November 21, 2016

ARTICLE REVIEW

Sepsis is a prominent cause of morbidity and mortality in critically ill patients. Indeed, sepsis is believed to induce immune suppression, paving the way for secondary infections and associated late mortality.

The authors of the article “Incidence, Risk Factors and Attributable Mortality of Secondary Infections in the Intensive Care Unit After Admission for Sepsis” set out to elucidate the clinical and host genomic characteristics, incidence and attributable mortality of intensive care unit (ICU)-acquired infections in critically ill patients.

Van Vught et al. describe a dual-centre prospective observational study involving 3640 admissions dichotomised based upon admission diagnosis: sepsis (n = 1719) vs non-sepsis (n = 1921). The primary outcome was the first occurrence of an ICU-acquired infection for which the clinical team commenced a new antibiotic regimen. Additionally, paired blood samples for microarray analysis were collected at ICU admission and at the onset of an ICU-acquired complication in both ICU-acquired infection (n = 19) and no ICU-acquired infection (n = 9) groups. 

All those with an admission diagnosis of sepsis had different gene expression profiles compared to healthy participants. However, there were no observed differences between those who went onto develop an ICU-acquired infection and those who did not. Interestingly, paired analysis did reveal that the onset of ICU-acquired infection was associated with reduced expression of genes involved in leucocyte glucose metabolism. 

ICU-acquired infections complicated 13.5% (n = 232) of admissions with sepsis and 15.1% (n = 291) of non-sepsis admissions. All but one admission diagnoses were equally distributed between patients who developed an ICU-acquired infection and those who did not; those with an admission diagnosis of ‘primary bacteraemia’ were significantly more likely to develop an ICU-acquired infection than not (5.2% vs 1.3%, p < 0.001).

Furthermore, patients from both study groups who went on to develop an ICU-acquired infection were more severely unwell on admission than those who did not e.g. for those with an admission diagnosis of sepsis, APACHE IV scores were 90 (IQR 72-107) and 79 (IQR 62-98) respectively [p < 0.001]. 

The population attributable mortality fraction of ICU-acquired infections at day 60 was 10.9% (95% CI, 0.9% – 20.6%; p = 0.03) for those admitted with sepsis and 21.1% (95% CI, 0.6% – 41.7%; p = 0.04) for those admitted without sepsis. Of those admitted to ICU with sepsis, mortality at day 60 was 2% higher in those who developed an ICU-acquired infection (95% CI, 0.2% – 3.8%, p < 0.03). This was mirrored in the non-sepsis admission group with mortality at day 60 being 2.8% higher in those who developed an ICU-acquired infection (95% CI, 0.1% – 5.6%; p < 0.05).

Limitations
The gene analyses utilised in this study provide only a partial insight into the immune system; immune pathways regulated at mRNA level in circulating leucocytes may not be representative of the overall situation. Also, for some of the study period a concomitant cluster randomised crossover trial on the effects of selective decontamination of the digestive tract (SDD) and selective oropharyngeal decontamination (SOD) was undertaken. In concordance with 2 large clinical trials, it was found that relative to SDD, SOD had no effect on mortality but was associated with higher incidence of ICU-acquired infections. However, the degree to which the SDD vs SOD trial may have impacted upon the current study is unclear.

Take home messages

  • This study found no difference in the incidence of ICU-acquired infections between those admitted to ICU with sepsis and those admitted to ICU with a non-sepsis diagnosis
  • An admission diagnosis of ‘primary bacteraemia’ or a higher disease severity (e.g. APACHE IV score) were independent risk factors for developing an ICU-acquired infection 
  • ICU-acquired infections led to a modest increase in mortality of those with both sepsis and non-sepsis admission diagnoses 
  • There was no observed gene expression profile with a preponderance for developing ICU-acquired infection
  • The onset of ICU-acquired infection was associated with reduced expression of genes involved in cellular gluconeogenesis and glycolysis suggesting a role for impaired glycolysis in immune suppression in those with sepsis

This study’s results suggest clinically relevant risk factors for ICU-acquired infections and the importance of avoiding such infections by demonstrating the associated increased mortality. Unfortunately, the team were unable to observe a gene expression profile which would allow prediction of susceptibility to secondary infection. However, their linkage of impaired leucocyte glycolysis with immune suppression at the time of ICU-acquired infection may stimulate further research in this area and lead to methods for early identification and thus earlier treatment of this potentially fatal complication.

This article review was prepared and submitted by John Batty on behalf of the ESICM Journal Review Club.

Reference

Van Vught et al. Incidence, Risk Factors and Attributable Mortality of Secondary Infections in the Intensive Care Unit After Admission for Sepsis. JAMA. 2016; 315(14):1469-79

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