The complexities of malaria disease manifestations with a focus on asymptomatic malaria

Dolie D Laishram 1 2 Patrick L Sutton 0 Nutan Nanda 2 Vijay L Sharma 1 Ranbir C Sobti 3 Jane M Carlton 0 Hema Joshi 2 0 Center for Genomics and Systems Biology, Department of Biology, New York University , 12 Waverly Place, New York, NY 10003 , USA 1 Department of Zoology, Panjab University , Chandigarh 160014 , India 2 National Institute of Malaria Research, Indian Council of Medical Research , Sector 8, Dwarka, New Delhi 110 077 , India 3 Department of Biotechnology, Panjab University , Chandigarh 160014 , India Malaria is a serious parasitic disease in the developing world, causing high morbidity and mortality. The pathogenesis of malaria is complex, and the clinical presentation of disease ranges from severe and complicated, to mild and uncomplicated, to asymptomatic malaria. Despite a wealth of studies on the clinical severity of disease, asymptomatic malaria infections are still poorly understood. Asymptomatic malaria remains a challenge for malaria control programs as it significantly influences transmission dynamics. A thorough understanding of the interaction between hosts and parasites in the development of different clinical outcomes is required. In this review, the problems and obstacles to the study and control of asymptomatic malaria are discussed. The human and parasite factors associated with differential clinical outcomes are described and the management and treatment strategies for the control of the disease are outlined. Further, the crucial gaps in the knowledge of asymptomatic malaria that should be the focus of future research towards development of more effective malaria control strategies are highlighted. - Background Malaria remains a serious global health burden, with an annual incidence of 247 million cases and nearly one million deaths, most of which afflict children living in Africa [1]. Of the four human malaria parasite species, Plasmodium falciparum is reported to cause the highest morbidity and mortality. Young children with nave immune systems [2] and pregnant women with potentially compromised immune systems are particularly vulnerable to this disease and so are considered to be the highest risk populations for malaria-related deaths. P. falciparum disease severity ranges from severe and complicated, to mild and uncomplicated, to asymptomatic [3,4]. Understanding the impact of P. falciparum on the human host across this range is critical for learning how to improve the management of the disease. Generally, severe or complicated malaria has been at the core of epidemiological studies because it is the principal cause of malaria-related deaths. Researchers and clinicians have established diagnostic criteria based on the clinical manifestations upon disease onset, which has aided in forming an integrated approach to improving the management and treatment of severe malaria. Severe malaria is now defined by at least one of the following clinical manifestations: unrousable coma (caused by cerebral malaria), convulsions, malarial anaemia, haemoglobinuria, hypoglycaemia, metabolic acidosis (associated with respiratory distress), acute pulmonary oedema, acute renal failure, jaundice, circulatory collapse, hyperparasitaemia, high fever electrolyte disturbance, and/or spontaneous bleeding [4]. In areas of high transmission, this full spectrum of clinical severity is primarily observed in children; severe malaria is negatively correlated with age due to the development of exposure-related immunity in adults [5,6]. This is further supported by finding that frequent exposure to P. falciparum malaria in high transmission regions typically reduces the period of risk for severe malaria, while in lower transmission regions infrequent exposure extends this period of risk [5]. In contrast, individuals with mild or uncomplicated malaria typically present clinically with fever and perhaps one or more of the following symptoms: chills and sweats, headache, vomiting, watery diarrhea, anaemia, jaundice, and swelling of the spleen (splenomegaly), but do not generally have any of the features identified in severe or complicated malaria [4]. If properly diagnosed and treated, recovery success is high for patients with uncomplicated malaria (reviewed in ref [6]). Uncomplicated malaria also occurs in endemic areas and is likely associated with the development of some exposurerelated immunity. For example, Gupta et al. [7] reported the development of clinical immunity to uncomplicated malaria after only one or two infective bites, highlighting the potential importance of strain-specific immunity. Diagnosing asymptomatic malaria is not as straightforward due to the obvious lack of clinical manifestations and often subpatent (undetectable by microscopy) level of parasites [8]. Asymptomatic malaria is prevalent in malaria endemic regions and has become a serious cause for concern as efforts are increasing towards eliminating the parasite [9]. Particularly, subpatent malaria is still transmissible and will complicate elimination of malaria in high transmission regions. For example, a study in Senegal suggested that more than 90% of exposed individuals are likely infected with chronic asymptomatic malaria [8], a situation in which the majority of this population can then inadvertently act as a reservoir for malaria transmission. For more than two decades, researchers have investigated the development of two types of immunity which may result in asymptomatic malaria: 1) an anti-disease immunity that allows one to carry parasite loads without symptoms; and 2) an anti-parasite immunity that may be responsible for the suppression of parasite loads after a certain age, which is likely a factor of exposure-related clinical immunity [10-12]. Interestingly, asymptomatic malaria is not only limited to regions of high transmission where exposure-related immunity is expected to develop; it has also been reported in the low transmission Amazonian regions of Peru, Brazil, and Columbia and also the Solomon Islands [13-21]. Exposure-related immunity may be achieved much earlier in life for individuals who live in low transmission regions due to predictably low parasite genetic diversity and few overlapping infections. Few reports are available on the study of asymptomatic malaria caused by species other than P. falciparum. However, like asymptomatic P. falciparum, asymptomatic Plasmodium vivax malaria has been reported in a range of endemic settings. For example, the low transmission setting of Temotu Province, Solomon Islands [20] and the highly endemic malaria area of Rio Negro in the Amazon State, Brazil [22] both report significant presence of asymptomatic P. vivax. Another Amazonia study reports that the prevalence of symptomless falciparum and vivax malaria infections are 4-5 times higher than the symptomatic ones, with a significant correlation of symptomless malaria with older age groups [21]. Unfortunately, the reports above were limited to general prevalence surve (...truncated)