Relationship Between Exposure, Clinical Malaria, and Age in an Area of Changing Transmission Intensity

Abstract

The relationship between malaria transmission intensity and clinical disease is important for predicting the outcome of control measures that reduce transmission. Comparisons of hospital data between areas of differing transmission intensity suggest that the mean age of hospitalized clinical malaria is higher under relatively lower transmission, but the total number of episodes is similar until transmission drops below a threshold, where the risks of hospitalized malaria decline. These observations have rarely been examined longitudinally in a single community where transmission declines over time. We reconstructed 16 years (1991-2006) of pediatric hospital surveillance data and infection prevalence surveys from a circumscribed geographic area on the Kenyan coast. The incidence of clinical malaria remained high, despite sustained reductions in exposure to infection. However, the age group experiencing the clinical attacks of malaria increased steadily as exposure declined and may precede changes in the number of episodes in an area with declining transmission.

Malaria Parasites in the Asymptomatic: Looking for the Hay in the Haystack

“…Several studies have shown a shift in the peak of acute malaria incidence toward older ages as malaria exposure wanes [14,63], which may precede changes in the number of episodes and disease spectrum in an area with declining transmission intensities [64]. These observations illustrate that sustained reduction in exposure to malaria infection leads to changes in mean age and presentation of disease [65].…”

Evaluating antidisease immunity to malaria and implications for vaccine design

“…Usually, high levels of antibodies correlate with reduced parasitaemias,54 whereas antidisease effector processes are more associated with reduced levels of proinflammatory mediators, and are strongly associated with increased prior exposures 52, 55, 56, 57, 58, 59. As immunity against clinical episodes of malaria is positively associated with increased prior exposure (or age) in endemic areas,60, 61 antidisease mechanisms (targeted at ameliorating inflammation induced pathology) might be an important mechanism mediating protection against clinical symptoms. For instance, asymptomatic carriers harbour parasites without showing clinical symptoms are mainly found at high levels of exposure34 and generally have lower levels of proinflammatory cytokines, including tumour necrosis factor (TNF)‐ α and interferon (IFN)‐ γ , than symptomatic individuals 36, 62, 63…”

“…The threshold parasitaemia associated with fever (pyrogenic threshold) differs depending on the prevailing transmission intensity, 94 such that in children from areas of low‐to‐moderate transmission intensities, symptomatic malaria is associated with comparatively lower parasitaemia58, 61, 95, 96 and fewer children harbour parasites in a healthy state (asymptomatic carriers) 34. In the high‐transmission areas, however, this is often not the case, as higher parasite prevalence is observed in a healthy state,95 and most importantly higher parasitaemias are observed during clinical bouts of uncomplicated malaria 58, 97.…”

“…Two Senegalese studies also recently reported a decline in seroprevalence of antibodies to both pre‐erythrocytic and erythrocytic stage antigens in children, as the entomological inoculation rate (EIR) declined over the years 102, 103. Clearly, high exposure levels are associated with higher antibody levels, and children harbour higher parasitaemia before manifesting clinical symptoms 58, 61, 96. This observation, however, raises a question: how is it that highly exposed children from endemic areas are able to prevent aggravated immunopathology which should, supposedly, ensue from comparatively higher antigenaemia (parasitaemia)?…”

“…Thus, we propose that every parasite encounter would, presumably, require a higher parasitaemia (antigen load) to stimulate and activate immune cells. This mechanism may be at play at high exposure levels, as children from these areas often present with higher parasitaemia when sick,58, 61, 96, 133 suggesting that high antigen levels are required to stimulate immune cells to produce proinflammatory cytokines, which cause immunopathology.…”