clinical presentations of malaria. The boxes show common signs and symptoms of the clinical malaria spectrum. In general, chil- dren, young adults and pregnant women are the groups that are the most susceptible to mild or severe forms of malaria. With increasing age and time residing in endemic areas, individuals are repeatedly exposed to bites from uninfected vectors and also to various Plas- modium infections. Consequently, some individuals develop immune responses against both the parasite and vectors, which leads to the rel- ative control of parasite biomass and the modulation of pathological host responses; this is commonly observed in asymptomatic malaria cases. DIC: disseminated intravascular coagulation. 

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... infected with Plasmodium , a human host generally presents with one of three major clinical out- comes: asymptomatic infection, mild disease or severe disease. These diverse clinical presentations are deter- mined by complex interactions between the host, the parasite and environmental factors ( Fig. 1). Parasite determinants include the different pathogenic potential of the various Plasmodium species. For example, P. fal- ciparum is well known to cause severe infections more frequently than other Plasmodium species because P. falciparum exhibits a number of unique characteristics that favour increased disease severity, including high multiplication rates in both erythrocytes and reticulo- cytes, strong cytoadherence to infected erythrocytes [reviewed in Schofield (2007)] and toxin-induced activa- tion of inflammatory responses [reviewed in Clark and Cowden (1999)]. Interestingly, cases of severe malaria caused by P. vivax (Andrade et al. 2010c) or uncommon Plasmodium species (Cox-Singh et al. 2010) display patterns of inflammation and immunopathology simi- lar to those seen in severe falciparum malaria cases. These findings suggest that different Plasmodium spe- cies can trigger strikingly similar host responses that can result in severe disease. A number of host factors have already been described as important determinants of clinical outcomes in malaria cases, including age and gender, ethnicity, concomitant chronic conditions, co-infections and diverse genetic polymorphisms. En- vironmental factors include deforestation, health care system infrastructure and access to effective antimalar- ial treatment, vector exposure and sociocultural factors. Within the clinical spectrum of Plasmodium infections, we consider the two opposite poles that remain to be fully understood of utmost importance: asymptomatic malaria, which is directly associated with clinical im- munity to infection and severe malaria, which underlies key processes in susceptibility to infection. Several epidemiological studies have shown that cases of asymptomatic malaria are highly prevalent in many endemic regions (Cucunubá et al. 2008, Baliraine et al. 2009, Marangi et al. 2009, Steenkeste et al. 2010). Individuals with asymptomatic Plasmodium infection can exhibit low parasitaemia for up to 60 days (Alves et al. 2002). Because of the absence of symptoms, these in- fected individuals do not seek health care at malaria ref- erence centres. Furthermore, active detection of asymp- tomatic malaria cases is hampered by the low sensitivity of microscopy-based detection techniques in identifying very low parasite burdens (Andrade et al. 2010b). More- over, despite low concentrations of circulating parasites, individuals with asymptomatic malaria infections can transmit Plasmodium to uninfected vectors (Alves et al. 2005). This phenomenon suggests that individuals with asymptomatic Plasmodium infections may serve as an important parasite reservoir in endemic areas. Major factors associated with asymptomatic ma- laria are related to the magnitude of parasite and vector exposure (Bejon et al. 2009). Indeed, it is well estab- lished that the occurrence of asymptomatic malaria is associated with increased age (Baird et al. 1991), time of residence in the endemic area and number of previ- ous malaria episodes (Rogier & Trape 1995). After many years of repeated infections, the host develops clinical immunity against Plasmodium . In these cases, the on- set of symptoms is prevented by limiting parasite bur- den and controlling inflammation (Fig. 2). Intriguingly, such asymptomatic carriers have developed just enough immunity to protect them from malarial illness, but not from malarial infection. Thus, the search for biomark- ers of clinical immunity must explore tools to estimate both parasite/vector exposure and the host’s own protec- tive responses. Important