Plasmodium knowlesi is now added to the known four Plasmodium species (P.vivax, P.falciparum, P.malariae, P.ovale) as a cause of malaria in humans because of the recent increasing rate of cases reported from countries of southeastern Asia. P.knowlesi which infects macaque monkeys (Macaca fascicularis and M.nemestrina) is transmitted to humans especially by Anopheles leucosphyrus and An.hackeri mosquitos. First human cases of P.knowlesi malaria have been detected in Malaysia which have reached high numbers in recent years and also have been reported from countries of Southeast Asia such as Thailand, Philippines, Myanmar, Singapore and Vietnam. However the number of cases reported from western countries are rare and limited only within voyagers. This report is the first presentation of an imported case of P.knowlesi malaria in Turkey and aims to draw attention to the point that it could also be detected in future. A 33-year-old male patient from Myanmar who has migrated to Turkey as a refugee, was admitted to a health center with the complaints of fever with a periodicity of 24 hours, headache, fatigue, cough, sore throat, anorexia, myalgia and arthralgia. He was prediagnosed as upper respiratory tract infection, however because of his periodical fever and background in Myanmar, thick and thin blood films were prepared and sent to our laboratory for further examinations. Microscopic examination of the thin blood films revealed erythrocytic stages compatible with P.knowlesi (three large early trophozoites in an erythrocyte, three late trophozoites with compact view, and three late band-form trophozoites). Upon this, both real-time polymerase chain reaction (Rt-PCR) targeting the small subunit ribosomal RNA (SSU-rRNA) genes of Plasmodium genus and DNA sequence analysis targeting P.knowlesi rRNA gene were performed. As a result, the suspected identification of P.knowlesi by microscopy was confirmed by Rt-PCR and DNA sequencing. The patient was treated with chloroquine and primaquine combination and in the follow-up on the seventh day after the treatment, his parasitemia and symptoms had ceased. Although there were some previous reports concerning about imported patients infected with different Plasmodium species in our country, no cases of P.knowlesi have been reported. This first case presented here emphasizes the occurence of P.knowlesi malaria in Turkey hereinafter due to the increasing number of refugees.
Treatment Failure with chloroquine is one of the challenges that faced the dedicated efforts to eradicate malaria This study aims at investigating the impact of treatment failure with chloroquine on the progression of the disease-induced histo-pathogenic and immunogenic outcomes. To achieve this, Rane's protocol with modifications was applied on a model of Plasmodium berghei ANKA infected ICR mice to determine the dose response curve of chloroquine and to screen the treatment impact on the disease progression. Chloroquine was given at 1, 5, 10, 15 and 20 mg/kg once the parasitemia reached to 20-30% (the experimental initiation point). During the subsequent days, the mice were monitored for changes in the clinical signs, hematology parameters and the progress of the parasitemia until the parasitemia reached to 60-70% (the experimental termination point) or up to 10 days after chloroquine administration in case of achieving a complete eradication of the parasite. At the end, the mice were exsanguinated and their blood and organs were collected for the biochemistry and the histology study. A complete eradication of the parasite was achieved at 20 mg/kg while recrudescence was observed at the lower doses. At 1 mg/kg, the parasite growth was comparable to that of the positive control. The histo-pathogenic and immunogenic changes were stronger in the groups that experienced recrudescence (at 5 and 10 mg/kg). All in all, the study highlights the possibility of having a worsened clinical condition when chloroquine is given at its sub-therapeutic doses during malaria treatment.
CYP2A6 gene encodes the principal enzyme involved in the metabolism of many drugs including artesunate. We developed a simplified duplex nested PCR method for the detection of the CYP2A61B, CYP2A62, CYP2A64, CYP2A67, CYP2A68 and CYP2A69 variant alleles highly prevalent among Malaysian population.
The simian parasite Plasmodium knowlesi causes severe human malaria; the optimal treatment remains unknown. We describe the clinical features, disease spectrum, and response to antimalarial chemotherapy, including artemether-lumefantrine and artesunate, in patients with P. knowlesi malaria diagnosed by PCR during December 2007-November 2009 at a tertiary care hospital in Sabah, Malaysia. Fifty-six patients had PCR-confirmed P. knowlesi monoinfection and clinical records available for review. Twenty-two (39%) had severe malaria; of these, 6 (27%) died. Thirteen (59%) had respiratory distress; 12 (55%), acute renal failure; and 12, shock. None experienced coma. Patients with uncomplicated disease received chloroquine, quinine, or artemether-lumefantrine, and those with severe disease received intravenous quinine or artesunate. Parasite clearance times were 1-2 days shorter with either artemether-lumefantrine or artesunate treatment. P. knowlesi is a major cause of severe and fatal malaria in Sabah. Artemisinin derivatives rapidly clear parasitemia and are efficacious in treating uncomplicated and severe knowlesi malaria.
