Biomarker Of Bacterial Infection Research Articles

Procalcitonin as a biomarker of bacterial infection in pediatric patients after congenital heart surgery.

Background:Bacterial infection (BI) after congenital heart surgery (CHS) is associated with increased morbidity and is difficult to differentiate from systemic inflammatory response syndrome caused by cardiopulmonary bypass (CPB). Procalcitonin (PCT) has emerged as a reliable biomarker of BI in various populations.Aim:To determine the optimal PCT threshold to identify BI among children suspected of having infection following CPB.Setting and Design:Single-center retrospective observational study.Materials and Methods:Medical records of all the patients admitted between January 2013 and April 2015 were reviewed. Patients in the age range of 0-21 years of age who underwent CHS requiring CPB in whom PCT was drawn between postoperative days 0-8 due to suspicion of infection were included.Statistical Analysis:The Wilcoxon rank-sum test was used for nonparametric variables. The diagnostic performance of PCT was evaluated using a receiver operating characteristic (ROC) curve.Results:Ninety-eight patients were included. The median age was 2 months (25th and 75th interquartile of 0.1-7.5 months). Eleven patients were included in the BI group. The median PCT for the BI group (3.42 ng/mL, 25th and 75th interquartile of 2.34-5.67) was significantly higher than the median PCT for the noninfected group (0.8 ng/mL, 25th and 75th interquartile 0.38-3.39), P = 0.028. The PCT level that yielded the best compromise between the sensitivity (81.8%) and specificity (66.7%) was 2 ng/mL with an area under the ROC curve of 0.742.Conclusion:A PCT less than 2 ng/mL makes BI unlikely in children suspected of infection after CHS.

The use and value of procalcitonin in solid organ transplantation.

Procalcitonin (PCT) has been increasingly used as a biomarker of bacterial infection and as a tool to guide antimicrobial therapy, especially in lower respiratory tract and bloodstream infections. Despite its increased use, data in patients with solid organ transplants are limited. Even without the presence of infection, PCT increases as a result of surgical procedures during transplantation, implantation of devices, and use of induction immunosuppressive therapy. The risk of infection is also higher in solid organ transplant recipients when compared to the general population. Monitoring PCT in the early post-transplant period seems to be a promising method for early detection of infectious complications. It has been shown that elevated PCT levels after one wk of transplantation are correlated with infectious complications. PCT may be a useful adjunctive biomarker that may improve early identification and guide appropriate treatment of infection or rejection, with the potential to further improve clinical outcomes. The use of serial PCT measurements may be more reliable than single values. It is important to recognize which factors may lead to PCT increases in the post-transplantation period, which in turn will help understand the kinetics and utility of this biomarker in this important patient population.

Neutrophil CD64 expression – comparison of two different flow cytometry protocols on EPICs MCL and the Leuko64™ assay on a Celldyn Sapphire haematology analyser

Objective. To evaluate the Trillium Diagnostics Leuko64™ assay on Abbott Celldyn Sapphire haematology analyser compared to two flow cytometry protocols on Beckman Coulter EPICS MCL flow cytometer. Materials and methods. CD64 expression on neutrophils was determined by two flow cytometry protocols and by a commercial assay on an automatic haematology analyser. The inclusion of study subjects was based on elevated procalcitonin (PCT) values, identifying patients where a systemic infection was suspected. Healthy blood donors were used as a reference group. Results. Statistically significant correlations between the Trillium Diagnostics Leuko64™ assay and the flow cytometry methods were found when measuring neutrophil CD64 expression. Conclusions. The good correlation between a reference method and an automated haematology analyser method for CD64 expression on neutrophils supports introduction of the latter assay for routine use as an independent biomarker of bacterial infection and inflammation.

PROCALCITONINA: PRIETEN SAU DUŞMAN ÎN TRATAMENTUL ANTIMICROBIAN?

According to WHO, infectious diseases remain in the top 10 of the most common causes of death worldwide, leading to an excessive consumption of antibiotics, often unnecessarily. Antibiotic stewardship policy aims to identify an useful surrogate marker for the differential diagnosis of the bacterial infections from viral or fungal infections. The aims of this strategy is to restrict the prescriptions of antibiotics in order to reduce morbidity associated with excessive antibiotic treatment, decrease of bacterial resistance and optimize the costs of patient care. Procalcitonin (PCT) has emerged in the early ‘90s as a specific biomarker for bacterial infections. Many clinical studies have shown a correlation between the use of PCT as a diagnostic marker of bacterial sepsis and decrease antibiotic consumption, without a secondary increase in mortality. However, the PCT has a number of limitations regarding sensitivity and specificity. Thus, it may be increased in non-infectious diseases or it may remain at low levels in bacterial infections. Also, PCT cannot replace clinical evaluation and bacteriological tests in facing a patient with suspected infectious disease. This review aims to summarize the available informations so far about pathophysiological mechanisms, biological role and clinical utility of PCT in the diagnostic and treatment algorithm of bacterial infections.

Antibiotic Treatment of Severe Exacerbations of Chronic Obstructive Pulmonary Disease with Procalcitonin: A Randomized Noninferiority Trial

BackgroundThe duration of antibiotic treatment of exacerbations of COPD (ECOPD) is controversial. Serum procalcitonin (PCT) is a biomarker of bacterial infection used to identify the cause of ECOPD.Methods and FindingsWe investigated whether a PCT-guided plan would allow a shorter duration of antibiotic treatment in patients with severe ECOPD. For this multicenter, randomized, non-inferiority trial, we enrolled 184 patients hospitalized with ECOPD from 18 hospitals in Italy. Patients were assigned to receive antibiotics for 10 days (standard group) or for either 3 or 10 days (PCT group). The primary outcome was the rate of ECOPD at 6 months. Having planned to recruit 400 patients, we randomized only 183: 93 in the PCT group and 90 in the standard group. Thus, the completed study was underpowered. The ECOPD rate at 6 months between PCT-guided and standard antibiotic treatment was not significant (% difference, 4.04; 90% confidence interval [CI], −7.23 to 15.31), but the CI included the non-inferiority margin of 15. In the PCT-guided group, about 50% of patients were treated for 3 days, and there was no difference in primary or secondary outcomes compared to patients treated for 10 days.ConclusionsAlthough the primary and secondary clinical outcomes were no different for patients treated for 3 or 10 days in the PCT group, the conclusion that antibiotics can be safely stopped after 3 days in patients with low serum PCT cannot be substantiated statistically. Thus, the results of this study are inconclusive regarding the noninferiority of the PCT-guided plan compared to the standard antibiotic treatment. The study was funded by Agenzia Italiana del Farmaco (AIFA-FARM58J2XH). Clinical trial registered with www.clinicaltrials.gov (NCT01125098).Trial RegistrationClinicalTrials.gov NCT01125098

Comparison of the Eosinophil Count to C –reactive protein, Leukocyte Count, and Neutrophil Count for the detection of bacterial infection in ill-appearing children with fever admitted to the Emergency Department

Introduction. From late 19th century to the present day, several authors have investigated the value of low eosinophil count as a biomarker of bacterial infection. In this study, we examined the value of eosinopenia for diagnosing bacterial infection in ill-appearing children admitted to the pediatric emergency department.Methods. Retrospective review of the medical records of children age 1 month to 14 years who appeared ill on admission to the emergency department (ED). Data collected included; C-reactive protein (CRP) level leukocyte, neutrophil, eosinophil counts, results of microbiological tests, radiologic evaluation, and treatment given in the ED. Final outcome data were also collected. Results. In total, 878 met our case definition and inclusion criteria. 521 patients had confirmed or presumed bacterial infection and 355 patients had presumed or confirmed viral infection. Nineteen patients died; all had bacterial infections. Neutrophil, eosinophil counts and CRP level were independent risk factors for bacterial infection in the multivariate analysis (p 0.05). The sensitivities of the leukocyte, neutrophil, and eosinophil counts and CRP level were 57.5%, 62.9%, 61%, and 57.1%, respectively. The specificities of them were 59.1%, 63.3%, 67%, and 77.4%, respectively.Conclusion. In our study population, although the accuracies of eosinophil, neutrophil counts, and CRP level were not enough, they had similar in distinguishing viral from bacterial infection in ill appearing febrile children. By comparison the leukocyte count had limited predictive value.

