Neutrophil to Lymphocyte Count Ratio as an Indicator of BSI
Neutrophil to Lymphocyte Count Ratio as an Indicator of BSI
Early diagnosis and initiation of timely broad spectrum antibiotics improves outcome in BSI. Consequently, it is a standard of care to draw blood for cultures before initiation of antibiotic therapy. However, fever and systemic inflammation do not indicate bacteraemia in every case, and there are adverse consequences to the inappropriate prescription of antibiotics including allergic reactions, Clostridium difficile infection and the emergence of antibiotic resistance. At present, there is no ideal biomarker for sepsis or bacteraemia, and the gold standard—isolation and identification of bacteria in the blood stream—may be delayed or absent. A suitable marker must provide additional information to that presently available, it must be able to distinguish bacterial infection from other causes of fever and it should be immediately available and cost effective.
The present study evaluated parameters that are readily accessible as part of the routine work-up of pyrexial adults in the ED. LC and NLCR performed best among these parameters, but offered no advantage over LC alone, in keeping with the findings of Wyllie et al who reported a large study of medically admitted patients. They suggested that the mechanism of the lymphocytopenia was widespread lymphocyte apoptosis induced by the TNF family.
The present findings also echo those of de Jager et al who investigated a small cohort of ED patients. The AUC for both NLCR and LC is similar in both studies (72 vs 73 and 71 vs 73, respectively). Also, both found an AUC for WCC of around 0.5, suggesting that it is a poor indicator of BSI. A notable difference between the two studies is the PPV for NLCR and LC, in the present study 0.20 and 0.21 respectively, compared with 0.70 and 0.68 reported by de Jager. This discrepancy is explained by methodological differences; de Jager et al investigated two groups of matched patients, the consequence of which was that the 'prevalence' of bacteraemia was 50%.
LRs were generally low for all the variables measured in the present study, indicative of poor diagnostic performance, the post-test probability being little different from pretest. The diagnostic utility was only marginally better than that of three biomarkers evaluated by Gamaz-Diaz et al in 2011. Among 631 ED patients in that Colombian study, sepsis (not BSI) was confirmed in 416 (67%). The authors concluded that the markers they evaluated, none of them widely available, were not sufficiently sensitive or specific for the diagnosis of sepsis.
In the present study, CRP yielded a PPV of 0.71 which was comparable with that of LC and NLCR, but the specificity was significantly poorer than either at 0.48.
The present study was carried out in a single centre and the design was retrospective. Although blood culture-positive and culture-negative groups were similar in terms of age and gender, there may have been other important differences between them. For example, information regarding diagnostic group, comorbidities and discharge status was not available. It was not possible to identify the duration of illness prior to ED presentation, or whether antibiotics had been administered prehospital. However, De Jager et al found no difference between bacteraemic and non-bacteraemic cohorts in terms of comorbidities in their study of 184 patients. Also in the present study, the relatively large sample size reduces the impact of such confounders.
The gold standard in the present study was the detection of viable bacteria in blood culture samples, interpreted at up to 5 days by a consultant microbiologist. False positive and false negative blood culture results are not uncommon, but are minimised here by a standard protocol for sampling and incubation, on-site laboratory and analysis by an experienced, medically qualified consultant microbiologist who took into account the patterns of positivity, the identity of the organism and the clinical context. The yield of positive blood cultures is similar to that reported in a German study of intensive care patients.
Culture-negative sepsis was not considered in the present study. It is known that a significant minority of patients with severe sepsis and septic shock have no documented evidence of infection due to prior antibiotic use, inadequate sampling techniques or organisms that are difficult to identify. It is, therefore, possible that some patients in the present study were inappropriately determined to be culture-negative. Nevertheless, the impact on mortality of documented bacteraemia is established and it remains an important endpoint.
Discussion
Early diagnosis and initiation of timely broad spectrum antibiotics improves outcome in BSI. Consequently, it is a standard of care to draw blood for cultures before initiation of antibiotic therapy. However, fever and systemic inflammation do not indicate bacteraemia in every case, and there are adverse consequences to the inappropriate prescription of antibiotics including allergic reactions, Clostridium difficile infection and the emergence of antibiotic resistance. At present, there is no ideal biomarker for sepsis or bacteraemia, and the gold standard—isolation and identification of bacteria in the blood stream—may be delayed or absent. A suitable marker must provide additional information to that presently available, it must be able to distinguish bacterial infection from other causes of fever and it should be immediately available and cost effective.
The present study evaluated parameters that are readily accessible as part of the routine work-up of pyrexial adults in the ED. LC and NLCR performed best among these parameters, but offered no advantage over LC alone, in keeping with the findings of Wyllie et al who reported a large study of medically admitted patients. They suggested that the mechanism of the lymphocytopenia was widespread lymphocyte apoptosis induced by the TNF family.
The present findings also echo those of de Jager et al who investigated a small cohort of ED patients. The AUC for both NLCR and LC is similar in both studies (72 vs 73 and 71 vs 73, respectively). Also, both found an AUC for WCC of around 0.5, suggesting that it is a poor indicator of BSI. A notable difference between the two studies is the PPV for NLCR and LC, in the present study 0.20 and 0.21 respectively, compared with 0.70 and 0.68 reported by de Jager. This discrepancy is explained by methodological differences; de Jager et al investigated two groups of matched patients, the consequence of which was that the 'prevalence' of bacteraemia was 50%.
LRs were generally low for all the variables measured in the present study, indicative of poor diagnostic performance, the post-test probability being little different from pretest. The diagnostic utility was only marginally better than that of three biomarkers evaluated by Gamaz-Diaz et al in 2011. Among 631 ED patients in that Colombian study, sepsis (not BSI) was confirmed in 416 (67%). The authors concluded that the markers they evaluated, none of them widely available, were not sufficiently sensitive or specific for the diagnosis of sepsis.
In the present study, CRP yielded a PPV of 0.71 which was comparable with that of LC and NLCR, but the specificity was significantly poorer than either at 0.48.
Limitations
The present study was carried out in a single centre and the design was retrospective. Although blood culture-positive and culture-negative groups were similar in terms of age and gender, there may have been other important differences between them. For example, information regarding diagnostic group, comorbidities and discharge status was not available. It was not possible to identify the duration of illness prior to ED presentation, or whether antibiotics had been administered prehospital. However, De Jager et al found no difference between bacteraemic and non-bacteraemic cohorts in terms of comorbidities in their study of 184 patients. Also in the present study, the relatively large sample size reduces the impact of such confounders.
The gold standard in the present study was the detection of viable bacteria in blood culture samples, interpreted at up to 5 days by a consultant microbiologist. False positive and false negative blood culture results are not uncommon, but are minimised here by a standard protocol for sampling and incubation, on-site laboratory and analysis by an experienced, medically qualified consultant microbiologist who took into account the patterns of positivity, the identity of the organism and the clinical context. The yield of positive blood cultures is similar to that reported in a German study of intensive care patients.
Culture-negative sepsis was not considered in the present study. It is known that a significant minority of patients with severe sepsis and septic shock have no documented evidence of infection due to prior antibiotic use, inadequate sampling techniques or organisms that are difficult to identify. It is, therefore, possible that some patients in the present study were inappropriately determined to be culture-negative. Nevertheless, the impact on mortality of documented bacteraemia is established and it remains an important endpoint.
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