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.     

Blood glucose levels in Malawian children before and during the administration of intravenous quinine for severe falciparum malaria

Hypoglycemia may develop in patients with severe untreated malaria and can complicate the course of treatment with parenteral quinine as a result of quinine-induced hyperinsulinemia. Intravenous quinine is used increasingly as the therapy of choice in patients with severe malaria, most of whom are children. To assess the importance of both pretreatment and quinine-related hypoglycemia in children in an area in which the disease is endemic, we prospectively studied 95 Malawian children with falciparum malaria and altered consciousness who were treated with intravenous quinine. Nineteen patients had hypoglycemia before treatment. Seven (37 percent) died, and five of the survivors (26 percent) had neurologic sequelae. The corresponding values for patients who were initially normoglycemic were 4 percent and 4 percent, respectively (P less than 0.0001). Hypoglycemia was associated with low plasma insulin concentrations and with elevated plasma concentrations of lactate, alanine, and 5'-nucleotidase--a finding that suggests that impaired hepatic gluconeogenesis but not hyperinsulinemia contributes to the pathogenesis of pretreatment hypoglycemia. All patients were given quinine dihydrochloride in a 5 percent dextrose infusion, and those with hypoglycemia received 50 percent dextrose. Hypoglycemia recurred in seven of the patients with pretreatment hypoglycemia, but these episodes were also not associated with hyperinsulinemia. Of the 76 children who were initially normoglycemic, none became hypoglycemic during the course of treatment with intravenous quinine. We conclude that hypoglycemia is a frequent complication of falciparum malaria in children and that it reflects severe disease and is associated with a poor prognosis. We did not find it to be a complication of quinine treatment.     

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.     

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.     

Intravenous immunoglobulin in the treatment of paediatric cerebral malaria.

Hyperimmune globulin can inhibit and reverse the cytoadherence between Plasmodium falciparum-infected erythrocytes and melanoma cells in vitro. Cytoadherence is believed to mediate disease in cerebral malaria. Therefore we studied the efficacy of i.v. immunoglobulin, purified from the plasma of local semi-immune blood donors, as an adjunct to standard treatment for cerebral malaria in Malawian children. The immunoglobulin preparation (IFAT antimalarial antibody titre 1:5120) recognized erythrocyte-associated antigens of each of 22 Malawian P. falciparum isolates studied, and reversed binding of Malawian isolates to melanoma cells. Immunoglobulin did not reverse binding to human monocytes or to cells of the human histiocytic lymphoma cell line U937. Thirty-one children with P. falciparum parasitaemia and unrousable coma were enrolled. All were treated with i.v. quinine dihydrochloride; in addition patients were randomized to receive either immunoglobulin (400 mg/kg by i.v. infusion over 3 h) or placebo (albumen and sucrose by similar infusion) in a double blind trial with sequential analysis. Of 16 patients receiving immunoglobulin, five (31%) died and five survivors had neurological sequelae. Of 15 patients receiving placebo, one (7%) died and two had sequelae. Parasite clearance, fever clearance and coma resolution times in survivors were similar in the two groups. Although the difference in outcome between the two groups was not significant, the trial was stopped because immunoglobulin was demonstrated not to be superior to placebo.     

Transfusion-transmitted malaria in the United States from 1963 through 1999.

BACKGROUND: Transfusion-transmitted malaria is uncommon in the United States. After the report of three cases of complicated Plasmodium falciparum infection acquired by transfusion, we reviewed all cases of transfusion-transmitted malaria reported to the Centers for Disease Control and Prevention (CDC) from 1963 through 1999. METHODS: Information on the patients was from surveillance reports sent to the CDC. Information about the implicated blood donors came from the National Malaria Surveillance System. To determine whether donors should have been excluded from donating blood, we compared their characteristics with the exclusion guidelines of the Food and Drug Administration and the American Association of Blood Banks. RESULTS: Of 93 cases of transfusion-transmitted malaria reported in 28 states, 33 (35 percent) were due to P. falciparum, 25 (27 percent) were due to P. vivax, 25 (27 percent) were due to P. malariae, 5 (5 percent) were due to P. ovale, 3 (3 percent) were mixed infections, and 2 (2 percent) were due to unidentified species. Ten of the 93 patients (11 percent) died. There were potentially 91 donors (in two cases, two patients received blood from the same donor), 67 of whom (74 percent) could be identified as infective. Of 64 implicated donors whose country of origin was reported, 38 (59 percent) were foreign born. Among those for whom complete information was available, 37 of 60 donors (62 percent) would have been excluded from donating according to current guidelines (in place since 1994), and 30 of 48 donors (62 percent) should have been excluded under the guidelines in place at the time of donation. CONCLUSIONS: Careful screening of donors according to the recommended exclusion guidelines remains the best way to prevent transfusion-transmitted malaria.     

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.     

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.     

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.     

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.     

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.     

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.     

A case of successfully treated acute respiratory distress syndrome complicating Plasmodium falciparum malaria

While endemic malaria has been eliminated in the United States, approximately 1200 mostly imported cases are reported annually in the country, with fewer than 20 recorded deaths. Because of the rarity of this disease in the United States, clinicians are often unfamiliar with its diagnosis and presentation. In a review of all malaria deaths in the United States from 1963 to 2001, failure to diagnose malaria on initial presentation, promptly initiate treatment, and/or prescribe appropriate antimalarial drugs were identified as contributing factors to death. Plasmodium falciparum can lead to a particularly severe type of malaria complicated by acute respiratory distress syndrome (ARDS), and physicians must be alert to the possibility of this diagnosis in immigrants and returning travelers. We report a case of successfully treated acute respiratory distress syndrome complicating imported P falciparum malaria at a large teaching hospital in Washington, DC.     

