Key PointsQuestion
What is the accuracy of presepsin for the diagnosis of neonatal early-onset sepsis?
Findings
In this systematic review and meta-analysis of 12 studies and 828 newborns, presepsin showed high pooled sensitivity and specificity; presepsin specificity was influenced by inclusion of only early-onset or all neonatal sepsis. Accuracy was not affected by gestational age, test type, country of the study, or risk of bias of the included studies.
Meaning
Presepsin appears to be an accurate biomarker of early-onset sepsis and should be studied in clinical trials in order to reduce early antibiotic exposure.
Importance
Neonatal early-onset sepsis (EOS) is a severe disease, particularly in preterm infants. Timely diagnosis can be challenging owing to unspecific presentation and questionable performance of the common markers of infection. Presepsin was recently proven to be a promising biomarker for the diagnosis of EOS.
Objective
To assess presepsin accuracy for the diagnosis of EOS.
Data Sources
PubMed Medline, EMBASE, Web of Science, and Google Scholar. No publication date restrictions were applied. The literature search was limited to the English language. Articles were checked for duplication.
Study Selection
Inclusion criteria were studies that (1) included term or preterm newborns (defined as newborns with gestational age ≥37 weeks or <37 weeks, respectively); (2) included a diagnosis of EOS, defined as culture-proven sepsis for primary analysis and as either clinical or culture-proven sepsis for secondary analysis; and (3) assessed presepsin values during the initial workup for suspected EOS. Exclusion criteria were studies that (1) did not include EOS cases; (2) lacked data on presepsin sensitivity and/or specificity; and (3) were case reports, commentaries, or reviews. Two independent reviewers performed the study selection.
Data Extraction and Synthesis
Two independent reviewers performed data extraction and quality assessment. Quality assessment was performed using the Quality Assessment for Studies of Diagnostic Accuracy 2 tool, and data were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were pooled using a random-effects model.
Main Outcomes and Measures
The outcomes of interest for both the primary and secondary analyses were presepsin sensitivity, specificity, and diagnostic odds ratio for the diagnosis of EOS.
Results
A total of 12 studies of 245 (4.9%) met inclusion criteria for the primary analysis. Twenty-three studies of 245 (9.4%) met the inclusion criteria for the secondary analysis. In the primary analysis, among 12 studies and 828 newborns of any gestational age, pooled sensitivity and specificity were 0.93 (95% CI, 0.86-0.95) and 0.91 (95% CI, 0.85-0.95), respectively; pooled diagnostic odds ratio was 131.69 (95% CI, 54.93-310.94). Subgroup analysis showed that presepsin specificity was associated with the inclusion of only EOS or all neonatal sepsis. Presepsin accuracy was not associated with gestational age, measurement with chemiluminescence enzyme immunoassay or enzyme-linked immunosorbent assay testing, country where the study was performed, or risk of bias judgment. In the secondary analysis, among 23 studies and 1866 newborns, accuracy was significantly associated with only test type.
Conclusions and Relevance
Results of this systematic review and meta-analysis suggest that presepsin was an accurate biomarker of EOS. Clinical trials are warranted to assess its usefulness and safety to reduce early antibiotic exposure, particularly in preterm newborns.
