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Original Article

A biomarker for bacteremia in pregnant women with acute pyelonephritis: soluble suppressor of tumorigenicity 2 or sST2

Carolyn Chattertona Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA;b Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USAView further author information
,
Roberto Romeroa Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA;c Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA;d Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA;e Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA;f Detroit Medical Center, Detroit, MI, USACorrespondence[email protected]
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Eunjung Junga Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA;b Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USAView further author information
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Dahiana M. Galloa Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA;b Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA;g Department of Gynecology and Obstetrics, Universidad del Valle, Cali, ColombiaView further author information
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Manaphat Suksaia Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA;b Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USAView further author information
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Ramiro Diaz-Primeraa Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA;e Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USAView further author information
,
Offer Ereza Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA;b Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA;h Department of Obstetrics and Gynecology, Soroka University Medical Center, Beer Sheva, IsraelView further author information
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Piya Chaemsaithonga Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA;b Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA;i Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandView further author information
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Adi L. Tarcaa Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA;b Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA;j Department of Computer Science, Wayne State University College of Engineering, Detroit, MI, USAView further author information
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Francesca Gotscha Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA;b Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USAView further author information
,
Mariachiara Boscoa Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA;b Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USAView further author information
&
Tinnakorn Chaiworapongsaa Pregnancy Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI, USA;b Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USACorrespondence[email protected]
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Article: 2183470 | Received 11 Jun 2022, Accepted 15 Feb 2023, Published online: 30 Mar 2023

Abstract

Objective

Sepsis is a leading cause of maternal death, and its diagnosis during the golden hour is critical to improve survival. Acute pyelonephritis in pregnancy is a risk factor for obstetrical and medical complications, and it is a major cause of sepsis, as bacteremia complicates 15–20% of pyelonephritis episodes in pregnancy. The diagnosis of bacteremia currently relies on blood cultures, whereas a rapid test could allow timely management and improved outcomes. Soluble suppression of tumorigenicity 2 (sST2) was previously proposed as a biomarker for sepsis in non-pregnant adults and children. This study was designed to determine whether maternal plasma concentrations of sST2 in pregnant patients with pyelonephritis can help to identify those at risk for bacteremia.

Study design

This cross-sectional study included women with normal pregnancy (n = 131) and pregnant women with acute pyelonephritis (n = 36). Acute pyelonephritis was diagnosed based on a combination of clinical findings and a positive urine culture. Patients were further classified according to the results of blood cultures into those with and without bacteremia. Plasma concentrations of sST2 were determined by a sensitive immunoassay. Non-parametric statistics were used for analysis.

Results

The maternal plasma sST2 concentration increased with gestational age in normal pregnancies. Pregnant patients with acute pyelonephritis had a higher median (interquartile range) plasma sST2 concentration than those with a normal pregnancy [85 (47–239) ng/mL vs. 31 (14–52) ng/mL, p < .001]. Among patients with pyelonephritis, those with a positive blood culture had a median plasma concentration of sST2 higher than that of patients with a negative blood culture [258 (IQR: 75–305) ng/mL vs. 83 (IQR: 46–153) ng/mL; p = .03]. An elevated plasma concentration of sST2 ≥ 215 ng/mL had a sensitivity of 73% and a specificity of 95% (area under the receiver operating characteristic curve, 0.74; p = .003) with a positive likelihood ratio of 13.8 and a negative likelihood ratio of 0.3 for the identification of patients who had a positive blood culture.

Conclusion

sST2 is a candidate biomarker to identify bacteremia in pregnant women with pyelonephritis. Rapid identification of these patients may optimize patient care.

Introduction

Acute pyelonephritis is a common medical complication of pregnancy [Citation1–4] and is responsible for 12% of antepartum admissions to the intensive care unit [Citation5,Citation6]. Pregnant patients with acute pyelonephritis are at increased risk for preterm labor [Citation7,Citation8], adult respiratory distress syndrome [Citation5,Citation9], septic shock [Citation10–14], and other complications of pregnancy [Citation1,Citation15–18]. Sepsis is a condition characterized by life-threatening dysregulated host response to infection [Citation19–21] or tissue injury [Citation19,Citation21] and accounts for 23% of maternal deaths [Citation22]. The diagnosis of sepsis during the golden hour is critical because a delay in treatment with antibiotics is associated with increased mortality [Citation23–27]. Pregnant women are known to be more susceptible to the effects of bacteria, viruses, and microbial products [Citation28,Citation29]. due to a state of mild intravascular inflammation [Citation30–32].

