Description and comparison of PIMS-TS innate cell signature and immunophenotype with a cohort of healthy children, severe viral and bacterial infections and Kawasaki Disease

A new clinical syndrome associated to SARS-CoV-2 has been described in children. It has been named as Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS). This new disease is a main cause of hospital and pediatric intensive care unit (PICU). In this work we describe the innate cell signature and immunophenotype of children admitted to PICU because of PIMS-TS. Also, we compare it with healthy controls and children admitted to PICU because bacterial infection, viral infection and Kawasaki disease. We made a prospective-retrospective observational study in a tertiary pediatric hospital. Children admitted to PICU because of PIMS-TS from March 2020 to September 2020 were consecutively included. They were compare with previous cohorts from our center. A total of 247 children were included: 183 healthy controls, 25 viral infections, 20 bacterial infections, 6 Kawasaki disease and 13 PIMS-TS. PIMT-TS showed the lowest percentage of lymphocytes and monocytes with higher relative numbers of CD4+ (p =0,000). At the same time, we describe a differential expression of CD64, CD11a and CD11b. Monocytes and neutrophils in PIMS-TS showed higher levels of CD64 expression compared to all groups (p = 0,000). Also, proteins involved in leukocyte tissue migration, like CD11a and CD11b were highly expressed compare to other severe viral or bacterial infections (p = 0,000). In PIMS-TS this increased CD11a expression could be a sign of the activation and trafficking of these leukocytes. These findings are congruent with an inflammatory process and the trend of these cells to leave the bloodstream. In conclusion, we compare for the first time the innate cellular response of children with PIMS-TS with other severe forms of viral or bacterial infection and Kawasaki disease. Our findings define a differential cell innate signature. These data should be further studied and may facilitate the diagnosis and management of these patients.

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PIMS-TS Innate Cell Signature and Immunophenotype, Description and Comparison with a Cohort of Healthy Children, Kawasaki Disease, Severe Viral and Bacterial Infections.

10.21203/rs.3.rs-602017/v1 ◽

2021 ◽

Author(s):

Alberto García-Salido ◽

Inés Leoz-Gordillo ◽

Anthony González-Brabin ◽

María Ángeles García-Teresa ◽

Amelia Martínez - de Azagra-Garde ◽

...

Keyword(s):

Kawasaki Disease ◽

Bacterial Infection ◽

Cellular Response ◽

Bacterial Infections ◽

Viral Infections ◽

Pediatric Intensive Care ◽

Clinical Syndrome ◽

Healthy Children ◽

Healthy Controls ◽

First Time

Abstract A new clinical syndrome named as Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS) has been described. This new disease is a main cause of hospital and pediatric intensive care unit (PICU). We made a prospective-retrospective observational study to describe the innate cell signature and immunophenotype of children admitted to PICU because of PIMS-TS (from March 2020 to September 2020). They were compared with previous cohorts of healthy controls and children admitted to PICU because bacterial infection, viral infection and Kawasaki disease (KD). Two hundred and forty seven children were studied: 183 healthy controls, 25 viral infections, 20 bacterial infections, 6 KD and 13 PIMS-TS. PIMT-TS showed the lowest percentage of lymphocytes and monocytes with higher relative numbers of CD4+ (p =0,000). Monocytes and neutrophils in PIMS-TS showed higher levels of CD64 expression (p = 0,000). Also, CD11a and CD11b were highly expressed compare to other severe viral or bacterial infections (p = 0,000). In conclusion, we describe and compare for the first time the innate cellular response of children with PIMS-TS with other severe forms of viral or bacterial infection and KD. These data should be further studied and may facilitate the diagnosis and management of these patients.

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Implementation of a Pragmatic Biomarker-Driven Algorithm to Guide Antibiotic Use in the Pediatric Intensive Care Unit: the Optimizing Antibiotic Strategies in Sepsis (OASIS) II Study

Journal of the Pediatric Infectious Diseases Society ◽

10.1093/jpids/piy113 ◽

2018 ◽

Vol 9 (1) ◽

pp. 36-43 ◽

Cited By ~ 2

Author(s):

Kevin J Downes ◽

Julie C Fitzgerald ◽

Emily Schriver ◽

Craig L K Boge ◽

Michael E Russo ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Bacterial Infection ◽

Pediatric Intensive Care Unit ◽

Bacterial Infections ◽

Pediatric Intensive Care ◽

Antibiotic Use ◽

Antibiotic Administration ◽

Period 2 ◽

Rate Ratios

Abstract Background Biomarkers can facilitate safe antibiotic discontinuation in critically ill patients without bacterial infection. Methods We tested the ability of a biomarker-based algorithm to reduce excess antibiotic administration in patients with systemic inflammatory response syndrome (SIRS) without bacterial infections (uninfected) in our pediatric intensive care unit (PICU). The algorithm suggested that PICU clinicians stop antibiotics if (1) C-reactive protein <4 mg/dL and procalcitonin <1 ng/mL at SIRS onset and (2) no evidence of bacterial infection by exam/testing by 48 hours. We evaluated excess broad-spectrum antibiotic use, defined as administration on days 3–9 after SIRS onset in uninfected children. Incidence rate ratios (IRRs) compared unadjusted excess length of therapy (LOT) in the 34 months before (Period 1) and 12 months after (Period 2) implementation of this algorithm, stratified by biomarker values. Segmented linear regression evaluated excess LOT among all uninfected episodes over time and between the periods. Results We identified 457 eligible SIRS episodes without bacterial infection, 333 in Period 1 and 124 in Period 2. When both biomarkers were below the algorithm’s cut-points (n = 48 Period 1, n = 31 Period 2), unadjusted excess LOT was lower in Period 2 (IRR, 0.53; 95% confidence interval, 0.30–0.93). Among all 457 uninfected episodes, there were no significant differences in LOT (coefficient 0.9, P = .99) between the periods on segmented regression. Conclusions Implementation of a biomarker-based algorithm did not decrease overall antibiotic exposure among all uninfected patients in our PICU, although exposures were reduced in the subset of SIRS episodes where biomarkers were low.

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Human Neutrophil Lipocalin as a Superior Diagnostic Means To Distinguish between Acute Bacterial and Viral Infections

Clinical and Vaccine Immunology ◽

10.1128/cvi.00347-15 ◽

2015 ◽

Vol 22 (9) ◽

pp. 1025-1032 ◽

Cited By ~ 17

Author(s):

Per Venge ◽

Lena Douhan-Håkansson ◽

Daniel Garwicz ◽

Christer Peterson ◽

Shengyuan Xu ◽

...

Keyword(s):

Whole Blood ◽

Human Neutrophil ◽

Bacterial Infections ◽

Viral Infections ◽

Response Times ◽

Clinical Performance ◽

Point Of Care ◽

Signs And Symptoms ◽

Healthy Controls ◽

Acute Infections

ABSTRACTThe distinction between causes of acute infections is a major clinical challenge. Current biomarkers, however, are not sufficiently accurate. Human neutrophil lipocalin (HNL) concentrations in serum or whole blood activated by formyl-methionine-leucine-phenylalanine (fMLP) were shown to distinguish acute infections of bacterial or viral cause with high accuracy. The aim was therefore to compare the clinical performance of HNL with currently used biomarkers. Seven hundred twenty-five subjects (144 healthy controls and 581 patients with signs and symptoms of acute infections) were included in the study. C-reactive protein (CRP), the expression of CD64 on neutrophils, procalcitonin (PCT), and blood neutrophil counts were measured by established techniques, and HNL concentrations were measured in whole-blood samples after activation with fMLP. All tested biomarkers were elevated in bacterial as opposed to viral infections (P< 0.001). CRP, PCT, and CD64 expression in neutrophils was elevated in viral infections compared to healthy controls (P< 0.001). In the distinction between healthy controls and patients with bacterial infections, the areas under the receiver operating characteristic (ROC) curves were >0.85 for all biomarkers, whereas for the distinction between bacterial and viral infections, only HNL concentration in fMLP-activated whole blood showed an area under the ROC curve (AUROC) of >0.90 and superior clinical performance. The clinical performance of HNL in fMLP-activated whole blood was superior to current biomarkers and similar to previous results of HNL in serum. The procedure can be adopted for point-of-care testing with response times of <15 min.

