Abstract
BackgroundPrevious investigations and meta-analyses on the effect of glucocorticoids on mortality in septic shock revealed mixed results. This heterogeneity might be evoked by genetic variations. Such candidate is a promoter polymorphism (-94ins/delATTG) of the gene encoding the ubiquitous transcription-factor nuclear-factor-κB (NF-κB) which binds to recognition elements in the promoter of several genes encoding for the innate immune-system. In turn, hydrocortisone inhibits NF-κB nuclear translocation and thus transcription of key immune-response regulators. Accordingly, we tested the hypotheses that hydrocortisone has a NFKB1 genotype dependent effect on 1) NF-κB1 nuclear translocation evoked by lipopolysaccharide (LPS) in monocytes in vitro, and 2) mortality in septic shock.MethodsMonocytes of volunteers with the homozygous insertion (II; n = 5) or deletion (DD; n = 6) NFKB1 genotype were incubated with 10 µgml-1 LPS ± hydrocortisone (10-5M), and NF-κB1 nuclear translocation was assessed (immunofluorescence). Furthermore, we analyzed 30-day-mortality in 160 patients with septic shock stratified for both genotype and hydrocortisone therapy.ResultsHydrocortisone inhibited LPS induced nuclear translocation of NF-κB1 in II (25%±11;p = 0.0001) but not in DD genotypes (51%±15;p = n.s.). Onehundredandfour of 160 patients with septic shock received hydrocortisone, at the discretion of the intensivist. NFKB1 deletion allele carriers (ID/DD) receiving hydrocortisone had a much greater 30-day-mortality (57.6%) than II genotypes (24.4%; HR:3.18, 95%-CI:1.61-6.28;p = 0.001). In contrast, 30-day mortality was 22.2% in ID/DD and 25.0% in II genotypes without hydrocortisone therapy. Results were similar when using propensity score matching to account for possible bias in the intensivists' decision to administer hydrocortisone.ConclusionHydrocortisone fails to inhibit LPS induced nuclear NF-κB1 translocation in deletion allele carriers of the NFKB1 promoter polymorphism (-94ins/delATTG). In septic shock, hydrocortisone treatment is associated with markedly increased 30-day-mortality only in such carriers. Accordingly, previous heterogeneous results regarding the benefit of hydrocortisone in septic shock may be reconciled by genetic variation of the NFKB1 promoter polymorphism.
Highlights
Over more than two decades studies have shown both positive and negative effects on mortality of hydrocortisone therapy in septic shock [1,2,3] While Annane et al reported a decreased 28day mortality with hydrocortisone therapy [4], others did not find an influence on mortality [1,2,5], and even an increased mortality has recently been reported [3]
The uncertainty of the therapeutic value of hydrocortisone therapy in septic shock is reflected by the current Surviving Sepsis Campaign guidelines, in which hydrocortisone administration in septic shock is recommended with an evidence grade 2C only [6]
A candidate gene is the gene encoding the ubiquitous nuclear transcription factor kB (NF-kB1), which binds to recognition elements in the promoter regions of several genes encoding for the innate immune system and induces an inflammatory response [7,8]
Summary
Over more than two decades studies have shown both positive and negative effects on mortality of hydrocortisone therapy in septic shock [1,2,3] While Annane et al reported a decreased 28day mortality with hydrocortisone therapy [4], others did not find an influence on mortality [1,2,5], and even an increased mortality has recently been reported [3]. Recently we revealed that this polymorphism is associated with increased NFKB1 gene expression as well as nuclear translocation of the NF-kB protein following lipopolysaccharide (LPS) stimulation [12]. This polymorphism is an independent risk factor for 30-day mortality in patients with severe sepsis [12]. Previous investigations and meta-analyses on the effect of glucocorticoids on mortality in septic shock revealed mixed results This heterogeneity might be evoked by genetic variations. Such candidate is a promoter polymorphism (-94ins/delATTG) of the gene encoding the ubiquitous transcription-factor nuclear-factor-kB (NF-kB) which binds to recognition elements in the promoter of several genes encoding for the innate immune-system. We tested the hypotheses that hydrocortisone has a NFKB1 genotype dependent effect on 1) NF-kB1 nuclear translocation evoked by lipopolysaccharide (LPS) in monocytes in vitro, and 2) mortality in septic shock
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