Association between high levels of blood macrophage migration inhibitory factor, inappropriate adrenal response, and early death in patients with severe sepsis.
BACKGROUND
Identification of new therapeutic targets remains an imperative goal to improve the morbidity and mortality associated with severe sepsis and septic shock. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine and counterregulator of glucocorticoids, has recently emerged as a critical mediator of innate immunity and experimental sepsis, and it is an attractive new target for the treatment of sepsis.


METHODS
Circulating concentrations of MIF were measured in 2 clinical trial cohorts of 145 pediatric and adult patients who had severe sepsis or septic shock caused predominantly by infection with Neisseria meningitidis or other gram-negative bacteria, to study the kinetics of MIF during sepsis, to analyze the interplay between MIF and other mediators of sepsis or stress hormones (adrenocorticotropic hormone and cortisol), and to determine whether MIF is associated with patient outcome.


RESULTS
Circulating concentrations of MIF were markedly elevated in 96% of children and adults who had severe sepsis or septic shock, and they remained elevated for several days. MIF levels were correlated with sepsis severity scores, presence of shock, disseminated intravascular coagulation, urine output, blood pH, and lactate and cytokine levels. High levels of MIF were associated with a rapidly fatal outcome. Moreover, in meningococcal sepsis, concentrations of MIF were positively correlated with adrenocorticotropic hormone levels and negatively correlated with cortisol levels and the cortisol:adrenocorticotropic hormone ratio, suggesting an inappropriate adrenal response to sepsis.


CONCLUSIONS
MIF is markedly and persistently up-regulated in children and adults with gram-negative sepsis and is associated with parameters of disease severity, with dysregulated pituitary-adrenal function in meningococcal sepsis, and with early death.
Emonts
Marieke
M
Department of Pediatrics, Erasmus MC-Sophia Children's Hospital University Medical Center, Rotterdam, The Netherlands.
Sweep
Fred C G J
FC
Grebenchtchikov
Nicolai
N
Geurts-Moespot
Anneke
A
Knaup
Marlies
M
Chanson
Anne Laure
AL
Erard
Veronique
V
Renner
Pascal
P
Hermans
Peter W M
PW
Hazelzet
Jan A
JA
Calandra
Thierry
T
D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000328:Adult; D000368:Aged; D016470:Bacteremia / Q000097:blood* / Q000382:microbiology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000097:blood*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D007223:Infant; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood*; D008297:Male; D008585:Meningitis, Meningococcal / Q000097:blood; D008875:Middle Aged; D009345:Neisseria meningitidis; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D011446:Prospective Studies
D008263:Macrophage Migration-Inhibitory Factors; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone