Role of biomarkers in antimicrobial stewardship: physicians' perspectives.

Biomarkers are playing an increasingly important role in antimicrobial stewardship. Their applications have included use in algorithms that evaluate suspected bacterial infections or provide guidance on when to start or stop antibiotic therapy, or when therapy should be repeated over a short period (6-12 h). Diseases in which biomarkers are used as complementary tools to determine the initiation of antibiotics include sepsis, lower respiratory tract infection (LRTI), COVID-19, acute heart failure, infectious endocarditis, acute coronary syndrome, and acute pancreatitis. In addition, cut-off values of biomarkers have been used to inform the decision to discontinue antibiotics for diseases such as sepsis, LRTI, and febrile neutropenia. The biomarkers used in antimicrobial stewardship include procalcitonin (PCT), C-reactive protein (CRP), presepsin, and interleukin (IL)-1ß/IL-8. The cut-off values vary depending on the disease and study, with a range of 0.25-1.0 ng/mL for PCT and 8-50 mg/L for CRP. Biomarkers can complement clinical diagnosis, but further studies of microbiological biomarkers are needed to ensure appropriate antibiotic selection.

Blood calprotectin as a biomarker for infection and sepsis - the prospective CASCADE trial.

BACKGROUND: Early in the host-response to infection, neutrophils release calprotectin, triggering several immune signalling cascades. In acute infection management, identifying infected patients and stratifying these by risk of deterioration into sepsis, are crucial tasks. Recruiting a heterogenous population of patients with suspected infections from the emergency department, early in the care-path, the CASCADE trial aimed to evaluate the accuracy of blood calprotectin for detecting bacterial infections, estimating disease severity, and predicting clinical deterioration. METHODS: In a prospective, observational trial from February 2021 to August 2022, 395 patients (n = 194 clinically suspected infection; n = 201 controls) were enrolled. Blood samples were collected at enrolment. The accuracy of calprotectin to identify bacterial infections, and to predict and identify sepsis and mortality was analysed. These endpoints were determined by a panel of experts. RESULTS: The Area Under the Receiver Operating Characteristic (AUROC) of calprotectin for detecting bacterial infections was 0.90. For sepsis within 72 h, calprotectin's AUROC was 0.83. For 30-day mortality it was 0.78. In patients with diabetes, calprotectin had an AUROC of 0.94 for identifying bacterial infection. CONCLUSIONS: Calprotectin showed notable accuracy for all endpoints. Using calprotectin in the emergency department could improve diagnosis and management of severe infections, in combination with current biomarkers. CLINICAL TRIAL REGISTRATION NUMBER: DRKS00020521.

Evaluation of mucosal-associated invariant T-cells as a potential biomarker to predict infection risk in liver cirrhosis.

BACKGROUND AND AIMS: Infection is a serious complication in patients with cirrhosis. Mucosal-associated invariant T (MAIT) cells are involved in the immune defense against infections and known to be impaired in several chronic conditions, including cirrhosis. Here, we evaluated if MAIT cell levels in peripheral blood are associated with risk of bacterial infections in patients with cirrhosis. METHODS: Patients with cirrhosis seen at the Karolinska University Hospital, Stockholm, Sweden, between 2016 and 2019 were included. Levels of MAIT cells in peripheral blood were determined using flow cytometry. Baseline and follow-up data after at least two years of follow-up were collected by chart review for the primary outcome (bacterial infection) and secondary outcomes (decompensation and death). Competing risk and Cox regression were performed. RESULTS: We included 106 patients with cirrhosis. The median MAIT cells fraction in the circulation was 0.8% in cirrhosis compared to 6.1% in healthy controls. In contrast to our hypothesis, we found an association in the adjusted analysis between relatively preserved MAIT cell levels, and a slightly higher risk to develop bacterial infections (adjusted subdistribution hazard ratio (aSHR) 1.15 (95%CI = 1.01-1.31). However, MAIT cell levels were not associated with the risk of hepatic decompensation (aSHR 1.19 (95%CI = 0.91-1.56)) nor with death (adjusted hazard ratio 1.10 (95%CI = 0.97-1.22)). CONCLUSIONS: Relatively preserved MAIT cell levels in blood of patients with cirrhosis were associated with a somewhat higher risk of bacterial infections. The clinical relevance of this might not be strong. MAIT cells might however be an interesting biomarker to explore in future studies.