Soluble suppressor of tumorigenicity 2 (sST2) is the decoy receptor for the alarmin interleukin (IL)-33. At the time of cellular stress, IL-33 binds to its transmembrane receptor, suppressor of tumorigenicity 2 (ST2) on Th2 cells, promoting a humoral inflammatory response [Citation33–41]. By contrast, the soluble isoform of the same receptor modulates IL-33 activity [Citation38,Citation42–45]. In non-pregnant adults and in children, elevated sST2 concentrations are associated with worse outcomes in several inflammatory conditions [Citation43,Citation46–50], and sST2 has been proposed as a biomarker for the prediction of morbidity and mortality. When evaluated alone, or in conjunction with other biomarkers (i.e. procalcitonin) or objective sepsis scoring systems, sST2 adds prognostic information in non-pregnant patients with sepsis [Citation51–55].

In normal pregnancy, the first and third trimesters are characterized by a predominant pro-inflammatory Th1 immune response [Citation31,Citation32,Citation56], which has been implicated in successful implantation [Citation57–60] and onset of labor [Citation61–64]. By contrast, the second trimester of pregnancy is characterized by an anti-inflammatory state [Citation31,Citation32]. The maternal plasma concentrations of sST2 are higher in the third trimester, which is consistent with a shift toward a Th1 state [Citation65,Citation66], and are elevated in patients with obstetrical conditions, including recurrent pregnancy loss [Citation67,Citation68], preeclampsia [Citation65,Citation69–72], preterm labor [Citation64], and fetal inflammatory response syndrome [Citation73]. Pro-inflammatory insults during a Th2 dominant state are responsible for the more severe clinical presentations of pyelonephritis and other infections during pregnancy [Citation32,Citation61].

It is unknown whether a maternal plasma sST2 concentration has value in the assessment of pregnant patients with acute pyelonephritis. The objective of this study was to evaluate whether maternal plasma concentrations of sST2 could be of value in identifying pregnant patients with acute pyelonephritis and bacteremia because patients with bloodstream infections are at a greater risk for severe complications.

Materials & methods

Study design and sample collection

This retrospective cross-sectional study included normal pregnant women (n = 131) and pregnant patients with acute pyelonephritis (n = 36). All women were enrolled at Hutzel Women’s Hospital of the Detroit Medical Center, (Detroit, Michigan, USA).

Patients were considered to have a normal pregnancy if they met the following criteria: (1) no medical, obstetrical, and surgical complications, (2) absence of labor at the time of venipuncture, and (3) delivery of a term (≥37 weeks of gestation) infant with a birthweight between the 10th and 90th percentiles for gestational age and without congenital anomalies. Patients with a multiple gestation and major fetal anomalies were excluded. Acute pyelonephritis was diagnosed when the patient presented with a fever (temperature ≥38 °C), clinical signs of upper urinary tract infection, pyuria, and a positive urine culture. Blood cultures were performed in 30 of the patients with pyelonephritis.

All patients provided written informed consent for the collection and use of the samples under protocols approved by the Institutional Review Boards of Wayne State University and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services (NICHD/NIH/DHHS). Many of these samples were previously used in other studies at our institution, including previous past studies on pyelonephritis.

Soluble ST2 immunoassay

Blood samples were collected in tubes containing EDTA, centrifuged at 1300 g for 10 min at 4 °C, and stored at −70 °C until analysis. Maternal plasma concentrations of sST2 were determined with a sensitive and specific enzyme-linked immunoassay (R&D Systems, Minneapolis, MN, USA), validated for determination of plasma sST2 concentration. The inter- and intra-assay coefficients of variation were 4.6% and 3.9% for sST2, respectively. The sensitivity of the assay was 17.5 pg/mL.

Statistical analysis

The sST2 concentration in each group did not follow a normal distribution after testing with the Kolmogorov-Smirnov test (even after logarithmic transformation). Non-parametric statistics were used for subsequent analysis. Mann-Whitney U and Kruskal-Wallis tests were applied to determine differences between and among continuous variables. Categorical variables were compared by using a contingency table or Chi-squared test. A Receiver Operating Characteristic (ROC) curve was generated to assess the diagnostic performance of sST2 concentration for the identification of patients with bacteremia. A threshold of sST2 concentration was selected to maximize sensitivity while preserving a specificity of at least 95%. A p value of < .05 was considered significant. Statistical analyses were performed with the IBM SPSS version 19.0 (IBM Corporation., Armonk, NY).