Procalcitonin, a valuable biomarker assisting clinical decision‐making in the management of community‐acquired pneumonia

Community-acquired pneumonia (CAP) is a leading cause of mortality, morbidity and hospital admission, which places strain on our healthcare system. Procalcitonin (PCT) is a biomarker of bacterial infection which may help gauge the severity and prognosis of patients with CAP. In addition to clinical predictors, PCT may assist in decisions pertaining to timing of discharge from hospital and the discontinuation of antibiotics. This study aimed to determine the predictive role of PCT measurement in reducing hospital admissions, length of stay (LOS) and antibiotic (AB) usage in patients with CAP. A prospective, single-blinded, externally controlled study of consenting adult patients admitted with CAP. PCT levels were obtained on day 1 and day 3 (when indicated). Investigator-evaluated clinical parameters, together with results of PCT levels, determined the timing of oral AB switch and discharge from hospital. This process was compared against standard practice, but was not actually implemented, for the purpose of this study. Sixty patients were included in the study. The mean age was 66.5 ± 21.2 years (56.3% male). The average Pneumonia Severity Index was 93 ± 39 (class IV) and the median CURB-65 was 2. The mean LOS for the standard practice cohort was 5.3 ± 4.6 days versus calculated LOS using the PCT guidance pathway of 3.7 ± 2.8 days. (P = 0.00006). Our study supports the hypothesis that by incorporation of PCT levels, hospital admission and LOS in patients with CAP can be reduced. A randomised prospective clinical trial is planned in an attempt to help confirm these findings.

PROCALCITONIN AS A BIOMARKER OF BACTERIAL INFECTION IN SICKLE CELL VASO-OCCLUSIVE CRISIS.

Sickle cell anaemia (SCA) patients with vaso-occlusive crisis (VOC) have signs of inflammation and it is often difficult to diagnose a bacterial infection in them. This study was undertaken to evaluate the role of serum procalcitonin (PCT) as a biomarker of bacterial infection in acute sickle cell vaso-occlusive crisis. Hundred homozygous SCA patients were studied at Sickle Cell Clinic and Molecular Biology Laboratory, V.S.S. Medical College, Burla, Odisha, India. All the patients were divided into three categories namely category-A (VOC/ACS with SIRS but without evidence of bacterial infection - 66 patients), category-B (VOC/ACS with SIRS and either proven or suspected bacterial infection - 24 patients) and category-C (SCA patients in steady state without VOC/ACS or SIRS - 10 patients). Complete blood count, C-reactive protein (CRP) estimation and PCT measurement were done in all the patients. There was no significant difference in TLC and CRP values between category-A and B. In category-A, the PCT level was <0.5 ng/mL in 83.3% and 0.5–2 ng/mL in 16.7% of cases. In category-B, all the patients had PCT value >0.5 ng/mL with 87.5% of patients having >2 ng/mL. In category-C, PCT value was <0.5 ng/mL. PCT had a high sensitivity (100%) and negative predictive value (100%) for bacterial infection at a cutoff value of 0.5 ng/mL; whereas the specificity is excellent at a cut-off value of 2 ng/mL. SCA patients with VOC/ACS and SIRS having a PCT level of <0.5 ng/mL have a low probability of bacterial infection whereas PCT value of >2 ng/mL is indicative of bacterial infection necessitating early antimicrobial therapy.

Diagnostic utility of broad range bacterial 16S rRNA gene PCR with degradation of human and free bacterial DNA in bloodstream infection is more sensitive than an in-house developed PCR without degradation of human and free bacterial DNA.

