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The use of exchange transfusions: a potentially useful adjunct in the treatment of fulminant falciparum malaria.

Fulminant falciparum malaria with greater than 500,000/mm3 parasites in the peripheral blood portends a poor prognosis. We recently managed a patient who had greater than 1.2 million/mm3 parasitized erythrocytes in her peripheral blood, following initially inadequate antimalarial therapy, with exchange transfusion in addition to conventional chemotherapy. This patient recovered from her disease despite severe cerebral involvement and acute failure. We feel that exchange transfusion was a useful adjunct and should be considered in patients with life threatening falciparum malaria when conventional measures fail to control the disease.

Adult

The treatment of severe falciparum malaria.

In severe falciparum malaria there is a pathophysiological cascade beginning with changes in the parasitized red blood cells which induce intermediate effects, in turn contributing to dysfunction of several organs. A low serum albumin is a common but often unrecognized finding which may contribute to oedema especially in the lung and brain. The only irreversible complication in falciparum malaria is the acute respiratory distress syndrome, manifested by cyanosis and rapid breathing, basically distinct from acute pulmonary oedema caused by therapeutic overhydration. The pathophysiology of falciparum malaria may be complex but the treatment is simple. Drugs, other than antimalarials, are rarely needed. Guidelines for cholorquine or quinine dosage in severe disease are proposed; each drug is given at a dose of 5 to 10 mg/kg in 10 ml/kg of fluid as an intravenous infusion in four hours at a frequency of dosing every 12 to 24 hours. When the disease has been brought under control the treatment should be changed from the intravenous to the oral route.

Adult

Sequential treatment with quinine and mefloquine or quinine and pyrimethamine-sulfadoxine for falciparum malaria.

Patients with falciparum malaria were studied in Thailand, an area of known chloroquine resistance. The patients were unselected and some had severe malaria, and they were randomly assigned to one of two sequential regimes. A short course of quinine (average 4 doses, equivalent to 2 g base) followed by a single dose of pyrimethamine-sulfadoxine (Fansidar) cured 92% of patients (36 out of 39), while a short course of quinine followed by a single 1-5-dose of mefloquine cured all of the 35 patients who could be followed up. Gastrointestinal side effects were minimal if at least 12 hours elapsed between the last dose of quinine and the mefloquine. Sequential quinine and mefloquine is the most effective treatment for patients with chloroquine-resistant falciparum malaria, including those with severe or complicated disease. Mefloquine, however, is not commercially available, and the similar regimen using Fansidar is almost as effective.

Adolescent

Lymphocyte mitogenic factor in sera from patients with falciparum malaria.

To test for the presence of a lymphocyte mitogenic factor in malaria, sera were obtained from 10 patients with malaria (9 with falciparum and one with vivax), and 10 noninfected controls. The sera from the malarial patients caused an increased blastogenesis in mouse splenic lymphocyte cultures and inhibited hemagglutination between lipid-A-coated erythrocytes and lipid-A antibodies. None of the sera were positive using the limulus amebocyte lysate test. These results could be interpreted to demonstrate that patients with falciparum malaria have a circulating mitogen which cross-reacts with endotoxin. However, alternate explanations must be considered, including an hypothesis that antiglobulins and/or immune complexes in the sera of malarious patients both caused the blastogenesis of mouse spleen cells and inhibited hemagglutination to lipid-A antibodies.

Adult

Longitudinal malaria studies in rural Northeast Thailand. Chloroquine treatment of falciparum malaria infections.

The efficacy of chloroquine in the treatment of falciparum malaria was studied in two villages in Northeast Thailand, an area endemic for chloroquine-resistant falciparum infections. Chloroquine did not appear to reduce the duration or density of parasitemias experienced by asymptomatic villagers, but did benefit, usually temporarily, many subjects with symptomatic or high-density infections. These observations suggest that the high prevalence of chloroquine-resistant infections in the villages is similar to data from the hospital and clinics serving the area. The question whether chloroquine should remain available to this population should be evaluated.

Adult

Chloroquine-resistant Plasmodium falciparum malaria in Kenya.

