The main findings in this study are that firstly, bacteremia is associated with poor outcome, and secondly that a higher percentage than previously reported of ICU patients with sepsis had positive blood cultures and other microbiological samples when analyzed with clinical chart reviewed sepsis diagnosis. Thirdly, blood culture positivity is affected by prior antibiotic treatment.
The high proportion of bacteremic patients, 54% in this study compared to 7–37% in other studies, may at least partially be explained by the manual chart review in the present study (2, 3, 6, 8, 11–13). Two prior studies classify patients as bacteremic depending on ICD-code, which might lead to a proportion of patients being misclassified as culture-negative (9, 11). Others define sepsis as blood cultures drawn in combination with, for example two Systemic Inflammatory Response Syndrome (SIRS) criteria or ICU care, which includes other diagnoses than sepsis as well (11–13).
We applied strict inclusion criteria of patients with at least blood cultures drawn and fulfilling an infection diagnosis and a corresponding sepsis-3 diagnosis. If we would have relied on administrative data like ICD-codes or electronic health record algorithms based on blood cultures for diagnosis, 95 (15%) patients not fulfilling infection or sepsis-3 definitions would have been included. Further, ICD-based strategies would even risk to include the 140 (18%) patients without blood cultures taken. As a poor accuracy of ICD-coding for sepsis is well documented, clinical chart reviews should be considered “gold standard” in sepsis epidemiology studies (20–23). Results from studies based on automated electronic health record data, should be interpreted with caution even if based on large amounts of data.
Another explanation for the high proportion of bacteremic sepsis might be the high morbidity in this cohort, since bacteremic patients had even higher severity of illness and higher mortality than their non-bacteremic counterparts. The sterile sepsis proportion is similar to the numbers described in a previous prospective study on patients with septic shock where 2651 patients (31%) had sterile sepsis (10). We also included other microbiological samples than culture, although they constituted only a small proportion of the pathogen-detected non-bacteremic sepsis group.
Sepsis is a highly heterogenous condition and different foci of infection have both different mortalities as well as different diagnostic yield of cultures and other microbiological analyses. In the present study propensity score match was used to reduce baseline differences between the groups and to estimate differences in morbidity and mortality with minimal bias.
Bacteremic patients demonstrated higher mortality rate than controls in the present study.
Previous studies have resulted in evidence both for and against bacteremia being associated with higher mortality (6, 24–28). In a large, prospective study by Phua et al mortality was not higher among culture-positive patients in a multivariate analysis and Gupta et al found higher mortality in culture-negatives, however antibiotic therapy preceding culture sampling was not included in the models (2, 9). Nannan Panday et al took prior antibiotic therapy into account when retrospectively analyzing a prospectively gathered cohort, and found higher mortality among bacteremic patients (6). We demonstrate that preceding antibiotic therapy is a confounder affecting mortality in non-bacteremic patients. Possibly, a proportion of non-bacteremic sepsis might be bacteremic but without growth in the blood cultures due to antibiotic therapy preceding culture sampling.
Higher mortality in bacteremic sepsis and in non-bacteremic sepsis with prior antibiotic treatment can also be indicative of bacterial load in blood being associated with sepsis severity, which previously has been demonstrated for isolated pathogens (29–32).
Still, 30% of the patients had sterile sepsis, i.e. negative in all microbiology samples, with a mortality of 44%. With the high incidence of sepsis and the emerging antimicrobial resistance, sterile sepsis is a substantial cause of morbidity which needs to be examined further. Sterile sepsis has been speculated to depend on misdiagnosis of other conditions, preceding antibiotic therapy, insufficient culture sampling, handling or culture techniques (6). The clinical chart review minimizes the misdiagnosis of other conditions and Kethireddy et al, who found similar mortalities in culture-positive and culture-negative patients with septic shock, demonstrated an increase in mortality with delayed antimicrobial therapy in both groups, indicating bacterial cause (10).
Our results suggest sterile and non-bacteremic sepsis to partially depend on prior antibiotic therapy. The proportion of sterile sepsis patients decreased from 43% with prior antibiotic therapy to 22% sterile sepsis patients without prior antibiotic therapy, and there was a similar decrease from 63% bacteremic patients without prior antibiotic therapy to 37% bacteremic sepsis patients with prior antibiotic therapy. Thus, antibiotic therapy seems to be a predictor for culture-negative sepsis. This is in contrast to Previsdomini et al, although they also noticed this trend but was possibly limited by a smaller sample size (13).
The LCA offers clinical subphenotypes in a classification, that might not be identified and its impact might not be tested assuming accepted standards. Neither the site nor the microbiology alone distinguished the classes, yet the combinations together with where the infection was acquired, immunosuppression and lactic acidosis were important for class distinction but also for outcome. This finding is in accordance with the propensity score analysis. When defining subphenotypes in sepsis, pathogen detection in microbial samples seems to have a high impact on probability of belonging to a class. This has previously been demonstrated for septic shock, while it was not a variable in a LCA used for ARDS and might have an impact in staging models like the PIRO system (predisposition, insult, response, organ dysfunction) (14, 15, 33).
The strengths of this study are the considering of the effect of antibiotic therapy prior to collection of microbiological samples, the inclusion of other microbial samples than cultures (e.g. PCR) and the data on and the high number of microbial samples collected. Further, the results do not solely rely on administrative or microbial data. All infection diagnoses and all data from microbial analysis have been reviewed by an infectious disease specialist. The proportion sterile sepsis might be underestimated since patients without an identified pathogen are less likely to obtain an infection diagnosis.
The major weakness of this study is the retrospective design. As microbiological samples were ordered as part of clinical workup, insufficient culture sampling might contribute to the microbiology negative cohorts. Fewer samples were drawn from blood, urine and wounds for microbiology-negative patients and fewer respiratory tract samples were withdrawn from bacteremic patients, although when cultures were compared to presumed infectious foci, there were no significant differences in ratio. Also, the handling of microbiological samples and laboratory techniques were part of clinical practice and out of study control. Other weaknesses of the study are the relatively small size and the single center conduct. The classes created by the LCA were created out of, and limited to observable characteristics of the variables entered.