The goal to eliminate malaria from the Asia-Pacific by 2030 will require the safe and widespread delivery of effective radical cure of malaria. In October 2017, the Asia Pacific Malaria Elimination Network Vivax Working Group met to discuss the impediments to primaquine (PQ) radical cure, how these can be overcome and the methodological difficulties in assessing clinical effectiveness of radical cure. The salient discussions of this meeting which involved 110 representatives from 18 partner countries and 21 institutional partner organizations are reported. Context specific strategies to improve adherence are needed to increase understanding and awareness of PQ within affected communities; these must include education and health promotion programs. Lessons learned from other disease programs highlight that a package of approaches has the greatest potential to change patient and prescriber habits, however optimizing the components of this approach and quantifying their effectiveness is challenging. In a trial setting, the reactivity of participants results in patients altering their behaviour and creates inherent bias. Although bias can be reduced by integrating data collection into the routine health care and surveillance systems, this comes at a cost of decreasing the detection of clinical outcomes. Measuring adherence and the factors that relate to it, also requires an in-depth understanding of the context and the underlying sociocultural logic that supports it. Reaching the elimination goal will require innovative approaches to improve radical cure for vivax malaria, as well as the methods to evaluate its effectiveness.
One hundred and ten consecutive patients with falciparum malaria were treated with Fansidar and primaquine. Of the 61 patients who were followed up at one week, 4 (6.5%) failed to clear their parasitemia (1 R III and 3 R Il treatment failures). Of the subsequent 40 patients who were seen again at one month, another 3 (7.5%) had recrudesced (R 1 treatment failure). A total of 7 patients thus experienced some form of treatment failure in the cohort of 40 who completed the one month follow up. Only 1 of these 7patients (with R III treatment) failure) failed to respond to repeat Fansidar treatment, and may be the only one with true Fansidar resistance. The overall treatment failure rate of 17.5% (95% confidence interval: 6-29%) in the cohort who completed the study is consistent with the known clinical efficacy of Fansidar. These results suggest no significant Fansidar resistance in falciparum malaria found in Sabah.
One hundred and ten consecutive patients with falciparum malaria were treated with Fansidar and primaquine. Of the 61 patients who were followed up at one week, 4 (6.6%) failed to clear their parasitaemia (1 R III and 3 R II treatment failures). Of the subsequent 40 patients who were seen again at one month, another 3 (7.5%) had recrudesced (R I treatment failure). A total of 7 patients thus experienced some form of treatment failure in the cohort of 40 who completed the one month follow up. Only 1 of these 7 patients (with R III treatment failure) failed to respond to repeat Fansidar treatment, and may be the only one with true Fansidar resistance. The overall treatment failure rate of 17.5% (95% confidence interval: 6-29%) in the cohort who completed the study is consistent with the known clinical efficacy of Fansidar. These results suggest no significant Fansidar resistance in falciparum malaria found in Sabah.
Malaria, one of the most deadly diseases of our time affects more than 200 million people across the globe and is responsible for about one million deaths annually. Until recently Plasmodium falciparum has been the main cause for malarial infection in human beings but now Plasmodium knowlesi from Malaysia remains as one of the most virulent parasite spreading fast not only in Malaysia but in different parts of the world. Hence there is urgent need for the global fight to control malaria. Global malaria eradication program by use of insecticide spraying has resulted in good response in the past. Treatment of malaria infected patients with anti-malarial drugs has helped to eliminate malarial infections successfully but with increased resistance displayed by malarial parasites to these drugs there is resurgence of malaria caused both by drug resistance as well as by infection caused by new malarial species like Plasmodium knowlesi. With recent advances on molecular studies on malarial parasites it is now clear that the pineal hormone melatonin acts as a cue for growth and development of Plasmodium falciparum. Same may be true for Plasmodium knowlesi also. Hence treatment modalities that can effectively block the action of melatonin on Plasmodium species during night time by way of using either bright light therapy or use of melatonin receptor blocking can be considered as useful approaches for eliminating malarial infection in man.