Early-onset sepsis (EOS) is defined as a blood or cerebrospinal fluid culture obtained during the first 72 hours of life that grows a pathogenic bacterial species.1-3 EOS incidence is reported to range from 0.5 to 1 in 1000 live births in full-term (term) newborns (≥37 weeks of gestational age) to 3% to 4% at 22 to 24 weeks of gestational age (GA).4-6 Case-fatality rate is 0% to 3% in term infants,4-6 30% at 25 to 28 weeks of age, and 54% at 22 to 24 weeks of age4-6; considerable risk of long-term neurodevelopmental impairment is demonstrated among survivors.7
EOS diagnosis is a frequent challenge in the neonatal intensive care unit, as clinical signs are equivocal1-3 and the common markers of infection, such as C-reactive protein and procalcitonin, physiologically increase during the first 48 hours of life in response to noninfective stimuli.8-11 Blood culture in EOS shows a median time to positivity of 21 hours.12 Pending blood culture results, 2% to 15% of term newborns admitted in the neonatal intensive care unit and 87% to 96% of extremely preterm infants (those ≤25 weeks of gestational age or weighing <1000 g at birth) are administered antibiotics.13-16 However, early empirical antibiotics without evidence of positive blood culture are associated with adverse outcomes, such as late-onset sepsis (LOS), necrotizing enterocolitis, death, bronchopulmonary dysplasia, and adverse neurodevelopmental outcomes in preterm newborns (<37 weeks of gestational age),17-21 and asthma, inflammatory bowel disease, obesity, and food allergies in term newborns.22-24
Presepsin results from the cleavage of CD14 by circulating bacterial proteases during sepsis.25,26 Two previous meta-analyses27,28 on the accuracy of presepsin for the diagnosis of neonatal sepsis concluded that presepsin is a favorable biomarker. However, studies including EOS and LOS were analyzed together, not taking into account that different timing of presepsin measurements may affect results, and that a single cutoff value for EOS and LOS may be inappropriate, as presepsin values were demonstrated to change over time during the first month of life.29 Patient populations may also significantly differ, as LOS occurrence is definitely prevalent in hospitalized preterm newborns, and presepsin values were shown to be affected by GA.30,31 A single meta-analysis that studied EOS and LOS separately found different cutoff values, but few studies were available for inclusion.32 Moreover, 2 different studies29,31 recently assessed presepsin reference ranges in healthy term and preterm newborns in the first 3 days of life, posing the basis for properly designed clinical trials including presepsin as an early biomarker of EOS. Therefore, the aim of the present systematic review and meta-analysis was to assess presepsin accuracy for the diagnosis of neonatal EOS.
The protocol for this systematic review and meta-analysis was published in PROSPERO International Prospective Register of Systematic Reviews, National Institute for Health Research, University of York, York, United Kingdom,33 registration number CRD42021234503.34 This study was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines.35 The literature search was conducted on March 15, 2021, using the following databases: PubMed Medline, EMBASE, and Web of Science; Google Scholar was used for an additional search. The following search terms were used: “presepsin” OR “P-SEP” OR “soluble CD 14 subtype” OR “sCD14-ST” AND “newborn” OR “infant” OR “neonat” OR “child” OR “pediatric.” No publication date restrictions were applied. The literature search was limited to the English language. Articles were checked for duplication.
Eligibility and Quality Assessment
Two reviewers (C.P., C.D.) independently assessed eligibility. Titles and abstracts of all retrieved articles were screened to identify potentially eligible studies, and all selected articles were analyzed in full text for conclusive evaluation. Eligibility criteria for the present study were as follows: (1) studies that included newborns, either term or preterm; (2) studies with a diagnosis of EOS as the evaluated outcome, defined as culture-proven sepsis for primary analysis and as either clinical or culture-proven sepsis for secondary analysis; and (3) studies where presepsin values were assessed during the initial workup for suspected EOS. Exclusion criteria were (1) studies not including EOS cases; (2) studies that lacked data on sensitivity and/or specificity of presepsin; and (3) studies that were case reports, commentaries, or reviews. Data on race and ethnicity were not available.
Two reviewers (C.P., C.D.) independently performed quality assessment of eligible studies using the Quality Assessment for Studies of Diagnostic Accuracy 2 tool, University of Bristol, Bristol, United Kingdom.36 The following 4 domains were analyzed to assess the risk of bias: patient selection, index test, reference standard, and flow and timing; the following 3 domains were analyzed to assess applicability: patient selection, index test, and reference standard.36 Risk of bias and applicability concerns were rated as low, high, or unclear if data were insufficient or inadequate to achieve a conclusive judgment. Any disagreement between the 2 reviewers was resolved through formal discussion in order to achieve a final judgment.
