quinine-induced arrhythmia in a patient with severe malaria

It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases.     

Tumor necrosis factor and disease severity in children with falciparum malaria

To investigate the role of tumor necrosis factor in Plasmodium falciparum infections, we measured serum concentrations of this cytokine in 65 Malawian children with severe falciparum malaria. Of these children (mean age, 5.3 years), 55 were unconscious and 10 had hypoglycemia at presentation. Although there was considerable overlap, the mean (+/- SEM) initial serum concentration of tumor necrosis factor was significantly higher in the 10 patients who died (709 +/- 312 pg per milliliter) than in the 55 who survived (184 +/- 32 pg per milliliter; P less than 0.02). The mortality rate increased with the concentration of tumor necrosis factor: at a level of less than 100 pg per milliliter, 1 of 24 patients died; at 100 to 500 pg per milliliter, 6 of 34 patients; and at more than 500 pg per milliliter, 3 of 7 patients. High concentrations of tumor necrosis factor were also associated with hypoglycemia (P less than 0.02), hyperparasitemia (P less than 0.002), age under three years (P less than 0.03), and severity of illness as measured by a prognostic index (P less than 0.0005). The highest serum concentrations of tumor necrosis factor were found in patients who died shortly after admission. The concentrations in cerebrospinal fluid were within the normal range in all patients. In serum samples obtained from 38 convalescent patients, the concentration of tumor necrosis factor declined to a mean of 16 +/- 3 pg per milliliter. We conclude that the level of tumor necrosis factor is frequently increased in patients with severe falciparum malaria, particularly in those with cerebral malaria or hypoglycemia. To determine whether it is important in the pathogenesis of the signs and symptoms of the disease requires further study.     

Plasmodium Falciparum malaria and perinatally acquired human immunodeficiency virus type 1 infection in Kinshasa, Zaire. A prospective, longitudinal cohort study of 587 children

BACKGROUND. It is uncertain whether Plasmodium falciparum malaria is more frequent or more severe in children with perinatally acquired human immunodeficiency virus type 1 (HIV-1) infection and whether P. falciparum infection accelerates the progression of HIV-related disease. METHODS. We conducted a prospective, longitudinal cohort study in Kinshasa, Zaire. Two hundred sixty children 5 to 9 months of age who had been born to HIV-1-seropositive mothers and 327 children of the same age who had been born to seronegative mothers were monitored intensively for malaria over a 13-month period. All episodes of fever were evaluated with blood smears for malaria, and children found to be infected with P. falciparum were treated with a standard regimen of oral quinine. RESULTS. A total of 2899 fevers were evaluated, with 271 cases of malaria identified. No statistically significant differences were found in the incidence, severity, or response to therapy of malaria among four well-defined groups of children: those with the acquired immunodeficiency syndrome (AIDS), those who were HIV-1-seropositive throughout the study, those who were born to HIV-1-seropositive mothers but reverted to seronegative, and those who were seronegative throughout the study. During the 13-month period the incidence of malaria in the 36 children with HIV infection in whom AIDS developed was lower, although not significantly so, than in the 37 in whom AIDS did not. CONCLUSIONS. In this study malaria was not more frequent or more severe in children with progressive HIV-1 infection and malaria did not appear to accelerate the rate of progression of HIV-1 disease.     

Severe malaria in Gambian children is not due to lack of previous exposure to malaria.

The reasons why only a small proportion of African children infected with Plasmodium falciparum develop severe or fatal malaria are not known. One possible reason is that children who develop severe disease have had less previous exposure to malaria infection, and hence have less acquired immunity, than children who develop a mild clinical attack. To investigate this possibility we have measured titres of a wide range of anti-P. falciparum antibodies in plasma samples obtained from children with severe malaria, children with mild malaria and from children with other illnesses. Mean antibody levels in patients with malaria were higher than those in patients with other conditions but, with only one exception, there were no significant differences in antibody titres between cases of severe or mild malaria. A parasitized-erythrocyte agglutination assay was used to estimate the diversity of parasite isolates to which children had been exposed; plasma samples obtained from children with cerebral malaria recognized as many isolates as did samples obtained from children with mild disease. Our findings do not provide any support for the view that the development of severe malaria in a small proportion of African children infected with P. falciparum is due to lack of previous exposure to the infection.     