Results

Demographic and clinical characteristics of the study groups are displayed in . There were no significant differences in all the variables evaluated except for gestational age at time of maternal venipuncture (acute pyelonephritis: 31 weeks, interquartile range (IQR) 25–36 weeks vs. normal pregnancy: 38 weeks, IQR 31–39 weeks; p = .001).

Table 1. Demographics and clinical characteristics of the study groups.

In normal pregnancies, maternal plasma sST2 concentrations increased with gestational age (Spearman’s Rho 0.8, p < .001) (). In pregnancies complicated by acute pyelonephritis, the median plasma concentration of sST2 was significantly higher than that of normal pregnancies (85 ng/mL, IQR 47–239 ng/mL vs. 31 ng/mL, IQR 14–52 ng/mL; p < .001) (). Blood cultures were positive in 11 women with acute pyelonephritis. Pregnant women with pyelonephritis and bacteremia had a significantly higher median sST2 concentration compared to those with a negative blood culture (258 ng/mL, IQR 75–305 ng/mL vs. 83 ng/mL, IQR 46-153 ng/mL; p = .03) ().

Figure 1. Scatterplot demonstrates increased sST2 concentrations among patients with acute pyelonephritis compared to patients with a normal pregnancy. The X axis shows gestational age (weeks), and the Y axis shows maternal plasma sST2 concentration (ng/mL). (A) In normal pregnancy, median maternal plasma sST2 concentrations increased with gestational age (Spearman’s Rho 0.8, p < .001). (B) Pregnancies complicated by pyelonephritis with negative blood culture alone (blue squares) are plotted against those with positive blood culture (red triangles).

Figure 1. Scatterplot demonstrates increased sST2 concentrations among patients with acute pyelonephritis compared to patients with a normal pregnancy. The X axis shows gestational age (weeks), and the Y axis shows maternal plasma sST2 concentration (ng/mL). (A) In normal pregnancy, median maternal plasma sST2 concentrations increased with gestational age (Spearman’s Rho 0.8, p < .001). (B) Pregnancies complicated by pyelonephritis with negative blood culture alone (blue squares) are plotted against those with positive blood culture (red triangles).

Figure 2. Plasma sST2 concentrations in normal pregnancy compared to pregnancy complicated by acute pyelonephritis. In pregnancies complicated by acute pyelonephritis, the median plasma sST2 concentration was significantly higher than that in normal pregnancies [median 85 ng/mL (IQR 47–239) vs. median 31 ng/mL (IQR 14–52); p < .001].

Figure 2. Plasma sST2 concentrations in normal pregnancy compared to pregnancy complicated by acute pyelonephritis. In pregnancies complicated by acute pyelonephritis, the median plasma sST2 concentration was significantly higher than that in normal pregnancies [median 85 ng/mL (IQR 47–239) vs. median 31 ng/mL (IQR 14–52); p < .001].

Figure 3. Plasma sST2 concentration in normal pregnancy compared to pregnancies complicated by acute pyelonephritis with a positive blood culture. The median plasma sST2 concentration was significantly higher in those with a positive blood culture than in those with a negative blood culture [median 258 ng/mL (IQR 75–305) vs. median 83 ng/mL (IQR 46–153); p = .03].

Figure 3. Plasma sST2 concentration in normal pregnancy compared to pregnancies complicated by acute pyelonephritis with a positive blood culture. The median plasma sST2 concentration was significantly higher in those with a positive blood culture than in those with a negative blood culture [median 258 ng/mL (IQR 75–305) vs. median 83 ng/mL (IQR 46–153); p = .03].

An elevated plasma concentration of sST2 > 215 ng/mL had a sensitivity of 73% and a specificity of 95% (area under the receiver operating characteristic curve, 0.74, 95% confidence interval 0.50 − 0.97; p = .003 compared to area 0.5) with a positive likelihood ratio of 13.8 and a negative likelihood ratio of 0.3 for the identification of patients who had a positive blood culture ().

Figure 4. Receiver Operating Characteristic (ROC) curve demonstrates an area under the curve (AUC) of 0.74 (95% confidence interval 0.50–0.97). A maternal plasma concentration of sST2 ≥ 215 ng/mL had a sensitivity of 73% and a specificity of 95% for identification of patients with a positive blood culture.

