CRB-65: Predictor for Intensive Care Unit Admission in Patients with Biliary Tract Infection Presenting to An Emergency Department

1. Introduction

Sepsis is a common cause for hospitalization and accounts for 750,000 cases annually in America, with the majority of patients presenting through the emergency department (ED) [1]. Among these patients, biliary tract infection (BTI) is the second most frequent cause of sepsis in elderly patients, whereas urinary tract infection is the leading cause [2]. BTI, including cholecystitis and cholangitis, is a common cause of bacteremia and is associated with high morbidity and mortality, particularly in older patients with comorbidities or when there is a delay in diagnosis and treatment [2]. Because BTI is a major cause of sepsis, especially in elderly patients, early screening for disease severity is important [2]. In patients with cholangitis and bacteremia, acute renal failure, septic shock, malignant obstruction, hyperbilirubinemia, and a high Charlson Comorbidity Index score $>$ 6 were reported to be predictors for mortality [3]. However, as these factors are based on laboratory or radiologic findings, it is difficult to determine the severity at an early stage. In addition, in the case of the Charslon Co-morbidity score, there is a limitation that the score cannot be ascertained in the absence of information on the medical history.

To easily determine the disease severity in the early stages of ED treatment, a scoring system consisting of physiologic parameters without including laboratory finding would be useful. The quick Sequential Organ Failure Assessment (qSOFA) is a well-known scoring system used for the definition of sepsis [4]. The CRB (confusion/respiration rate/blood pressure) and CRB-65 (confusion/respiration rate/blood pressure/65 years older) were developed for community-acquired pneumonia and are tools that have been validated in many studies [5], and the score consist of the patient’s mental status, respiration, blood pressure, and age. In this study, we aimed to validate the clinical utility of the CRB, CRB-65, qSOFA, and Systemic Inflammatory Response Syndrome (SIRS) for predicting the clinical outcomes of BTI patients and compare the performance of these screening tests with each other.

2. Methods

3. Results

3.3 Validation of CRB, CRB-65, qSOFA, and SIRS for ICU Admission and In-hospital Mortality

The ROC curves of qSOFA, CRB, CRB-65, and SIRS are depicted in Fig. 1. The AUROC values for predicting ICU admission were as follows: CRB, 0.774 (95% CI 0.742 – 0.803); CRB-65, 0.816 (95% CI 0.786 – 0.843), qSOFA, 0.779 (95% CI 03747 – 0.808), and SIRS 0.686 (95% CI 0.651 – 0.719). (Table 3) AUROC of CRB-65 was 0.8 or higher, and showed good performance as a predictor. [8] In comparisons between the two criteria, the CRB-65 vs CRB (p = 0.004), CRB-65 vs SIRS (p $<$ 0.001), CRB vs SIRS p = 0.009), and qSOFA vs SIRS (p = 0.004) findings were significantly different (Table 4, Fig. 1A).

Table 3.Validation of CRB, CRB - 65, qSOFA, and SIRS for ICU admission and in - hospital mortality.

	Cutoff value	AUROC (95% CI)	Sensitivity % (95% CI)	Specificity % (95% CI)	+LR (95% CI)	- LR (95% CI)	PPV % (95% CI)	NPV % (95% CI)
ICU admission
CRB	1	0.774	0.742–0.803	69.44	59.8 – 77.9	82.49	79.3 – 85.4	3.97	3.2 – 4.9	0.37	0.3 – 0.5	40.3	35.4 - 45.5	94.1	92.2 - 95.5
CRB - 65	2	0.816	0.786 – 0.843	62.04	52.2 – 71.2	86.91	84.0 – 89.4	4.74	3.7 – 6.1	0.44	0.3 – 0.6	44.7	38.6 - 50.9	93.1	91.3 - 94.5
qSOFA	1	0.779	0.747 – 0.808	65.74	56.0 – 74.6	86.28	83.4 – 88.9	4.79	3.8 – 6.1	0.40	0.3 – 0.5	44.9	39.1 - 50.9	93.7	91.9 - 95.1
SIRS	2	0.686	0.651 - 0.719	65.74	56.0 – 74.6	71.45	67.8 – 74.9	2.30	1.9 – 2.8	0.48	0.4 – 0.6	28.2	24.6 - 32.0	92.4	90.4 - 94.1
In - hospital mortality
CRB	1	0.707	0.673 – 0.739	60.00	36.1 – 80.9	75.59	72.3 – 78.7	2.46	1.7 – 3.6	0.53	0.3 – 0.9	6.3	4.4 - 9.0	98.6	97.6 - 99.2
CRB - 65	2	0.735	0.702 – 0.766	50.00	27.2 – 72.8	80.28	77.2 – 83.1	2.53	1.6 – 4.0	0.62	0.4 – 1.0	6.5	4.2 - 10.0	98.3	97.4 - 98.9
qSOFA	1	0.724	0.690 – 0.755	60.00	36.1 – 80.9	79.45	76.3 – 82.3	2.92	2.0 – 4.3	0.50	0.3 – 0.9	7.5	5.2 - 10.6	98.6	97.7 - 99.2
SIRS	2	0.659	0.623 - 0.693	65.00	40.8 – 84.6	66.76	63.2 – 70.2	1.96	1.4 – 2.7	0.52	0.3 – 1.0	5.1	3.7 - 7.0	98.6	97.4 - 99.2
CRB: Confusion, Respiratory rate, Blood pressure; CRB - 65: Confusion, Respiratory rate, Blood pressure, age $>$ 65; qSOFA: quick Sequential Organ Failure Assessment; SIRS: Systemic Inflammatory Response Syndrome; ICU: intensive care unit; AUROC: area under the receiver operating characteristic; CI: confidence interval; +LR: positive likelihood ratio; - LR: negative likelihood ratio; PPV: positive predictive value; NPV: negative predictive value.