Performance of Febrile Infant Algorithms by Duration of Fever.

OBJECTIVES: To analyze the performance of commonly used blood tests in febrile infants ≤90 days of age to identify patients at low risk for invasive bacterial infection (bacterial pathogen in blood or cerebrospinal fluid) by duration of fever. METHODS: We conducted a secondary analysis of a prospective single-center registry that includes all consecutive infants ≤90 days of age with fever without a source evaluated at 1 pediatric emergency department between 2008 and 2021. We defined 3 groups based on caregiver-reported hours of fever (<2, 2-12, and ≥12) and analyzed the performance of the biomarkers and Pediatric Emergency Care Applied Research Network, American Academy of Pediatrics, and Step-by-Step clinical decision rules. RESULTS: We included 2411 infants; 76 (3.0%) were diagnosed with an invasive bacterial infection. The median duration of fever was 4 (interquartile range, 2-12) hours, with 633 (26.3%) patients with fever of <2 hours. The area under the curve was significantly lower in patients with <2 hours for absolute neutrophil count (0.562 vs 0.609 and 0.728) and C-reactive protein (0.568 vs 0.760 and 0.812), but not for procalcitonin (0.749 vs 0.780 and 0.773). Among well-appearing infants older than 21 days and negative urine dipstick with <2 hours of fever, procalcitonin ≥0.14 ng/mL showed a better sensitivity (100% with specificity 53.8%) than that of the combination of biomarkers of Step-by-Step (50.0% and 82.2%), and of the American Academy of Pediatrics and Pediatric Emergency Care Applied Research Network rules (83.3% and 58.3%), respectively. CONCLUSIONS: The performance of blood biomarkers, except for procalcitonin, in febrile young infants is lower in fever of very short duration, decreasing the accuracy of the clinical decision rules.

Serum interleukin-33 and soluble suppression of tumorigenicity 2 in pediatric leukemia with febrile neutropenia.

The purpose of this study was to evaluate the association between interleukin-33 (IL-33) and its receptor Soluble Suppression of Tumorigenicity-2 (sST2) levels and bacterial infections during febrile neutropenia (FN) in pediatric patients with acute lymphoblastic leukemia (ALL). In this prospective, case-control study, participants were divided into 3 groups: ALL patients with FN (Group A), ALL patients without neutropenia and fever (Group B), and healthy children without infection and chronic disease (Group C). There were 30 cases in each group. Blood samples for IL-33 and sST2 have been drawn from patients in Group A before the initiation of treatment and on days 1 and 5 of treatment, and from patients in Groups B and C at initiation. At admission, mean IL-33 level (39.02 ± 26.40 ng/L) in Group B and mean sST2 level (185.3 ± 371.49 ng/ml) in Group A were significantly higher than the other groups (p = 0.038, p < 0.001, respectively). No difference was observed in the mean IL-33 and sST2 levels in the 5-day follow-up of patients in Group A (p = 0.82, p = 0.86, respectively). IL-33 and sST2 levels were not associated with fever duration, neutropenia duration or length of hospitalization. While C-reactive protein (CRP) was significantly higher in patients with positive blood culture (p = 0.021), IL-33 (p = 0.49) and sST2 (p = 0.21) levels were not associated with culture positivity.  Conclusion: IL-33 and sST2 levels were not found valuable as diagnostic and prognostic markers to predict bacterial sepsis in patients with FN. What is Known: • Neutropenic patients are at high risk of serious bacterial and viral infections, but the admission symptom is often only fever. • Febrile neutropenia has a high mortality rate if not treated effectively. What is New: • Febrile neutropenia is not only caused by bacterial infections. Therefore, new biomarkers should be identified to prevent overuse of antibiotics. • Specific biomarkers are needed to diagnose bacterial sepsis in the early phase of febrile neutropenia.

