Low adiposity during early infancy is associated with a low risk for developing dengue hemorrhagic fever: a preliminary model

Dengue virus (DENV) infections range from asymptomatic or mild illness to a severe and potentially life threatening disease, dengue hemorrhagic fever (DHF). DHF occurs in primary DENV infections during early infancy. A prospective clinical study of DENV infections during infancy was conducted in San Pablo, Philippines. We found that infants who developed DHF with a primary DENV infection had higher WHO weight-for-age z scores before and at the time of infection compared to infants with primary DENV infections who did not develop DHF. In addition, TLR 7/8-stimulated tumor necrosis factor-alpha (TNF-alpha) production from myeloid-derived cells was higher among well-nourished infants. Leptin augmented TLR 7/8-mediated TNF-alpha production in monocytes and decreased intracellular cAMP levels. Circulating leptin levels were elevated during early infancy and correlated with WHO weight-for-age z scores. Our data support a plausible hypothesis as to why well-nourished infants are at risk for developing DHF with their first DENV infection

Effect of leptin pre-treatment on (a) tumor necrosis factor (TNF)-α production and (b) intracellular cAMP levels in CD14+ monocytes.

<p>Recombinant human (rh) leptin was added to CD14+ monocytes from non-obese adult male donors 1 h before stimulating with R-848 (5 µM) (<i>n</i> = 6 independent experiments). Cell-free culture supernatants were collected 6 h later for TNF-α ELISAs, and cell lysates were collected for cAMP ELISAs. Bars and error bars are median values and S.D., respectively. * p = 0.03 compared to no leptin pre-treatment. † p = 0.046 compared to no leptin pre-treatment.</p

Intracellular cytokine staining for tumor necrosis factor-α (TNF-α) production in R-848 (1 µM) stimulated infant peripheral blood mononuclear cells (PBMC) from the first study visit in an undernourished/malnourished state (WHO weight-for-age (w-a) z score<−2) compared to a well-nourished state (WHO w-a z score ≥−2).

<p>Bars are median values. P-values are from non-parametric statistical tests. (a) Percentage of TNF-α+ monocytes, and (b) TNF-α median fluorescence intensity (MFI) in monocytes. Unstimulated condition subtracted from the values for each donor.</p

Longitudinal assessment of plasma leptin levels in <i>n</i> = 38 healthy infants over the first year of life.

<p>Symbols and error bars are median values and 95% confidence intervals.</p

World Health Organization (WHO) weight-for-age z scores of infants with primary dengue virus (DENV) infections (a) at the time of acute illness and (b) at the first study visit, before the primary DENV infection.

<p>Boxplot bars are median values, box outlines are 25^th and 75^th percentiles, and error bars are 10^th and 90^th percentiles. Ages are presented as median [95% confidence interval]. ^† p-values for primary DENV-infected infants with unambiguous dengue hemorrhagic fever (DHF) compared to those without DHF (non-parametric statistical tests).</p