Investigating Differences in Nutritional Parameters in Ugandan Children with Plasmodium falciparum Severe Malaria

Background: In 2018, malaria produced an estimated 272,000 deaths in children <5 years of age, accounting for 67% of all malaria deaths worldwide, with a majority in the WHO African Region. Malnutrition is an important risk factor for malaria. Wasting, Stunting and Underweight are crucial indicators of malnutrition. Annually, 14 million children <5 are classified as wasted and 59 million children are classified as stunted.   
Objective: The objective of this study is to determine the association between each of the major manifestations of severe malaria (SM) and nutritional parameters – weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ) – in children from the Ugandan cities Mulago and Jinja.   
Methods: To assess differences in WAZ, HAZ, and WHZ by the five types of SM and community controls (CC), we evaluated Z-scores from children <5 years old enrolled in a prospective cohort study (NDI, Neurodevelopmental Impairment in Children with Severe Malaria) at enrollment and 12-month follow-up.   
Results: WAZ and WHZ at baseline were significantly lower among SM groups than in CC (p<0.001), but there were no significant differences observed at 12-month follow-up. There were no major differences in HAZ between the SM and CC groups. WAZ and HAZ at baseline were significantly lower among High Mortality (HM) versus Low Mortality (LM) groups (p<0.01). At 12-month follow-up, HAZ remained significantly lower in HM versus LM (p<0.01). There were no major differences in WHZ between the HM and LM groups. Compared to those who survived, the 27 children who died had significantly lower WAZ (p<0.05), but no major differences in HAZ or WHZ.  
Conclusion: Underweight, stunting, and wasting may be risk factors for SM. Overall, a more comprehensive understanding of how SM elicits adverse effects in children is necessary. Nutrition intervention programs must be implemented to prevent child stunting, wasting, underweight, and mortality. 

Ø are infected with P. falciparum each year in Sub-Saharan Africa. 1   Ø In 2018, malaria produced an estimated in children <5 years. 1   Ø Worldwide, are among children <5 years. 1   Ø Uganda carries of the global malaria burden.

STATISTICAL ANALYSIS
Nutritional Markers of Interest: Ø WAZ0 and WAZ12, Weight-for-Age Z-score at 0 and 12 months, <2SD is underweight Ø HAZ0 and HAZ12, Height-for-Age Z-score at 0 and 12 months, <2SD is stunting Ø WHZ0 and WHZ12, Weight-for-Height Z-score at 0 and 12 months, <2SD is wasting a Z-score is widely recognized as the most important descriptor for analysis and presentation of malnutrition data in children.WAZ and WHZ at baseline were significantly lower (p<0.001)among SM groups than in community controls (CC).

Characteristic
WAZ and HAZ at baseline were significantly lower (p<0.01)among high mortality (HM) groups than in low mortality (LM) groups.At 12-month follow-up, HAZ remained significantly lower (p<0.01) in HM vs. LM.Children who died at admission or following discharge (CM, N=20; RDS, N=7).had significantly lower WAZ (p<0.05) compared to those who survived.

DISCUSSION
Malaria as a Causal Agent for Malnutrition: In Ethiopia, previous exposure to P. falciparum infection was a predictor for the manifestation of malnutrition in children <5, and children previously exposed to malaria were 1.87 times more likely to be malnourished than children unexposed to malaria (Gone et al., 2017).
A study of P. vivax in the Brazilian Amazon suggested that children who had previously suffered malaria episodes presented worse anthropometric parameters, notably reduced linear velocity (Alexandre et al., 2015).
In Niger, children with malaria infection at admission and subsequently treated with an artemisinin-based combination therapy had reduced height gain, at -0.002 mm/day.Malaria infection may impair height gain (Oldenberg et al., 2018).

These findings are substantiated by other studies on malnutrition and malaria:
Malnutrition as a Causal Agent for Malaria: Stunting, but not wasting, has been shown to be significantly associated with down-regulation of the anti-P.falciparum antibodies in pre-school children in Senegal, thereby modulating the overall immune response and increasing risk of infection (Fillol et al., 2009).

Stunting as a Protective Agent Against Malaria:
A study from Papua New Guinea found that stunting decreased susceptibility to malaria-related morbidity in children.They proposed that parasites cannot proliferate in a host that is protein-deprived; therefore, there may be potentially beneficial effects of micronutrient deficiencies, particularly vitamin E and riboflavin (Genton et al., 1998).
However, we have shown that stunting was the only nutritional parameter that remained significantly lower in HM groups at the 12month follow-up.ØUnderweight, stunting, and wasting may be risk factors for severe malaria.

These findings conflict with older studies on malaria and stunting:
ØOverall, improving nutritional status among children in Uganda is necessary to prevent malnutrition, to combat child mortality, and to reduce the global disease burden caused by severe malaria.
ØFuture directions include studying undernutrition as a causative risk factor for development of severe malaria by isolating children who acquired malaria during the study.

Figure 4a .Figure 4b .
Figure 4a.Nutritional markers according to disease group at baseline

Table 2a .
Nutritional markers according to disease group at baseline

Table 2b .
Nutritional markers according to disease group at 12 months a For variables for which N is less than the total N listed for group, N's for that variable and group are noted in table a For variables for which N is less than the total N listed for group, N's for that variable and group are noted in table