Therapeutic response of multidrug-resistant Plasmodium falciparum and P. vivax to chloroquine and sulfadoxine-pyrimethamine in southern Papua, Indonesia

To determine the level of antimalarial drug resistance in southern Papua, Indonesia, we assessed the therapeutic efficacy of chloroquine plus sulfadoxine-pyrimethamine (CQ+SP) for Plasmodium falciparum infections as well as CQ monotherapy for P. vivax infections. Patients with P. falciparum failing therapy were re-treated with unsupervised quinine+/-doxycycline therapy and those with P. vivax with either unsupervised quinine+/-doxycycline or amodiaquine. In total, 143 patients were enrolled in the study (103 treated with CQ+SP and 40 with CQ). Early treatment failures occurred in four patients (4%) with P. falciparum and six patients (15%) with P. vivax. The failure rate by Day 28 for P. vivax was 65% (95% CI 49-81). After PCR correction for re-infections, the Day 42 recrudescence rate for P. falciparum infections was 48% (95% CI 31-65). Re-treatment with unsupervised quinine+/-doxycycline resulted in further recurrence of malaria in 48% (95% CI 31-65) of P. falciparum infections and 70% (95% CI 37-100) of P. vivax infections. Eleven patients with recurrent P. vivax were re-treated with amodiaquine; there were no early or late treatment failures. In southern Papua, a high prevalence of drug resistance of P. falciparum and P. vivax exists both to first- and second-line therapies. Preliminary data indicate that amodiaquine retains superior efficacy compared with CQ for CQ-resistant P. vivax.     

Sulfadoxine-pyrimethamine plus artesunate compared with chloroquine for the treatment of vivax malaria in areas co-endemic for Plasmodium falciparum and P. vivax: a randomised non-inferiority trial in eastern Afghanistan

Chloroquine (CQ) is an effective treatment of choice for vivax malaria in most settings, but with the spread of CQ-resistant Plasmodium falciparum, many countries now use artemisinin-based combination therapy for treatment of falciparum malaria. In areas co-endemic for falciparum and vivax malaria incorrect differential diagnosis is always a risk. In Afghanistan the adoption of sulfadoxine-pyrimethamine plus artesunate (SP+AS) as first-line falciparum treatment raises the prospect of a significant proportion of vivax malaria being misdiagnosed and treated with the combination. SP is considered to have limited efficacy against vivax malaria, and the efficacy of SP+AS against Plasmodium vivax has not been established in areas that are using SP+AS. A randomised, non-inferiority trial comparing SP+AS with CQ monotherapy was undertaken on 190 vivax malaria patients in eastern Afghanistan. Standard WHO procedures for in vivo evaluation of antimalarial drugs were followed. A total of 180 individuals completed the trial to day 42. Using a per protocol analysis, both regimens resulted in > or =96% treatment success at 28 d, but significantly more cases failed in the CQ arm (46%) than in the SP+AS arm (24%) by day 42. In areas where vivax infections might be misdiagnosed as falciparum infections and treated with SP+AS, patient management would be as good, or better than, with the standard CQ treatment.     

A qPCR-based multiplex assay for the detection of Wuchereria bancrofti, Plasmodium falciparum and Plasmodium vivax DNA

The purpose of this study was to develop real-time multiplex quantitative PCR (qPCR) assays for the simultaneous detection of Wuchereria bancrofti (Wb), Plasmodium falciparum (Pf) and P. vivax (Pv) in mosquitoes. We optimized the assays with purified DNA samples and then used these assays to test DNA samples isolated from Anopheles punctulatus mosquitoes collected in villages in Papua New Guinea where these infections are co-endemic. Singleplex assays detected Wb, Pf and Pv DNA in 32%, 19% and 15% of the mosquito pools, respectively, either alone or together with other parasites. Multiplex assay results agreed with singleplex results in most cases. Overall parasite DNA rates in mosquitoes, estimated by PoolScreen 2 software, for Wb, Pf and Pv were 4.9%, 2.7% and 2.1%, respectively. Parasite DNA rates were consistently higher in blood-fed mosquitoes than in host-seeking mosquitoes. Our results show that multiplex qPCR can be used to detect and estimate prevalence rates for multiple parasite species in arthropod vectors. We believe that multiplex molecular xenodiagnosis has great potential as a tool for non-invasively assessing the distribution and prevalence of vector-borne pathogens such as W. bancrofti and Plasmodium spp. in human populations and for assessing the impact of interventions aimed at controlling or eliminating these diseases.     