A case of chloroquine-resistant Plasmodium falciparum malaria in a non-immune male is reported. Primary attack came 19 days after return to a non-malarious country from a visit to Kenya. Recrudescences occurred three times with intervals of 30 to 33 days after standard chloroquine treatment. The WHO extended field test for sensitivity of falciparum malaria to chloroquine was followed by recrudescence 31 days later. Treatment with Fansidar terminated the infection. If continuous treatment of the patient with lithium does not interfere with the schizontocidal action of chloroquine, this strain shows a resistance pattern of R I delayed recrudescence.

Adult

Amodiaquine resistant falciparum malaria in Thailand.

Amodiaquine cured 38% (13/34) of patients with falciparum malaria in Southeast Thailand. Chloroquine cured 0% (0/13). The cure rates with amodiaquine were the same whether a 1.5 g or 2.0 g course was used. Most patients were resistant to amodiaquine at the RI level and to chloroquine at the RII level. In hospital, amodiaquine cleared parasitemia more frequently than did chloroquine. With the 2.0 g course of amodiaquine, the parasite clearance time was 77 hours; the fever clearance time of 36 hours was low and suggests that amodiaquine does not cause a drug fever. Because of resistance, chloroquine should not be used for falciparum malaria in Thailand. Routine use of amodiaquine is not indicated because more effective drugs are available.

Administration, Oral

Haemostatic defect in non-immune patients with falciparum malaria: no evidence of diffuse intravascular coagulation.

Nine non-immune patients with imported falciparum malaria were examined for signs of diffuse intravascular coagulation (DIC). Although all had thrombocytopenia initially and some later had a decline in plasma fibrinogen concentrations, DIC was never detected, even in severely affected patients with coma and kidney damage. None of the patients were given heparin and all recovered without residual symptoms. Heparin administration should probably be considered only when clear-cut DIC, which possibly never occurs in falciparum malaria, has been demonstrated.

Blood Coagulation Tests

Direct Coombs antiglobulin reactions in Gambian children with Plasmodium falciparum malaria. I. Incidence and class specificity.

Gambian children with past or present Plasmodium falciparum malaria were investigated for the incidence of Coombs positivity using monospecific antisera. Approximately 50% were positive and the most frequent form of erythrocyte sensitization was with C3d. Other specificities, EIgG, EIgGC3d and EIgGC4bC3d were less common. Erthyrocytes were never found sensitized with IgA or IgM. There was no correlation between a positive test and age, tribal status or level of parasitaemia at presentation, although a positive test was often found in association with anaemia. Sensitized erythrocytes were present in the circulation for a period of up to 6 weeks following initial observation. The mechanism of erythrocyte sensitization is not known, but the results suggest a Type III complex-mediated hypersensitivity involving parasite antigen-antibody complexes. It is likely that these reactions contribute to the pathogenesis of the anaemia in falciparum malaria.

Anemia

Chloroquine-resistant falciparum malaria in East Kalimantan, Indonesia.

Following the discovery of four imported chloroquine-resistant P. falciparum infections in the Province of Yogyakarta (Island of Java) sensitivity tests were carried out in the Province of East Kalimantan Island of Borneo). Twenty subjects were given 25 mg. of chloroquine base per kilogram of body weight over three days. Two infections were found resistant at the RII level and a third at the RI level with early recrudescence on day 7. In the other 17 cases followed up to day 21, six were found again with asexual parasites between day 9 and day 14 and a seventh on day 21. These results confirm the presence of chloroquine resistance in P. falciparum in East Kalimantan and, together with previous findings, suggest a widespread distribution of chloroquine-resistant falciparum malaria in this Province of Indonesia. It is particularly interesting to note that chloroquine-resistant falciparum malaria has now been detected in almost all the area of dispersion of A. balabacensis.

Adolescent

Falciparum malaria in seamen.

Three cases of Plasmodium falciparum malaria in seamen, all acquired while working off tropical West Africa, and all in patients coming in for treatment at a New Orleans hospital during one six-week period, are described in the context of the importance of considering recent travel history for arrival at the correct diagnosis and treatment. Two of the three patients whose cases are reported had taken some form of malarial chemoprophylaxis during their voyage.

