The late phase of sepsis is characterized by an increased microbiological burden and death rate

Despite aggressive supportive care to improve treatment options and outcome, sepsis and its sequelae remain a leading cause of death in intensive care units [1]. Extensive studies investigating the host responses during sepsis have revealed that the late phase of sepsis is dominated by a status of immune suppression with respect to missing or widespread depressed innate, as well as adaptive, immune defense mechanisms. Since various authors introduced the intriguing model of a phase-dependent variation of immune activity [2‐4], the concept of an anergic immune system is held responsible as a principal mechanism and cause of death in patients with sepsis [5, 6]. However, the concept itself, but more the impact of sequential hyper- and hypo-inflammatory phases, has been discussed controversially [7‐9]. The lack of tools assessing the individual immune status of patients at the bedside and the complex pathophysiological processes, which are often overlapping, have so far limited the meaning of such concepts describing hyper- and hypo-inflammatory immune phases for the clinician. Confirmatory studies demonstrating the clinical significance, especially of the so-called late phase in sepsis, are largely missing. We, therefore, thought to investigate whether a so-called late phase during the course of sepsis would be accompanied by higher death rates and higher rates of positive blood culture results, especially by typically opportunistic bacteria. The latter might be interpreted as a hint for an underlying immune suppressive status, which has been suggested by many studies investigating separate immune defense mechanisms in patients suffering from sepsis [2, 3, 6, 9].

To clarify this question we used a large database of patient records from daily practice and performed a retrospective trial enrolling patients admitted from 1 January 2006 to 31 December 2009 to the intensive care unit of the Jena university hospital. The study was approved by the institutional review board of Friedrich Schiller University Hospital, Jena, Germany (3080-03/11). Informed consent was waived due to the anonymous nature of the analysis. A total of 16,041 patients were screened according to the criteria of the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) for severe sepsis or septic shock [10, 11]. We identified 999 patients qualifying for severe sepsis or septic shock and evaluated demographics, clinical characteristics, disease severity measured by SOFA score [12, 13], procalcitonin levels (PCT), requirement of renal replacement therapy and mechanical ventilation, and outcome of patients, as well as the results of microbiological blood cultures and antimicrobial treatment.

By the observed trajectory of mortality, periods with different mortality rates were identified and classified by the nadirs, yielding in the definition of three distinct phases: Phase I from Day 1 until Day 5, phase II from Day 6 until Day 15 and phase III from Day 16 until the end of the observation period at Day 150. To investigate the relevance of the various phases, analyses of all obtained blood cultures with respect to their date of sampling during patients' hospital stay were performed. In addition, samples taken 10 days prior to clinical diagnosis of sepsis were included and this time period was defined as phase 0 (Day -10 to Day -1). Coagulase negative staphylococci (CNS) were interpreted as skin contamination of no importance and presented separately. Furthermore, epidemiology of microorganisms in the different phases was analyzed. Beside the total number of positive findings, the relative numbers of drawn blood cultures in relation to the number of patients alive during that period and, in particular, the rate of positive findings per obtained samples during the corresponding phase were also analyzed. Additionally, the practice of antimicrobial treatment and clinical characteristics of patients were studied dependent of the defined phases and dependent of the results from the obtained blood cultures at the day of sampling.

Our findings demonstrate in a large retrospective clinical study, the presence of three distinct mortailty peaks and two nadirs in the course of the monitored mortality rates. We were, therefore, able to identify three clinical phases, phase I - approximately until Day 5 after the onset of sepsis, phase II - the following days until Day 15, and phase III - beginning at Day 16, strictly determined by such peaks and nadirs. A total of 63.3% of all deaths occurred during the defined late phases II and III, which implicates a broad clinical significance. Furthermore, our data demonstrate a significantly renewed rate of positive blood cultures occurring in phase III of sepsis, as well as the highest rates of TOB in this phase. High positive rates of blood cultures, and especially the rise of TOB during this phase, may indicate either an inability to overcome underlying infections or a possible increase in secondary infections. The rate of drawn blood culture samples is comparable overall to data from available literature and representative of practice patterns [14, 15]. However, we observed an expected and significant reduction in the numbers of drawn specimens per patient in phase II and, surprisingly, a significant increase in phase III.

In this retrospective review, we attempt to explore the clinically impacted and microbiological pattern of the late phase of sepsis as a cause of late morbidity and mortality by dividing sepsis, according to the observed mortality peaks, into three periods. We detected a significant increase of positive blood cultures drawn in patients with sepsis at a later time point with higher rates of TOB, which may indicate an anergic immune system. It needs to be understood that such implications have a number of important drawbacks due to the design of this study. First, the demonstrated higher frequency rate of positive cultures will be very sensitive to existing practice patterns. In our ICU the decision to draw cultures will be taken according to the guidelines recommending a sampling by signs and symptoms of infections as a new onset of fever, chills, hypothermia, leukocytosis, PCT (demonstrated by the high levels in bc^+/- patients at the sampling day) or a raise in CRP, neutropenia or left shift in differential blood count. In our opinion, sampling based on guidelines without a prospective investigative protocol reflects the situation on ICU more reliably. The sampling rate clearly shows a drop from 88.3% in phase I to 52% in phase II and a rise up to 66.2% in phase III. This might demonstrate the still ongoing inflammatory response in these patients, especially after phase I and II in which almost all of our patients had already received guideline-appropriate antibiotic treatment. In contrast to the early phase, in which well described guidelines for the sampling indication and procedure exist, the indication for blood culture sampling during the late time points are often also determined by the clinical phenotype and may not be as precisely captured when compared to the onset phase. This fact represents a confounder which is very difficult to control. Within this study, we used a definition of TOB. However, a precise definition of TOB does not exist, and it must be pointed out that our classification was based on data from the literature and the expert opinion of microbiologists and intensive care physicians, which may also represent a drawback with respect to derived implications. A further limitation of this study might be that there is important informative censoring going on; patients who die early contribute to the initial blood culture sampling quota but obviously not to the later ones. In contrast, patients who did well and left the ICU and were sampled later were still included in our analyses. Patients who did well and left the hospital were not observed further. However, all three scenarios provoke no bias for the rate of positive blood cultures. Also limiting might be the fact that the number and the duration of uses of a central venous catheter were not included in our analyses. Only the requirement of mechanical ventilation and renal replacement therapy as additional risk factors for infections were analyzed in greater detail. This study shows that patients with sepsis treated on our ICU at a later time point (>16 days) were still or even more likely to exhibit a positive blood culture in comparison to earlier time points and that such patients are more prone to develop TOBs. Of course, these results are not necessarily a legitimate or validated proxy for an anergic immune system, but due to the absence of a clinically established and relevant indicator for immune suppression in daily practices, the data might serve as further hints for this hypothesis, which has been much more clearly described in models of experimental sepsis.

Most of the adjunctive clinical trials that were conducted with the aim to treat sepsis focused on early and anti-inflammatory mechanisms abrogating hyper-inflammation, with most of them failing to deliver the anticipated results [16‐22]. Only a few trials were designed with a strategy aimed at the later phases or at improving immune suppression [23‐25]. However, both strategies have so far not resulted in new therapeutics capable of significantly improving outcomes of septic patients. Our data demonstrate that the later phase of sepsis is associated with a significant re-increase of positive blood culture results, especially opportunistic bacteria and fungi, and that a majority of all deaths occurred after Day 5. These data have a large potential impact on treatment, monitoring and outcome of septic patients. However, the underlying mechanisms are so far not well understood. It, therefore, appears to be warranted to pay more attention to the late phase of sepsis and to develop strategies detecting the patients' host immune response level.