Abstract - OsepS PhD verkætlan

Sepsis is a serious condition with a high morbidity and mortality affecting an increasing number of patients. There is a need of developing new diagnostic modalities for identifying infected patients with and without the systemic inflammatory response syndrome. The biochemical tests used in clinical routine today are characterized by reasonable sensitivities but low specificities. Several new markers have during the last years been suggested as possible markers of infection and sepsis in the clinical setting. During the last years there has also been an increased attention on the anti-inflammatory aspects in serious infections. The introduction of the SIRS criteria were based upon a paradigm focusing on the pro-inflammation in sepsis. Many animal and human trials focused upon blockage of different pro-inflammatory pathways in sepsis. In general the human studies were disappointing. During the last few years a new paradigm in sepsis has focused on pro-inflammation and anti-inflammation either consecutively or in parallel in different focus/body compartments. This has urged research to look for new methods to evaluate the immune status of each individual sepsis patient. An effective way of assessing the immune status of the individual sepsis patient could maybe be followed by specific immuno-modulating therapy on the individual level.

 

The aims of this study was a. to evaluate several new candidate molecules for diagnosing infection and sepsis and b.to evaluate levels of  several newly described pro-and anti-inflammatory molecules in infection and sepsis. The study design was a prospective observational clinical study including patients in the milder end of the sepsis spectrum in 3 cohorts from a department of internal medicine at a Danish university hospital. The 3 cohorts covered the entire spectrum of infection and sepsis at a department of internal medicine. Patients were sampled and plasma/serum/whole blood were stored until laboratory analyzes were performed in batches.

Cohort A.1: One hundred and eighty-five adult patients suspected of having severe community-acquired sepsis were included in a prospective manner over a 23 months period. These patients were sampled on a daily basis in up to five days depending on their outcome or discharge time. Levels of HMGB1, PCT, LBP, IL-6, CRP, WBC and neutrophils were measured. The aim of this study was to evaluate levels of the pro-inflammatory cytokine HMGB1, the infection marker PCT and the acute phase protein LBP in infection/sepsis of different severity. The diagnostic test abilities of HMGB1, PCT and LBP in diagnosing the presence of bacteremia were also evaluated.

Cohort A.2: One hundred and ninety-four adult patients suspected of having community-acquired infections were included in a prospective manner over a 5 months period. These patients were sampled once immediately after admission to hospital. Levels of HMGB1, sCD163, PCT, LBP, IL-6, CRP, WBC and neutrophils were measured. The aim of this study was to evaluate PCT, LBP, IL-6 and CRP as diagnostic test markers for infection and sepsis in patients admitted to a department of internal medicine. Another aim was to evaluate the pro-inflammatory cytokine HMGB1 and sCD163 as molecular markers in mild infections and sepsis.

Cohort B: One hundred and ten patients admitted to a department of internal medicine with microbiologically verified bacteremia were included in a prospective manner in a 19 months period. These patients were sampled on a daily basis in up to five days depending on their outcome or discharge time. Levels of HMGB1, sCD163, PCT, LBP, IL-6, IL-10, CRP, WBC and neutrophils were measured. The aim of this study was to evaluate the pro-inflammatory cytokine HMGB1 and sCD163 as immunological and prognostic markers in patients with a robust gold-standard for the presence of infection.

In conclusion our data do not suggest that PCT should be introduced as a routine test in diagnosing infection and sepsis in patients with suspected community acquired mild infections/sepsis admitted to a department of internal medicine. PCT and LBP are severity markers in sepsis and PCT is a marker for the presence of bacteremia. LBP and IL-6 seem to perform equally to CRP as diagnostic test markers for community-acquired mild infections/sepsis in patients admitted to a department of internal medicine. LBP did not discriminate between gram-negative and gram-positive bacteremia. sCD163 and HMGB1 did not discriminate between non-infected patients and infected patients. Levels of sCD163 were only elevated in severe sepsis and bacteremia. sCD163 and IL-6 were prognostic markers in patients with bacteremia. sCD163 correlated to the measured anti-inflammatory markers suggesting an anti-inflammatory role for sCD163. Levels of HMGB1 were elevated in infected patients compared to healthy controls. HMGB1 correlated to the measured pro-inflammatory markers suggesting a pro-inflammatory role for this cytokine.

There is still a need to continue efforts in identifying new possible candidates for diagnostic biochemical markers in infection and sepsis. These should have higher sensitivities and especially higher specificities than the markers used in clinical routine today. Increased insight in the immunopathogenesis of sepsis would offer the potential to generate new diagnostic and treatment options in sepsis.


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