Two reviewers (C.P., C.D.) performed data extraction. The following data were recorded for each eligible study: study design, year of publication, inclusion and exclusion criteria, reference standard application and results, proportion of EOS cases for studies enrolling a mixed population of EOS and LOS cases, sample size, GA of enrolled patients, index test method, and country where the study was performed. Data regarding presepsin performance for the diagnosis of EOS included descriptive values measured in newborns with EOS and healthy controls (expressed as mean [SD], median [IQR], or median and range), calculated cutoff, sensitivity, specificity, area under curve, and, if available, positive predictive value and negative predictive value. Number of true positives, true negatives, false positives, and false negatives for each included study were computed using the provided estimates of sensitivity and specificity.
Statistical analysis and data synthesis were conducted in accordance with the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy, Chapter 10.37
Results of sensitivity and specificity with 95% CIs were descriptively presented in a forest plot and area under the receiver operating characteristic (ROC) curve space. As no threshold outcome was detected from inspection of the forest plot, we fitted a bivariate model using the METADAS macro in SAS (SAS Institute)38 and reported pooled estimates of sensitivity, specificity, and summary ROC (SROC) curve. Furthermore, we formally explored heterogeneity by subgroup analysis using the following study-level covariates: percentage of EOS cases (100% or mixed population of EOS and LOS cases), GA (full-term or preterm newborns or mixed population), presepsin test type (chemiluminescence enzyme immunoassay [CLEIA] or enzyme-linked immunosorbent assay [ELISA]), country where the study was performed (Egypt or any other country), and risk of bias (all green domains or not). We also provided SROC curves for subgroup analysis. Reference standard (culture proven or clinical sepsis) was added among covariates for secondary analysis. Quality assessment data were recorded and elaborated with RevMan software, version 5.4.1 (Cochrane Collaboration).
Study selection is reported in Figure 1. The literature search identified 245 records that potentially qualified for inclusion. Full texts were screened, and 34 studies met the inclusion criteria. Two studies39,40 were excluded from meta-analysis, as data regarding presepsin sensitivity and specificity were not provided. After excluding reviews on presepsin for the diagnosis of neonatal sepsis,27,28,32,41 studies on presepsin reference ranges29-31,42,43 were also excluded because they enrolled only uninfected newborns. Among the 23 remaining studies,44-66 12 (4.9%) considered positive blood culture as a reference standard44-55 and were all included in the primary analysis after quality assessment. Eleven studies56-66 considered clinical sepsis as reference standard, and, after quality assessment of these, all 23 studies (9.4%)44-66 enrolling newborns with either positive blood culture or clinical sepsis were included in secondary analysis.
Characteristics of studies included in the primary analysis are reported in Figure 2A and eTable 1 in the Supplement. A total of 828 newborns were considered, including 460 newborns with EOS and 368 uninfected newborns. Two of the 12 studies (16.7%)45,51 enrolled only newborns with EOS, including 122 newborns, whereas 10 of 12 studies (83.3%)46-49,52-54 enrolled a mixed population of newborns with EOS and LOS, with EOS accounting for 31% to 78% of all cases; 3 studies44,50,55 did not specify the proportion of EOS. Four of 12 studies (33.3%)45,47,52,54 included only term newborns, and 2 of 12 studies (16.7%)49,51 included only preterm newborns, whereas the other 6 studies (50.0%)44,46,48,50,53,55 enrolled both term and preterm newborns. Six of 12 studies (50.0%)44-47,52,54 were performed in Egypt, whereas the other 6 (50.0%)48-51,53,55 were performed in Europe and Asia. Presepsin sensitivity ranged from 0.79 to 1.00, specificity from 0.69 to 1.00, and the optimal cutoff of presepsin from 200 to 1066 pg/mL. The area under curve was reported by 10 of 12 studies (83.3%) and ranged from 0.76 to 0.99. A total of 1866 newborns were considered for secondary analysis (eFigure 3A, eTable 2 in the Supplement), including 1040 newborns with EOS and 826 uninfected newborns. Seven of 23 studies (30.4%)45,51,56,60,62,64,65 enrolled only newborns with EOS.
