Infection is the pathologic phenomenon induced by microorganisms, and sepsis is the systemic response to infection. Severe sepsis occurs when organ dysfunction appears, and septic shock is a sustained reduction of arterial blood pressure that impairs adequate tissue perfusion [1, 2]. In previous years, the diagnosis and treatment of sepsis appeared chaotic, partly because of a lack of uniform terminology [1, 3]. Consequently, one of the most important advancements was the ACCP/SCCM consensus, which unified the criteria and definitions for diagnosing the syndrome [1]. The process has traditionally been understood as a linear sequence spanning different clinical stages [4], from infection to septic shock. However, with few exceptions such a clinical trial carried out almost two decades ago [5], some theoretical models with mathematical simulations [6, 7], and cohort studies with highly selected patients, whether by ICU admission [8] or by the specific diagnosis of pneumonia [9]; a formal and adequate characterization of the potential progression from infection without systemic manifestations to septic shock or death has not been attempted. To understand this clinical behavior, and to know the timeline and the timing of relevant events within the sepsis syndrome, might be a cornerstone of the real dynamic behind infection and host’s response.

In Colombia, we have found some particular features that suggest differences in the natural history and clinical course of bacterial infections with regard to other places in the world [10, 11]. Under these circumstances, which are probably valid for most of the third world, complete clinical characterization of that potential progression may make it possible to propose more effective strategies to face the problem. This would be especially valuable for reducing mortality, which varies with the clinical stages: in patients with infection without sepsis, with sepsis, with severe sepsis, and with septic shock, the mortality rates are 3%, 7,3%, 21,9%, and 45,6%, respectively [11]. The aim of this research is to describe the evolution of the stages of sepsis in a multicenter cohort of patients with bacterial infections requiring hospitalization. The study also aims to identify the determinants of the progression of these stages, as well as their relationship with 7 and 28-day mortality.

Of the 2681 patients enrolled, 136 (5.1%) were classified as having infection without sepsis, 575 (21.4%) with sepsis, 1576 (58.8%) with severe sepsis, and 394 (14.7%) with septic shock at the moment of inclusion in the study. The mean age was 55 yrs (SD = 21 yrs), 1365 (51%) were female, the mean Acute Physiologic and Chronic Health Evaluation II (APACHE II) score was 11.5 (SD = 7), and the mean Sequential Organ Failure Assessment (SOFA) score was 3,8 (SD = 3). The most common associated conditions were trauma or surgery in 28,5% (n = 764), diabetes mellitus in 15,2% (n = 408), chronic renal disease in 10,5% (n = 281), heart failure in 9,9% (n = 266), and chronic obstructive pulmonary disease in 9,9% (n = 265). Among the total cohort, 879 patients (33%) did not have any comorbidity. The overall 7-day and 28-day mortality rate was 9.2% (n = 247) and 18.5% (n = 497), respectively.

Considering the clinical stage at the moment of inclusion, the mean age was 48,5 years (SD = 20,4) for the group of patients with infection without sepsis, and 57,2 years (SD = 20,2) for the septic shock group. In the first group, community-acquired infection accounted for 73,5% of cases, with infection of the urinary tract as the most frequent diagnosis in 31%, followed by soft-tissue infection with 29%; as opposite to the septic shock group, in which pneumonia was the most common infection with 29,4% of cases, followed by intraabdominal infection in 16.5% of patients (Table 1). More than half of the patients at all clinical stages had at least one comorbidity, with trauma or surgery as the most frequent. SOFA and APACHE scores, as well as the median length of hospital stay and 28-day mortality, increased proportionally with the progression of the clinical stages (Table 1). From day 1 to 2, the proportion of patients with infection without sepsis increased from 5% to 21% and the proportion of septic patients increased from 21% to 34%, whereas the proportion of patients with severe sepsis decreased from 59% to 32%. The frequency of septic shock did not change substantially, and maintained a similar distribution over the first week. Likewise, the proportion of discharges due to death reduced daily over the first week. It is noteworthy that most deaths during that period of time occurred at stages of severe sepsis and septic shock (Figure 1).

Our analysis showed that progression from infection to sepsis, severe sepsis or septic shock is strongly determined by the source of infection, independent of the initial values of SOFA and APACHE II scores. Similarly, this progression between clinical stages jointly with severity scores, age and the respiratory source of infection were the main determinants of mortality during the first week. We use specialized statistical models in order to fully explore the timeline of progression of the clinical stages of sepsis. Previously, Clermont et al. worked on dynamic microsimulation models to predict the temporal patterns of multiple outcomes in critically ill patients [23]. However, such approaches address mainly issues of prediction and forecasting and are not suitable enough for identification of individual covariates.