PCT, IL-6, and IL-10 facilitate early diagnosis and pathogen classifications in bloodstream infection.

BACKGROUND: In the diagnosis of bloodstream infection (BSI), various inflammatory markers such as C-reactive protein (CRP), procalcitonin (PCT), interleukins (IL), white blood cell count (WBC), neutrophil percentage (NE%), platelet count (PLT), and erythrocyte sedimentation rate (ESR) have been extensively utilized. However, their specific roles in distinguishing BSI from local bacterial infection (LBI) and in classifying BSI pathogens remain uncertain. METHODS: A historical cohort study was conducted, involving the enrollment of 505 patients with BSI and 102 patients with LBI. To validate the reliability of the clinical data obtained from this cohort, mouse models of BSI were utilized. RESULTS: Our findings revealed that patients with BSI had significantly higher levels of inflammatory markers, including CRP, PCT, IL-6, IL-10, WBC, NE%, and ESR, compared to those with LBI (p < 0.05). The receiver operating characteristic (ROC) curve analysis demonstrated that CRP, PCT, IL-6, IL-10, ESR and NE% exhibited excellent diagnostic efficacy for BSI. Additionally, we observed significant differences in CRP, PCT, IL-6, and IL-10 levels between patients with BSI caused by Gram-positive bacteria (GP-BSI) and Gram-negative bacteria (GN-BSI), but no significant variations were found among specific bacterial species. Furthermore, our study also found that CRP, PCT, and IL-10 have good discriminatory ability for vancomycin-resistant Enterococcus (VRE), but they show no significant diagnostic efficacy for other multidrug-resistant organisms (MDROs) such as carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and methicillin-resistant Staphylococcus aureus (MRSA). In our mouse model experiments, we observed a remarkable increase in PCT, IL-6, and IL-10 levels in mice with GN-BSI compared to those with GP-BSI. CONCLUSION: Our study has confirmed that PCT, IL-6, and IL-10 are efficient biomarkers for distinguishing between BSI and LBI. Furthermore, they can be utilized to classify BSI pathogens and differentiate between VRE and vancomycin-susceptible Enterococcus. These findings are extremely valuable for clinicians as they enable timely initiation of empiric antibiotic therapies and ultimately lead to improved clinical outcomes for patients with BSI.

Value of combined detection of serum amyloid A, C-reactive protein and procalcitonin in differential diagnosis of respiratory tract infection in children of China.

OBJECTIVE: To explore the diagnostic value of combined detection of serum amyloid A (SAA), C-reactive protein (CRP) and procalcitonin (PCT) in children with bacteria or non-bacterial respiratory tract infection. METHODS: 200 children with respiratory tract infections diagnosed in our hospital were included in the study. According to the results of the aetiological examination, they were divided into bacterial infection group and non-bacterial infection group. At the same time, 100 healthy children admitted to the hospital for physical examination during the same period were selected as the healthy subjects control group. Changes in serum SAA, PCT and CRP in three groups were compared. Comparison of a positive rate of the single index and combined detection were performed. Children with bacterial infections were treated with conventional antibiotics. The changes in serum SAA, PCT and CRP in the infection group before and after treatment were compared. The efficacy of SAA, PCT and CRP alone and in combination was compared. RESULTS: The serum SAA, PCT and CRP levels in the bacterial infection group were higher than those in the non-bacterial infection group and healthy children, and the differences were statistically significant. The positive detection rates and combined detection rates of serum SAA, PCT and CRP in the bacterial infection group were higher than those in the non-bacterial infection group and the healthy subject's control group. After conventional antibiotic treatment, serum SAA, PCT and CR levels in children with bacterial infection were significantly decreased. CONCLUSION: The combined detection based on SAA, CRP and PCT can effectively identify and diagnose respiratory tract infection in children, providing a certain reference for the promotion of the diagnostic scheme. Key messagesSerum SAA, PCT and CRP were highly expressed in children with respiratory tract infection, and the expression level was the highest in children with bacterial pneumonia.The combined detection of serum SAA, CRP and PCT indicators have higher diagnostic efficiency and can effectively make a differential diagnosis of respiratory tract infection in children.