Figure 4. Receiver Operating Characteristic (ROC) curve demonstrates an area under the curve (AUC) of 0.74 (95% confidence interval 0.50–0.97). A maternal plasma concentration of sST2 ≥ 215 ng/mL had a sensitivity of 73% and a specificity of 95% for identification of patients with a positive blood culture.

Discussion

Principal findings of the study

(1) Pregnant women with acute pyelonephritis had a significantly higher median plasma sST2 concentration than women with a normal pregnancy; (2) among patients with acute pyelonephritis, those with bacteremia had a higher median plasma concentration of sST2 than patients with a negative blood culture; and (3) maternal plasma sST2 concentration ≥ 215 ng/mL is predictive of positive blood cultures in pregnant patients with acute pyelonephritis with a positive likelihood ratio of 13.8 and a negative likelihood ratio of 0.3. This is the first study to report on sST2 plasma concentrations in pregnant women with acute pyelonephritis.

What is sST2?

There are two forms of the IL-33 receptor: the transmembrane ST2 and its soluble counterpart, sST2. IL-33, a member of the IL-1 family [Citation34,Citation38,Citation74], is expressed by endothelial cells, epithelial cells, fibroblasts, and myofibroblasts [Citation33,Citation35,Citation75–77]. IL-33 is usually localized in the nucleus [Citation76,Citation78,Citation79]; however, it is released into the extracellular space at the time of tissue damage, mechanical stress, or necrosis [Citation74,Citation80–84]. When IL-33 binds to the transmembrane ST2 receptor, it serves as an alarmin, promoting Th2-like activity [Citation33–37,Citation40,Citation74,Citation85–92]. By contrast, sST2 sequesters IL-33 and attenuates the Th2 response in favor of a Th1 profile [Citation37–39,Citation41,Citation42,Citation75,Citation93–96]. Both ST2 and sST2 are encoded by the same gene on chromosome 2 [Citation97,Citation98] and their expression is modified by alternative gene splicing [Citation99,Citation100].

Pro-inflammatory stimuli, such as IL1-β, TNF-α, [Citation101] and lipopolysaccharide [Citation95,Citation102], stimulate sST2 production in several cell types including endothelial cells [Citation101], placenta explants [Citation65], cardio-myocytes, and lung alveolar epithelial cells [Citation95]. Elevated plasma sST2 concentrations are associated with increased disease severity in sepsis [Citation33,Citation51,Citation53,Citation55,Citation94,Citation103], asthma and allergies [Citation42,Citation46,Citation104–106], idiopathic pulmonary fibrosis [Citation107], rheumatoid arthritis [Citation108–110], Sjogren syndrome [Citation111–113], other autoimmune diseases [Citation47], acute myocardial infarction [Citation49,Citation114,], diabetic kidney disease [Citation115], and several great obstetrical syndromes [Citation64,Citation65,Citation69–73]. More recently, sST2 concentrations have also been associated with in-hospital mortality and a need for mechanical ventilation in patients with COVID-19 [Citation116,Citation117,].

Pregnant patients with acute pyelonephritis have elevated sST2 plasma concentrations

Our data demonstrate that maternal plasma sST2 concentrations increase as a function of gestational age in normal pregnancy, and this evidence is consistent with studies previously published [Citation65,Citation66], reporting a shift toward a Th1 response before the onset of labor [Citation61–64,Citation118,Citation119]. In our study population, pregnant patients with acute pyelonephritis, regardless of their blood culture results, had a higher median plasma sST2 concentration than women with a normal pregnancy. This observation is consistent with previous reports that the peripheral whole blood transcriptome of patients with pyelonephritis during pregnancy showed upregulation of genes involved in cytokine-cytokine interactions as well as complement and coagulation cascades [Citation120,Citation121,]. We previously described that pyelonephritis during pregnancy is associated with changes in the profile of cytokines [Citation122] such as CXCL10 [Citation123] and TRAIL [Citation124] as well as with changes in angiogenic factors [Citation125], complement [Citation121], coagulation [Citation126], and adipokines [Citation127–129].

sST2 as a biomarker for bacteremia in pregnant patients with acute pyelonephritis

The findings that pregnant patients with acute pyelonephritis and bacteremia have a higher plasma sST2 concentration than those with a negative blood culture suggests that these patients had a more intense engagement of the innate immune system. In non-pregnant adults and in children, sST2 has been proposed as a biomarker for sepsis because elevated concentrations correlate with worse outcomes and in-hospital mortality [Citation51–54].