In primary analysis, 3 of 12 studies (25%)45,52,54 presented high risk in the patient selection domain as enrollment was not consecutive, and a case-control or mixed approach was used, and 2 of 12 (16.7%)50,53studies had unclear risk as the enrollment strategy was not fully stated (Figure 3). Seven of 12 studies (58.3%)44,46-49,51,55 presented all green domains. Results of quality assessment for studies included in the secondary analysis are reported in eFigure 2 in the Supplement.
According to the bivariate model analysis, in the primary analysis (Table), presepsin pooled sensitivity and specificity were 0.93 (0.89-0.96) and 0.91 (0.85-0.95), respectively, and pooled diagnostic odds ratio (DOR) was 131.69 (54.93-310.94), indicating a high accuracy for the diagnosis of EOS. The SROC is presented in Figure 2B. Heterogeneity among included studies as well as the threshold outcome was judged not relevant after inspection of the forest plot (Figure 2A). Secondary analysis showed presepsin pooled sensitivity and specificity of 0.93 (95% CI, 0.89-0.96) and 0.91 (95% CI, 0.87-0.94), respectively, and pooled DOR of 141.9 (95% CI, 68.6-293.5) (eTable 3, eFigure 3B in the Supplement).
The results of subgroup analysis for primary analysis are reported in the Table, Figure 4, and eFigure 1 in the Supplement. Studies enrolling only newborns with EOS showed higher specificity compared with those enrolling a mixed population of EOS and LOS (0.99; 95% CI, 0.80-1.00 vs 0.89; 95% CI, 0.82-0.93; P = .003) but not a significantly different sensitivity (0.96; 95% CI, 0.85-0.99 vs 0.92; 95% CI, 0.85-0.96; P = .35) or DOR (1922.59; 95% CI, 80.15-4612.1 vs 91.36; 95% CI, 41.16-202.79; P = .07). Presepsin accuracy was not associated with GA, measurement with CLEIA or ELISA testing, country where the study was performed, or risk of bias judgment. No differences in presepsin accuracy were detected between studies enrolling only term45,47,52,54 vs only preterm newborns,49,51 whereas studies44,46,48,50,53,55 enrolling term and preterm newborns showed significantly lower specificity (0.85; 95% CI, 0.78-0.90 vs 0.96; 95% CI, 0.87-0.99; P = .005) in comparison to those enrolling only term newborns but not significantly different sensitivity (0.93; 95% CI, 0.80-0.99 vs 0.92; 95% CI, 0.83-0.96; P = .78) or DOR (78.86; 95% CI, 23.89-266.98 vs 248.58; 95% CI, 78.24-789.76; P = .18). In the secondary analysis, among 23 studies44-66 and 1866 newborns, accuracy was significantly associated with only test type (eTable 3, eFigures 4 and 5 in the Supplement). Presepsin determination by ELISA test showed significantly higher sensitivity (0.96; 95% CI, 0.91-0.98 vs 0.90; 95% CI, 0.84-0.94; P = .04), specificity (0.95; 95% CI, 0.90-0.97 vs 0.88; 95% CI, 0.82-0.92; P = .04), and DOR (462.3; 95% CI, 157.2-1359 vs 67.4; 95% CI, 32.7-138.9; P = .003) vs CLEIA test.
