Year: 2018
Type: editorial
Abstract: (See the Major Article by Imwong et al on pages 695–702.) In the mid-20th century, a series of careful studies showed that multiple Plasmodium parasites for which nonhuman primates are hosts could be transmitted to humans in a laboratory setting [1]. These studies and, in 1965, the report of a case of natural infection with Plasmodium knowlesi raised the possibility of a significant burden of zoonotic transmission of monkey parasites occurring in regions with suitable vectors [1]. While initial studies in Malaysia did not confirm this, it took the development of polymerase chain reaction (PCR)–based molecular diagnostic tests and almost 40 years before the recognition of a large cluster of human knowlesi malaria in Sarawak [2]. Zoonotic knowlesi malaria has now been reported from all countries of Southeast Asia where humans come into contact with Anopheles leucosphyrus–group mosquitoes and the macaque reservoir [3]. However, because of difficulties with diagnosis, the true prevalence of infection and the disease burden are not known. Rapid diagnostic tests are insensitive and nonspecific for zoonotic species. In routine microscopy, P. knowlesi is indistinguishable from Plasmodium malariae and, in areas of coendemicity is frequently misdiagnosed as Plasmodium malariae, Plasmodium falciparum, or Plasmodium vivax, and vice versa [4]. Accurate detection requires the use of sensitive and specific molecular tools, particularly PCR. The use of PCR has confirmed that P. knowlesi is the most common cause of malaria across Malaysia [5, 6] and some regions of western Indonesia [7, 8] and the only cause of malaria in Brunei and Singapore. Asymptomatic P. knowlesi parasitemia is also reported in this region, albeit with relatively insensitive PCR analyses of small volumes of blood [9]. Although molecular confirmation of all clinical cases is now routine in Malaysia, systematic molecular surveillance for zoonotic malaria elsewhere in Southeast Asia has been limited, particularly in the Greater Mekong Subregion. The molecular surveillance study in Cambodia by Imwong et al in this issue of The Journal of Infectious Diseases [10] is a welcome addition to understanding the epidemiology of zoonotic malaria in Southeast Asia. Using highly specific and sensitive PCR protocols in a rigorous cross-sectional sampling methodology, they report a prevalence of asymptomatic parasitemia with zoonotic Plasmodium species in a population in western Cambodia of 0.4%, comprising almost 2% of all those with malaria parasites [10]. As well as providing useful data on the prevalence of asymptomatic P. knowlesi in this region, they show, for the first time, asymptomatic human infection with the relapsing monkey parasite, Plasmodium cynomolgi. Indeed, in this setting, the prevalence of P. cynomolgi was at least as common as that of P. knowlesi, which, perhaps, is not surprising, given that the macaque reservoirs are often coinfected [10]. There have been only 2 other reports of natural P. cynomolgi infection in humans, describing 6 cases of symptomatic malaria, a single uncomplicated P. cynomolgi monoinfection in peninsular Malaysia [11], and 5 mixed P. knowlesi–P. cynomolgi infections in Sarawak [12]. What are the reasons for the paucity of reported human P. cynomolgi infections? While it is probable that the true incidence of cynomolgi malaria is indeed low, P. cynomolgi is morphologically indistinguishable from P. vivax on routine microscopy [1]. Just as P. knowlesi was misdiagnosed for many years as P. malariae or other human-only species [2], it is likely that, in settings of coendemicity, some cases of P. cynomolgi malaria have been misdiagnosed as P. vivax malaria. Moreover, in experimental human sporozoite-induced infections, the median peak P. cynomolgi parasitemia was much lower than that for P. vivax, with symptoms often occurring at parasite counts below the lower limit of detection by routine microscopy [1]. A propensity for low-level parasitemia was also seen in asymptomatic infection in Cambodia, with a geometric mean parasitemia level significantly lower in P. cynomolgi infection (4 parasites/µL) than in P. knowlesi infection (52 parasites/µL) [10]. With such low parasitemia, a significant proportion of symptomatic natural P. cynomolgi infections and, likely, nearly all asymptomatic infections in P. cynomolgi–endemic settings may be missed by either routine microscopy or genus-specific rapid diagnostic tests. The study by Imwong et al also showed that, with the genetic similarity between P. cynomolgi and P. vivax, there can be cross-reactivity with some widely used PCR methods [10]. Their initial use of nonspecific PCR analyses resulted in P. cynomolgi being misdiagnosed as P. vivax, and, depending on PCR methodology, it is possible that this may have previously occurred in other cross-sectional surveys in Southeast Asia. Because P. falciparum and P. vivax remain the major causes of malaria morbidity and mortality in most areas of the Asia-Pacific Region, the elimination agenda rightfully targets these 2 species. So, do the zoonotic malarias really matter? From a clinical perspective, they do. The most common zoonotic malaria parasite, P. knowlesi, is now well recognized to cause severe and fatal disease, with 6%–9% of symptomatic cases developing severe malaria [5]. Although P. knowlesi can cause high parasitemia, severe disease commonly