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.

Human Infections and Detection of Plasmodium knowlesi

The derivation of detailed epidemiological maps, at the relevant spatial resolution, is being increasingly recognized as vital to the effective design and implementation of successful programmes for the control of parasites and their vectors. Geographical information systems (GIS) and a recently complied database on the distribution of lymphatic filariasis in India have now been used to develop the first maps at district-level (i.e. the level at which control against this parasite will be enacted in India) of filariasis endemicity in this country. The derived maps indicate both the substantial extent as well as the marked variability in the geographical distribution of this disease in India. The causative infection and/or the symptomatic disease were detected in most (257) of the 289 districts surveyed up to 1995. Currently there may be up to 27.09 million microfilaraemics, 20.83 million cases of symptomatic filariasis, and about 429.32 million individuals potentially at risk of infection in the country. Probability mapping, based on data quantiles, clearly indicates that the risk of filarial infection in India is not constant throughout the country but exhibits strong regional trends. Filariasis in general may be a particular problem of the eastern half of the country. The results indicate the potentially vital role that GIS-based mapping approaches can play in the development of filariasis-control campaigns in India and elsewhere.

Mapping of lymphatic filariasis in India.

Plasmodium knowlesi is a cause of symptomatic and potentially fatal infections in humans. There are no studies assessing the detailed parasitological response to treatment of knowlesi malaria infections in man and whether antimalarial resistance occurs. A prospective observational study of oral chloroquine and primaquine therapy was conducted in consecutive patients admitted to Kapit Hospital, Sarawak, Malaysian Borneo with PCR-confirmed single P. knowlesi infections. These patients were given oral chloroquine for three days, and at 24 hours oral primaquine was administered for two consecutive days, primarily as a gametocidal agent. Clinical and parasitological responses were recorded at 6-hourly intervals during the first 24 hours, daily until discharge and then weekly to day 28. Vivax malaria patients were studied as a comparator group. Of 96 knowlesi malaria patients who met the study criteria, 73 were recruited to an assessment of the acute response to treatment and 60 completed follow-up over 28 days. On admission, the mean parasite stage distributions were 49.5%, 41.5%, 4.0% and 5.6% for early trophozoites, late trophozoites, schizonts and gametocytes respectively. The median fever clearance time was 26.5 [inter-quartile range 16-34] hours. The mean times to 50% (PCT50) and 90% (PCT90) parasite clearance were 3.1 (95% confidence intervals [CI] 2.8-3.4) hours and 10.3 (9.4-11.4) hours. These were more rapid than in a group of 23 patients with vivax malaria 6.3 (5.3-7.8) hours and 20.9 (17.6-25.9) hours; P = 0.02). It was difficult to assess the effect of primaquine on P. knowlesi parasites, due to the rapid anti-malarial properties of chloroquine and since primaquine was administered 24 hours after chloroquine. No P. knowlesi recrudescences or re-infections were detected by PCR. Chloroquine plus primaqine is an inexpensive and highly effective treatment for uncomplicated knowlesi malaria infections in humans and there is no evidence of drug resistance. Further studies using alternative anti-malarial drugs, including artemisinin derivatives, would be desirable to define optimal management strategies for P. knowlesi.

/pdf/clinical-and-parasitological-response-to-oral-chloroquine-3igrdb7ml4.pdf

Clinical and parasitological response to oral chloroquine and primaquine in uncomplicated human Plasmodium knowlesi infections

The mode of action of sulphonamides, proguanil and pyrimethamine on Plasmodium gallinaceum.

During the last decade, scale-up of vector control tools such as long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) contributed to the reduction of malaria morbidity and mortality across the continent. Because these first line interventions are now affected by many challenges such as insecticide resistance, change in vector feeding and biting behaviour, outdoor malaria transmission and adaptation of mosquito to polluted environments, the World Health Organization recommends the use of integrated control approaches to improve, control and elimination of malaria. Larviciding is one of these approaches which, if well implemented, could help control malaria in areas where this intervention is suitable. Unfortunately, important knowledge gaps remain in its successful application. The present review summarises key parameters that should be considered when implementing larviciding efficacy or effectiveness trials.

/pdf/implementing-a-larviciding-efficacy-or-effectiveness-control-30yllxyczu.pdf

Implementing a larviciding efficacy or effectiveness control intervention against malaria vectors: key parameters for success.

1. (1) A high degree of resistance to proguanil was developed in a strain of P. knowlesi which was subjected to periodic exposure to the drug at varying intervals for one year. 2. (2) The effect was persistent even after 8 months during which time no further proguanil was administered during serial passages. 3. (3) The proguanil-resistant strain was found to be refractory to daraprim and bromoguanide but not so to sulphadiazine, M 3349 nor chloroquin.

Acquired resistance to proguanil in Plasmodium knowlesi

National Filaria Control Programme in India: a review (1955-59).

Daraprim (50-63) in simian malaria.

Screening of Antimalarials against P. gallinaceum. In Chicks. Part I. Preliminary Studies.

Isolation of strain of P. inui from mixed infection in Malayan monkey.

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