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Identification of etiological agents of selected bacterial and viral infections based on serological tests

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0012.8266 ◽

2018 ◽

Vol 72 ◽

pp. 1162-1178

Author(s):

Aleksandra Lewandowicz-Uszyńska ◽

Piotr Naporowski ◽

Gerard Pasternak ◽

Danuta Witkowska

Keyword(s):

False Positive ◽

Cellular Response ◽

Bacterial Infections ◽

Viral Infections ◽

False Negative ◽

Main Role ◽

Serological Tests ◽

Negative Results ◽

False Negative Results ◽

Positive Results

The human immune system’s response to infection is closely related with the type of pathogen. First, a rapid, metabolically inexpensive and non-specific innate immunity is induced, then a specific acquired immunity is activated. In bacterial infections caused by intracellular pathogens, the main role is played by cellular response. In infections caused by bacterial extracellular pathogens, a crucial role is played by antibodies. The clinical symptoms of bacterial and viral infections very often are similar, which is why diagnosing them based only on medical history and physical examination is insufficient. To identify the etiological factors of infections differentiating media, biochemical tests, molecular methods and serological tests are used. The detection of microorganisms or their genetic material can be performed within a short time after the occurrence of an infection. The detection of antibodies is possible only in the appropriate time called the serological window. In a serological diagnostic of infections there are problems with an appropriate interpretation of obtained results. Cross-reactivity can give false positive results for the diagnosis of Chlamydophila pneumonia infection. The problem with the detection of Borrelia burgdorferi infection can be caused by a simultaneous coinfection with different spirochetes, syphilis, mononucleosis or HIV. In serological diagnostics of bacterial infections, the administration of antibiotics to patients before taking serum samples can be responsible for false negative results. Another reason for such results can be a weak humoral response in infected patients. In viral infections, false positive results can be caused by a coinfection of different viruses, especially from the same family or by bacterial or protozoal coinfections or by autoimmune diseases. False-negative results in viral infections often are caused by the early phase of an infection. To properly recognize an etiological factor of infection it is necessary to use an appropriate method, precision of test and collect samples at the appropriate time.

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Type I Interferon in Children with Viral or Bacterial Infections

Clinical Chemistry ◽

10.1093/clinchem/hvaa089 ◽

2020 ◽

Vol 66 (6) ◽

pp. 802-808 ◽

Cited By ~ 2

Author(s):

Sophie Trouillet-Assant ◽

Sébastien Viel ◽

Antoine Ouziel ◽

Lucille Boisselier ◽

Philippe Rebaud ◽

...

Keyword(s):

Bacterial Infection ◽

Bacterial Infections ◽

Viral Infections ◽

Type I Interferon ◽

Area Under The Curve ◽

Pediatric Emergency ◽

Type I ◽

Discriminative Performance ◽

Antibiotic Overuse ◽

Reactive Protein

Abstract Background Fever is one of the leading causes of consultation in the pediatric emergency department for patients under the age of 3 years. Distinguishing between bacterial and viral infections etiologies in febrile patients remains challenging. We hypothesized that specific host biomarkers for viral infections, such as type I-interferon (IFN), could help clinicians’ decisions and limit antibiotic overuse. Methods Paxgene tubes and serum were collected from febrile children (n = 101), age from 7 days to 36 months, with proven viral or bacterial infections, being treated at pediatric emergency departments in France. We assessed the performance of an IFN signature, which was based on quantification of expression of IFN-stimulated genes using the Nanostring® technology and plasma IFN-α quantified by digital ELISA technology. Results Serum concentrations of IFN-α were below the quantification threshold (30 fg/mL) for 2% (1/46) of children with proven viral infections and for 71% (39/55) of children with bacterial infections (P < 0.001). IFN-α concentrations and IFN score were significantly higher in viral compared to bacterial infection (P < 0.001). There was a strong correlation between serum IFN-α concentrations and IFN score (p-pearson = 0.83). Both serum IFN-α concentration and IFN score robustly discriminated (Area Under the Curve >0.91 for both) between viral and bacterial infection in febrile children, compared to C-reactive protein (0.83). Conclusions IFN-α is increased in blood of febrile infants with viral infections. The discriminative performance of IFN-α femtomolar concentrations as well as blood transcriptional signatures could show a diagnostic benefit and potentially limit antibiotic overuse. Clinical Trials Registration clinicaltrials.gov (NCT03163628).