Exchange transfusion in complicated pediatric malaria: A critical appraisal

Complicated falciparum malaria is a killer disease resulting in high mortality in spite of appropriate treatment. Some workers have reported improved survival when adjunct exchange blood transfusion is included in the treatment modality while others opine against it. This review is an effort to address and critically appraise current evidence for the treatment mode for severe malaria. The literature was searched with a specified search strategy to identify reports of children who underwent exchange transfusion for severe malaria. Total 23 children who underwent exchange transfusion for severe falciparum malaria published by 9 authors were identified. Age ranged from 5 months to 16 years with a mean age of 6.4 years. The average preprocedure parasite index (PI) was 41.4% (95confidence interval [CI]; 31.2-51.4). The average blood volume exchanged was 118.6% (95% CI; 94.7-143) of the circulating blood volume. The average postexchange reduction in PI was 34.1% (95% CI; 25.4-42.8). Three out of 23 children encountered some complications. All the children survived     

Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls

Inflammatory cytokines play an important role in human immune responses to malarial disease. However, the role of these mediators in disease pathogenesis, and the relationship between host protection and injury remains unclear. A total of 248 cases of severe Plasmodium falciparum malaria among children aged 3 months to 14 years residing in Bandiagara, Mali, were matched to cases of uncomplicated malaria and healthy controls. Using modified World Health Organization criteria for defining severe malaria, we identified 100 cases of cerebral malaria (coma, seizure, and obtundation), 17 cases of severe anemia (hemoglobin, <5 g/dl), 18 cases combined cerebral malaria with severe anemia, and 92 cases with hyperparasitemia (asexual trophozoites, >500,000/mm3). Significantly elevated levels (given as geometric mean concentrations in picograms/milliliter) of interleukin-6 (IL-6; 485.2 versus 54.1; P = <0.001), IL-10 (1,099.3 versus 14.1; P = <0.001), tumor necrosis factor alpha (10.1 versus 7.7; P = <0.001), and IL-12(p70) (48.9 versus 31.3; P = 0.004) in serum were found in severe cases versus healthy controls. Significantly elevated levels of IL-6 (485.2 versus 141.0; P = <0.001) and IL-10 (1,099.3 versus 133.9; P = <0.001) were seen in severe malaria cases versus uncomplicated malaria controls. Cerebral malaria was associated with significantly elevated levels of IL-6 (754.5 versus 311.4; P = <0.001) and IL-10 (1,405.6 versus 868.6; P = 0.006) compared to severe malaria cases without cerebral manifestations. Conversely, lower levels of IL-6 (199.2 versus 487.6; P = 0.03) and IL-10 (391.1 versus 1,160.9; P = 0.002) were noted in children with severe anemia compared to severe malaria cases with hemoglobin at >5 g/dl. Hyperparasitemia was associated with significantly lower levels of IL-6 (336.6 versus 602.1; P = 0.002). These results illustrate the complex relationships between inflammatory cytokines and disease in P. falciparum malaria.     

Generation of reactive oxygen species by blood monocytes in human Plasmodium falciparum and P. vivax infections

Generation of reactive oxygen radicals by peripheral blood monocytes was measured by luminol-dependent chemiluminescence in 23 P. vivax- and 7 P. falciparum-infected patients. The chemiluminescence index (CLI) was not found to be significantly higher in P. vivax-infected cases than in healthy controls. But in patients with P. falciparum infection, the CLI was significantly higher compared to controls as well as to P. vivax-infected patients. In two severe and complicated P. falciparum-infected cases, CLI was found to be higher than in mild cases. As immunosuppression is more marked in falciparum malaria than in vivax cases, the role of oxygen radical generation in immunopathology and causation of immunosuppression in falciparum malaria needs further investigation.     

Mannose-binding lectin is a disease modifier in clinical malaria and may function as opsonin for Plasmodium falciparum-infected erythrocytes

Variant alleles in the mannose-binding lectin (MBL) gene (mbl2) causing low levels of functional MBL are associated with susceptibility to different infections and are common in areas where malaria is endemic. Therefore, we investigated whether MBL variant alleles in 551 children from Ghana were associated with the occurrence and outcome parameters of Plasmodium falciparum malaria and asked whether MBL may function as an opsonin for P. falciparum. No difference in MBL genotype frequency was observed between infected and noninfected children or between children with cerebral malaria and/or severe malarial anemia and children with uncomplicated malaria. However, patients with complicated malaria who were homozygous for MBL variant alleles had significantly higher parasite counts and lower blood glucose levels than their MBL-competent counterparts. Distinct calcium-dependent binding of MBL to the membrane of P. falciparum-infected erythrocytes, which could be inhibited by mannose, was observed. Further characterization revealed that MBL reacted with a P. falciparum glycoprotein identical to the 78-kDa glucose-regulated stress protein of P. falciparum. MBL seems to be a disease modifier in clinical malaria and to function as an opsonin for erythrocytes invaded by P. falciparum and may thus be involved in sequestration of the parasite, which in turn may explain the association between homozygosity for MBL variant alleles and high parasite counts.     

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.     

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.