For pregnant patients, sepsis risk stratification has been dependent on several bedside scoring systems, including the Modified Obstetric Early Warning System (MOEWS), the Sepsis in Obstetrics Score (SOS), and the Obstetric Modified Quick Sepsis Related Organ Failure Assessment (omqSOFA) [Citation130–132]. The only scoring system that employs biomarkers (leukocyte count, immature neutrophils, and lactic acid) is the SOS [Citation130]. None of the currently proposed biomarkers for sepsis in pregnant women includes procalcitonin or C-reactive protein, frequently used in non-pregnant populations [Citation133–135]. Similarly, none of the currently used scoring systems uses cytokine profiles [Citation136], which are predictive of the outcome of patients with suspected sepsis. Further research is warranted to determine the utility of maternal plasma sST2 and other cytokine profiles in conjunction with existing sepsis scoring systems in pregnancy.

Given that a maternal plasma sST2 concentration ≥215 ng/mL is associated with bacteremia, plasma sST2 may be a useful method to select patients for blood culture collection. Although there is debate about the utility of performing blood cultures, the detection of bacteremia is likely to identify patients at risk for sepsis and multiple organ failure [Citation137–143]. In pregnant patients with acute pyelonephritis who are not clinically ill, an sST2 concentration <215 ng/mL may be an alternative to forego blood culture collection. The implementation of plasma sST2 in clinical practice is easier given the availability of rapid immunoassays [Citation144,Citation145]. However, future studies are required to determine whether plasma sST2 provides any additional value over models incorporating standard risk factors for predicting patients who do or do not need blood culture collection in pregnant women with acute pyelonephritis.

Clinical and research implications

The standard treatment of pyelonephritis during pregnancy consists of the administration of parenteral broad-spectrum antimicrobial agents. The goal is to administer adequate concentrations of antibiotics to the site of infection (i.e. renal tissue, blood, or both) and not only the urine [Citation146]. The first choice is broad-spectrum beta-lactam antibiotics and third-generation cephalosporins (e.g. ceftriaxone) are favored over first- (e.g. cefazolin) and second-generation (e.g. ceforanide). Parenteral antibiotics are administered until the patient is afebrile for 48 h and then switched to oral therapy, which consists of antimicrobial agents guided by the culture susceptibility results for 10–14 days [Citation147–151]. Oral antimicrobials recommended are beta-lactams. Trimethoprim-sulfamethoxazole has been considered an alternative in the second trimester. Nitrofurantoin and fosfomycin achieve adequate concentrations only in the urine and are not considered appropriate for the treatment of pyelonephritis [Citation146,Citation152]. The treatment of patients with bacteremia during pregnancy is less clear. The standard recommendation has been to administer a course of antibiotics for 14 days; however, a recent randomized clinical trial in non-pregnant subjects reported that 7-day treatment of patients with Gram-negative bacteremia was not inferior to 14 days [Citation150,Citation151]. A trial is in progress [Citation153] [Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE)] to address this question in non-pregnant subjects. Biomarkers to monitor response to therapy could be of great value. sST2, alone or in combination with other cytokines or markers such as procalcitonin, could be useful to guide antibiotic treatment. A recent patient-level meta-analysis has shown that procalcitonin-guided antibiotic treatment in non-pregnant subjects with bacteremia can decrease antibiotic exposure without increasing mortality [Citation154] We envision that sST2, or a biomarker panel, could be performed at the time of admission to determine if blood cultures should be performed to identify bacteremia [Citation137,Citation141,Citation142].

Strengths and limitations

This is the first study to report on sST2 plasma concentrations in pregnant patients with acute pyelonephritis and to determine that concentrations of 215 ng/mL or greater are predictive of bacteremia. In our study population, there was evidence of bacteremia in 36.7% (11/30) of women with pyelonephritis, which is higher than that previously reported (ranging from 10% to 20%) [Citation16,Citation137,Citation140]. A limitation of this study is that six patients with pyelonephritis did not have blood cultures obtained.

Conclusion

We report that plasma sST2 concentrations are elevated in pregnant patients with pyelonephritis and, in particular, those with bacteremia. These findings are consistent with those observed in non-pregnant patients with sepsis and other inflammatory disorders. Based on these observations, we propose sST2 as a candidate biomarker to identify the patient at risk for bacteremia.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was supported, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); and, in part, with Federal funds from NICHD/NIH/DHHS under Contract No. HHSN275201300006C. Dr. Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government.

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