We compared a commercial broad range 16S rRNA gene PCR assay (SepsiTest) to an in-house developed assay (IHP). We assessed whether CD64 index, a biomarker of bacterial infection, can be used to exclude patients with a low probability of systemic bacterial infection. From January to March 2010, 23 patients with suspected sepsis were enrolled. CD64 index, procalcitonin, and C-reactive protein were measured on admission. Broad range 16S rRNA gene PCR was performed from whole blood (SepsiTest) or blood plasma (IHP) and compared to blood culture results. Blood samples spiked with Staphylococcus aureus were used to assess sensitivity of the molecular assays in vitro. CD64 index was lower in patients where possible sepsis was excluded than in patients with microbiologically confirmed sepsis (P = 0.004). SepsiTest identified more relevant pathogens than blood cultures (P = 0.008); in three patients (13%) results from blood culture and SepsiTest were congruent, whereas in four cases (17.4%) relevant pathogens were detected by SepsiTest only. In vitro spiking experiments suggested equal sensitivity of SepsiTest and IHP. A diagnostic algorithm using CD64 index as a decision maker to perform SepsiTest shows improved detection of pathogens in patients with suspected blood stream infection and may enable earlier targeted antibiotic therapy.

Presepsin (soluble CD14 subtype) and procalcitonin levels for mortality prediction in sepsis: data from the Albumin Italian Outcome Sepsis trial

IntroductionSepsis, a leading cause of death in critically ill patients, is the result of complex interactions between the infecting microorganisms and the host responses that influence clinical outcomes. We evaluated the prognostic value of presepsin (sCD14-ST), a novel biomarker of bacterial infection, and compared it with procalcitonin (PCT).MethodsThis is a retrospective, case–control study of a multicenter, randomized clinical trial enrolling patients with severe sepsis or septic shock in ICUs in Italy. We selected 50 survivors and 50 non-survivors at ICU discharge, matched for age, sex and time from sepsis diagnosis to enrollment. Plasma samples were collected 1, 2 and 7 days after enrollment to assay presepsin and PCT. Outcome was assessed 28 and 90 days after enrollment.ResultsEarly presepsin (day 1) was higher in decedents (2,269 pg/ml, median (Q1 to Q3), 1,171 to 4,300 pg/ml) than in survivors (1,184 pg/ml (median, 875 to 2,113); P = 0.002), whereas PCT was not different (18.5 μg/L (median 3.4 to 45.2) and 10.8 μg/L (2.7 to 41.9); P = 0.31). The evolution of presepsin levels over time was significantly different in survivors compared to decedents (P for time-survival interaction = 0.03), whereas PCT decreased similarly in the two groups (P = 0.13). Presepsin was the only variable independently associated with ICU and 28-day mortality in Cox models adjusted for clinical characteristics. It showed better prognostic accuracy than PCT in the range of Sequential Organ Failure Assessment score (area under the curve (AUC) from 0.64 to 0.75 vs. AUC 0.53 to 0.65).ConclusionsIn this multicenter clinical trial, we provide the first evidence that presepsin measurements may have useful prognostic information for patients with severe sepsis or septic shock. These preliminary findings suggest that presepsin may be of clinical importance for early risk stratification.

Analysis of Cytokines in Presumed Acute Infectious Endophthalmitis Following Cataract Extraction

Objective: To analyze the involvement of cytokines in acute infectious endophthalmitis following cataract extraction surgery.Methods: Vitreous humor samples were collected from 18 patients. The multiplex technique was used to measure IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, basic FGF, eotaxin, GCSF, GM-CSF, IFN-γ, MCP-1, MIP-1a, MIP-1b, PDGF-BB, RANTES, TNF-α and VEGF for comparison with levels in 39 patients undergoing vitrectomy for a non-infectious disease (control).Results: IL-1ra, IL-2, IL-4, IL-6, IL-8, IL-9, IL-10, IL-15, IL-17, eotaxin, bFGF, G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1a, MIP-1b, PDGF-BB, RANTES and TNF-α levels were significantly higher (p <0.05) in eyes with endophthalmitis. There were no significant differences between groups for IL-5, IL-12 (p70), IL-13 and VEGF levels. IL-7 levels were higher in the control group (p=0.0229). Considering the different diagnosis in the control group, only IL-5 was not significantly different between groups (p=0.1764). There was a positive correlation between TNF-α and the initial visual acuity (r=0.59, p=0.0096). There was no correlation with the final visual acuity for the cytokines measured. The concentration of IL-8 was higher in patients with endophthalmitis and positive cultures (p=0.0250).Conclusions: Infectious endophthalmitis following cataract extraction stimulates the production of cytokines. Levels of TNF-α may be related to the severity of the initial inflammatory processes. IL-8 levels are correlated with positive bacterial cultures, suggesting that IL-8 could be used as a biomarker for bacterial infection.

