Non-traumatic coma in younger kids in Benin: are viral and bacterial infections gaining floor on cerebral malaria? | Infectious Ailments of Poverty

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We attempted to fill a gap of knowledge on the etiologies, clinical history, clinical and biological profiles, management and outcome of non-traumatic coma in small children from West Africa, a part of the world where access to investigations is limited most of the times to malaria diagnosis. Our prospective study was performed in teaching hospitals and specifically designed to decipher the etiologies of non-traumatic comas, with the help of an independent panel of experts in order to limit the risk of misdiagnosis, provided that non-malarial etiologies could represent a substantial part of the cases. We identified only six children with no evidence of malaria. Three of them had a potentially lethal infection [measles, dengue fever, and E. coli bloodstream infection (BSI)]. The remaining three had no evidence of meningitis or BSI and had a favorable outcome. These findings contrast with those from other parts of the world where non-infectious (metabolic, vascular) etiologies of comas are more prevalent [15, 16].

A study performed in 2013 in Malawi showed that adenovirus infection is the most common cause of viral CNS infection leading to hospitalization or death. Our results do not corroborate this finding. Five types of viruses, including two arboviruses (one dengue virus and one WNV), were identified in eight children. A measles epidemic occurred during the study period, and we found five children with specific measles IgM as indirect diagnosis of measles, three of whom were coinfected with malaria. The infection could have been prevented in the 3 unvaccinated children. The first confirmed cases of dengue fever acquired in Benin were reported in 2010; Since then, few cases have been reported [17]. Endemicity of WNV in animals and humans has been reported in Nigeria, a country neighboring Benin [18], but we found no case reports of WNV infections from Benin in the literature, including in returning travelers: so it will be the first report. While dengue is transmitted during the day by the bite of a mosquito of the genus Aedes, WNV is transmitted by mosquitoes of the genus Culex which have a nocturnal activity like the anopheles which transmit malaria. The use of mosquito nets thus ensures a prevention of the transmission of these 2 infections. In our study, mortality was higher in children with coinfections, but the small number of children predicted drawing firm conclusions. According to a large study on the role of viral CNS coinfections in CM, viral CNS infections are unlikely to contribute to coma [19].

Overall, three BSIs were identified at admission (two coinfections with malaria, one of which was potentially nosocomial). Therefore, tracking BSI is essential in the management of non-traumatic coma. We assume that the child with malaria and an aseptic purulent meningitis coinfection died of meningitis. In a systematic review of invasive bacterial coinfection in African children with P. falciparum malaria, the proportion of BSI was estimated at 6.4% [20], and this proportion was not higher in the study setting. Because it is recommended that all children presenting with severe malaria in areas of intermediate and high transmission receive broad-spectrum antibiotics in addition to antimalarial therapy [21]we believe that this also applies to the management of non-traumatic coma, although only a minority of the children was prescribed antibiotics in this study.

CM was the most common cause of non-traumatic coma. In this part of Africa, as well as in other areas endemic for malaria, public health policy efforts have focused on implementing strategies for malaria prevention (eg, distribution of bed nets) and severe malaria prevention (eg, affordable, efficient drugs for uncomplicated malaria ). Despite this, the remaining substantial burden of severe disease related to malaria should not be neglected. It has been advocated that continuing investment for clinical research on severe malaria is needed [22]. Health policies should also not overlook the need for health facilities that can provide adequate care to children with life-threatening forms of the disease. This is especially true when it comes to access to blood transfusions [23]. Among the planned standardized care procedures and given the large proportion of children with severe anemia in this study, blood transfusions were the most challenging treatment to provide to these children in an emergency. This is an important issue, with many children who had hemoglobin concentrations above the currently recommended transfusion threshold receiving as many transfusions as possible in both hospitals, because this is reportedly associated with improved survival in children with coma and hyperlactatemia [24].

A large majority of the children reported one or more visits with a healthcare professional before admission. For most children in whom CM was eventually diagnosed, missed opportunities for early and effective antimalarial treatment were found. Effort is thus needed to enhance access to affordable and efficient drugs for uncomplicated malaria [8, 25].

Our study also provides information on the risk factors of early death in this population, some of them being unexpected. Mortality remained high despite access to standardized care including intravenous artesunate, and broad-spectrum antibiotics, performed by an experienced teaching hospital staff. Most deaths occurred within a few hours of admission. This is likely because this study involved the most severe forms of CM in the majority of children, sepsis, and other life-threatening diseases. However, malaria and/or another infection were found in all children who died. Some of these children could have benefited from intensive care. As in many other low income countries [26], there is a growing appreciation of the importance of pediatric acute care at the study sites. This is why we evaluated characteristics at admission associated with mortality.

Among the biological anomalies encountered in sepsis, regardless of its etiology, Jaundice and/or increased bilirubin, as well as lactate above 5 mmol/L at admission were the strongest predictors of subsequent death. This is not surprising because these are additional severity criteria for coma in severe malaria [27]. Furthermore, an increased bilirubin level increases the sequential organ failure assessment score [28]and the total bilirubin and lactate levels are key parameters in a validated mortality risk model for pediatric sepsis [29].

Unexpectedly, a history of antibiotic intake declared before admission and a vaccination against yellow fever were predictors of a better outcome in these children. Antibiotics might have had a protective effect against mortality because some of the children had a bacterial monoinfection or coinfection with malaria. Most deaths occurred shortly after admission, before any emergency antibiotic prescription could have been effective. Antibiotics given before admission may play a role in protecting against a fatal outcome, including in children with CM. It may also be an indicator of a better overall management of these children, independently of the treatment administered.

Yellow fever was not among the diseases screened for in this study; therefore, it is not possible to state that no yellow fever co-infection existed. More frequent yellow fever co-infections in the children who died might have worsened their prognosis. Another explanation for the protective effect of the yellow fever vaccine could be a non-specific protective effect of this live vaccine. Non-specific effects of live vaccines have been described for the smallpox, BCG, oral polio, and measles vaccines in experimental and observational studies [30]. In Burkina Faso, before mass vaccinations against meningitis and measles, a measles and yellow fever vaccine was associated with reduced mortality [31]. In Guinea-Bissau, measles and yellow fever vaccines were associated with stronger beneficial effects in girls than in boys [32]. In South Benin, the measles and yellow fever vaccines are administered in principle on the same day, but shortages sometimes occur, which may explain why the respective vaccination rates sometimes differ between the two vaccines, leading to a discrepancy in their protective effect against mortality in our analysis.

This study has several limitations. Data on clinical history, based on parents/guardians interview at admission and health booklet review may have not been exhaustive. We raised no brain imaging data and we may have missed for example cerebral tumors or bleeding as a cause of coma. The study was not designed to diagnose measles: there was no repeated serologies, and the diagnosis is less robust than for other etiologies. However, we are confident that the diagnoses of CM and infections by non-malaria pathogens have been quite exhaustive and reliable, due to the high quality of laboratory testing and the use of a panel of experts to ensure the best classification of the patients. Finally, despite the fact that this study ranks among the largest cohorts of severe comas in African children and the only one performed in West Africa, it may have lacked power to extensively identify the factors associated with death outcomes. Although NeuroCM was mainly a case–control study to explore inflammation in comatose vs non-comatose malaria infected children [11]not specifically designed to define the risk factors of early death in the former population, it still allowed to clearly evidence significant variables, usual (hyperlactatemia and elevated bilirubin) as well as more novel (antibiotics intake, yellow fever immunization).

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