Most families and communities in rural sub-Saharan Africa have little or no access to educational or rehabilitation resources and are ill-equipped to care for disabled children. If a child survives CM with severe, or even mild neurological deficits, their entire family may be subject to stigma, discrimination, and social isolation from their community . In countries such as Malawi—where most of the population live below the poverty line—financial strain, cultural pressure and the burdens of daily life leave little capacity to cope with additional adversity. As well as alienating the family from their community, stigma and discrimination have been shown to have a detrimental effect on post-CM care of the patient .
There is an increasing awareness of the burden of neurological sequelae post-CM [28,29,30] however there remains a knowledge gap as to its pathogeneses, causes and clinical associations . Previous studies have revealed that age, seizure frequency, prolonged fever and duration of coma symptoms are risk factors for cognitive impairment post-CM [9,10,11, 21, 22]. In this study coma duration prior to admission and younger age were identified as two significant drivers of neurosequelae in CM survivors (Fig. 2).
CM is typically more common in younger children. Other studies have also shown younger age to be associated with worse outcomes in CM survivors, children under the age of 5 showing considerably greater developmental delays one month after discharge, as well as more abnormal MRIs and associated impairment in cognitive ability, attention, and associative memory [21, 22]. Younger brains may be more vulnerable to CM as critical events in brain growth and development occur between birth and age 5 years . It is uncertain, however, whether the increased neuroplasticity at this age facilitates more rapid recovery from injury, contributes to more serious and sustained neurological damage, or both [31,32,33].
As the disease is frequently lethal, patients with CM should be given the highest level of available attention, preferably in an intensive care unit or local equivalent [3, 14]. Immediate anti-malarial medication, antipyretics, and anticonvulsants should be administered, with ACT being regarded as the “first-line of defence” in the outpatient setting . Clinical trials have established artemisinin-based combinations as being superior to other anti-malarials [34, 35] and they are now widely recommended as first-line drugs for treatment of malaria . Although prior treatment with ACT did not affect clinical outcome in this study, it showed a trend toward decreasing sequelae, which was not seen with mortality. The lack of a statistically significant result could be due to the relatively recent introduction of outpatient ACT, which limited the number of cases in the analysis.
Lactic acidosis is frequently observed in patients with severe malaria and is a prognostic factor for both mortality and poor outcome, [6, 36,37,38,39] with prolonged periods of hyperlactataemia possibly leading to neuronal dysfunction as well as death . A number of factors could potentially contribute to lactic acidosis in this setting, including parasite metabolism, aerobic glycolysis by activated immune cells, anaerobic glycolysis in hypoxic cells and tissues due to parasite sequestration and anaemia, and impeded clearance of lactate in the liver or kidneys . Studies in Ghana and Thailand showed that dichloroacetate decreased lactate levels but did not specifically decrease overall mortality in severe malaria cases [38, 40]. In one study in South Africa, HIV positive patients with severe malaria were significantly more likely to have lactic acidosis than HIV negative patients . Positive HIV status is a known risk factor for complicated malaria, increasing incidence and severity, as well as reducing the likelihood of successful treatment [17,18,19,20]. Although blood lactate concentration was strongly associated with mortality in this study, the effect of HIV on outcome was not significant when controlling for lactate levels.
Despite the advantages of readily available and effective medication, these benefits cannot be fully realised if children are delayed in reaching medical care. Extended coma duration prior to admission at hospital is an indicator of this delay to presentation in CM patients. Determinants of delay in seeking treatment for uncomplicated malaria have been studied in Ethiopia, Nigeria, Equatorial Guinea, and Tanzania [41,42,43,44,45], and the primary contributors are household duties and dynamics, socioeconomic status, and transportation problems. In Tanzania, diagnosis and treatment of uncomplicated malaria within 24 h of the onset of symptoms reduced progression to severe malaria and was associated with decreased mortality . These previous studies considered uncomplicated malaria, whereas this is the first to investigate the effect of coma duration prior to admission on clinical outcomes in CM specifically.
Coma duration prior to hospitalization surfaced as the most significant variable associated with sequelae in this analysis. A prolonged delay prior to appropriate hospital care could be due to multiple reasons. More than half of the patients whose comas lasted for ≥ 24 h prior to admission to hospital were linked to an institutional cause associated with the health care system and referral routes (Fig. 2, Table 3).
When considering the effect of delay to presentation on clinical outcome, it was originally hypothesised that a longer delay would lead to higher rates of both mortality and sequelae. On finding that there was a distinct contrast in the way the two outcomes were influenced, the differences between them became a point of interest for the study and two additional hypotheses were considered:
Clinical outcome evolves on a spectrum, from infection to death, with full recovery and variable states of survival with neurosequelae in between. This hypothesis assumes that all outcomes would be influenced by the same driving factors.
There are different causal pathways leading to full recovery, sequelae, and death, each with their own distinct drivers. This hypothesis assumes that the outcomes have independent pathways.
The results from the multinomial regression analysis suggested that the variables of interest influenced death and neurological sequelae differently, supporting the second hypothesis.
This study has the advantage of using data from one of the longest standing studies of the pathogenesis of CM, spanning 20 years and including over 1600 well-characterized cases from a single study site. Nevertheless, there were some limitations. Over the course of the study, both the standard of living and health care system in Malawi changed. Increased availability of transport could have made it easier for patients to reach hospital faster, for instance. Increased numbers of staff and more district health care centres may have led to more prompt treatment prior to arriving at the referral hospital. These are potential confounders. In addition, the determination of sequelae was made at discharge only, thus failing to capture both sequelae that developed over time, and the resolution of any sequelae seen at discharge. Extensive follow up data are being collected on a subset of these patients and further analysis will be informative. Data on time to presentation was collected via questionnaire completed by the parent or guardian in conjunction with research staff. Reporter bias might be inherent, with parents or guardians tending to minimize the amount of time that they delayed prior to taking action. In addition, the individual providing the history at the hospital may not be the same as the one present during the initial phases of the disease: for example, aunts and grandmothers often accompany the patient to the hospital when the mother is occupied at home with housework and care for the patient’s siblings. In addition, the parents or guardians may have an inaccurate perception of ‘coma’. These all lead to the measure of ‘coma duration prior to admission’ being a variable to be interpreted with care. In addition, there are possibly a subset of children that die quickly prior to reaching QECH. It is currently impossible to document these cases given the diagnostic and reporting capabilities in the more rural referral areas. This could lead to a selection bias in the cases being considered at the referral hospital. Each of these weaknesses would decrease the effect on outcome, however the presence of a striking differential effect of coma duration on sequelae and mortality emphasizes that there is still value in considering this variable. Finally, only a small number of comprehensive patient histories were available to determine reasons for delay to presentation, with fifty-seven of these having a coma duration of 24 h or longer.