Sepsis-Induced Immunosuppression in Neonates

Hib­bert et al, Front Pedi­atr. 2018

Abstract

Neonates, espe­cial­ly those born preterm, are at increased risk of sep­sis and adverse long-term effects asso­ci­at­ed with infec­tion-relat­ed inflam­ma­tion. Dis­tinct neona­tal immune respons­es and dys­reg­u­lat­ed inflam­ma­tion are cen­tral to this unique sus­cep­ti­bil­i­ty. The tra­di­tion­al sep­a­ra­tion of sep­sis into an ini­tial hyper-inflam­ma­to­ry response fol­lowed by hypo-inflam­ma­tion is con­tin­u­al­ly under review with new devel­op­ments in this area of research. There is evi­dence to sup­port the asso­ci­a­tion of mor­tal­i­ty in the ear­ly acute phase of sep­sis with an over­whelm­ing hyper-inflam­ma­to­ry immune response. Emerg­ing evi­dence from adults sug­gests that hypo- and hyper-inflam­ma­tion can occur dur­ing any phase of sep­sis and that sep­sis-immuno­sup­pres­sion is asso­ci­at­ed with increased mor­tal­i­ty, mor­bid­i­ty, and risk to sub­se­quent infec­tion. In adults, sep­sis-induced immuno­sup­pres­sion (SII) is char­ac­terised by alter­ations of innate and adap­tive immune respons­es, includ­ing, but not lim­it­ed to, a promi­nent bias toward anti-inflam­ma­to­ry cytokine secre­tion, dimin­ished anti­gen pre­sen­ta­tion to T cells, and reduced acti­va­tion and pro­lif­er­a­tion of T cells. It is unclear if sep­sis-immuno­sup­pres­sion also plays a role in the adverse out­comes asso­ci­at­ed with neona­tal sep­sis. This review will focus on explor­ing if key char­ac­ter­is­tics asso­ci­at­ed with SII in adults are observed in neonates with sep­sis.

Conclusions

Sep­sis mor­tal­i­ty in neonates may be asso­ci­at­ed with alter­ations in immune func­tion that are in agree­ment with SII find­ings in adults. Whether immune cell dys­func­tion or impair­ment under­pins immuno­sup­pres­sion in neona­tal sep­sis requires fur­ther inves­ti­ga­tion and stronger evi­dence. Large, col­lab­o­ra­tive lon­gi­tu­di­nal stud­ies, from birth through to child­hood, are essen­tial to eval­u­ate immune changes in neonates with sep­sis, includ­ing the role for SII. Yet, first a defin­i­tive con­sen­sus on the def­i­n­i­tion of neona­tal sep­sis and sever­i­ty needs to be estab­lished. Until then, sep­sis sever­i­ty could be mea­sured by mor­tal­i­ty. Advances in fur­ther under­stand­ing the immuno­log­i­cal mech­a­nisms behind immuno­sup­pres­sion may lead to effec­tive tar­get­ed treat­ment ther­a­pies for revers­ing or mod­u­lat­ing SII and improve out­comes. Immuno­sup­pres­sion rever­sal with PD-1/PD-L1 anti­body block­ade is cur­rent­ly being tri­alled in adult can­cer patients who share sim­i­lar immune defects as those with SII (151). Fur­ther­more, pen­tox­i­fylline, an immune mod­u­la­to­ry drug, is cur­rent­ly being tri­alled to improve long-term out­comes, pri­mar­i­ly neu­rode­vel­op­ment impair­ment, asso­ci­at­ed with neona­tal sep­sis (ANZCTR ACTRN12616000405415). Assess­ing the impact of such inter­ven­tions on SII-asso­ci­at­ed mark­ers may pro­vide a mech­a­nis­tic insight into the suc­cess or fail­ure of these inter­ven­tions in pre­vent­ing short and long-term neg­a­tive sep­sis out­comes.

  • Next Conference Port-Said Neonatology 15/10/2019