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Introduction: Clinical signs of infection with elevated WBC or fever while on extracorporeal membranous oxygenation (ECMO) are difficult for the clinician to discern systemic infective processes from systemic inflammatory reactions induced by the ECMO circuit. This false information triggers the clinician to initiate possibly unwarranted or prolonged antibiotic therapy and/or diagnostic investigations. Utilizing procalcitonin (PCT) as a bio-marker of bacterial infection, we evaluated the effectiveness of PCT measurement in patients on ECMO with clinical signs of infection. Methods: An algorithmic protocol was utilized to measure PCT as part of a clinical workup for infectious processes. This protocol was utilized on all ECMO patients with elevated WBC (14.1 ± 5.3 B/L) and clinical signs of infection. Antibiotics (Abx) treatment was considered when PCT was ≥ 2 ng/mL. After initiating Abx treatment, PCT was trended until it decreases below 2 ng/mL with negative cultures; discontinuation of the antibiotics was done. Retrospective data was accumulated for the patients on ECMO from Jan/2012 to Jun/2013 and analyzed to validate our protocol. Results: During this study period, a total of 20 patients with 21 episodes of suspected infection were identified. 48% of patients had infections based on positive cultures (5 blood sepsis; 4 pneumonia). PCT levels of patients with and without infection were 23.4 ± 31.8 ng/ml and 1.78 ± 1.74 ng/dl respectively. PCT was able to predict infection with sensitivity of 90%, specificity of 79%; positive predictive value of 82% and negative predictive value of 90%. All of patients in true positive group, defined as having both elevated PCT levels and subsequent positive culture findings, received antibiotics treatment. 89% of patients in true negative group, defined as having no elevation in PCT and subsequent negative culture results, avoided unnecessary treatment. Conclusions: PCT is an effective test for differentiating infection from inflammation in patients on ECMO utilizing PCT ≥ 2 ng/ml as diagnosis of infection. Using our protocol, empiric antibiotics treatment could be minimized, and PCT trending could reflect the response to treatment or possible recurrence in an infected patient.

Procalcitonin kinetics: a reliable tool for diagnosis and monitoring of the course of bacterial infection in critically ill patients with autoimmune diseases

Dear Editor, Early diagnosis of infection in patients with autoimmune diseases is important but can be challenging [1, 2]. Procalcitonin (PCT) has been proposed as a biomarker of bacterial infection. However, its role is still disputed and has not been assessed in critically ill patients with autoimmune diseases, especially its kinetics [3, 4]. We determined the value of PCT kinetics for monitoring the cause of sepsis in this population. After approval by the ethics committee of our hospital, 81 autoimmune disease patients with systemic inflammatory response syndrome (SIRS) admitted to intensive care unit (ICU) were screened between January 2008 and December 2010. Sixty were enrolled (70.7 ± 12.7 years, 38 females) and grouped as bacterial infection (n = 31) or without bacterial infection (n = 29) (Fig. 1). The Acute Physiology and Chronic Health Evaluation (APACHE) II score was 17.3 ± 8.9, and 28-day ICU crude mortality was 38.3 %. PCT was collected on day 1 and day 2, and at 2 weeks or on the day of discharge from ICU (day-e) and determined by immunoluminometric assay (BRAHMS, Berlin, Germany). The serum PCT level [median (range), lg/L] was 1.53 (0.08–32.5) in all patients on day 1, being significantly higher in patients with bacterial infections than in other patients [1.88 (0.12–32.5) versus 0.57 (0.08–7.83), p = 0.002], but with no difference between subgroups of nonbacterial infection (n = 17) and disease flare (n = 12) [0.61 (0.08–7.83) versus 0.55 (0.10–7.78), p = 0.472] (Fig. 2). In receiver operating characteristic (ROC) curve analysis, PCT on day 1 was the earliest predictor for bacterial infection [area under curve (AUC) = 0.787; 95 % confidence interval (CI): 0.615–0.929; p = 0.006], and the threshold of 1.05 lg/L had sensitivity of 74.2 %, specificity of 86.2 %, positive likelihood ratio of 5.37, and negative likelihood ratio of 0.29. Furthermore, PCT levels for survivors (n = 37) did not differ significantly from nonsurvivors (n = 23) on day 1 [1.51 (0.08–32.5) versus 1.55 (0.08–29.8), p = 0.537] or day 2 [1.59 (0.10–105.0) versus 1.57 (0.10–110.5) lg/L, p = 0.479], but were significantly higher in nonsurvivors on day-e [5.12 (0.87–110) versus 0.23 (0.08–2.87) lg/L, p = 0.001] and had a strong correlation with outcome (r = 0.66, p = 0.007). On the contrary, PCT declined gradually in survivors with or without bacterial infection from day 1 to day-e [bacterial infection

