Both very low- and very high in vitro cytokine responses were associated with infant death in low-birth-weight children from Guinea Bissau.
BACKGROUND
The mechanisms behind heterologous immunity and non-specific effects of vaccines on mortality are not well understood. We examined associations between cytokine responses and subsequent mortality in low-birth-weight infants in Guinea-Bissau.


METHODS
A low-birth-weight trial randomized children to Bacille Calmette-Guérin (BCG) at birth or later according to local policy. Blood samples were obtained from a sub-group at age 6 weeks. Interleukin (IL)-5, IL-10, IL-13, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α were measured in whole-blood cell cultures stimulated with lipopolysaccharide (LPS), phytohaemagglutinin (PHA), or purified protein derivative (PPD). The outcome was mortality between bleeding and 1 year of age. Non-linear associations between cytokine responses and mortality were examined.


RESULTS
Cytokine measurements were available from 390 children. The mortality rate (MR) was high (6.8/100 person-years-observation (PYO)). Both low and high cytokine responses to LPS and PHA were associated with high mortality (MR up to 25/100 PYO in the lowest 10% and 9.2/100 PYO in the highest 10%). In BCG-vaccinated children, higher IFN-γ responses to PPD were associated with better survival (MR ratio = 0.43 (0.24-0.77)).


CONCLUSIONS
Data presented a rare opportunity to explore associations between cytokine responses and mortality. Both low and high cytokine responses were associated with high mortality; a balanced response to invading pathogens seems preferable.
Research Center for Vitamins & Vaccines (CVIVA), Bandim Health Project, Statens Serum Institute, Copenhagen, Denmark; Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau.
Andreas
A
Andersen
Research Center for Vitamins & Vaccines (CVIVA), Bandim Health Project, Statens Serum Institute, Copenhagen, Denmark; Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau.
Kristoffer J
KJ
Jensen
Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
Christian
C
Erikstrup
Research Center for Vitamins & Vaccines (CVIVA), Bandim Health Project, Statens Serum Institute, Copenhagen, Denmark; Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau.
Henrik
H
Ravn
Research Center for Vitamins & Vaccines (CVIVA), Bandim Health Project, Statens Serum Institute, Copenhagen, Denmark; Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau.
Ane B
AB
Fisker
Department of Pathology, Herlev University Hospital, Herlev, Denmark.
Ida M
IM
Lisse
Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.
Erliyani
E
Sartono
Research Center for Vitamins & Vaccines (CVIVA), Bandim Health Project, Statens Serum Institute, Copenhagen, Denmark; Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau.
Peter
P
Aaby
Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.
Maria
M
Yazdanbakhsh
Research Center for Vitamins & Vaccines (CVIVA), Bandim Health Project, Statens Serum Institute, Copenhagen, Denmark; Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau; OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark.
Christine S
CS
Benn
D001500:BCG Vaccine / Q000009:adverse effects* / Q000276:immunology; D002423:Cause of Death; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D005260:Female; D006169:Guinea-Bissau / Q000453:epidemiology; D006801:Humans; D064789:Immunity, Heterologous; D007223:Infant; D007230:Infant, Low Birth Weight / Q000097:blood / Q000276:immunology*; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D009026:Mortality; D014611:Vaccination / Q000009:adverse effects
D001500:BCG Vaccine; D016207:Cytokines; D008070:Lipopolysaccharides; D007371:Interferon-gamma