general concepts related to bi- omarkers are presented in Fig. 3. The hallmark symptom of malaria is fever, which can be followed by a wide range of other symptoms including headache, chills, diarrhoea, lethargy, cough- ing fits and abdominal or muscular pain (Greenwood et al. 2005). Further, more severe manifestations of ma- laria also vary and include anaemia, hypoglycaemia, hypotension, intense haemolysis, metabolic acidosis, spontaneous bleeding, hepatitis, acute kidney failure, respiratory distress, convulsion, coma and multiple or- gan failure (WHO 2000). Notably, while the parameters defining severe malaria are standardised with regard to P. falciparum infections, there are as yet no consensus criteria measuring severity of vivax malaria infections. One simple approach that has been explored is based on outcomes of clinical and laboratory tests, which are used to predict overall mortality and specific complications (Mishra et al. 2007, Winkler et al. 2008). Unlike in cases of asymptomatic malaria, parasitological diagnosis is not a major concern in severe cases, as most patients present with high levels of parasitaemia that are easily detected by microscopy-based techniques. In these situations, the critical point is to exclude mixed Plasmodium infections and other comorbidities, such as bacterial sepsis, lep- tospirosis, dengue, viral hepatitis and acquired immune deficiency syndrome, that can result in similar clinical presentations. Thus, the search for highly specific mark- ers should be prioritised to facilitate diagnosis. Never- theless, less specific markers, such as those that indicate inflammatory status, are also extremely important in the light of their high sensitivity in predicting disease sever- ity (Andrade et al. 2010d). Intense research focused on the immunopathogenesis of severe malaria will contrib- ute to the identification of useful surrogate and specific biomarkers for cases of severe malaria. The identification of reliable biomarkers for suscep- tibility to infection and for disease severity can provide important insights into the diagnosis and management of malaria. Here, we review recent research advances in the identification of malaria biomarkers, focusing on biomarkers specifically related to parasite exposure and susceptibility to disease. We also present a critical analysis of the priorities for research regarding biomar- kers for severe malaria. Biomarkers of exposure - Plasmodium is transmitted through the bites of Anopheles mosquitoes. As the insect takes a blood meal, arthropod saliva is injected into the vertebrate host. Vector saliva is essential to the Plasmo- dium life cycle (Choumet et al. 2007), facilitating blood feeding by inhibiting host coagulation and inflammatory responses [reviewed in Andrade et al. (2005)]. These ef- fects may be directly linked to changes in host immune response (Depinay et al. 2006); furthermore, several of the active molecules present in vector saliva are immu- nogenic to vertebrate hosts, resulting in the initiation of an anti-saliva immune response. Immediate, delayed and systemic hypersensitivity reactions to vector saliva have been described [reviewed by Andrade et al. (2005)]. Ver- tebrate responses to arthropod salivary components have been used as epidemiological markers for vector expo- sure for ticks (Schwartz et al. 1991), phlebotomines (Bar- ral et al. 2000, Gomes et al. 2002), Triatoma (Nascimento et al. 2001), Glossina (Poinsignon et al. 2008b) and Aedes mosquitoes (Remoue et al. 2007). In the case of malaria, the host immune response against vector saliva can be used as a biomarker of exposure to Anopheles . Two points related to the detection of biomarkers in saliva must, however, be clarified. First, detection of a host immune response against saliva does not necessar- ily imply host protection. This is a controversial point, as both host-protective (Donovan et al. 2007) and non- protective (Kebaier et al. 2010) findings have been re- ported. Currently, we utilise anti- Anopheles saliva im- mune responses as a marker of exposure of potential epidemiological significant. Second, the evaluation of host responses against mosquito saliva should not be confounded with diagnostic approaches that detect plasmodial products in host saliva (Wilson et al. 2008, Nwakanma et al. 2009, A-Elgayoum et al. 2010, Buppan et al. 2010, Gbotosho et al. 2010). Antibodies against Anopheles gambiae saliva have been described in young children from a region in Sen- egal with seasonal malaria transmission (Remoue et al. 2006). Travellers transiently exposed to An. gambiae bites in endemic areas of Africa also develop ...