Dengue virus infection usually causes a severe flu like illness, although symptoms may be mild in young children. DHF, however, is a severe and sometimes fatal complication of dengue virus infection that affects about half a million people every year after infection with any one of the four dengue virus (DENV) serotypes. DHF patients usually fall into two groups; children and adults who become infected with a second dengue virus serotype after an initial primary dengue virus infection with a different serotype, and infants with primary dengue virus infections born to mothers who have some dengue virus immunity. The widely accepted explanation for the pathogenesis of DHF in these settings, particularly during infancy, is antibody-dependent enhancement (ADE) of DENV infection.
Researchers conducted a prospective nested case-control study of DENV infections during infancy. Clinical data and blood samples were collected from 4,441 mothers and infants in up to two pre-illness study visits, and surveillance was performed for symptomatic and inapparent DENV infections. Pre-illness plasma samples were used to measure the associations between maternally derived anti-DENV3 antibody-neutralizing and enhancing capacities at the time of DENV3 infection and development of infant DHF. The study examined 60 infants with DENV infections across a wide spectrum of disease severity. DENV3 was the predominant serotype among the infants with symptomatic (35/40) and inapparent (15/20) DENV infections, and 59/60 infants had a primary DENV infection. The estimated in vitro anti-DENV3 neutralizing capacity at birth positively correlated with the age of symptomatic primary DENV3 illness in infants. At the time of symptomatic DENV3 infection, essentially all infants had low anti-DENV3 neutralizing activity and measurable DENV3 ADE activity. The infants who developed DHF did not have significantly higher frequencies or levels of DENV3 ADE activity compared to symptomatic infants without DHF. A higher weight-for-age in the first 3 mo of life and at illness presentation was associated with a greater risk for DHF from a primary DENV infection during infancy. This prospective nested case-control study of primarily DENV3 infections during infancy has shown that infants exhibit a full range of disease severity after primary DENV infections.
The current model for development of DHF in infants around 6 months old is that anti-dengue virus antibodies transferred from a dengue-immune mother to her child somehow enhance dengue virus infection, resulting in more severe symptoms (the antibody-dependent enhancement model). These results support an initial in vivo protective role for maternally derived antibody. There was no significant association between DENV3 ADE activity at illness onset and the development of DHF compared with less severe symptomatic illness. The results of this study should encourage rethinking or refinement of the current ADE pathogenesis model for infant DHF and stimulate new directions of research into mechanisms responsible for the development of DHF during infancy.
A Prospective Nested Case-Control Study of Dengue in Infants: Rethinking and Refining the Antibody-Dependent Enhancement Dengue Hemorrhagic Fever Model. PLoS Med 6(10): e1000171 doi:10.1371/journal.pmed.1000171