The changed clinical spectrum of malaria due to drug resistance

The clinical spectrum of 14 cases of Plasmodium falciparum malaria (PF) who received empirical treatment and suffered from initial prolonged mild illness culminating into severe complicated malaria are presented. The empirical treatment (ET) consisted of adequate doses of chloroquine in 9, chloroquine with pyrimethamine-sulphadoxine combination in 3 and pyrimethamine-sulphadoxine alone in 2 cases. Moderate fever and weakness persisted for 7 to 28 days leading to anaemia and progressive hepatosplenomegaly in all patients. Other clinical features noticed included jaundice in 5, sudden shock with pulmonary oedema in 4, cerebral malaria and renal failure in 3 each and multiorgan in 4 cases. Subsequent investigations revealed PF rings in 9 cases, mixed PF and vivax infection in 3 and PF gametocytaemia only in 2 patients. Seven patients received quinine, 4 quinine with doxycycline and 3 were given quinine followed by injection artemether. Exchange transfusion was carried out in two cases. Four patients died. The empirical treatment with first line antimalarials alters the clinical profile of resistant PF, makes it milder temporarily, delays in confirming the diagnosis and leads to high mortality. There is urgent need for more diligent early workup for these patients who linger on with moderate pyrexia, progressive hepatosplenomegaly, anaemia and jaundice after ET till better diagnostic methods are available to avoid the prolonged illness and high mortality.     

Ventricular fibrillation in a 5-year-old child on therapeutic dose of quinine dihydrochloride infusion for acute malaria

Malaria is no doubt a disease of public health significance in the tropics. Plasmodium falciparum resistant to majority of the first-line antimalarial drugs now causes most of the infections treated in sub-Saharan Africa. Although there is increasing use of artemisinin-based combination therapy in many African nations, quinine still remains a commonly used drug for severe and chloroquine-resistant malaria. Cardiotoxicity associated with quinine has been largely reported. However, this was often more common with toxic doses. This case report is on a 5-year-old African Nigerian who was on treatment for uncomplicated malaria with quinine dihydrochloride infusion. All the laboratory investigations done were within normal limits except for positive blood films for malarial parasites. However, pre-treatment electrocardiographic evaluation of the patient was not carried out. She developed ventricular fibrillation and died less than one and a half hour into the quinine infusion.     

Severe imported malaria in adults: a retrospective study of 32 cases admitted to intensive care units

INTRODUCTION: Few studies have focused on severe imported malaria in patients admitted to intensive care units. We, therefore, undertook a retrospective study in the University Hospital of Montpellier. MATERIAL AND METHODS: All patients, more than 15 years-old with falciparum malaria who were admitted to intensive care units between October 1997 and April 2004 were included. Main epidemiological features, criteria of admission, treatment and outcome were investigated. RESULTS: Thirty-two patients were included, representing 9% of falciparum malaria cases diagnosed in the same period. The mean age was 44 years. All patients acquired falciparum malaria in sub-Sahara Africa and 25 patients were nonimmune. Chemoprophylaxis was absent or inadequate in 94%. The mean time from symptom onset and treatment initiation was 6 days. Mean parasitemia on admission was 15%. Criteria of admission were impaired consciousness in 69%, acute renal failure in 19% and isolated high parasitemia in 19% of the cases. All, but one received quinine therapy and a loading dose was performed in 34%. Seven patients (22%) had community-acquired coinfections and six (19%) had nosocomial infections. Mortality was 16%. Causes of death were refractory shock, cerebral edema, and acute respiratory distress syndrome. CONCLUSION: Severe imported malaria remains associated with a bad outcome. Improving chemoprophylaxis and an earlier diagnosis may reduce significantly this mortality.     

