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      Diagnostic Accuracy of Procalcitonin Compared to C-Reactive Protein and Interleukin 6 in Recognizing Gram-Negative Bloodstream Infection: A Meta-Analytic Study

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          Abstract

          Objective

          Gram-negative bloodstream infections (GNBSIs), especially those caused by antibiotic-resistant species, have become a public health challenge. Procalcitonin (PCT) showed promising potential in early diagnosis of GNBSI; however, little was known about its performance under different clinical settings. We here systematically assessed the diagnostic accuracy of PCT in recognizing GNBSI and made direct comparisons with C-reactive protein (CRP) and interleukin 6 (IL-6).

          Methods

          PubMed, Embase, ISI Web of Knowledge, and Scopus were searched from inception to March 15th, 2019. Area under the summary receiver operating characteristic curve (AUC), pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated. Hierarchical summary receiver operating characteristic (HSROC) model was used for the investigation of heterogeneity and for comparisons between markers.

          Results

          25 studies incorporating 50933 suspected BSI episodes were included. Pooled sensitivity and specificity for PCT were 0.71 and 0.76, respectively. The overall AUC was 0.80. The lowest AUCs were found in patients with febrile neutropenia (0.69) and hematological malignancy (0.69). The highest AUC was found in groups using electrochemiluminescence immunoassay (0.87). In direct comparisons, PCT showed better overall performance than CRP with the AUC being 0.85 (95% CI 0.81–0.87) for PCT and 0.78 (95% CI 0.74–0.81) for CRP, but the relative DORs varied with thresholds between PCT and CRP ( p < 0.001). No significant difference was found either in threshold ( p < 0.001). No significant difference was found either in threshold ( p < 0.001). No significant difference was found either in threshold (

          Conclusions

          PCT was helpful in recognizing GNBSI, but the test results should be interpreted carefully with knowledge of patients' medical condition and should not serve as the only criterion for GNBSI. Further prospective studies are warranted for comparisons between different clinical settings.

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          Most cited references66

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          Procalcitonin increase after endotoxin injection in normal subjects.

          C Bohuon, J. Love, M Assicot … (1994)
          As procalcitonin concentrations have been shown to be elevated in patients with septicemia and gram-negative infections in particular, we proceeded to investigate the effect of endotoxin, a product of gram-negative bacteria, on procalcitonin concentrations in normal human volunteers. Endotoxin from Escherichia coli 0113:H10:k, was injected i.v. at a dose of 4 mg/kg BW into these healthy volunteers. Blood samples were obtained before and 1, 2, 4, 6, 8, and 24 h after injection of the endotoxin. Each patient's cardiovascular and overall clinical status was monitored over this period. The patients developed chills and rigors, myalgia, and fever between 1-3 h. Tumor necrosis factor-alpha levels increased sharply at 1 h and peaked at 90 min, reaching the baseline concentration thereafter by 6 h. Interleukin-6 levels increased more gradually, peaking at 3 h and reaching the baseline concentration at 8 h. The procalcitonin concentration, which was undetectable (< 10 pg/mL) at 0, 1, and 2 h, was detectable at 4 h and peaked at 6 h, maintaining a plateau through 8 and 24 h (4 ng/mL). There was no elevation of calcitonin concentrations, which remained below 10 pg/mL, the lowest sensitivity of the assay. Procalcitonin was measured by a two-antibody immunoradiometric assay specific for this peptide, with no cross-reactivity with calcitonin, katacalcin, or calcitonin gene-related peptide. We conclude that endotoxin induces the release of procalcitonin systemically, that this increase is not associated with an increase in calcitonin, and that the increase in procalcitonin associated with septicemia in patients may be mediated through the effect of endotoxin described here. Whether procalcitonin participates in the mechanisms underlying inflammation remains to be investigated.
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            Characteristics and outcomes of culture-negative versus culture-positive severe sepsis