Quinine for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan

An observational clinical trial was conducted in New Halfa, eastern Sudan, in November and December 2003. Sixty-two patients with uncomplicated Plasmodium falciparum malaria were treated with oral quinine (10 mg/kg thrice daily for 7 d); 47 (76%) of these patients were followed-up to day 28, and 5 (10.6%) of them appeared to have late treatment failures. The parasitological failures were early R1 in two (4.3%) patients and late R1 in three (6.4%) patients. The reappearance of parasites in three of these five patients were true recrudescences rather than a re-infection, based on genetic evidence. The present results and those of earlier investigations indicate that the response to quinine in this area may be faltering.     

Retinal haemorrhage in vivax malaria

Retinal haemorrhage is often observed in patients with Plasmodium falciparum, especially when combined with cerebral malaria. However, few cases of retinopathy have been reported in P. vivax malaria. Benign tertian malaria has re-emerged among soldiers in the South Korean demilitarized zone since 1993. We report an indigenous case of retinal haemorrhage caused by P. vivax and review the relevant literature.     

Haematinic treatment of anaemia increases the risk of Plasmodium vivax malaria in pregnancy

Nutritional deficiency and malaria are 2 major causes of anaemia during pregnancy in tropical areas. The relationship between anaemia, its treatment with iron and folate, and malaria was studied in a prospective cohort of 2112 pregnant Karen women on the north-western border of Thailand between 1993 and 1997. The development of Plasmodium vivax malaria was associated with a past mean haematocrit > 30% (hazard ratio = 1.5, 95% CI 1.2-2, P = 0.001) and recent (< or = 30 d) iron and folate supplementation (hazard ratio = 1.7, 95% CI 1.1-2.6, P = 0.01). There were no associations with P. falciparum infections. Plasmodium vivax has a predilection for young erythrocytes, and these results suggest that pregnant women with larger numbers of circulating young red cells are at greater risk of developing P. vivax malaria. In P. vivax-endemic areas, systematic iron and folate supplementation confers both benefit and risk in pregnancy.     

Complications and mortality patterns due to Plasmodium falciparum malaria in hospitalized adults and children,Rourkela, Orissa,India

Of 1857 Plasmodium falciparum malaria patients hospitalized from 1995 to 1998, 608 had severe malaria and 83 died. Acute renal failure, jaundice and respiratory distress were common in adults whereas children frequently had severe anaemia. Cerebral malaria occurred equally in adults and children but recovery from coma was quicker in children. Multiple complications caused high mortality in adults.     

Acute respiratory distress syndrome in Plasmodium vivax malaria: case report and review of the literature

Plasmodium vivax infection can cause acute respiratory distress syndrome (ARDS). This complication of P. vivax infection is being increasingly recognised and was life threatening in a traveller returning from Gujarat, India. Nineteen other published cases of P. vivax with respiratory symptoms are also reviewed and confirm that ARDS was the underlying complication in most cases. Plasmodium vivax-associated ARDS is a clinically recognisable condition whose underlying pathophysiology is likely to reflect processes that are independent of parasite sequestration in the pulmonary microvasculature.     

Distribution of Plasmodium falciparum genotypes in clinically mild and severe malaria cases in Orissa, India

A cross-sectional study was conducted in a malaria hyperendemic state of India to ascertain the distribution of Plasmodium falciparum genotypes in patients with mild (n=40) and severe (n=35) malaria. PCR and nested PCR were used to determine the glutamate-rich protein (GLURP), merozoite surface proteins 1 and 2 (MSP1 and MSP2) and knob-associated histidine-rich protein (KAHRP) for characterization of the parasite. The results indicate that (i) the 200bp allele of the MAD20 family of MSP1 and the 550bp allele of the 3D7 family of MSP2 show over-representation in severe malaria cases; (ii) the multiplicity of infection with respect to MSP2 alleles is significantly higher (P<0.001) in severe cases than in mild cases; and (iii) comparison with the findings of other studies leads to the conclusion that the distribution of P. falciparum genotypes between different clinical groups differs geographically.     