To our knowledge, this was the largest systematic review and meta-analysis on presepsin diagnostic performance in the neonatal population, and the first one specifically addressing presepsin accuracy for the diagnosis of EOS. We showed a presepsin pooled sensitivity of 0.93 (95% CI, 0.86-0.96), a pooled specificity of 0.91 (95% CI, 0.85-0.95), and a pooled DOR of 131.7 (95% CI, 54.9-310.9), suggesting that presepsin was a robust biomarker of EOS. Our findings are in agreement with previous meta-analyses on presepsin accuracy for the diagnosis of neonatal sepsis without definition of the timing of onset,27,28,32,41 which showed pooled sensitivity of 0.81 to 0.91,27,32 pooled specificity of 0.86 to 0.91,27,32 and pooled DOR of 121 to 170.28,32
In contrast to previous meta-analyses, we analyzed presepsin accuracy for the diagnosis of EOS instead of neonatal sepsis in general. Studies enrolling only newborns with EOS vs those enrolling a mixed population of newborns with EOS and LOS showed higher specificity (0.99; 95% CI, 0.80-1.00 vs 0.89; 95% CI, 0.82-0.93; P = .003) but not significantly different sensitivity (0.96; 95% CI, 0.85-0.99 vs 0.92; 95% CI, 0.85-0.96; P = .35) and DOR (1922.59; 95% CI, 80.15-461.21 vs 91.36; 95% CI, 41.16-202.79; P = .0661). In a previous meta-analysis32 including either culture-proven or clinical sepsis, patients with EOS showed significantly lower pooled presepsin levels in comparison to those with LOS and exhibited a significant increase in presepsin levels within the first 24 hours from the first measurement, in contrast with newborns with LOS. These differences might reflect the fact that presepsin in patients with EOS is probably determined in a more precocious stage of the disease32 but also that very preterm newborns, who have different basal levels in comparison with more mature newborns, account for the vast majority of LOS cases.30,31 Therefore, specific cutoff values should be provided for the diagnosis of EOS and LOS.
Primary analysis included studies with positive blood culture as a reference standard, as the concept of culture negative sepsis was heavily questioned,3,67 and the reduction of early empirical antibiotics was identified as a crucial area for antibiotic stewardship implementation.3 However, because in intensive care settings a certain amount of clinical sepsis is still treated as bacteremia, secondary analysis included studies considering either culture-proven or clinical sepsis as a reference standard. We found no differences in sensitivity and specificity between studies, including culture-proven vs clinical sepsis, in agreement with prior demonstration of a lack of an association of the proportion of positive blood culture with presepsin accuracy for the diagnosis of neonatal sepsis in general.28 Accordingly, risk of bias, which was influenced by the reference standard definition, was not associated with presepsin accuracy. Nonetheless, the risk of misdiagnosis remains considerable among studies enrolling clinical sepsis, as noninfectious conditions likely account for a certain proportion of cases, possibly leading to overestimation of presepsin accuracy.
No differences in presepsin accuracy were detected between studies enrolling term vs preterm newborns, which is in line with previous observations regarding a lack of association of GA with presepsin accuracy for the diagnosis of neonatal sepsis in general.27,28 Only studies44,46,48,50,53,55 enrolling a mixed population compared with those enrolling only term newborns45,47,52,54 showed significantly lower specificity whereas no differences were observed in sensitivity and DOR. EOS accounted for 41% to 100% of cases in studies enrolling term newborns but 31% to 78% of those enrolling a mixed population, possibly affecting presepsin accuracy results.