The proper use of antimalarial drugs currently available

French medical practitioners have at their disposal several antimalarial drugs for giving chemoprophylaxis to people travelling to a malaria endemic country or treating an imported malaria case in a patient. The choice depends on the contre-indications and indications of each drug, essentially subordinated to the presence and level of Plasmodium falciparum chemosensitivity in the visited area. For prevention, chloroquine alone can be taken in the areas where P. falciparum is absent or not chloroquine resistant; elsewhere, the choice between chloroquine/proguanil or mefloquine depends on knowing the prevalence and level of falciparum chloroquine resistance in these areas. For treatment, the only indications of chloroquine are imported malaria cases either due to P. vivax, P. ovale or P. malariae, or caused by P. falciparum contracted in one of the rare countries where the species is still sensitive to chloroquine. For uncomplicated falciparum malaria cases acquired in a chemoresistance area, mefloquine, halofantrine, sulfadoxine-pyrimethamine or oral quinine is selected, depending on the observed chemoprophylaxis, the contra-indications and the suspicion of chemoresistance type. Whatever the provenance area, P. falciparum in a patient with one or several serious symptoms or possibly profuse vomiting is treated by intravenous quinine, associated with tetracycline if the patient comes from an area known for a low quinine sensitivity of this species. The spectrum of falciparum malaria treatment has recently broadened to include new drugs such as artemisinin, artemether or atovaquone/proguanil, the latter being as yet unauthorized in France.     

TNFalpha-308A associated with shorter intervals of Plasmodium falciparum reinfections

A mutation at position -308 of the tumor necrosis factor alpha (TNF-308A) gene promoter has previously been associated with particular manifestations of infectious and non-infectious diseases. In a longitudinal study on malariological parameters in Gabon, TNF promoter variants of 98 children initially presenting with severe Plasmodium falciparum malaria, followed by a total of 504 reinfection events within 52 months, and 100 children initially presenting with mild malaria followed by a total of 342 reinfections were analyzed. Symptomatic P. falciparum reinfections occurred more quickly (median 11 weeks) in carriers of the TNF-308A allele, with severe malaria at enrollment, compared to carriers of other TNF promoter variants (median 16 weeks). The results show that this particular TNF promoter allele increases the risk of reinfection with the malaria parasite P. falciparum.     

Cerebral malaria

Cerebral malaria is a rapidly progressive potentially fatal complication of Plasmodium falciparum infection. It is characterized by unarousable and persistent coma along with symmetrical motor signs. Children, pregnant women and non-immune adults are more susceptible to have cerebral malaria. Several clinical, histopathological and laboratory studies have suggested that cytoadherence of parasitized erythrocytes (mechanical hypothesis), and neuronal injury by malarial toxin and excessive cytokine (e.g. tissue necrosis factor-alpha) production (cytotoxic hypothesis) are possible pathogenic mechanisms. Several associated systemic complications like hypoglycemia, hypovolemia, hyperpyrexia, renal failure, bleeding disorders, anemia, lactic acidosis and pulmonary oedema may contribute in the pathogenesis of coma, and are responsible for high mortality. The meticulous supportive care along with intravenous administration of antimalarial drugs are corner-stone of the treatment. Quinine is currently, drug of choice. Artimisinin derivatives are equally effective and can be used by intramuscular route. In severe cases exchange blood transfusion may be an effective alternative. Corticosteroids has no place in the management of cerebral malaria. The occurrence of convulsions are common in children, these can be prevented with the use of single intramuscular administration of phenobarbitone. Despite advances in the management mortality and morbidity have not changed much. A large number of surviving patients are left with permanent neurological sequelae. There is a need to search for effective malaria prevention and interventional strategies to avert high mortality and morbidity associated with cerebral malaria.     

Low interleukin-12 activity in severe Plasmodium falciparum malaria

We compared interleukin-12 (IL-12) and other cytokine activities during and after an acute clinical episode in a matched-pair case-control study of young African children who presented with either mild or severe Plasmodium falciparum malaria. The acute-phase, pretreatment plasma IL-12 and alpha interferon (IFN-alpha) levels, as well as the acute-phase mitogen-stimulated whole-blood production capacity of IL-12, were significantly lower in children with severe rather than mild malaria. IL-12 levels, in addition, showed strong inverse correlations both with parasitemia and with the numbers of circulating malaria pigment-containing neutrophils. Acute-phase plasma tumor necrosis factor (TNF) and IL-10 levels were significantly higher in those with severe malaria, and the concentrations of both of these cytokines were positively correlated both with parasitemia and with the numbers of pigment-containing phagocytes in the blood. Children with severe anemia had the highest levels of TNF in plasma. In all the children, the levels in plasma and production capacities of all cytokines normalized when they were healthy and parasite free. The results indicate that severe but not mild P. falciparum malaria in young, nonimmune African children is characterized by down-regulated IL-12 activity, contrasting markedly with the up-regulation of both TNF and IL-10 in the same children. A combination of disturbed phagocyte functions resulting from hemozoin consumption, along with reduced IFN-gamma responses, may contribute to these differential effects.