Treatment of acute vivax malaria with tafenoquine

Tafenoquine is an 8-aminoquiniline related to primaquine with pre-clinical activity against a range of malaria species. We treated two acute cases of vivax malaria with tafenoquine (800 mg over three days) alone, instead of conventional chloroquine (1500 mg over three days) and primaquine (420 mg over 14 days). In addition to the convenience of this regimen, the rapid parasite clearances observed, coupled with a good clinical response and lack of recrudescence or relapse, indicate that further investigation of tafenoquine in the treatment of vivax malaria is warranted.     

Polyuria in association with Plasmodium falciparum malaria in a region of unstable transmission

During a recent epidemic of Plasmodium falciparum malaria in Hlabisa district, KwaZulu Natal, polyuria was recognized in a subset of adults presenting to hospital with severe disease. In January to May 2000, following consent, cases of severe malaria provided blood spots for HIV testing, clinical data, and blood and urine samples for investigation of the polyuria. Four hundred and eleven adults with malaria were admitted, of whom 175 had severe malaria and 37 had polyuria (21% of severe cases). In those with polyuria the mean 24-h urine output was 3018 ml or 2.85 ml/kg/h. Ten of 15 (66%) patients investigated had urine and plasma osmolalities consistent with diabetes insipidus. There was no significant association between polyuria and sex, age, HIV status or features of severe malaria. Whether the polyuria in these non-immune adults is a localized problem unrelated to malaria, or a hitherto unrecognized complication of severe malaria is not clear. Physicians are alerted to this observation, and the need for more clinical and pathophysiological studies.     

Efficacy of combined chloroquine and sulfadoxine-pyrimethamine in uncomplicated Plasmodium falciparum malaria in Bangladesh

A study of the therapeutic efficacy of combined chloroquine and sulfadoxine-pyrimethamine (SP) for the treatment of uncomplicated Plasmodium falciparum malaria was carried out from June to November 2002, using the standard protocol recommended by the WHO for a low-to-moderate transmission area, in two sentinel sites in Bangladesh: Alikadam Upazilla in Bandarban district and Matiranga Upazilla in Khagrachari district. A total of 133 patients was followed-up to 28 d. Total failure rates were 25.9 and 30.7% in Alikadam and Matiranga, respectively. No severe side effects due to the drugs were encountered during the study period. Chloroquine and SP is not a suitable combination for the first-line treatment of P. falciparum in Bangladesh.     

Estimates of short- and long-term incubation periods of Plasmodium vivax malaria in the Republic of Korea

With the current epidemic of vivax malaria closely associated with the demilitarised zone along the border between North and South Korea, it has been suggested that the incubation period tends, in part, to be prolonged. Based on the detailed travel history of cases from 2000 to 2003 who reside in non-malarious areas, statistical estimates of the incubation periods were obtained. The data suggest that cases fall into two categories with short- and long-term incubation periods, respectively. Of 416 cases with available information, 72 and 79 successfully met our criteria for inferring the durations of short- and long-term incubation periods. The mean short- and long-term incubation periods were estimated to be 26.6 days (95% CI 21.0-32.2) and 48.2 weeks (95% CI 46.8-49.5), respectively. The maximum likelihood method was used to fit gamma and normal distributions to the short- and long-term incubation periods, assisting prediction of the frequency distribution of the overall incubation period, which exhibited a bimodal pattern. We postulate that the observed distribution reflects adaptation of the parasite to the seasonal population dynamics of the vector, Anopheles sinensis, ensuring continued transmission of vivax malaria in this temperate zone.     

