The major finding of the present study is the importance of prompt and adequate antibiotic therapy on admission to hospital in patients with sepsis. Timely adequate antibiotic administration is associated with decreased mortality and a reduction in the impairment of inflammatory response, whereas there are no strong associations between selected TNF and IL-10 polymorphisms and outcomes.
The main purpose of identifying factors independently associated with mortality among septic patients is to recognize those variables associated with high risk for death. From a practical point of view, identified factors should be modifiable with medical interventions or be incorporated into our therapeutic arsenal if they are to achieve a reduction in mortality. The impact on outcome of early antibiotic treatment has been demonstrated for infections such as community-acquired pneumonia [22
], although in patients with community-acquired meningitis there was a trend only in those who were less severely ill [23
]. Interestingly, the impact of early adequate antibiotic therapy in patients with sepsis has never been assessed.
By multivariate analysis, we found that the risk for in-hospital mortality increased by 9% for every hour of delay to administration of the correct antibiotic regimen. Moreover, in patients with septic shock, the only independent predictor of in-hospital mortality was delayed administration of adequate antibiotic therapy. This finding is of great importance because septic shock is associated with high mortality rates, and the association of septic shock with death persists after adjusting for prognostic factors such as organ failure [2
]. Valles and coworkers [4
] found that inadequate antibiotic therapy was the most important determinant of survival in bacteraemic patients, and this finding was even more marked in patients with septic shock.
In the present study, mortality rates of septic patients with and without nosocomial infection were similar, although the incidence of sepsis in our study was lower than that in other series [24
]. It should not be overlooked that one-fifth of our patients were not admitted to the ICU, we only noted severe nosocomial infections (urinary and wound infections were not noted), and community-acquired infection is a protective factor with respect to nosocomial infection in the ICU [25
]. In any case, the impact on outcome of hospital-acquired infection seems not to be crucial in patients with sepsis at admission, and mortality is more directly related to the severity of illness and the initial management.
Approximately half of the patients presenting with sepsis deteriorated to a more severe stage in the inflammatory response during subsequent days [26
]. In a recent multicentre study, Alberti and coworkers [27
] proposed a score to forecast which patients may present with a deteriorating clinical state. In the present study, using two different approaches, delayed initiation of adequate antibiotic therapy was an independent predictor of impairment in inflammatory response. This is of the utmost importance because the more severe the inflammatory response, the greater the mortality rate.
Genetic variations within the TNF and IL-10 genes may influence mortality rates in patients with sepsis. Polymorphisms in these genes may determine the concentrations of proinflammatory and anti-inflammatory cytokines, and may influence whether patients have a marked hyper-inflammatory or anti-inflammatory response to infection. A delicate balance between inflammation and anti-inflammation is required if the adverse effects associated with predominance of either state is to be avoided. In sepsis, that elevated IL-10 serum levels have been associated with poor outcome might be a result of the development of immunoparalysis and increased risk for multiple organ dysfunction syndrome [9
Previous studies have yielded conflicting findings on the impact on outcome of the two TNF polymorphisms in septic patients. In the case of the -308 (G/A) polymorphism, the frequency of TNF-2 (containing 'A') was higher among those septic shock patients who died, and this genotype was an independent predictor of mortality on multivariate analysis [10
]. This association was also found by other investigators [28
], but others were unable to demonstrate an association between this polymorphism and outcome in patients with sepsis [11
]. Similar contradictory findings have been reported in the case of TNF-β (Nco
I polymorphism); mortality in severe sepsis was higher in TNFB2 (AA) individuals [29
], although other investigations found no such association [31
]. A recent study enrolling 213 patients with severe sepsis [32
] found no association between these polymorphisms and mortality. In our series, 72.5% of those who were GG homozygous for TNF-α-308 were AA homozygous for TNF-β' polymorphism, which is in agreement with a recent study that found these two polymorphisms to be in strong linkage disequilibrium [33
Two studies conducted in patients with community-acquired pneumonia [34
] found no association between the two TNF polymorphisms or the IL-10-1082 polymorphism and risk for developing septic shock or mortality. Moreover, patients with invasive pneumococcal disease who were GG homozygous for the IL-10-1082 polymorphism exhibited greater risk for septic shock, whereas mortality was unaffected [36
]. In this study, the two TNF polymorphisms were not associated with a worse evolution of disease.
There is currently extensive disagreement on the value of association studies for the detection of genetic variants that contribute to death, especially in complex situations such as sepsis. Diverse methodological pitfalls may account for many contradictory results. Moreover, it must be acknowledged that the biological role of many of these polymorphisms remains to be elucidated. Thus, recent functional studies suggest that the much studied 308 G/A polymorphism is not functional, whereas the function of other TNF polymorphism remains controversial [37
We acknowledge several limitations of our study. First, although a protocol following current recommendations for treatment of sepsis and septic shock was used (intravenous corticosteroids, continuous infusion of insulin and mechanical ventilation with low tidal volumes), we did not control certain variables that could have influenced outcomes, such as the total amount of fluid infused in the first few hours [38
]. Second, the use of recombinant activated protein C in our study was very restricted, although this is not unusual in clinical practice [39
]. Third, only three polymorphisms of two mediators were evaluated. Given the vast number of mediators that have been implicated in the response to an infectious agent, we cannot exclude the possibility that other polymorphisms not genotyped in the present study or specific haplotypes could influence survival [40
]. Finally, our study may be underpowered to detect statistically significant differences, especially in septic shock patients, given the small sample size.
Despite these limitations, the study is unique in that it included an ethnically homogeneous population of patients admitted to the hospital with a diagnosis of sepsis, and evaluated the progression of the syndrome and the factors associated with mortality following their admission to the hospital. Among the factors analyzed, all enrolled patients were genotyped for three polymorphisms of two key mediators, following recent recommendations for genetic association studies [41
]. Our findings emphasize that better use of conventional treatments is necessary before sophisticated interventions should be introduced into the clinical setting; we were unable to detect strong associations between these three polymorphisms and mortality in patients with sepsis at admission to hospital [42