Diagnostic value of procalcitonin for bacterial infections in patients undergoing hemodialysis: a systematic review and meta-analysis.

BACKGROUND: The diagnostic value of procalcitonin (PCT) in patients undergoing hemodialysis (HD) remains unclear. METHODS: We searched multiple databases (PubMed, EMBASE, and Cochrane Library) for studies published through August 2021 that evaluated the diagnostic performance of PCT in patients undergoing HD and having suspected bacterial infections. The bivariate fixed effects model was used to calculate pooled sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and summary receiver operating characteristic (SROC) curves. RESULTS: We identified a total of 1799 studies, of which seven diagnostic studies comprised 1444 patients and 430 bacterial infection episodes. Bivariate pooled sensitivity and specificity for PCT were 0.90 (95% CI: 0.85-0.94) and 0.83 (95% CI: 0.56-0.95), respectively. Furthermore, pooled DOR, PLR, NLR, and area under the curve (AUC) were 47 (95% CI: 11-209), 5.4 (95% CI: 1.7-16.9), 0.12 (95% CI: 0.07-0.20), and 0.92 (95% CI: 0.90-0.94), respectively. We also compared the diagnostic accuracy of PCT and C-reactive protein (CRP), and our results showed that the diagnostic accuracy parameters for PCT were significantly higher than those for CRP. CONCLUSIONS: PCT is a useful marker for diagnosis of bacterial infections in patients undergoing HD at a cutoff value of 1.5 ng/ml.

Procalcitonin is associated with postnatal respiratory condition severity in preterm neonate.

INTRODUCTION: Postnatal respiratory failure is common in preterm neonates and is difficult to distinguish from early-onset neonatal bacterial infection by clinical symptoms. Similar to C-reactive protein (CRP), procalcitonin (PCT) is used as a marker of bacterial infection. Recently, it has been reported that the serum PCT levels increase because of respiratory failure immediately after birth. However, there is insufficient information concerning the relationship between biological inflammation markers, such as PCT and CRP, and postnatal respiratory condition severity. METHODS: Preterm neonates were classified according to the received respiratory management as follows: nonrespiratory support (NRS), respiratory support (RS), surfactant administration therapy (STA), and STA with nitric oxide inhalation therapy (NO). The median serum PCT and CRP levels at 12-36 h postnatally were compared among the four groups. Additionally, the median serum PCT and CRP levels in the STA group were compared by STA timing and STA number. RESULTS: The PCT levels for the NRS, RS, STA, and NO groups were 1.04, 6.46, 12.93, and 86.79 µg/L, respectively; the CRP levels were 0.40, 0.80, 1.10, and 16.40 mg/L, respectively. The PCT levels were significantly lower among neonates receiving STA in the birth subgroup (4.82 µg/L) than among those receiving STA in the admission subgroup (14.71 µg/L). The PCT levels were significantly higher among the STA multiple-dose subgroup (24.87 µg/L) than among the STA single-dose subgroup (12.47 µg/L). No significant differences in the CRP levels were observed. CONCLUSION: The serum PCT levels in preterm neonates were associated with postnatal respiratory condition severity.

Childhood Invasive Bacterial Disease in Kathmandu, Nepal (2005-2013).