Risk of Plasmodium vivax malaria reintroduction in Uzbekistan: genetic characterization of parasites and status of potential malaria vectors in the Surkhandarya region

Plasmodium vivax malaria was eradicated from Uzbekistan in 1961. Due to resurgence of the disease in neighbouring states and massive population migration, there has been an increase of P. vivax malaria, imported from Tajikistan, resulting in a number of indigenous cases being identified in areas bordering that country. A molecular study using the merozoite surface protein 1 (msp-1) gene as a marker was performed on 24 P. vivax genomic isolates from 12 indigenous and 10 imported malaria cases that occurred in the Surkhandarya region during the summer of 2002. Results have shown a significant difference in the frequency of msp-1 types between indigenous and imported isolates, the latter showing greater genetic heterogeneity. An entomological investigation in the area suggested that three Anopheles species, namely A. superpictus, A. pulcherrimus and A. hyrcanus may have a potential role in the endemic transmission of P. vivax.     

Plasmodium falciparum serine repeat antigen 5 (SE36) as a malaria vaccine candidate

A devastating disease spread by mosquitoes with high-efficiency, malaria imposes an enormous burden for which no licensed vaccine currently exists. Although the genome complexity of the parasite has made vaccine development tenuous, an effective malaria vaccine would be a valuable tool for control, elimination and eventual eradication. The Plasmodium serine repeat antigen 5 (SERA5) is an abundant asexual blood stage antigen that does not show any antigenic variation and exhibits limited polymorphism, making it a suitable vaccine candidate. Identified by comparing the IgG status of people in endemic areas with protective immunity and those with malaria symptoms, the vaccine potential of the N-terminal domain of Plasmodium falciparum SERA5 is also strongly supported by experimental data and immune responses both measured in vitro and in animal challenge models. The current understanding of SERA5 will be presented, particularly in relation to its path towards clinical development. The review highlights lessons learned and sorts out issues upon which further research efforts are needed.     

Epidemic of Plasmodium falciparum malaria in Central India, an area where chloroquine has been replaced by artemisinin-based combination therapy

India contributes greatly to the global incidence of malaria. The factors influencing malaria in India are highly diverse and vary greatly from the epidemiological setting of any other country. Central India is the most vulnerable area to malaria in India. This study was carried out in three community health centres in Dindori District, Madhya Pradesh (Central India). Dindori District is mesoendemic for malaria, with both Plasmodium falciparum and P. vivax being present in all age groups. Anopheles culicifacies and A. fluviatilis are highly efficient vectors of malaria. In this study, an epidemic of malaria among indigenous ethnic group Baigas was investigated to determine the causes of the epidemic and the population involved in order to aid in disease containment. The existence of sporozoite-positive A. culicifacies and A. fluviatilis indicates either that spraying had not been done properly or the presence of insecticide resistance. A combination of factors propagated the epidemic. Evidence suggests that the non-availability of artemisinin-based combination therapy and rapid diagnostic tests along with an immunogenically vulnerable population each played an important role. As the global prevalence of malaria decreases owing to initiatives to control or eliminate the disease, more areas will become mesoendemic or hypoendemic for malaria. Detection and control of epidemics requires greater attention, and mechanisms to ensure the quality of interventions are essential.     

Targeting the human malaria parasite Plasmodium falciparum: in vitro identification of a new antiplasmodial hit in 4-phenoxy-2-trichloromethylquinazoline series

From the promising results we previously obtained in quinazoline series and to complete the evaluation of the in vitro antiplasmodial activity of original 2-trichloromethylquinazolines, we synthesized new quinazolines possessing a variously substituted phenoxy group at position 4 through a simple and efficient two-step-synthesis approach. The studies of their activity toward the multi-resistant W2 Plasmodium falciparum strain and of their cytotoxicity on the human hepatocyte HepG2 cell line highlighted a hit compound (molecule 7) displaying a W2 IC₅₀ value of 1.1 μM and a HepG2 CC₅₀ value of 50 μM, comparable to chloroquine and doxycycline. Structure-activity- and toxicity relationships indicate that the trichloromethyl group plays a key role in the antiplasmodial activity of such chemical scaffold and also that the phenoxy group substitution as a direct influence on the molecules selectivity. Moreover, molecule 7 displays significant specific activity against the Plasmodium genus in comparison with Toxoplasma and does not show any mutagenic property at the Ames test.