            Jason Phua, Wang Jee Ngerng, Kay Choong See … (2013)
            Introduction Culture-negative sepsis is a common but relatively understudied condition. The aim of this study was to compare the characteristics and outcomes of culture-negative versus culture-positive severe sepsis. Methods This was a prospective observational cohort study of 1001 patients who were admitted to the medical intensive care unit (ICU) of a university hospital from 2004 to 2009 with severe sepsis. Patients with documented fungal, viral, and parasitic infections were excluded. Results There were 415 culture-negative patients (41.5%) and 586 culture-positive patients (58.5%). Gram-positive bacteria were isolated in 257 patients, and gram-negative bacteria in 390 patients. Culture-negative patients were more often women and had fewer comorbidities, less tachycardia, higher blood pressure, lower procalcitonin levels, lower Acute Physiology and Chronic Health Evaluation II (median 25.0 (interquartile range 19.0 to 32.0) versus 27.0 (21.0 to 33.0), P = 0.001) and Sequential Organ Failure Assessment scores, less cardiovascular, central nervous system, and coagulation failures, and less need for vasoactive agents than culture-positive patients. The lungs were a more common site of infection, while urinary tract, soft tissue and skin infections, infective endocarditis and primary bacteremia were less common in culture-negative than in culture-positive patients. Culture-negative patients had a shorter duration of hospital stay (12 days (7.0 to 21.0) versus 15.0 (7.0 to27.0), P = 0.02) and lower ICU mortality than culture-positive patients. Hospital mortality was lower in the culture-negative group (35.9%) than in the culture-positive group (44.0%, P = 0.01), the culture-positive subgroup, which received early appropriate antibiotics (41.9%, P = 0.11), and the culture-positive subgroup, which did not (55.5%, P < 0.001). After adjusting for covariates, culture positivity was not independently associated with mortality on multivariable analysis. Conclusions Significant differences between culture-negative and culture-positive sepsis are identified, with the former group having fewer comorbidities, milder severity of illness, shorter hospitalizations, and lower mortality.
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              The diagnostic accuracy of procalcitonin for bacteraemia: a systematic review and meta-analysis.

              S H Hoeboer, P J van der Geest, D. Nieboer … (2015)
              The diagnostic use of procalcitonin for bacterial infections remains a matter of debate. Most studies have used ambiguous outcome measures such as sepsis instead of infection. We performed a systematic review and meta-analysis to investigate the diagnostic accuracy of procalcitonin for bacteraemia, a proven bloodstream infection. We searched all major databases from inception to June 2014 for original, English language, research articles that studied the diagnostic accuracy between procalcitonin and positive blood cultures in adult patients. We calculated the area under the summary receiver-operating characteristic (SROC) curves and pooled sensitivities and specificities. To minimize potential heterogeneity we performed subgroup analyses. In total, 58 of 1567 eligible studies were included in the meta-analysis and provided a total of 16,514 patients, of whom 3420 suffered from bacteraemia. In the overall analysis the area under the SROC curve was 0.79. The optimal and most widely used procalcitonin cut-off value was 0.5 ng/mL with a corresponding sensitivity of 76% and specificity of 69%. In subgroup analyses the lowest area under the SROC curve was found in immunocompromised/neutropenic patients (0.71), the highest area under the SROC curve was found in intensive-care patients (0.88), sensitivities ranging from 66 to 89% and specificities from 55 78%. In spite of study heterogeneity, procalcitonin had a fair diagnostic accuracy for bacteraemia in adult patients suspected of infection or sepsis. In particular low procalcitonin levels can be used to rule out the presence of bacteraemia. Further research is needed on the safety and efficacy of procalcitonin as a single diagnostic tool to avoid taking blood cultures.
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                Author and article information

                Contributors
                Liying Lai:
                ORCID: https://orcid.org/0000-0002-4802-4082
                Journal
                Journal ID (nlm-ta): Dis Markers
                Journal ID (iso-abbrev): Dis. Markers
                Journal ID (publisher-id): DM
                Title: Disease Markers
                Publisher: Hindawi
                ISSN (Print): 0278-0240
                ISSN (Electronic): 1875-8630
                Publication date Collection: 2020
                Publication date (Electronic): 23 January 2020
                Volume: 2020
                Electronic Location Identifier: 4873074
                Affiliations
                1Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, China
                2Department of Functional Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
                3Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
                4Department of Infectious Diseases, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
                Author notes

                Academic Editor: Vincent Sapin

                Author information
                https://orcid.org/0000-0002-4802-4082
                https://orcid.org/0000-0001-6184-5750
                Article
                DOI: 10.1155/2020/4873074
                PMC ID: 7008263
                PubMed ID: 32076461
                SO-VID: 33a20df0-675d-4dec-98cc-4f84c4cd9e00
                Copyright © Copyright © 2020 Liying Lai et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 15 July 2019
                Date accepted : 23 December 2019
                Categories
                Subject: Research Article

                Data availability:

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