Malaria remains a global health problem affecting more than 515 million people all over the world including Malaysia. It is on the rise, even within unknown regions that previous to this were free of malaria. Although malaria eradication programs carried out by vector control programs are still effective, anti-malarial drugs are also used extensively for curtailing this disease. But resistance to the use of anti-malarial drugs is also increasing on a daily basis. With an increased understanding of mechanisms that cause growth, differentiation and development of malarial parasites in rodents and humans, new avenues of therapeutic approaches for controlling the growth, synchronization and development of malarial parasites are essential. Within this context, the recent discoveries related to IP3 interconnected signalling pathways, the release of Ca2+ from intracellular stores of Plasmodium, ubiquitin protease systems as a signalling pathway, and melatonin influencing the growth and differentiation of malarial parasites by its effects on these signalling pathways have opened new therapeutic avenues for arresting the growth and differentiation of malarial parasites. Indeed, the use of melatonin antagonist, luzindole, has inhibited the melatonin's effect on these signalling pathways and thereby has effectively reduced the growth and differentiation of malarial parasites. As Plasmodium has effective sensors which detect the nocturnal plasma melatonin concentrations, suppression of plasma melatonin levels with the use of bright light during the night or by anti-melatonergic drugs and by using anti-kinase drugs will help in eradicating malaria on a global level. A number of patients have been admitted with regards to the control and management of malarial growth. Patents related to the discovery of serpentine receptors on Plasmodium, essential for modulating intra parasitic melatonin levels, procedures for effective delivery of bright light to suppress plasma melatonin levels and thereby arresting the growth and elimination of malarial parasites from the blood of the host are all cited in the paper. The purpose of the paper is to highlight the importance of melatonin acting as a cue for Plasmodium faciparum growth and to discuss the ways of curbing the effects of melatonin on Plasmodium growth and for arresting its life cycle, as a method of eliminating the parasite from the host.
Goniothalamus scortechinii, Andrographis paniculata and Aralidium pinnatifidum were selected for the study based on their ethnomedicinal values. They were screened for anti-malarial activity towards Plasmodium falciparum in vitro using the lactate dehydrogenase (LDH) assay. The crude extract of G. scortechinii exhibited the most potent schizonticidal activity compared to the other extracts. It is effective against both the chloroquine resistant isolate, Gombak A and the sensitive strain, D10 of Plasmodium falciparum. Furthermore a better IC(50) value was obtained against the resistant strain, (9 microg/ml) compared to the sensitive strain, 40 microg/ml. When the crude extract was fractionated into 3 fractions, the chloroform fraction yielded the best activity, exhibiting equipotency against both strains of parasite used; IC(50) of 23.53 microg/ml against Gombak A and 21.06 microg/ml against D10.
Plasmodium knowlesi, a simian malaria parasite, is now recognised as the fifth cause of human malaria and can lead to fatal infections in humans. Knowlesi malaria cases are widely distributed in East and West Malaysia and account for more than 50% of admissions for malaria in certain hospitals in the state of Sarawak. This paper will begin with a description of the early studies on P. knowlesi, followed by a review of the epidemiology, diagnosis, clinical and laboratory features, and treatment of knowlesi malaria.
To determine whether glucose turnover is increased in acute falciparum malaria compared to enteric fever in children, steady-state 6,6-D2-glucose turnover was measured in 9 Malaysian children with uncomplicated malaria (6 males and 3 females; median age 10 years, body weight 22 kg) and in 12 with uncomplicated enteric fever (8 males and 4 females; median age 10 years, body weight 24 kg) in acute illness, after quinine (5 malaria patients) and in convalescence. Baseline plasma glucose concentrations in malaria and enteric fever were similar (all values are medians [ranges in brackets]) 5.6 [3.2-11.3] vs. 5.5 [4.2-8.0] mmol/L), as were serum insulin levels (5.6 [0.4-26.5] vs. 6.8 [1.1-22.5] milliunits/L; P > 0.4). Glucose turnover in the malaria patients was higher than in patients with enteric fever (6.27 [2.71-6.87] vs. 5.20 [4.50-6.08] mg/kg.min; P = 0.02) and in convalescence (4.74 [3.35-6.79] mg/kg.min; P = 0.05 vs. acute malaria study), and fell after quinine together with a rise in serum insulin (P = 0.03). Basal plasma lactate concentrations were higher in enteric fever than in malaria (3.4 [1.8-6.4] vs. 0.8 [0.3-3.8] mmol/L; P < 0.0001) and correlated inversely with glucose turnover in this group (rs = -0.60; n = 12; P = 0.02). These data suggest that glucose turnover is 20% greater in malaria than in enteric fever. This might reflect increased non-insulin-mediated glucose uptake in falciparum malaria and/or impaired gluconeogenesis in enteric fever, and may have implications for metabolic complications and their clinical management in both infections.
