Sepsis is a leading cause of mortality and morbidity globally. Early diagnosis of sepsis and early initiation of evidence-based bundle care can greatly improve the outcome of sepsis.

Yu et al (2019) investigated whether PCT can improve the performance of quick sequential organ failure assessment (SOFA) score in predicting sepsis mortality

Unfortunately, early and accurate diagnosis of sepsis is difficult. Sepsis is a complex clinical syndrome with a wide range of manifestations. Although the systemic inflammatory response syndrome (SIRS) criteria were part of the prior definition of sepsis, it has been shown to be unable to differentiate severe from uncomplicated infections. The latest Sepsis-3 definition describes sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection, with life-threatening organ dysfunction defined as a change in the sequential organ failure assessment (SOFA) score of more than two points in intensive care unit (ICU) patients.

In clinical settings outside the ICU where calculating the SOFA score is not routine, a simplified score – quick sepsis-related organ failure assessment (qSOFA) was introduced as a screening tool for patients with sepsis.

Since the introduction of qSOFA, concerns have been raised. None of the elements in qSOFA are specific for the detection of infection, and subsequent validation studies showed suboptimal overall discrimination and sensitivity (reported sensitivity 32%) under the recommended cut-off. In addition, diagnosing sepsis relies on the accuracy of the physician’s clinical suspicion of infection. Infectious disease biomarkers such as C reactive protein (CRP) and procalcitonin (PCT), on the contrary, have been shown to accurately predict infection and mortality.

These two markers were accepted as part of the diagnostic criteria in Sepsis-2, but were not included in the Sepsis-3 definition. Combining biomarker information with the qSOFA score would potentially enhance its ability to predict the mortality risk from sepsis. In this study, the authors sought to evaluate whether adding either CRP or PCT to the qSOFA score would improve its ability to predict in-hospital mortality in a multicentre cohort of patients who presented with clinical symptoms of systemic infection.

PCT is a biomarker used to diagnose bacterial infections and shows a high correlation with sepsis severity.

The biomarker is expressed upon stimulation of cytokines such as IL-6, TNF in almost all parenchymal cells. Distinct algorithms have been defined through several thousand studies in order to use PCT as a diagnostic and prognostic tool in indications such as sepsis, respiratory infections, paediatric and neonatal sepsis. The biomarker test is often run in the ICU wards where sepsis prevalence is high. In addition, PCT has shown to play a pivotal role in antibiotic stewardship by reducing the number of antibiotic treatment days.

The gold standard for sepsis and bacterial infection diagnosis rely on blood cultures, which has been deemed highly unspecific. Advantages of PCT over other biomarkers such as CRP and presepsin include high specificity and sensitivity, rapid increase (three-four hours after onset of infection), and half-life of 24 hours.

Multiple clinical trials have shown positive outcomes using a PCT approach compared to traditional approaches in relation to hospital length of stay, reduction in antibiotic exposure and overall improvement of the clinical outcomes in patients. PCT have been included in numerous clinical guidelines where adherence plays a crucial role in the clinical outcome of PCT subjected patients.

The following observational study highlights the use of PCT in conjunction with other sepsis diagnostic tools such as the quick sepsis-related organ failure assessment (qSOFA) score. It is shown that by using the qSOFA score and PCT in parallel, sepsis diagnosis is increased to 90%.

Observational study

Yu et al (2019) investigated whether PCT can improve the performance of quick sequential organ failure assessment (SOFA) score in predicting sepsis mortality. They conducted a retrospective multicentre cohort study with independent validation in a prospectively collected cohort in three tertiary medical centres. Patients with presumed sepsis were included. Serum PCT levels were measured at admission.

qSOFA score and systemic inflammatory response syndrome (SIRS) criteria were calculated for each patient. PCT levels were assigned into 0, 1, and 2 points for a serum level of <0.25, 0.25 to 2, and >2ng/mL, and added to the quick sepsis-related organ failure assessment (qSOFA) score. The incremental value of PCT to qSOFA was then evaluated by logistic regression, receiver-operating characteristic (ROC) curve, and reclassification analysis.

In all, 1 318 patients with presumed severe infection were enrolled with a 30-day mortality of 13%. Serum level of PCT showed a high correlation with qSOFA score and 30-day in-hospital mortality. The area under the ROC curve was 0.56 for SIRS criteria, 0.67 for

qSOFA score, and 0.73 for qSOFA PCT in predicting 30-day mortality. The risk prediction improvement was reflected by a net reclassification improvement of 35% (17%–52%).

Methods

Study design and locations

This was a multicentre retrospective cohort study performed at the Sichuan Provincial People Hospital (SCPH) in Chengdu City, First People’s Hospital of Foshan (FSFPH) in Guangdong province of China, and National Taiwan University Hospital Yunlin Branch (NTUH) in Douliou city. All three hospitals are tertiary-care urban medical centres.