BACKGROUND: Invasive bacterial disease (IBD; including pneumonia, meningitis, sepsis) is a major cause of morbidity and mortality in children in low-income countries. METHODS: We analyzed data from a surveillance study of suspected community-acquired IBD in children <15 years of age in Kathmandu, Nepal, from 2005 to 2013 before introduction of pneumococcal conjugate vaccines (PCV). We detailed the serotype-specific distribution of invasive pneumococcal disease (IPD) and incorporated antigen and PCR testing of cerebrospinal fluid (CSF) from children with meningitis. RESULTS: Enhanced surveillance of IBD was undertaken during 2005-2006 and 2010-2013. During enhanced surveillance, a total of 7956 children were recruited of whom 7754 had blood or CSF culture results available for analysis, and 342 (4%) had a pathogen isolated. From 2007 to 2009, all 376 positive culture results were available, with 259 pathogens isolated (and 117 contaminants). Salmonella enterica serovar Typhi was the most prevalent pathogen isolated (167 cases, 28% of pathogens), followed by Streptococcus pneumoniae (98 cases, 16% pathogens). Approximately, 73% and 78% of pneumococcal serotypes were contained in 10-valent and 13-valent PCV, respectively. Most cases of invasive pneumococcal disease (IPD) were among children ≥5 years of age from 2008 onward. Antigen and PCR testing of CSF for pneumococci, Haemophilus influenzae type b and meningococci increased the number of these pathogens identified from 33 (culture) to 68 (culture/antigen/PCR testing). CONCLUSIONS: S. enterica serovar Typhi and S. pneumoniae accounted for 44% of pathogens isolated. Most pneumococcal isolates were of serotypes contained in PCVs. Antigen and PCR testing of CSF improves sensitivity for IBD pathogens.

Increased cytokines/chemokines and hyponatremia as a possible cause of clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with acute focal bacterial nephritis.

OBJECTIVE: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), the second most common encephalopathy syndrome in Japan, is most often associated with viral infection. Bacterial MERS has been rarely reported but is mostly associated with acute focal bacterial nephritis (AFBN) for an unknown reason. We examined cytokines and chemokines in four MERS patients with AFBN to determine if they play an important role in the pathogenesis. METHODS: We examined the clinical charts and MRI results in four MERS patients with AFBN, and measured 10 cytokines and chemokines in serum and cerebrospinal fluid in the acute phase. These were analyzed using the Mann-Whitney U test, compared with the control group (cases with a non-inflammatory neurological disease). Longitudinal changes in the serum cytokine and chemokine levels were evaluated in two patients. RESULTS: Hyponatremia was observed in all four patients with MERS associated with AFBN (128-134 mEq/L). CSF analysis revealed increased cytokines/chemokines associated with Th1 (CXCL10, TNF-α, IFN-γ), T reg (IL-10), Th17 (IL-6), and neutrophil (IL-8 and CXCL1). In serum, upregulation was observed in those associated with Th1 (CXCL10, TNF-α, IFN-γ), Th17 (IL-6), and inflammasome (IL-1ß). The increased serum cytokines/chemokines in the acute stage normalized within 2 weeks in patients 1 and 2, so examined, in accordance with their clinical improvement. CONCLUSION: Increased cytokines/chemokines and hyponatremia may be factors that explain why AFBN is likely to cause MERS.

Ratio of serum amyloid A to C-reactive protein is constant in the same patients but differs greatly between patients with inflammatory diseases.

