Nor Diyana Dian, Mohd Amirul Fitri A Rahim, Zulkarnain Md Idris,2?

1Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia

2Infectious Disease Group, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia

Malaria remains a public health problem in many parts of the world. It is a disease that can endanger human life if left untreated,especially among young children and pregnant women. In Malaysia,the number of malaria cases has decreased significantly since the introduction of the Malaria Elimination Program in 1961 in Malaysia Borneo, and in 1967 in Peninsular Malaysia. Since 1988, malaria has been on the notifiable disease list under the Communicable Diseases Act of Malaysia that mandates notification within 7 days. The significant progress towards the national elimination programme and effective disease notification on malaria has resulted in zero indigenous human malaria cases in 2018[1]. However, the emergence of zoonotic malaria in recent years has less been tractable to conventional malaria control and elimination programme in the country. Malaria cases shifted from predominantly human malaria to non-human primate malaria species in the early 2000s, and are now responsible for the majority of malaria case in less developed areas of both Peninsular Malaysia and Malaysia Borneo[2]. The main key driver to the apparent emergence of zoonotic malaria infection in Malaysia is the ongoing environmental and ecological changes (i.e. deforestation, less biodiversity, migration of macaques to forest fringes) and likely to shape changing risk to the infection.Deforestation and other landscape changes for economic exploitation are known to impact the distribution, susceptibility and behaviour of human populations, wildlife reservoir (i.e. macaques) and vector(i.e. Anopheles leucosphyrus) dynamics, thus exacerbating the risk of zoonotic malaria infections in the country[3].

Although Plasmodium (P.) knowlesi is the most widely reported zoonotic malaria species, there is notably increased epidemiological evidence on naturally acquired human infection of P. cynomolgi in Malaysia. The first case of naturally acquired human cynomolgi malaria infection was recorded in a 39-year-old woman from the east coast of Peninsular Malaysia (i.e. Hulu Terengganu) in 2014[4].Since then, there have been four more published studies (i.e. as of December 2021) reported on P. cynomologi infection, including symptomatic infection of a tourist travelling to Peninsular Malaysia and multiple asymptomatic infection cases in Malaysia Borneo[5-8](Figure 1). In the first reported case study, the patient’s blood sample was diagnosed as P. vivax malaria infection microscopically but was confirmed by molecular PCR method as P. cynomolgi. Due to morphologic similarities between P. cynomolgi and P. vivax, it is difficult to identify P. cynomolgi parasites correctly by conventional microscopy. Both species have similar biological capabilities including exoerythrocytic dormant stages in the liver with associated hypnozoites and favouring infecting reticulocytes[9]. Therefore, if solely relying on microscopy examination, it is highly likely that there will be more misdiagnosed or undetected sub-microscopic infections of P. cynomolgi in the population. A recent study in the state of Sarawak (Malaysia Borneo) also noted that P. cynomolgi parasites made a low percentage of the parasites consisted of P.cynomologi in the two individuals whose blood films were analysed,which explains why microscopy analysis detected only single P.knowlesi infections in those patients[7]. The difference in the period of development in the liver and the duration of the erythrocytic cycle between P. knowlesi and P. cynomolgi accounts for P. knowlesi dominance over P. cynomolgi hence, making it harder to detect P.cynomolgi malaria in case of mixed infection[7,9]. Besides that, P.cynomolgi infections in humans are mild or even asymptomatic. In the reported symptomatic natural infection, the patient experienced cyclical fevers, myalgia, general malaise, cephalgia and abdominal pain that were described as generalised non-specific flu-like syndrome[4,5]. This suggests very low parasite densities and the need for improved diagnostic methods to detect these infections.Furthermore, due to the limited disease severity of P. cynomolgi and its morphological similarity to P. vivax, which makes accurate microscopic speciation difficult, the true incidence rates of P.cynomolgi are likely to be significantly higher than what is currently thought.

Figure 1. Map of Malaysia showing location of the positive Plasmodium cynomolgi areas. Pie charts represent number of cases and percentages of Plasmodium cynomologi and Plasmodium knowlesi malaria infections determined by species-specific PCR from five studies[4-8] (2014-2021).

Although co-infection of P. cynomolgi with other zoonotic malaria species has recently been documented from archived blood samples of the indigenous population in Malaysia[7], there is a risk of P. cynomolgi being underdiagnosed because the molecular characterization of the P. cynomolgi parasite is not commonly performed. Hence, any co-infections would be assigned only to the other malaria species involved. Furthermore, zoonotic malaria cases are widely reported in Malaysian Borneo (i.e. Sarawak and Sabah)as many studies are conducted there[2]. In Peninsular Malaysia,fewer epidemiological studies were conducted in regards to zoonotic malaria. There were only 13 malaria epidemiological studies that have been carried out in Peninsular Malaysia over the past 40 years,mostly by using conventional microscopy examination[2]. The low number of malaria epidemiological surveys in Peninsular Malaysia particularly among indigenous communities could lead to an underreport of the real incidence of zoonotic malaria in this hard-to-reach population.

Albeit P. cynomolgi infections may not yet pose a significant health risk, any new infections make it increasingly challenging for public health officials to eliminate zoonotic diseases[10]. The significance of P. cynomolgi that is transmissible cannot be ignored given the increasing identification of infection. Further studies and continued surveillance of P. cynomolgi and other zoonotic malarias in Malaysia are necessary through the use of sensitive molecular methods such as developing molecular analysis with specific primers for P. cynomolgi and abolishing the requirement for genotyping analyses in order to obtain accurate and relevant data for the detection and reporting of these emerging zoonotic malaria. Research involving the mosquito vector is needed to determine the importance of P. cynomolgi malaria in mosquitos and its implications for human public health and malaria control. Furthermore, more research into the biology of P.cynomolgi, the possibility of relapses/recurrences and asymptomatic infections, all of which have a direct impact on malaria epidemiology is required.

Conflict of interest statement

We declare that there is no conflict of interest.

Funding

It was supproted by the Southeast Asia One Health University(SEAOHUN) Small Grant Program (FF-2021-457) and the Faculty of Medicine, Universiti Kebangsaan Malaysia (FF-2021-350).

Authors’ contributions

The conceptualization was done by NDD and ZMI. The literature and drafting of the manuscript were conducted by NDD and MAFAR. The editing and supervision were performed by ZMI. All authors have read and agreed to the final version of the manuscript.