Sepsis mimics among presumed sepsis patients at intensive care admission: a retrospective observational study

Abstract

Background: Diagnosing sepsis remains a challenge because of the lack of gold-standard diagnostics. Since there are no simple, broadly accepted criteria for infection, there is a risk of misclassifying sepsis patients (sepsis mimics) among patients with organ failure. The main objective of this study was to investigate the proportion of non-infected patients (sepsis mimics) in ICU patients with presumed sepsis at intensive care unit (ICU) admission.

Methods: Adult patients were screened retrospectively during 3.5 years in four ICUs in Sweden for fulfilment of the sepsis-3 criteria at ICU admission (presumed sepsis). Proxy criteria for suspected infection were sampled blood culture(s) and concomitant antibiotic administration. Culture-negative presumed sepsis patients were screened for infection according to the Linder-Mellhammar Criteria of Infection (LMCI). Sepsis mimics were defined as without probable infection according to the LMCI. Confirmed sepsis was defined as presumed sepsis after the exclusion of sepsis mimics.

Results: In the ICU presumed sepsis cohort (2664 patients), 25% were considered sepsis mimics. The most common reasons for ICU admission among sepsis mimics were acute heart failure and unspecific respiratory failure. Comparing sepsis mimics and confirmed sepsis showed that confirmed sepsis patients were slightly more severely ill but had similar mortality. C-reactive protein had modest discriminatory power (AUROC 0.71) with confirmed sepsis as the outcome.

Conclusions: One-fourth of a presumed ICU sepsis population identified with the sepsis-3 criteria could be considered sepsis mimics. The high proportion of sepsis mimics has a potential dilutional effect on the presumed sepsis population, which threatens the validity of results from sepsis studies using recommended sepsis criteria.

Keywords: Biomarkers; C-reactive protein; Critical care; Infections; Leukocytes; Sepsis; Septic; Shock.

Fig. 1

Flow chart of sepsis inclusion and exclusion. Sepsis-3 criteria fulfilment was defined as SOFA-score$\ge$2 and suspected infection at ICU admission. Proxy criteria for suspected infection were blood cultures sampled and antibiotic therapy administered. Culture negativity was defined as no clinically relevant cultures within 48 h before to 48 h after ICU admission. The Linder-Mellhammar criteria of infection (LMCI) is an infection classification tool published in 2022, which classifies a patient as infected with four degrees of certainty: no, possible, probable or proven infection. The patients who had presumed sepsis but were culture negative and had no or possible infection according to LMCI were labelled as sepsis mimics. After excluding sepsis mimics, the remaining presumed sepsis patients were labelled confirmed sepsis. ICU intensive care unit, EMR Electronic medical record, LMCI Linder-Mellhammar criteria of infection

Fig. 2

Sepsis mimics diagnoses. The chart illustrates diagnoses (outer circle) and diagnostic categories (inner circle) among sepsis mimics. Diagnoses with less than 1.5% of patients are not presented in the chart. The exact number of patients with each diagnosis can be found in Supplement 2. AMI acute myocardial infarction, CA cardiac arrest, ICH intracranial haemorrhage, ICU intensive care unit, HT hypertensive, COPD chronic obstructive pulmonary disease

Fig. 3

Proportion of patients with shock within each diagnostic category. The outer circle of the chart illustrates the proportion of patients within each diagnostic category fulfilling shock criteria (vasopressor use and lactate>2 at ICU admission). The proportion with shock was highly variable, ranging from 30% in the renal category to 85% in liver failure. Subsequently, the pattern of diagnoses would be different if only patients who fulfilled shock criteria were included

Fig. 4

Boxplots of commonly used clinical variables. CRP, PCT and WBC are displayed on a log-10 scale because of non-normal distribution and outliers. Differences between sepsis mimics and confirmed sepsis were statistically significant according to a p-value <0.05 for all variables. CRP C-reactive protein, PCT procalcitonin, WBC white blood cell count

Fig. 5

Sensitivity analyses of proportion of sepsis mimics with changing criteria for presumed sepsis and sepsis mimics. The main result of this study was that 25% of sepsis patients could be considered sepsis mimics when operational sepsis-3 criteria were used. When only sepsis patients with shock were included, the proportion of sepsis mimics fell to 21%. If only sepsis patients who received $\ge$4 days of antibiotics were included, the proportion of sepsis mimics fell to 20%. If the cutoff for infection was altered according to the Linder-Mellhammar criteria of infection (LMCI), the proportion of sepsis mimics was 29% with the stricter criteria (proven infection) and 14% with the more liberal criteria (at least possible infection). LMCI Linder-Mellhammar criteria of infection