C-reactive protein (CRP) is commonly monitored to track the activity of inflammation and has become the gold standard in the management of all inflammatory diseases. Indeed, serum amyloid A (SAA) have seemed to correlate moderately with CRP, but the discrepancy of CRP and SAA levels has often been reported, especially in rheumatoid arthritis. Then, we examined CRP reflects a real magnitude of inflammation in patients with rheumatic and infectious inflammatory diseases. A total of 414 patients with infectious and non-infectious inflammatory diseases were enrolled. At initial visit, each patient underwent a clinical assessment and had also laboratory tests such as SAA and CRP. In each patient, we carried out a longitudinal analysis of CRP and SAA levels. We determined the inter-individual correlation between SAA and CRP and also clarified intra-individual changes of SAA/CRP ratio. SAA and CRP levels changed approximately linearly over time within individuals irrespective of rheumatic and infectious inflammatory diseases. However, SAA/CRP ratios differed dramatically between patients (from 0.117 to 50.8, median 5.71). In patients with high SAA/CRP ratio (>8.44), SAA is a better predictor of inflammation than CRP. In contrast, CRP is a better predictor in patients with low ratio (<3.52). Our results suggest that the SAA/CRP ratio differed greatly between individuals but was constant in intra-individuals. Low CRP levels could be accompanied by SAA levels predicting any degree of inflammation, implying that CRP is not reflecting a real magnitude of inflammation. To evaluate the real magnitude of inflammation, to access the SAA/CRP ratio in advance is essential.

Application of serum exosomal hypoxia-inducible factor-1 alpha (HIF-1α) as potential circulating biomarker for bacterial peritonitis.

Bacterial peritonitis is a severe disease that diagnosis remains challenging for clinicians. Measuring biomarkers might be a rapid diagnostic method. The objective of this study was to analyze and evaluate the dynamic changes in HIF-1α concentration in serum exosomes during bacterial peritonitis. The pre-clinical application value of serum exosomal HIF-1α was evaluated via imipenem and cilastatin sodium (ICS) intervention in the bacterial peritonitis model. The new colorimetric method to quantitate dynamic expression changes of HIF-1α in serum exosomes during bacterial peritonitis was established by our team via using the gold seed-coated with aptamer-functionalized Au @ Au core-shell peroxidase mimic. The typical inflammatory cytokines of bacterial peritonitis were also measured. Following intramuscular administration with ICS, In-Vivo Xtreme imaging system was used to visualize abdominal infection extent. Meanwhile, HIF-1α concentration in rat serum exosomes and pro-inflammatory factors levels in serum were detected. The serum typical inflammatory cytokines levels were elevated in GFP-labeled E.coli induced bacterial peritonitis. The serum exosomal HIF-1α levels clearly increased at 12 h, reached the peak during 24-48 h, and then gradually decreased at 72 h. Following intramuscular administration with ICS, the abdominal infection extent, HIF-1α concentration in serum exosomes, and the serum pro-inflammatory factors levels were reduced at 24 h in GFP-labeled E. coli induced bacterial peritonitis model. The serum exosomal HIF-1α can be used as a biomarker in the early stage of bacterial peritonitis, which might provide the basic research in the pre-clinical for further predicting and monitoring the pathological process of bacterial peritonitis.

Unique characteristics of new complete blood count parameters, the Immature Platelet Fraction and the Immature Platelet Fraction Count, in dengue patients.

The advanced platelet parameters Immature Platelet Fraction and Immature Platelet Fraction Count have been implemented in clinical practice as measures of thrombopoietic activity, mainly in hematologic disorders that cause thrombocytopenia. The purpose of this observational study was to examine thrombopoiesis as reflected by these 2 new CBC parameters in patients infected with dengue. The study was conducted in infectious disease referral hospital in Metro Manila, the Philippines. We enrolled hospitalized patients at admission who were diagnosed with acute dengue or community acquired bacterial infection (CABI). Immature Platelet Fraction (IPF) and Immature Platelet Fraction Count were evaluated at admission and during hospitalization. A total of 606 patients were enrolled from May 1, 2017 to June 1, 2018. The participants consisted of 152 patients with dengue infection, 180 confirmed CABI, and 274 suspected CABI patients. At admission, the percent IPF (IPF%) of the patients with dengue was significantly higher than that of the confirmed CABI patients (median 3.7% versus 1.9%; p <0.001). In a time course evaluation, there was no significant difference of IPF% between the patients with dengue infection and the confirmed CABI patients in the febrile phase (median 1.9% versus 2.4%; p = 0.488), however, the IPF% of the patients with dengue infection increased to be significantly higher than that of the confirmed CABI patients in the critical phase (median 5.2% versus 2.2%; p <0.001). Our study elucidated the unique characteristics and time-course trends of IPF percent and number (IPF#) in the patients with dengue infection. IPF% and IPF# are potentially valuable parameters in dengue and further investigation is required for the optimal use in clinical practice.