Secondary analysis revealed significantly higher sensitivity, specificity, and DOR of studies using the ELISA vs CLEIA test. Although these data are not representative of a direct comparison between the 2 test types, the observed difference may be attributed to the fact that the ELISA test was performed by the central laboratory on 1-mL venous or arterial blood samples, whereas the CLEIA test was performed on 75-μL samples obtainable also by heel puncture by a point-of-care automated analyzer.31 Not only might smaller volumes be negatively associated with accuracy, but heel puncture is also known to determine a certain degree of hemolysis,68 and improper sample agitation may further contribute to nonsepsis-related presepsin increase.69 Nevertheless, the point-of-care test still offers the advantages of a 15-minute turnaround time and lower risk of iatrogenic anemia, particularly in preterm infants.31
Among studies included in the primary analysis, 9 of 12 studies44,47-50,52-55 performed presepsin measurements once, at the onset of symptoms. One study51 performed repeated measurements during the first 48 hours of life and showed the best accuracy at 24 hours of life; however, data on timing of onset and antibiotic administration were not provided. Presepsin was measured in the first day of life in 1 study45 and repeated on day 3 in patients with sepsis, and results showed a significant decline in survivors. Finally, 1 study46 determined presepsin at birth and at onset and found a significant difference between patients with sepsis and those without infection only at onset but included both EOS and LOS; however, the latter group is not expected to have high presepsin levels at birth. Available data suggest that presepsin is accurate at the onset of symptoms; however, the optimal timing of presepsin measurement and whether presepsin may be useful before the onset of symptoms remain to be determined. Considering that the majority of very preterm newborns present at birth with clinical signs overlapping those of EOS, determination of presepsin at birth and further measurement within 12 to 24 hours appear to be a wise strategy for early diagnosis of EOS, also taking into account that presepsin reference ranges do not significantly vary during the first 48 hours of life.29-31
This systematic review and meta-analysis had some limitations. A relatively moderate proportion of patients with EOS was included; studies enrolling only patients with EOS accounted for 112 of 828 patients, and among 460 cases of sepsis, 209 EOS were included (although 3 studies enrolling a mixed population of EOS and LOS did not report the relative amount of cases).44,50,55 Moreover, a relatively high ratio of cases to controls (1:1.25) was observed because 3 of 12 studies used a case-control approach, and 2 other studies putatively used a case-control strategy, although it was not clearly stated. In addition, studies declaring consecutive enrollment showed a ratio of approximately 1:1 and regional differences in EOS incidence70 could partially contribute to an increase EOS prevalence in these studies. As a case-control approach in the setting of a high pretest probability may overestimate positive predictive value and underestimate the negative predictive value, presepsin predictivity EOS diagnosis cannot be assessed. Nevertheless, sensitivity and specificity maintain reliability irrespective of study design, and risk of bias, which was rated high in 5 of 12 studies because of study design, did not influence presepsin accuracy. Finally, none of the included studies defined a prespecified presepsin cutoff but only provided the optimal calculated cutoff value, possibly leading to overestimation of presepsin accuracy.
Publication bias may have occurred as a result of inclusion of only published reports in English language. However, the effect of publication bias on the results of a meta-analysis on diagnostic test accuracy is considered unclear, and adequate methods of testing for publication bias in this context have not yet been identified.37 Deeks test was not performed, as it possesses modest to low power.37
In this systematic review and meta-analysis, evidence suggests that presepsin was a promising biomarker for the diagnosis of EOS. Based on the results presented in this meta-analysis, specifically designed randomized clinical trials are needed to ascertain the usefulness and safety of early presepsin measurement to guide early empirical antibiotic treatment, particularly in preterm newborns.
Accepted for Publication: February 17, 2022.
Published Online: May 31, 2022. doi:10.1001/jamapediatrics.2022.1647
Corresponding Author: Chiara Poggi, MD, PhD, Neonatology and Neonatal Intensive Care, Department of Mother and Child Care, Careggi University Hospital, Largo Brambilla 3, Florence 50141, Italy (poggich@gmail.com).
Author Contributions: Drs Poggi and Lucenteforte had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Poggi, Lucenteforte, Dani.
Acquisition, analysis, or interpretation of data: Poggi, Lucenteforte, Petri, De Masi.
Drafting of the manuscript: Poggi, Lucenteforte, Petri.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Poggi, Lucenteforte, Petri.
Administrative, technical, or material support: Poggi.
Supervision: Poggi, Lucenteforte, De Masi, Dani.
Conflict of Interest Disclosures: Dr Lucenteforte reported receiving personal fees from Angelini consultancy outside the submitted work and being involved as investigator of an observational study funded by the pharmaceutical company Galapagos in compliance with the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance code of conduct. No other disclosures were reported.
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