Adult

Chemotherapy of falciparum malaria: regional differences in responsiveness to treatment.

A review of chloroquine and sulfa-antifol combination treated falciparum malaria patients revealed a high incidence of chloroquine-resistance, wither R1 or R2, in patients infected in Southeast Asia or Oceania. In addition, more than one tenth of the patients infected in Laos or Thailand were resistant to sulfa-antifol combinations. Chloroquine-resistant cases were sensitive to sulfa-antifol combinations. On the other hand, while all patients treated in Tokyo who had been infected in Africa or Sri Lanka were sensitive to chloroquine, a field study suggested the presence of chloroquine-resistant P. falciparum in the area near Kaduna, Nigeria. One patient infected in Nigeria showed partial resistance to the MP (sulfamonomethoxine-pyrimethamine) combination, and another patient infected in the Central African Empire showed resistance to the MP combination, increasing from R1 to R3 within a short period. The incidence of resistance to sulfa-antifol combination therapy was high in the West African tropical region. The continent, county and area of infection should be taken in consideration when selecting antimalarial drug(s) for the treatment and suppression of falciparum malaria.

Adult

A prospective study of the effects of ultralow volume (ULV) aerial application of malathion on epidemic Plasmodium falciparum malaria. IV. Epidemiologic aspects.

In the Miragoane Valley of Haiti a consistent pattern in the incidence of Plasmodium falciparum malaria over a 10-year period made it possible to predict an annual outbreak and perform a prospective study to test the effects of aerial ultralow volume (ULV) malathion on epidemic levels of this disease. At the end of October 1972, after epidemic levels (100 cases/month/10,000 population) had been reached, spray operations were begun. The first spray cycle produced a sharp and immediate drop in populations of the vector Anopheles albimanus, followed 4 weeks later by a decrease in the incidence of malaria throughout the valley. Although the incidence of malaria was similar in sprayed and unsprayed areas prior to the effect of ULV malathion (176.1 and 198.7 cases/month/10,000 population, respectively), it was significantly different during the subsequent 3 months (16.8 cases/month/10,000 population in sprayed areas and 65.4 in unsprayed; p less than 0.001). Travel histories indicated that only 4% of all cases had spent a night away from home during the 4 weeks prior to onset of symptoms; therefore, we concluded that these incidence data represent malaria transmission in the valley. Results of the study indicate that aerial spraying of ULV malathion can interrupt epidemic transmission of P. falciparum malaria by a susceptible vector.

Adolescent

Artemether-lumefantrine for the treatment of Plasmodium falciparum malaria in Laos: a therapeutic efficacy study coupled with genomic and in vitro phenotypic analyses.