Local and Systemic Cytokine, Chemokine, and FGF Profile in Bacterial Chondronecrosis with Osteomyelitis (BCO)-Affected Broilers.

Complex disease states, like bacterial chondronecrosis with osteomyelitis (BCO), not only result in physiological symptoms, such as lameness, but also a complex systemic reaction involving immune and growth factor responses. For the modern broiler (meat-type) chickens, BCO is an animal welfare, production, and economic concern involving bacterial infection, inflammation, and bone attrition with a poorly defined etiology. It is, therefore, critical to define the key inflammatory and bone-related factors involved in BCO. In this study, the local bone and systemic blood profile of inflammatory modulators, cytokines, and chemokines was elucidated along with inflammasome and key FGF genes. BCO-affected bone showed increased expression of cytokines IL-1ß, while BCO-affected blood expressed upregulated TNFα and IL-12. The chemokine profile revealed increased IL-8 expression in both BCO-affected bone and blood in addition to inflammasome NLRC5 being upregulated in circulation. The key FGF receptor, FGFR1, was significantly downregulated in BCO-affected bone. The exposure of two different bone cell types, hFOB and chicken primary chondrocytes, to plasma from BCO-affected birds, as well as recombinant TNFα, resulted in significantly decreased cell viability. These results demonstrate an expression of proinflammatory and bone-resorptive factors and their potential contribution to BCO etiology through their impact on bone cell viability. This unique profile could be used for improved non-invasive detection of BCO and provides potential targets for treatments.

Genetic Analyses of Common Infections in the Avon Longitudinal Study of Parents and Children Cohort.

The burden of infections on an individual and public health is profound. Many observational studies have shown a link between infections and the pathogenesis of disease; however a greater understanding of the role of host genetics is essential. Children from the longitudinal birth cohort, the Avon Longitudinal Study of Parents and Children, had 14 antibodies measured in plasma at age 7: Alpha-casein protein, beta-casein protein, cytomegalovirus, Epstein-Barr virus, feline herpes virus, Helicobacter pylori, herpes simplex virus 1, influenza virus subtype H1N1, influenza virus subtype H3N2, measles virus, Saccharomyces cerevisiae, Theiler's virus, Toxoplasma gondii, and SAG1 protein domain, a surface antigen of Toxoplasma gondii measured for greater precision. We performed genome-wide association analyses of antibody levels against these 14 infections (N = 357 - 5010) and identified three genome-wide signals (P < 5×10-8), two associated with measles virus antibodies and one with Toxoplasma gondii antibodies. In an association analysis focused on the human leukocyte antigen (HLA) region of the genome, we further detected 15 HLA alleles at a two-digit resolution and 23 HLA alleles at a four-digit resolution associated with five antibodies, with eight HLA alleles associated with Epstein-Barr virus antibodies showing strong evidence of replication in UK Biobank. We discuss how our findings from antibody levels complement other studies using self-reported phenotypes in understanding the architecture of host genetics related to infections.

Rapid detection of bacterial infection using a novel single-tube, four-colour flow cytometric method: Comparison with PCT and CRP.

