title: Febrile illness and pro-inflammatory cytokines are associated with lower neurodevelopmental scores in Bangladeshi infants living in poverty.
abstract: BACKGROUND
  An estimated one-third of children younger than 5 years in low- and middle-income countries fail to meet their full developmental potential. The first year of life is a period of critical brain development and is also when most of the morbidity from infection is suffered. We aimed to determine if clinical and biological markers of inflammation in the first year of life predict cognitive, language, and motor outcomes in children living in an urban slum in Bangladesh.
  
  
  METHODS
  Children living in Dhaka, Bangladesh were observed from birth until 24 months of age. Febrile illness was used as a clinical marker of inflammation and elevated concentrations of inflammation-related cytokines (IL-1β, IL-6, TNF-α, IL-4, IL-10) in sera collected from a subset of the cohort (N = 127) at 6 months of age were used as biomarkers of inflammation. Psychologists assessed cognitive, language, and motor development using a culturally adapted version of the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 12 (N = 398) and 24 months of age (N = 210). We tested for the ability of febrile illness and elevated cytokine levels to predict developmental outcomes, independent of known predictors of stunting, family income, and maternal education.
  
  
  RESULTS
  Every additional 10 days of fever was associated with a 1.9 decrease in language composite score and a 2.1 decrease in motor composite score (p = 0.005 and 0.0002, respectively). Elevated levels of the pro-inflammatory cytokines IL-1β (> 7.06 pg/mL) and IL-6 (> 10.52 pg/mL) were significantly associated with a 4.9 and 4.3 decrease in motor score, respectively. Conversely, an elevated level of the Th-2 cytokine IL-4 (> 0.70 pg/mL) was associated with a 3.6 increase in cognitive score (all p < 0.05).
  
  
  CONCLUSIONS
  Clinical and biological markers of inflammation in the first year of life were significantly associated with poor neurodevelopmental outcomes. Conversely, a Th2-like response was associated with a better outcome. These findings suggest that markers of inflammation could serve as prognostic indicators and potentially lead to immune-based therapies to prevent developmental delays in at-risk children.
authors.forename: Nona M
authors.initials: NM
authors.lastname: Jiang
authors.forename: Fahmida
authors.initials: F
authors.lastname: Tofail
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Moonah
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Scharf
authors.forename: Mami
authors.initials: M
authors.lastname: Taniuchi
authors.forename: Jennie Z
authors.initials: JZ
authors.lastname: Ma
authors.forename: Jena D
authors.initials: JD
authors.lastname: Hamadani
authors.forename: Emily S
authors.initials: ES
authors.lastname: Gurley
authors.forename: Eric R
authors.initials: ER
authors.lastname: Houpt
authors.forename: Eduardo
authors.initials: E
authors.lastname: Azziz-Baumgartner
authors.forename: Rashidul
authors.initials: R
authors.lastname: Haque
authors.affiliation: Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, PO Box 801340, Charlottesville, VA 22908, USA. wap3g@virginia.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Petri
mesh_terms: D001459:Bangladesh; D001921:Brain / Q000254:growth & development*; D002657:Child Development; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D005260:Female; D005334:Fever / Q000097:blood / Q000276:immunology* / Q000503:physiopathology*; D006801:Humans; D007223:Infant; D008297:Male; D011203:Poverty; D011446:Prospective Studies
chemical_list: D016207:Cytokines