Procalcitonin: Does It Have a Role in the Diagnosis, Management and Prognosis of Patients with Sepsis?

There is growing interest in the use of procalcitonin as a biomarker of bacterial infection. In particular, focus has been on the use of procalcitonin to facilitate a more timely diagnosis of sepsis and to guide the appropriate duration of antibiotic therapy. However, there is a lack of consensus in the literature concerning the role of measuring procalcitonin levels in clinical practice. This article reviews the evidence surrounding the utility of this biomarker for patients with sepsis in the intensive care environment. It is concluded that raised procalcitonin levels add little as a diagnostic criterion, however evidence supports the incorporation of procalcitonin-based algorithms relating to antibiotic stewardship in this patient population.

Usefulness of Plasma Procalcitonin to Predict Severity in Elderly Patients with Community-Acquired Pneumonia

BackgroundCommunity-acquired pneumonia (CAP) is one of the leading causes of death among the elderly. Several studies have reported the clinical usefulness of serum procalcitonin, a biomarker of bacterial infection. However, the association between the levels of procalcitonin and the severity in the elderly with CAP has not yet been reported. The aim of this study was to evaluate usefulness of procalcitonin as a predictor of severity and mortality in the elderly with CAP.MethodsThis study covers 155 CAP cases admitted to Pusan National University Hospital between January 2010 and December 2010. Patients were divided into two groups (≥65 years, n=99; <65 years, n=56) and were measured for procalcitonin, C-reactive protein (CRP), white blood cell, confusion, uremia, respiratory rate, blood pressure, 65 years or older (CURB-65) and pneumonia severity of index (PSI).ResultsThe levels of procalcitonin were significantly correlated with the CURB-65, PSI in totals. Especially stronger correlation was observed between the levels of procalcitonin and CURB-65 in the elderly (procalcitonin and CURB-65, ρ=0.408 with p<0.001; procalcitonin and PSI, ρ=0.293 with p=0.003; procalcitonin and mortality, ρ=0.229 with p=0.023). The correlation between the levels of CRP or WBC and CAP severity was low. The existing cut-off value of procalcitonin was correlated with mortality rate, however, it was not correlated with mortality within the elderly.ConclusionThe levels of procalcitonin are more useful than the levels of CRP or WBC to predict the severity of CAP. However, there was no association between the levels of procalcitonin and mortality in the elderly.

Role of procalcitonin in guiding antibiotic therapy

The role of procalcitonin in guiding antibiotic therapy is reviewed. Procalcitonin is a prohormone for calcitonin, which is secreted by the parafollicular cells of the thyroid gland. The biological activity of procalcitonin is significantly different from calcitonin and is believed to be part of the complex inflammatory cascade of the immune system. Procalcitonin has been shown to be elevated in bacterial infections but not in viral infections or other inflammatory conditions. The first published study that suggested that procalcitonin levels increased in the presence of bacterial infection was conducted in France in the early 1990s. Numerous studies have been conducted using procalcitonin-guided therapy to reduce antibiotic use. These studies were performed in one of three clinical settings: outpatient primary care (two multicenter, noninferiority studies of patients with upper- and lower-respiratory-tract infections), emergency room and inpatient (five studies in patients with chronic obstructive pulmonary disease, exacerbation, bronchitis, or community-acquired pneumonia), and the intensive care unit (ICU) (two studies in medical ICU patients and two in postoperative ICU patients with infection or sepsis). Based on the findings of these studies, a cutoff value of 0.25 μg/L in non-ICU patients or of 0.5 μg/L in ICU patients seems appropriate for making a decision about the initiation and discontinuation of antibiotic therapy. In patients with a significantly elevated baseline procalcitonin level, a subsequent drop of >80% appears to be reasonable for discontinuing antibiotics. Published evidence supports the use of procalcitonin as a biomarker of bacterial infection that can be used to reduce antibiotic exposure.