occurs at relatively low parasite counts: those with a parasitemia of >15000 parasites/µL are 16 times more likely to develop severe malaria [5]. In P. knowlesi–endemic settings of Southeast Asia, prompt and accurate diagnosis and early treatment are therefore essential, including intravenous artesunate therapy for those with a parasitemia of >15000/µL, a lower threshold than that recommended for the major human-only species causing severe malaria, P. falciparum [5]. Microscopic misdiagnosis of P. knowlesi malaria as P. malariae and P. vivax malaria and consequent delays in administration of artesunate has led to fatal outcomes [6]. The other Southeast Asian zoonotic malaria parasite, P. cynomolgi, is not known to progress to high parasitemia or severe malaria [1, 10, 11], although experimental human infection causes a significant febrile illness and a propensity to relapse [1]. What are the public health implications of zoonotic malaria? While human contact with the monkey reservoir and the relevant mosquito vectors continues or indeed increases, zoonotic malaria will not be eliminated by current measures targeting the transmission of human-only Plasmodium species [3]. As these elimination measures are rolled out, the reduction in malaria cases due to the human-only Plasmodium species occurring in P. knowlesi–endemic areas will lead to a consequent increase in the proportion of malaria cases that are due to zoonotic Plasmodium species. The wider use of molecular diagnostic tests to confirm Plasmodium species in P. knowlesi–endemic regions will also mean that some infections microscopically diagnosed as due to P. falciparum, P. vivax, and P. malariae will be recognized as actually being due to P. knowlesi, as recently seen in both Malaysia [4] and western Indonesia [7]. Without such molecular surveillance, these microscopic misdiagnoses will underestimate the success of the elimination efforts targeting the human-only Plasmodium species, as will the use in malariometric surveys of nonspecific PCR methods in which P. knowlesi and P. cynomolgi cross-react with P. vivax. With the success of national malaria control programs in moving toward elimination of the human-only species, P. falciparum and P. vivax, some countries have seen parallel rises in zoonotic malaria due to P. knowlesi. Importantly, the rising incidence of P. knowlesi malaria in some regions cannot be attributed merely to increased ascertainment arising from the rollout of molecular diagnostic tests. Longitudinal data from Malaysia, where molecular confirmation of malaria cases is now routine and where P. falciparum and P. vivax are approaching elimination, show a continuing rise in the incidence of PCR-confirmed P. knowlesi [6]. Although human-to-human transmission has been demonstrated experimentally, available evidence to date indicates that natural human transmission of these monkey malaria episodes remains zoonotic [3, 10]. The reasons for the rise in the P. knowlesi malaria incidence are multifactorial, with greater acquisition risk arising from changes in human land use and deforestation, with both influencing vector bionomics and the monkey reservoir, changes in human behavior, and, potentially, parasite adaptation [3]. There is serological cross-reactivity between P. vivax and both P. knowlesi and P. cynomolgi, and in some early malariotherapy studies, infection with P. knowlesi was more difficult to induce in those with previous P. vivax infection [1]. Whether declining cross-reactive immunity to P. vivax following its near elimination in Malaysia is contributing to the rise in clinical disease from P. knowlesi is not known. If it is contributing, there may be an increase in clinical cases of zoonotic malaria in other regions of Southeast Asia as they, too, approach elimination of P. vivax. With the limited public health options available for control of zoonotic malaria, any cross-protective immunity would raise the possibility that a future P. vivax vaccine could also be potentially deployed against these zoonotic malaria cases. Although the distribution of human P. knowlesi in Southeast Asia is limited by the distributions of A. leucosphyrus–group mosquitoes and the long- and pig-tailed macaque reservoir, P. cynomolgi is infective to a broader range of anopheline mosquitoes in experimental conditions and naturally infects a larger number of macaque species [1]. It is therefore possible that the geographical area in which humans are at risk may be broader than that for P. knowlesi. Wider surveillance in humans for the range of non-human primate Plasmodium species is warranted. However, given the greater virulence of P. knowlesi in humans, the greater public health need is enhanced molecular surveillance for human P. knowlesi infections across at-risk areas in Southeast Asia, in both clinical malaria cases and malariometric surveys. The careful study by Imwong et al [10] highlights the need to use highly specific and sensitive PCR methods for accurate detection of both the zoonotic and human-only Plasmodium species. Financial support. This work was supported by the National Health and Medical Research Council of Australia (fellowships 1135820 and 1138860 to N. M. A. and M. J. G.). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Authors: Nicholas M Anstey, Matthew J Grigg
Institution: Menzies School of Health Research
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2896667116