Study population

Patients were enrolled retrospectively using consecutive sampling of cases from each hospital from January 1, 2015 to December 31, 2016. All adult patients (≥18 years old) who presented to the emergency department or were admitted to the hospital floor were eligible for inclusion. Patients were included if they had symptoms that indicated systemic infection; and PCT (VIDAS BRAHMS PCT) and blood culture tests within 24 hours of admission. Exclusion criteria were missing data, transfer from other hospitals, leucopenia, do-not-resuscitate (DNR) orders, lost to follow-up, or history of pre-existing thyroid disease that may affect procalcitonin levels.

Participating investigators from the three sites independently reviewed all retrieved medical records to confirm the presence of infection as a reason for admission. The study focused on qSOFA score, which targeted the sepsis patients outside the ICU. So, patients who developed sepsis in ICU were excluded. A cohort that prospectively collected 493 consecutive emergency department (ED) patients with presumed sepsis was used for independent validation. Patients with presumed sepsis was defined patients who fulfilled at least two of the three SIRS criteria (temperature >38°C or <36°C, pulse rate ≥90 beats per minute, and respiratory rate ≥20/min) upon ED admission with a presumed diagnosis of systemic infection by treating physicians. This study was approved by the Research Committees and Institutional Review Boards for all institutions, and it met criteria for exemption from informed consent.

Results

Patient characteristics and outcome

During the study period, 604 patients from NTUH, 503 from SCPH, and 515 from FSFPH fulfilled the inclusion criteria. After the exclusion of 304 ICU patients, the final cohort included a total of 1 318 patients.

In all, 867 (65%), 208 (15%), and 752 (53%) patients were diagnosed with sepsis according to the SIRS criteria and qSOFA score, respectively. In all, 205 (15%) patients had clinical significant bacteraemia, with a higher prevalence of gram-negative bacteraemia (7%) than gram-positive bacteraemia (6%). The median age of the study sample was 64.0 (interquartile range 47–75) years old. The overall in-hospital mortality rate was 13%. The mortality of patients with clinical significant bacteraemia was 19%.

In general, non-survivors were older, had a higher burden of comorbidities and organ dysfunction, had lower respiratory tract infections, more bloodstream infection and polymicrobial infection, and had a greater proportion of patients with PCT, SIRS, or qSOFA scores higher than reference levels.

Discussion

In the retrospective validation of the Sepsis-3 definitions using multicentre cohorts, the authors confirmed that the qSOFA score is superior in mortality prediction compared with SIRS in terms of discrimination, model fit, reclassification, and calibration statistics.

They also demonstrated that PCT has better correlation with clinical severity than WBC count or CRP. They found that combining PCT and the qSOFA score by simply adding the ordinal scale of PCT to the qSOFA score can significantly enhance its mortality prediction capability in all dimensions of model performance indicators. Clinically, PCT enhanced qSOFA, or qSOFA PCT, has the best sensitivity (86%) and can be served as a screening tool to quickly identify patients with sepsis who may benefit from early intervention. qSOFA alone has the best specificity (87%) and can subsequently serve as a quick confirmation tool to aid in the decision to pursue more invasive treatment.

The original Sepsis-3 definitions proposed using the simple qSOFA score as the initial screening tool, followed by the comprehensive SOFA score as the confirmation tool for sepsis. In the original work, the sensitivity of a qSOFA score ≥2 was reported to be low at 55%, albeit with a high specificity (84%), whereas a change of SOFA score of ≥2 had a higher sensitivity (68%), but a lower specificity (67%). The sensitivity and specificity profiles of qSOFA and SOFA, however, are contradictory to their proposed clinical use. A screening tool requires high sensitivity, whereas a confirmation tool requires high specificity.

This study, like other external validation studies, confirmed the low sensitivity and high specificity of the qSOFA score.

The authors propose incorporating PCT levels into qSOFA to correct for its low sensitivity. The high sensitivity (86%) and high NPV (95%) of qSOFA PCT ≥2 justify the combined score as an initial screening tool. They would like to preserve the qSOFA as a confirmation tool for two reasons. First, it is validated as a simple but highly specific tool with a specificity (84%) higher than the proposed delta SOFA greater than two (specificity 67%). Second, in clinical settings outside the ICU such as the ED, the comprehensive SOFA score may not be easily obtained. In summary, the study authors believe the newly proposed algorithm, using high-sensitivity qSOFA PCT as a screening tool and the high-specificity qSOFA score as the confirmation tool, is the most optimal use of biomarker information and the best clinical decision rule in clinical settings outside of the ICU.

