The results of the meta-analysis show that there is a large variation in the strength of the association between the different WHO-defined criteria of severe malaria and death. Renal failure, coma, hypoglycemia, shock, and respiratory distress represent those with the highest prognostic value. These manifestations were also those with the highest prognostic value for death in the original paper by Marsh [12], which was supportive of the WHO definition of severe malaria. Similarly, impaired consciousness, prostration, hyperpyrexia, hyperparasitaemia, and severe anemia were weak predictors both in the present systematic review and in Marsh’s paper [12]. While 5039 (35.7%) of children from the enclosed studies suffered from severe anemia, its association with death, though widely acknowledged, was insignificant. This can possibly be explained by the fact that anemic children receive blood transfusion upon admission or by the lack of other concomitant feature such as respiratory distress or neurological impairment. On the other hand, hypoglycemia, which similarly to severe anemia could be reversed if early detected, remains a significant marker of severity, which can be possibly explained by its dependency on other severe markers. Conditions such as malnutrition or HIV co-infection have not been addressed in this analysis since they are not part of the definition of severe malaria. They are, however, very important contributors of mortality and should definitively be considered together with other clinical features when assessing a sick child.

The current systematic review recognizes coma (defined as Blantyre coma scale (BCS) ≤ 2) and deep breathing as robust prognostic factors of pediatric life-threatening malaria that can simply be determined and recorded by skilled observers in all types of settings. Deep breathing, as a crucial respiratory sign of severe malaria, is commonly a compensatory manifestation of underlying metabolic acidosis [44] and is more predictive than respiratory distress accompanied by signs of variable severity. These findings are nearly in line with the results from a prospective study [12] of 1844 patients in Kenya, which identified respiratory distress and impaired consciousness (defined as prostration or coma) as highly associated with death and, except for prostration, with the Lambaréné Organ Dysfunction Score, which combines coma, prostration, and deep breathing [10].

Although there is no definite consensus regarding the strongest predictors of death within the WHO clinical definition of severe malaria, the WHO distinguished three groups [1] classing clinical and laboratory features of the disease in a way to facilitate appropriate treatment. A major contrast of our results with the clinical features included in the WHO Group 1 symptoms (prostrate but conscious, prostrate with impaired consciousness, coma, mild/severe respiratory distress, shock), which are supposedly more severe and for which parenteral treatment is recommended, is that a child with prostration or impaired consciousness appears to be at a low risk of death when compared with the presence of any other listed signs and symptoms. One possible explanation for this unexpected finding is that, in some studies, the definition of impaired consciousness was less stringent than that of the WHO (BCS < 3). Interestingly, in the differentiated group of 1289 Gabonese children, Issifou et al. [36] applied a BCS between 3 and 4 to classify cases of moderate malaria. On the other hand, our findings are consistent with the WHO Group 2 clinical features (severe anemia, two or more convulsions in past 24 hours, hemoglobinuria, jaundice), which indicate a disease of lower severity and for which a supervised oral therapy is recommended.

The present attempt to rank clinical features according to their prognostic values was performed to potentially better distinguish children that should definitely be receiving parenteral treatment versus those that could be considered for prompt oral treatment with artemisinin-based combinations. At present, the WHO recommends injectable artesunate for all children with asexual forms of P. falciparum in peripheral blood and at least one criterion of severity [45]. In the light of the very different prognostic values of the different features, Kopel et al. [46] suggested that oral treatment could be a successful alternative for patients with a detected parasitemia and a criterion considered as less severe, e.g., jaundice. Certainly, all prognostic indicators that are able to be detected at the bedside need to be searched for, and finding a low-prognostic symptom or sign does not remove the need for parenteral treatment if a high-prognostic one is present. Identifying a subset of patients with moderately severe malaria who could be safely managed with oral treatment at the primary care level would simplify the patients’ management in settings where referral to hospital for injectable treatment is difficult, and allow better resources allocation. A simplified approach may be easier to implement. Already, in settings where laboratory facilities are unavailable, the laboratory tests used to define severe malaria are not considered in the classification of the disease. This new approach should be carefully assessed in a prospective multicentric clinical trial to demonstrate its safety.

To our knowledge, this is the first systematic review and meta-analysis of predictors of death drawn from all relevant studies of African children with strictly defined severe malaria. Methodological quality was assessed by using a priori adjusted and defined rules of the latest version of QUADAS-2 tool, which allowed better evaluation of risk of biases in several domains. In addition, this review assessed the disease severity criteria used in the SMAC studies [19]. Indeed, this represents the largest sample size ever recruited. The fact that the results did not change much when including or not prognostic indicators from the SMAC studies increases the robustness of the findings.

The main limitation of our analysis comes from the methodological or reporting weaknesses of some studies, of which the most important one is the lack of reproducibility of reported clinical symptoms and signs. Indeed, the inter-observer (clinician) agreement on the assessment of some of the signs, such as impaired consciousness or prostration for example, can be very low. Additionally, heterogeneity between studies regarding availability of laboratory data, threshold used to define abnormality, and quality of healthcare, especially with regards to blood transfusion and management of renal failure, need to be taken into account in results interpretation. Another limitation of our review is that it did not consider combinations of clinical and laboratory features of severe malaria because of the unavailability of individual records. It has been shown that having more than one manifestation of severe malaria increases the risk of dying [13] and this has to be taken into account in a child assessment of severity, and hence in case management. Furthermore, due to lack of data in the included studies, this meta-analysis could not explore the impact of other concurrent complications that do not form part of the definition of severe malaria but are known for increasing the risk of death such as, for example, bacteremia. In addition, since all data were aggregated in each study, we were not able to analyze predictors by age group or sex. This should not alter much the relevance of our findings since approximately 80% patient population was < 5 years of age and WHO has never considered a differential definition of severe malaria for children and adults or male and female. Finally, studies reporting less than 100 cases were excluded to reduce complexity, but some of those could have brought relevant information.