BACKGROUND: A key factor behind the unnecessary use of antibiotics is the lack of rapid and accurate diagnostic tests. In this study, we developed a novel and fast flow cytometric single-tube method to detect bacterial infections within 30 minutes. METHODS: Quantitative flow cytometric four-colour analysis of host biomarkers CD35, CD64, CD329, and MHC class I expression on neutrophils and lymphocytes was performed on samples taken from 841 febrile patients with suspected infection. Obtained data was incorporated into the four-colour bacterial infection (FCBI)-index, using the developed bacterial infection algorithm. FINDINGS: In distinguishing between microbiologically confirmed bacterial (n = 193) and viral (n = 291) infections, the FCBI-index method was superior to serum C-reactive protein (CRP) and procalcitonin (PCT). In 269 confirmed viral respiratory tract infections, 43% (95% CI: 37-49%) of the patients had an increased FCBI-index, suggesting probable bacterial coinfection. INTERPRETATION: The proposed FCBI-index test might be a potent additional tool when assessing appropriateness of empiric antibiotic treatment. FUNDING: This study has been financially supported by Turku University Hospital (Turku, Finland) and The Finnish Medical Foundation.

Heritability and genetic correlations of plasma metabolites of pigs with production, resilience and carcass traits under natural polymicrobial disease challenge.

Metabolites in plasma of healthy nursery pigs were quantified using nuclear magnetic resonance. Heritabilities of metabolite concentration were estimated along with their phenotypic and genetic correlations with performance, resilience, and carcass traits in growing pigs exposed to a natural polymicrobial disease challenge. Variance components were estimated by GBLUP. Heritability estimates were low to moderate (0.11 ± 0.08 to 0.19 ± 0.08) for 14 metabolites, moderate to high (0.22 ± 0.09 to 0.39 ± 0.08) for 17 metabolites, and highest for L-glutamic acid (0.41 ± 0.09) and hypoxanthine (0.42 ± 0.08). Phenotypic correlation estimates of plasma metabolites with performance and carcass traits were generally very low. Significant genetic correlation estimates with performance and carcass traits were found for several measures of growth and feed intake. Interestingly the plasma concentration of oxoglutarate was genetically negatively correlated with treatments received across the challenge nursery and finisher (- 0.49 ± 0.28; P < 0.05) and creatinine was positively correlated with mortality in the challenge nursery (0.85 ± 0.76; P < 0.05). These results suggest that some plasma metabolite phenotypes collected from healthy nursery pigs are moderately heritable and genetic correlations with measures of performance and resilience after disease challenge suggest they may be potential genetic indicators of disease resilience.

Multiple vector-borne pathogens of domestic animals in Egypt.

Vector Borne Diseases (VBDs) are considered emerging and re-emerging diseases that represent a global burden. The aim of this study was to explore and characterize vector-borne pathogens in different domestic animal hosts in Egypt. A total of 557 blood samples were collected from different animals using a convenience sampling strategy (203 dogs, 149 camels, 88 cattle, 26 buffaloes, 58 sheep and 33 goats). All samples were tested for multiple pathogens using quantitative PCR and standard PCR coupled with sequencing. We identified Theileria annulata and Babesia bigemina in cattle (15.9 and 1.1%, respectively), T. ovis in sheep and buffaloes (8.6 and 7.7%, respectively) and Ba. canis in dogs (0.5%) as well as Anaplasma marginale in cattle, sheep and camels (20.4, 3.4 and 0.7%, respectively) and Coxiella burnetii in sheep and goats (1.7 and 3%; respectively). New genotypes of An. centrale, An. ovis, An. platys-like and Borrelia theileri were found in cattle (1.1,3.4, 3.4 and 3.4%, respectively), An. platys-like in buffaloes (7.7%), An. marginale, An. ovis, An. platys-like and Bo. theileri in sheep (3.4, 1.7, 1.7 and 3.4%, respectively), An. platys, An. platys-like and Setaria digitata in camels (0.7, 5.4 and 0.7%, respectively) and Rickettsia africae-like, An. platys, Dirofilaria repens and Acanthocheilonema reconditum in dogs (1.5, 3.4, 1 and 0.5%, respectively). Co-infections were found in cattle, sheep and dogs (5.7, 1.7, 0.5%, respectively). For the first time, we have demonstrated the presence of several vector-borne zoonoses in the blood of domestic animals in Egypt. Dogs and ruminants seem to play a significant role in the epidemiological cycle of VBDs.