Table 4.Comparison of ROC curves between CRB, CRB - 65, qSOFA and SIRS for ICU admission and in - hospital mortality.

		Difference between areas (95% CI)	p-value
ICU admission
CRB	CRB-65	0.042	(0.014 - 0.071)	0.004
	qSOFA	0.005	( - 0.032 - 0.042)	0.793
	SIRS	0.088	(0.022 - 0.153)	0.009
CRB-65	qSOFA	0.037	( - 0.007 - 0.081)	0.098
	SIRS	0.130	(0.068 - 0.192)	$<$ 0.001
qSOFA	SIRS	0.093	(0.029 - 0.156)	0.004
In-hospital mortality
CRB	CRB-65	0.028	( - 0.043 - 0.099)	0.435
	qSOFA	0.017	( - 0.008 - 0.041)	0.178
	SIRS	0.048	( - 0.078 - 0.174)	0.455
CRB-65	qSOFA	0.012	( - 0.065 - 0.088)	0.769
	SIRS	0.076	( - 0.060 - 0.212)	0.271
qSOFA	SIRS	0.065	(0.058 - 0.187)	0.299
ROC: receiver operating characteristic; CRB: Confusion, Respiratory rate, Blood pressure; CRB - 65: Confusion, Respiratory rate, Blood pressure, age $>$ 65; qSOFA: quick Sequential Organ Failure Assessment; SIRS: Systemic Inflammatory Response Syndrome; ICU: intensive care unit; CI: confidence interval.

Fig. 1.The receiver operating characteristic curve for CRB, CRB-65, qSOFA, and SIRS for the ICU admission (A) and In-hospital mortality (B).

For the in-hospital mortality, the AUROCs of CRB, CRB-65, SIRS, and qSOFA were 0.707 (95% CI 0.673 – 0.739), 0.735 (95% CI 0.0.702 – 0.766), 0.724 (95% CI 0.690 – 0.755), and 0.659 (95% CI 0.623 – 0.693), respectively. (Table 3) A comparison of the two criteria for in-hospital mortality showed no significant differences between criteria (Table 4, Fig. 1B).

The cutoff values for the sensitivity and specificity of each criteria are shown in Table 3. A CRB-65 score $$ 2 had a sensitivity and specificity of 69.44 % (95% CI 52.2 – 71.2) and 82.49% (95% CI 79.37 – 85.4) for ICU admission and 60.0% (95% CI 36.1 – 80.9) and 75.59% (95% CI 72.3 – 78.7) for in-hospital mortality, respectively. Similarly, for CRB $$ 1, the sensitivity and specificity were 69.44% (95% CI 59.8 – 77.9) and 82.49% (95% CI 79.3 – 85.4) for ICU admissions and 60% (95% CI 36.1 – 80.9) and 75.59% (95% CI 72.3 – 78.7) for in-hospital mortality, respectively. A qSOFA $\ge$ 1 had a sensitivity and specificity of 65.74% (95% CI 56.0 – 74.6) and 82.28% (95% CI 83.4 – 88.9) for ICU admissions and 60% (95% CI 36.1 – 80.9) and 79.45% (95% CI 76.3 – 82.3) for in-hospital mortality, respectively.

4. Discussion

The early recognition of sepsis and its severity are important for appropriate treatment, improving outcomes, and reducing costs [4]. Therefore, many screening tools have been proposed to identify disease severity, including the SOFA, qSOFA, Acute Physiology and Chronic Health Evaluation, Multiple Organ Dysfunction Score (MODS), National Early Warning Score (NEWS), and CURB-65 (confusion, urea $>$ 7 mmol/L, respiratory rate $\ge$ 30/minute, low systolic [ $<$ 90 mmHg] or diastolic [$\le$ 60 mmHg] blood pressure, and age $\ge$ 65 years) [9, 10, 11].