CD64, a Reliable Biomarker of Bacterial Infection in Intensive Care Units?

CD64, a Reliable Biomarker of Bacterial Infection in Intensive Care Units?

Reply to Dr. Rashmi Ranjan Das on the question, “Should procalcitonin be used as a routine biomarker of bacterial infection?”

We thank Dr. Rashmi Ranjan Das for his relevant comments on our article [1]. The prospective design of our study was aimed at distinguishing bacterial and viral etiology of infection in order to support the use of empirical antibiotic therapy. We enrolled the most common infectious diseases that are associated with elevated inflammatory markers and characteristic clinical signs. We agree with Dr. Ranjan Das that the comparison of viral and bacterial infections of the same organ, such as the central nervous system (CNS), would have been a better approach, since we could have excluded the effects of local inflammatory response. However, bacterial meningitis (BM) is significantly less common than viral encephalitis or meningoencephalitis in the Czech Republic; the data are available from the Epidat (English version)—the database of the incidence of infectious diseases in the Czech Republic (http://www.szu.cz or also [2]). Furthermore, the majority of patients with BM are hospitalized in the intensive care unit (ICU) and our study was not designed to enroll ICU patients. Similarly, the incidence of viral pneumonia is much lower than that of community-acquired bronchopneumonia (CABP) in the Czech Republic. Nevertheless, we agree that some cases of viral pneumonia, such as 2009 H1N1 influenza A viral pneumonia, can be associated with elevated procalcitonin (PCT) serum levels and it would be interesting to find out whether this elevation represents fibroproduction associated with the development of acute respiratory distress syndrome (ARDS) or, rather, secondary bacterial infections [3]. It is well known that, in the majority of cases of CABP due to Mycoplasma and Chlamydophila spp., PCT serum levels are below 0.5 ng/mL [4]. However, three patients with pneumonia due to Chlamydophila pneumoniae in our study demonstrated PCT serum levels above 0.5 ng/mL (data not shown). This observation might evoke doubts as to whether the chlamydial pneumonia really exists [5]. Thus, we agree with Dr. Ranjan Das that advanced molecular diagnostics should be used in future studies, aimed at evaluating the potential biomarkers of infection. It is true that we did not comment on the significant difference of PCT serum levels between the groups of patients with CABP and uroinfection. Since the prevalent etiology of uroinfections is Gram-negative Enterobacteriaceae, the high serum levels detected in the patients with pyelonephritis or urosepsis were probably caused by a systemic effect of endotoxin. It was demonstrated that endotoxin is a strong inducer of PCT synthesis and release [6]. Also, some studies indicated significantly higher PCT serum levels in Gram-negative infections compared to Gram-positive infections [7]. In conclusion, we strongly support the implementation of serum PCT measurement in routine diagnostic panels used for the rapid clinical diagnosis of bacterial infections. Besides PCT, these panels should include not only the erythrocyte sedimentation rate (ESR), number of white blood cells (WBC), neutrophil and lymphocyte counts, and C-reactive protein (CRP), but they may also consist of the neutrophil to lymphocyte count ratio (NLCR), as has been recently suggested [8].

Should procalcitonin be used as a routine biomarker of bacterial infection?