Plasmodium knowlesi is a malaria parasite that is found in nature in long-tailed and pig-tailed macaques. Naturally acquired human infections were thought to be extremely rare until a large focus of human infections was reported in 2004 in Sarawak, Malaysian Borneo. Human infections have since been described throughout Southeast Asia, and P. knowlesi is now recognized as the fifth species of Plasmodium causing malaria in humans. The molecular, entomological, and epidemiological data indicate that human infections with P. knowlesi are not newly emergent and that knowlesi malaria is primarily a zoonosis. Human infections were undiagnosed until molecular detection methods that could distinguish P. knowlesi from the morphologically similar human malaria parasite P. malariae became available. P. knowlesi infections cause a spectrum of disease and are potentially fatal, but if detected early enough, infections in humans are readily treatable. In this review on knowlesi malaria, we describe the early studies on P. knowlesi and focus on the epidemiology, diagnosis, clinical aspects, and treatment of knowlesi malaria. We also discuss the gaps in our knowledge and the challenges that lie ahead in studying the epidemiology and pathogenesis of knowlesi malaria and in the prevention and control of this zoonotic infection.
The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using established population compartmental pharmacokinetic models. Parasite clearance was prompt (median parasite clearance time, 24 h), and there were no serious adverse events. Consistent with studies in healthy adults (S. Salman, D. Bendel, T. C. Lee, D. Templeton, and T. M. E. Davis, Antimicrob Agents Chemother 59:3197-3207, 2015, http://dx.doi.org/10.1128/AAC.05013-14), the absorption of sublingual artemether was biphasic, and multiple dosing was associated with the autoinduction of the metabolism of artemether to DHA (which itself has potent antimalarial activity). In contrast to studies using healthy volunteers, pharmacokinetic modeling indicated that the first absorption phase did not avoid first-pass metabolism, suggesting that the drug is transferred to the upper intestine through postdose fluid/food intake. Simulations using the present data and those from an earlier study in older Melanesian children with uncomplicated malaria treated with artemether-lumefantrine tablets suggested that the bioavailability of sublingual artemether was at least equivalent to that after conventional oral artemether-lumefantrine (median [interquartile range] areas under the concentration-time curve for artemether, 3,403 [2,471 to 4,771] versus 3,063 [2,358 to 4,514] μg · h/liter, respectively; and for DHA, 2,958 [2,146 to 4,278] versus 2,839 [1,812 to 3,488] μg · h/liter, respectively; P ≥ 0.42). These findings suggest that sublingual artemether could be used as prereferral treatment for sick children before transfer for definitive management of severe or moderately severe malaria.
Epidemic foci of Plasmodium knowlesi malaria have been identified during the past ten years in Malaysia, in particular in the States of Sarawak and Sabah (Malaysia Borneo), and in the Pahang region (peninsular Malaysia). Based on a review of the available recent international literature, the authors underline the importance of molecular biology examinations, polymerase chain reactions (PCR), performed with primers specific for P. knowlesi, since the current microscopic examination (haemoscope) may fail to distinguish P. knowlesi from Plasmodium malariae, due to the very similar appearance of the two parasites. P. knowlesi has been described as the causal agent of life-threatening and lethal forms of malaria: its clinical picture is more severe when compared with that of P. malariae, since the disease is characterized by greater parasitaemia, as opposed to that documented in the course of P. malariae disease. The most effective carrier is Anopheles leucosphyrus: this mosquito is attracted by both humans and monkeys. Among primates, the natural hosts of P. knowlesi are Macaca fascicularis and Macaca nemestina, while Saimiri scirea and Macaca mulatta, which cannot become infected in nature, may be useful in experimental models. When underlining the potentially severe evolution, we note the key role played by prompt disease recognition, which is expected to be more straightforward in patients monitored in endemic countries at high risk, but should be carefully implemented for subjects being admitted to hospital in Western countries suffering from the typical signs and symptoms of malaria, after travelling in South-East Asia where they were engaged in excursions in the tropical forest (trekking, and similar outdoor activities). In these cases, the diagnosis should be prompt, and suitable treatment should follow. According to data in the literature, in non-severe cases chloroquine proves very effective against P. knowlesi, achieving the disappearance of signs and symptoms in 96% of cases after only 24 hours after treatment start. In the light of the emerging epidemiological data, P. knowlesi should be added to Plasmodium vivax, Plasmodium ovale, P. malariae, and Plasmodium falciparum, as the fifth aetiological agent of malaria. During the next few years, it will become mandatory to plan an appropriate surveillance program of the epidemiological evolution, paying also great attention to the clinical features of patients affected by P. knowlesi malaria, which are expected to worsen according to the time elapsed; some studies seem to point out greater severity according to increased parasitaemia, paralleling the increased interhuman infectious passages of the plasmodium.