In this study, the qSOFA, CRB, and CRB-65 were used for severity scoring in BTI patients. Both SOFA and qSOFA are representative screening tools for determining disease severity. The European Society of Intensive Care Medicine developed the SOFA in 1994 to determine the extent of organ dysfunction/failure or to measure the likelihood of it mortality [12]. The SOFA consists of six items that can determine the functions of respiration, coagulation, liver, cardiovascular, central nervous, and renal systems. With the new definition of sepsis in 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) task force proposed the qSOFA as a simple clinical criterion that can be used at the bedside [4]. The items of qSOFA include altered mentation, SBP $\le$ 100 mmHg, and respiratory rate $\ge$ 22/min. Since the qSOFA was proposed, a number of validation studies have been published, including a comparison with the existing SIRS criteria, and various results have been reported [13, 14, 15, 16, 17]. The qSOFA has been reported to be a useful tool for predicting the clinical outcome of patients with pneumonia [18, 19] and blunt trauma [20]. According to the findings in a study by Singer et al, the qSOFA was a useful indicator for predicting the mortality of adult ED patients with and without suspected infection (AUROC of qSOFA for mortality 0.76 95% CI 0.73 – 0.78) [21]. In this study, the AUROC of the qSOFA for ICU admission and in-hospital mortality of BTI patients who were admitted to the ED was 0.779 and 0.724, respectively. The entity of study groups were different, but showed similar results as that in the previous studies.

The other scoring systems used in this study are the CRB and CRB-65. The CURB-65 was developed for predicting the outcomes of patients with community-acquired pneumonia and is widely used in the clinical setting [22, 23]. The CURB-65 has been verified in many studies and may be applied to diseases other than community-acquired pneumonia [24, 25, 26]. The CRB-65, which excludes the urea level from the CURB-65, has the advantage of being able to determine the disease severity of a patient without any laboratory findings. In previous studies, the CRB and CRB-65 showed similar predictive ability to that of CURB-65 [27, 28]. Most of CRB-65 studies were conducted on pneumonia, sepsis, and infection-related diseases. According to a study by Kordo et al, the AUROC of CRB-65 for 28-day mortality of patients with suspected infection presenting to the ED was 0.77 (95% CI 0.72–0.81) [29]. In this study, the AUROC of CRB-65 for ICU admission and in-hospital mortality of BTI patients was 0.816 and 0.735, and was the highest among the qSOFA, CRB, CRB-65, and SIRS. In particular, the AUROC for ICU admission showed good performance at 0.816.

In case of CRB-65 and qSOFA, there are common factors, such as consciousness, respiration, and blood pressure, and there are many studies that have compared the two [5, 30, 31, 32, 33]. A comparison of qSOFA and CRB-65 performance showed various results for each study. Although there may be differences in the AUROC, both are commonly reported as tools that can be used to measure clinical prognosis. In this study, the qSOFA, CRB, and CRB-65 were found to be scoring tools with “adequate” performance, with an AUROC of 0.7 or higher. However, only the AUROC of CRB-65 for ICU admission showed the highest value above 0.8, which was also statistically significant when compared to the AUROC of CRB.

In this study, we attempted to verify the severity screening tools that can be easily applied at the bedside without laboratory findings in BTI patients in the ED. Of the many proposed screening tools, the CRB, CRB-65, and qSOFA were selected, and a comparative analysis was conducted. The CRB-65 showed the highest AUROC for predicting ICU admission (0.816 [95% CI 0.786 – 0.843]) and in-hospital mortality (0.735 [95% CI 0.0.702 – 0.766]), whereas the CRB and qSOFA showed acceptable predictive ability with an AUROC $>$ 0.7. The SIRS showed poor performance, with AUROCs of 0.686 and 0.659 for ICU admission and mortality, respectively.

This study had several limitations. First, this was a single-center retrospective study. Thus, a selection bias may be existed due to the limited sample size and study conduct at a single institute. Caution should be exercised in generalizing the results of this study, and further studies with multicenter, prospective design are required. Second, patients with BTI, especially those who were older adults, tended to have comorbidities, which may have resulted in multiorgan dysfunction syndrome and affected the prognosis. Third, as a large tertiary academic hospital that was a referral center, the institution received patients who were in poor condition and transferred from smaller hospitals and primary healthcare institutions.

5. Conclusions

The CRB-65 had good predictive performance for the initial assessment of patients with BTI and can be used as a useful screening tool to predict ICU admission in patients with BTI on presentation to the ED.

Acknowledgments

We would like to acknowledge our ED staffs for their support.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Funding information

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education (No. 2020R1I1A1A01070555). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors’ contributions

Conception and design: Y. H. Choi, J. H. Lee; Acquisition, analysis, and interpretation of data: H. Yeo, S. J. Bae, J. H. Lee; Drafting the manuscript for intellectual content: H. Yeo, S. J. Bae, J. H. Lee, K Kim; Statistical analysis: S. J. Bae, J. H. Lee. All authors reviewed, revised, and approved the manuscript for submissions. Study supervision: Y. H. Choi.