BACKGROUND: Artemisinin-based combination therapies (ACTs) have played a crucial role in decreasing the impact of malaria worldwide. Since 2005, artemether-lumefantrine (AL) has been the main first-line treatment for uncomplicated Plasmodium falciparum malaria in Laos. Herein, we aimed to study the efficacy of AL in the context of malaria elimination in Laos. METHODS: Between Aug 1, 2019, and June 11, 2023, AL efficacy was evaluated in four provinces of southern Laos: Attapeu, Champassack, Salavan, and Savannakhet. Adults and children (aged 1-60 years) with microscopically confirmed P falciparum malaria received oral AL twice a day for 3 days, with follow-up on days 7, 14, 21, and 28. The primary outcome was PCR-adjusted adequate clinical and parasitological response (ACPR) by day 28. Resistance to dihydroartemisinin (DHA) and lumefantrine (LM) was assessed by an in vitro phenotypic analysis, and mutations in P falciparum kelch13 (pfkelch13), P falciparum multidrug resistance 1 (pfmdr1), P falciparum plasmepsin 2 (pfpm2), and P falciparum chloroquine resistant transporter (pfcrt) were characterised in parasites collected from enrolled patients. Safety outcomes included the frequency and nature of adverse events and serious adverse events. FINDINGS: A total of 198 patients (median age 16 years [IQR 10-28]; 124 [63%] male and 74 [37%] female) were initially enrolled, of whom three were lost to follow-up, resulting in 195 patients who received the 3-day AL regimen. At day 28, the PCR-adjusted ACPR was 96% (95% CI 92-98), with a treatment failure rate of 2% (1-5) and a reinfection rate of 2% (1-5). Among the four PCR-confirmed recrudescent isolates, one showed markedly reduced LM susceptibility (LM 50% inhibitory concentration [IC50] 59·9 nM, 2·5 times higher than the median IC50 of other isolates) and high artemisinin resistance in vitro (ring-stage survival survival rate 35·8%), which was associated with the pfkelch13 R539T mutation and day-3 microscopy-positive parasitaemia. Among 190 isolates with successfully determined pfkelch13 sequencing, nine (5%) carried the pfkelch13 mutation R539T and 43 (23%) carried the C580Y mutation, and both were associated with day-3 microscopy-positive parasitaemia (p=0·044). No amplification of pfmdr1 or pfpm2, nor any mutations in pfmdr1 and pfcrt, were associated with treatment failure. INTERPRETATION: Our findings indicate the potential emergence of LM resistance in Laos. Although AL remains efficacious, vigilance for decreasing efficacy and close monitoring of LM efficacy should be considered to support the country's goal of eliminating malaria by 2030. Importantly, none of the known pfmdr1 or pfcrt haplotypes were uniquely associated with treatment failure, including the isolate with the highest LM IC50, underscoring the need to identify reliable molecular markers for LM resistance. FUNDING: Bill and Melinda Gates Foundation and The Global Fund.

Humans

Frequency of blood group antigens in Nigerian children with falciparum malaria.

The frequencies of the following blood group antigens: A, B, O, M, N, S, s, U, Fya, FyB, Lea, Jsa and K have been determined in Nigerian children with severe falciparum malaria. The frequency distribution of M, N, S, s, U, Fya and Fyb were not significantly different in children with life-threatening falciparum malaria and controls. The frequencies of A, B, O, Lea, Jsa and K found in the children with severe malaria were similar to those previously reported for healthy adults in this population. The Duffy blood group antigens Fya and Fyb were virtually absent from both infected and control children. This finding is in variance with a Fya frequency of 23% reported by Worlledge et al. (1974) for healthy adults in this population.

ABO Blood-Group System

Fatal falciparum malaria among narcotic injectors.

Eleven narcotic injectors from a prison in Saigon were hospitalized with falciparum malaria. Coma and intense parasitemia were common and eight patients died soon after admission. Two of three autopsied cases also had purulent pulmonary infections. No non-addicted prisoners were hospitalized for malaria. Nine more unsuspected falciparum infections were found among 29 other addicts in the prison. The clustering of malaria infections among narcotic injectors who had not been in malarious areas indicates that the malaria was transmitted by the common use of needles and syringes. Cerebral malaria in an addict may be misdiagnosed as drug intoxication. Malaria surveillance is recommended for the increasing addict population in the cities of Southeast Asia.

Adolescent

A prospective study of the effects of ultralow volume (ULV) aerial application of malathion on epidemic Plasmodium falciparum malaria. I. Study design and perspective.

A large-scale prospective study was designed to test the effects of aerial ultralow volume (ULV) application of malathion on epidemic Plasmodium falciparum malaria. The study was conducted during 1972 to 1973, in the Miragoane Valley of Haiti, an area having annual anticipated outbreaks of malaria, which allowed prospective assessment. Spraying of malathion at a dosage of 4.5 fluid ounces per acre reduced populations of adult Anopheles albimanus to less than 1% of prespray levels and interrupted epidemic transmission of P. falciparum malaria. No change was measured in susceptibility of the vector mosquito to malathion after six applications of spray during a period of 50 days. Ecologic study revealed no significant impact on nontarget vertebrates. Factors that contributed to the success of this method in Haiti were: 1) a susceptible population of mosquitoes; 2) suitable topography and climate conditions for spraying; and 3) treatment of an area sufficiently large to minimize the influence of immigration of mosquitoes from unsprayed areas.

Aircraft