I read with great interest the article by Chalupa et al. [1]. The authors have conducted a prospective hospital-based study comparing the potential biomarkers used to diagnose infection in subjects with bacterial and viral infection. The authors concluded that only procalcitonin (PCT) demonstrated superiority over the routine parameters in the differentiation of bacterial from viral infections. Based on this, the authors strongly support the use of the PCT serum level as a routine biomarker of bacterial infection. However, there a few points that need to be highlighted in order for the result to be more meaningful. It is not clear why the authors have used bacterial infection of the lungs (community-acquired bacterial pneumonia [CABP]) and urinary tract (urosepsis) to compare with the viral infections in sites other than these (i.e., of the central nervous system [CNS], liver, etc.). For the results to be meaningful and to supplement clinical decision regarding whether to start or withhold antibiotics in an individual case scenario, the authors could have compared the two infections (either bacterial or viral) at these two sites (either CABP or urosepsis) only. CABP would have been better, as urosepsis is not viral. Moreover, though the authors strongly support the use of PCT as a biomarker for bacterial infection, this issue is still debated [2, 3]. In the recent 2009 H1N1 pandemic, a higher PCT threshold was required to discriminate between bacterial and viral pneumonia, suggesting that severe viral pneumonia alone may elevate PCT [4, 5]. In another important study, 22/23 of patients with community-acquired pneumonia (CAP) with positive serology (three being atypical pneumonia and the rest were viral) were given antibiotics per their PCT algorithm [6]. Patients with atypical pneumonia (due to Mycoplasma and Chlamydia) may have low PCT levels [7]. Even patients who were bacteremic from various sources can have lower PCT levels (\0.5 ng/ml), as found in a recent study [8]. As PCT levels are documented to distinguish viral from bacterial meningitis [9, 10], the authors could have compared the PCT levels between viral or bacterial CNS infection (meningitis or encephalitis) instead of CABP or urosepsis. Another important observation that is not even included in the discussion is that, if PCT is a sensitive indicator of bacterial infection, then why there is a significant difference in the levels of PCT between patients with CABP and urosepsis (as both are presumed to be bacterial), as shown in Table 3 of the paper. As the isolated value of PCT in discriminating between bacterial and viral infection is still not clear, advanced molecular diagnostics should possibly be used to validate the ability of the serum PCT in this regard. In addition, such analysis should be able to clarify PCT responses in mixed viral and bacterial infections, which are detailed elsewhere [11]. If both pathogens (viral and bacterial) are identified, PCT levels should assist in the interpretation of the result also (e.g., colonization with one organism ersus infection with another and vice versa). In spite of all these limitations, PCT serum levels have several advantages when compared with the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level as a biomarker for invasive bacterial disease, and I congratulate the authors for adding further data to support the use of PCT in the diagnosis of bacterial infection. R. R. Das (&) Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India e-mail: dr_rashmipgi@yahoo.com

The sensitivity of neutrophil CD64 expression as a biomarker of bacterial infection is low in critically ill patients

CD64 expression on the surface of neutrophils has recently been proposed as an early marker of bacterial infection. The goal of this study was to determine whether the CD64 index allows differentiation of bacterial sepsis from viral and fungal sepsis and other inflammatory states in a critical-care setting. This was an observational prospective study conducted in a medical ICU of a university hospital. All patients admitted between September 2009 and March 2010 with at least two criteria for systemic inflammatory response syndrome (SIRS) were eligible for inclusion. Upon admission, hematological exams were conducted by flow cytometry, allowing quantification of CD64 expression (Leuko64™ kit, Trillium Diagnostics LLC, USA). ROC curve analysis was performed to evaluate the utility of the CD64 index in the diagnosis of bacterial infection. Patients with suspected infection were excluded when infection could not be microbiologically confirmed. Our study included 293 patients with a SAPS II score of 45 (31-59). Bacterial infection was found in 148 patients and SIRS or non-bacterial infection was documented in 145 patients. A CD64 index greater than 2.2 predicted bacterial infection with a sensitivity and specificity of 63% (55-71%) and 89% (83-94%), respectively. The area under the ROC curve was 0.8 (0.75-0.84). Positive and negative likelihood ratios were 5.7 (5.0-6.5) and 0.4 (0.3-0.7), respectively. The CD64 index is specific for bacterial infection among ICU patients. As a result of its weak sensitivity, the CD64 index may not be practically recommended, but it may be useful in combination with a more sensitive biological marker.