In addition to the contradiction between the sensitivity and specificity profiles of qSOFA and SOFA, another major concern regarding replacing SIRS with qSOFA is the absence of clinical indicators of infection in the qSOFA score. PCT has been shown to be a reasonably sensitive marker in differentiating sepsis from sterile SIRS. In a large meta-analysis with 3 244 patients, PCT alone had a sensitivity of 77% and a specificity of 79% in the diagnosis of sepsis. The accuracy of PCT has been shown to be valid for various sites of infection and for different populations such as the elderly, patients with renal impairment, and patients with autoimmune disease. Therefore, the addition of PCT to the qSOFA score may complement its lack of infection indicators. However, the accuracy of PCT may be compromised in patients with neutropenia, hyper functioning thyroid cancer, and in patients with certain subacute infectious diseases such as infective endocarditis. The qSOFA PCT should be used cautiously in these specific populations.

In clinical settings where testing for PCT is not readily available, the SIRS criteria would retain its value as a simple and low-cost screening tool. In multiple validation studies, SIRS ≥2 consistently demonstrates a higher sensitivity than qSOFA.

The authors propose that when PCT cannot be obtained, SIRS should remain as a screening tool with qSOFA as the confirmation tool.

Although they showed that the AUC of qSOFA PCT is higher than qSOFA alone, the confidence intervals overlapped. The limitations of the c-statistic, or AUC, as a measure of clinical model performance, have been discussed extensively in the literature. AUC is based exclusively on ranks, and it only measures how well the predicted values can rank order the responses. It may not be as sensitive as the likelihood function in choosing between models, and it is less clinically relevant as a calibration measure that directly cross-classifies the predicted risk categories with the observed risk. The magnitude of IDI, defined as the difference in discrimination slopes, has a direct interpretation. In this study, qSOFA PCT, compared with qSOFA, had an IDI of 0.0097. This indicates that the new model increases the mean difference of predicted probabilities for death and non-death by 0.97%. In the reclassification analysis, NRI is calculated as the sum of the net percentages of correctly reclassified patients with and without the event of interest. NRI is the favoured metric when assessing the true discriminatory potential of a new predictor compared with other predictors.

It captures the incremental strength of the new predictor after accounting for correlations with variables included in the baseline model. NRI values above 0.6 are considered strong, 0.4 intermediate, and below 0.2 weak. In this case, the NRI comparing qSOFA PCT with qSOFA is 0.35, which suggests a medium number of patients were reclassified to more appropriate risk categories. This change was found to be significant (P=.00011).

Since its publication of Sepsis-3 criteria and qSOFA in 2016, numerous attempts have been made to assess the performance of qSOFA. A recent meta-analysis collecting 45 studies showed low sensitivity and good specificity when the qSOFA is used as a screening tool for sepsis (pooled sensitivity was 61%, and specificity was 72%). In contrast, SIRS criteria resulted in a pooled sensitivity of 88%, but with only 26% specificity. This study demonstrates that combing PCT and qSOFA, rather than PCT and SIRS, can achieve the best sensitivity. The simple qSOFA PCT score will help clinicians identify at-risk patients and those with high likelihood for deterioration. A prospective external validation of this simple score is needed to verify the generalisability of this modified score.

This work has both strengths and limitations. The study authors were the first in the literature to prove the added prognostic value of PCT to the qSOFA score by a rigorous statistical analysis. They proposed a practical strategy for clinical use: The highly sensitive qSOFA PCT score used as a screening tool, followed by the highly specific qSOFA score used as the confirmation tool. In addition, this multicentre design has a relatively large population, which increases the generalisability of this work. A key limitation of this study was the retrospective nature of this work. However, the patient characteristics of the study cohort are comparable with prospectively collected continuous samples. In addition, as these sepsis patients were not enrolled in ICU, common severity scores such as SAPS, APACHE II, or SOFA score were not available.

Incorporation of PCT into the qSOFA model could raise the sensitivity to 86.5% (95% confidence interval 80%–91%). In the validation cohort, qSOFA PCT greatly improved the sensitivity to 90%.

A simple modification of qSOFA score by adding the ordinal scale of PCT value to qSOFA could greatly improve the suboptimal sensitivity problem of qSOFA and may serve as a quick screening tool for early identification of sepsis.

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Conclusion

This work confirmed that qSOFA has low sensitivity and high specificity in predicting sepsis mortality. The incorporation of the ordinal scale of PCT to the qSOFA model could enhance sensitivity and reclassify patients into risk groups that better reflect their actual short-term mortality risk. The authors propose using qSOFA PCT as a screening tool followed by qSOFA alone as a confirmation tool for the identification of patients with sepsis in settings outside of the ICU.