Sepsis remains a global challenge, with an estimated 50 million people suffering from sepsis worldwide in 2017 alone. This comprehensive review presents evidence demonstrating that a combined qSOFA and CRP score improved the prognostic performance of qSOFA alone for mortality prediction, which has previously been shown to be suboptimal. In all three included studies, the addition of a CRP score resulted in improved AUROC values for mortality prediction compared to qSOFA alone.[19, 22, 24] Furthermore, in the two studies with available data, adding CRP to the qSOFA tool increased the sensitivity and NPV compared to qSOFA.[19, 22] In contrast, the addition of CRP to qSOFA resulted in a reduced specificity and PPV for mortality prediction.[19, 22] This is expected as sensitivity and specificity are inversely related, and therefore an increase in a test’s sensitivity will cause a decrease in its specificity. As sepsis is a highly-fatal and time-critical condition having a higher sensitivity results in a greater likelihood of identifying septic patients earlier in the disease course, and consequently, offers improved chances of better outcomes. Therefore, it is acceptable to have a lower specificity in favour of a higher sensitivity for the early identification of sepsis.
Our findings present an opportunity for improved early detection of patients with a higher risk of poor outcomes from sepsis, especially in the emergency setting. qSOFA combined with CRP is most suited to fast paced, high patient flow-through settings where the emphasis is on rapid and sensitive risk stratification assessments. Furthermore, as CRP is one of the earliest biomarkers to rise in response to infection, it is well placed to be implemented in a clinical environment where patients are initially presenting. Use of qSOFA combined with CRP is less beneficial in ward and intensive care environments as there is more time, patient history and resources to inform clinical decision making. Moreover, a CRP value is easily obtainable via venous collection and is a relatively inexpensive test with results obtainable quickly. Due to its early rise in infection, ease of access, cost-effectiveness, and broad applicability, CRP is an ideal biomarker to combine with qSOFA for use in the emergency setting.
The patient populations of the included papers presented with a spectrum of conditions, including complicated abdominal infections, community acquired pneumonia, and symptoms suggesting systemic infection.[19, 22, 24] This reflects the variation in sepsis presentations and impacted patient populations. In addition, the patient populations in these studies had comorbidities widely present in the community including diabetes, hypertension, malignancy, and chronic renal and liver disease. Therefore, this review presents initial evidence showing qSOFA combined with CRP is useful in a spectrum of patient populations, including those with common comorbidities.
Implications of this novel research are particularly prominent for developing countries. Research has shown the need for a test to facilitate early septic patient detection in low resource settings, as they carry the majority of sepsis incidence and mortality globally.[1, 29] We defined low resource setting according to a recent systematic review that thematically approaches the term. We applied the themes: financial pressure, geographical and environmental factors, to define low resource settings. Importantly, CRP measurement can be achieved through inexpensive and rapid PoC testing, which can be performed at the bedside.[31, 32] Similarly, the qSOFA score components are simple and inexpensive bedside measurements. Thus, the combined qSOFA and CRP score offers a low-cost prognostic and risk stratification tool that incorporates clinical and biochemical scores to improve the timely identification of patients with a high risk of sepsis-related poor outcomes.[15, 16] Earlier recognition of such patients can improve time to antibiotics initiation, and hence could improve mortality and morbidity rates of sepsis.[16, 17] Therefore, the combined qSOFA and CRP score shows promise as a tool for early sepsis identification in low resource settings and is a valuable area for further research.
The studies included in this systematic review implemented a wide spectrum of CRP cut-off values, ranging from 60mg/L to 128.8mg/L.[19, 22, 24] One study included two cut-off values for the combined qSOFA and CRP score and all three studies used similar CRP thresholds of 100-128.8mg/L. The CRP threshold chosen will influence the risk stratification of patients. Some previous studies have indicated that the optimal CRP cut-off value for sepsis identification in adults is 61 to 84mg/L.[7, 12] However, the optimal CRP threshold could be influenced heavily by age.[34–36] In addition, studies included in this review involved patients with community acquired pneumonia, complicated abdominal infections, and a range of comorbidities.[19, 22, 24] As sepsis impacts a diverse range of patients with varying and often complex medical histories, future research should investigate the role of age, comorbidities, and common concurrent conditions on the reliability of CRP cut-off values for the diagnosis of sepsis. Furthermore, future studies investigating CRP in combination with qSOFA should endeavour to use an evidence-based and consistent threshold as a cut off, to improve validity and reliability between studies.
Other biomarkers, such as procalcitonin (PCT), can be added to the combination of CRP and qSOFA to further increase the sensitivity or specificity of the score. Recent studies have shown merit of using a combination of PCT and CRP in diagnosing sepsis in both neonatal and adult populations.[37, 38] Further research should investigate the role of other biomarkers in combination with CRP and qSOFA.
The quality of evidence presented in this review is of an acceptable standard, evaluated using the QUADAS-2 tool. All studies were recently published, using the most up to date definition of sepsis, sepsis-3. A key methodological limitation across all studies is that it is unclear if the reference standard results, qSOFA, were interpreted without knowledge of results of the index test, qSOFA combined with CRP. However, as all studies were retrospective analyses, there is a low possibility for the introduction of bias, as the data has already been collated. Overall, as evidenced in the QUADAS-2 risk of bias assessment, the three studies included in this review were of low risk of bias with low concerns regarding applicability of studies.
A strength of this review is the systematic and comprehensive literature search with a robust search strategy that included multiple databases, grey literature and hand searching. Thereby, obtaining the best likelihood that all relevant papers were included. A limitation of this review is it was restricted to papers written in English or those with an English translation readily available. This was done due to time and financial constraints. Additionally, a valid meta-analysis could not be performed for two primary reasons. Firstly, there was not enough data to calculate standardised effect sizes. Study authors were contacted via email to seek additional information, however, only one replied and supplied additional data. Secondly, the limited number of studies included (n=3) displayed substantial heterogeneity in the clinical setting, CRP cut-off values and included patient populations.