On the other hand, it has been reported in the literature that mortality has differential behavior according to the complexity and the source of the infection; with mortality rates usually higher at the stages of severe sepsis and septic shock, as well as in patients with pneumonia [1, 3, 5, 8, 24–27]. Our results confirm that septic shock as initial clinical stage, in addition to several sources of infection, increases the 28-day hazard of death. However, when stage shifts over the first week are assessed, it is clear that progression to severe sepsis and/or to septic shock are also independent determinants of mortality and the respiratory source of infection remained as a significant prognostic factor.

In order to compare our findings with those of other investigations, it is necessary to take into account all the differences of our study population. Our cohort consists of patients with community- and hospital-acquired infections, hospitalized in ICU or in general wards, whose mean age shows a young population, 33% of whose individuals have no comorbidities. In terms of the quantification of severity by SOFA and APACHE II scores, our data are comparatively low in comparison with those of other populations, even in the septic shock group [7–9, 28–30].

Alberti et al. [8] published a multicenter study that enrolled 3443 ICU patients diagnosed with infection, 1531 of whom did not present with severe sepsis or shock. Eleven percent (n = 167) and 13% (n = 201) of these patients progressed to severe sepsis and septic shock, respectively, at some moment of their ICU stay before day 30. One of the chief factors of that progression to severe sepsis or septic shock was the source of infection; the risk was highest in cases of bacteremia (HR = 1,81; 95% CI =1,18-2,76), followed by peritonitis (HR = 1,51; 95% CI = 1,07-2,13) and pneumonia (HR = 1,47; 95% CI = 1,18-1,82). These results are in keeping with our own. Besides including only ICU patients and not estimating the effect of clinical progression on mortality, that study carried out an analysis based only on the time elapsed between admission and the appearance of severe sepsis or septic shock using a Cox model with competing risks. Such a model is not able enough to capture daily changes in clinical stages, which are outcomes that can appear repeatedly in a given patient during his/her hospital stay. Moreover, the authors found that growth of Gram-positive cocci and Gram-negative bacilli in blood increases the risk of progression to severe sepsis or septic shock during the first 30 days of ICU. In our study population, in which infections caused by Gram-negative bacilli were predominant in contradistinction to other current series across the world [11, 31], the type of microorganism was not associated with progression to more advanced clinical stages. The apparent “protective association” of Gram-negative bacilli in blood with first-week mortality in our cohort is explained by a survival bias, given by a higher mortality in patients with Gram-negative bacteremia beginning during the second week. This was confirmed by the analysis with 28-day mortality, which showed no association with this type of microorganism (HR = 1,02; 95% CI = 0,75-1,40).

Dremsizov et al. [9] carried out a study in patients presenting to the emergency room with pneumonia, aimed at determining the onset and timing of severe sepsis and the ability of the Systemic Inflammatory Response Syndrome (SIRS) criteria and the Pneumonia Severity Index (PSI) to predict its development. Of 1339 patients with pneumonia, 882 did not have severe sepsis on admission, and 20,6% (n = 182) of these patients progressed to that stage at some moment of their hospital stay. The authors found that using 2 or 3 SIRS criteria does not predict the risk of progression to severe sepsis or septic shock or 30-day mortality, in contradistinction to PSI, which was associated with the development of severe sepsis. Besides considering only a specific type of infection and a specific type of risk score, that study did not analyze the factors from the perspective of their change over time, neither for exposure variables nor for outcome variables. Glickman et al. [32] carried out an investigation in patients presenting to the emergency room in order to determine the incidence, the mortality, and the factors associated with progression over the first 72 hours from sepsis to septic shock. The study included 472 patients without shock at the moment of evaluation in the emergency room, whose median age was 52 years and median APACHE II score was 9 points. The most common source of infection in the whole population was the respiratory, and the factors associated with progression to septic shock were catheter-related infection, age, female sex, temperature, and chronic lung disease. Besides the relative lack of ability of the logistic regression analysis to explore the behavior of variables that change over time, the study might have limitations related with the sample size necessary for a multivariable analysis.

The strengths of our study include the great diversity of clinical and epidemiologic aspects of its population, the quality of the data and the reproducibility of the definitions. Our study showed that severity scores not only increase with higher complexity of the infection [24–26] and predict mortality or organ dysfunction [13, 14], which is what they were designed for, but also determine the risk of progression to more severe clinical stages. The latter suggest an additional advantage of severity scores, as potential tools for exploring the complexity of sepsis physiopathology. The limitations of our study include the lack of assessment of the impact of adequate treatment and resuscitation strategies on progression from one clinical stage to another [33, 34], and the absence of biochemical markers used in clinical practice such as C-reactive protein, procalcitonin, or lactate.

This study showed that source of infection, independent of the initial values of severity scores, increase the risk of progression to more severe stages of sepsis, and that there is a differential effect on first-week mortality according with those stages and their progression. Further studies are required to validate these conclusions and to identify interventions capable of modifying risk factors for progression as well as the mortality outcome in patients with severe infections that require management in hospital.