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Abstract 217: Difference of Coronary Artery Lesions or associated Pathogens between the Two Phenotypes of Kawasaki Disease

Circulation ◽

10.1161/circ.131.suppl_2.217 ◽

2015 ◽

Vol 131 (suppl_2) ◽

Author(s):

Kyung Lim Yoon ◽

Song Ee Youn ◽

Mi Young Han ◽

Sung Ho Cha

Keyword(s):

Coronary Artery ◽

Kawasaki Disease ◽

Skin Lesion ◽

Influenza A ◽

Bacterial Infections ◽

Viral Infections ◽

Skin Lesions ◽

University Hospital ◽

Ivig Treatment ◽

Coronary Artery Lesions

Introduction: There are several reports that coronary artery lesions (CALs) are increased/or not increased in patients who predominantly showed arthritis in patients with Kawasaki disease (KD). Patients with eczematoid skin lesions which seem like atopic dermatitis have not been reported in association with CALs. We intended to evaluate the risk of development of CALs in patients with two different phenotypes. Materials and methods: We retrospectively reviewed the medical records in 220 patients who diagnosed as KD and received IVIG treatment in Kyung Hee University Hospital at Gangdong from August 2006 to December 2013. In both patients groups (6 patients with arthritis and 52 patients with eczematoid skin lesion), we reviewed the state of coronary artery, clinical characteristics, associated viral or bacterial infections. Results: In patients with eczematoid lesions (52/220, 23.6%), the ages of patients were significantly older, the duration of fever was longer, and the prevalence of CAL was significantly higher than that of controls ( P =.000, P =.041, P =.033, respectively). In patients with arthritis (6/220, 3%), there were higher incidence of methylprednisolone or infliximab therapy ( P =.000, P =.004, respectively), and higher incidence of viral infection like influenza A and B, rhinovirus, parainfluenza 2, metapneumovirus, and coronavirus OC43 ( P =.018). Conclusions: The incidence of CAL was higher in group of eczematoid skin lesion in KD patients than in group of patients with arthritis. Associated viral infections were higher in arthritis group, therefore, it is better to find associated pathogens aggressively that might be a certain trigger of the development of KD in this group of patients.

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Cytokines and Chemokines as Biomarkers of Community-Acquired Bacterial Infection

Mediators of Inflammation ◽

10.1155/2013/190145 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 27

Author(s):

Michal Holub ◽

David A. Lawrence ◽

Nancy Andersen ◽

Alžběta Davidová ◽

Ondřej Beran ◽

...

Keyword(s):

Bacterial Infection ◽

Bacterial Infections ◽

Viral Infections ◽

Elevated Serum ◽

Serum Concentrations ◽

C Reactive Protein ◽

Reactive Protein ◽

Cytokines And Chemokines ◽

Luminex Technology ◽

Limited Usefulness

Routinely used biomarkers of bacterial etiology of infection, such as C-reactive protein and procalcitonin, have limited usefulness for evaluation of infections since their expression is enhanced by a number of different conditions. Therefore, several inflammatory cytokines and chemokines were analyzed with sera from patients hospitalized for moderate bacterial and viral infectious diseases. In total, 57 subjects were enrolled: 21 patients with community-acquired bacterial infections, 26 patients with viral infections, and 10 healthy subjects (control cohorts). The laboratory analyses were performed using Luminex technology, and the following molecules were examined: IL-1Ra, IL-2, IL-4, IL-6, IL-8, TNF-α, INF-γ, MIP-1β, and MCP-1. Bacterial etiology of infection was associated with significantly (P<0.001) elevated serum concentrations of IL-1Ra, IL-2, IL-6, and TNF-αin comparison to levels observed in the sera of patients with viral infections. In the patients with bacterial infections, IL-1Ra and IL-8 demonstrated positive correlation with C-reactive protein, whereas, IL-1Ra, TNF-α, and MCP-1 correlated with procalcitonin. Furthermore, elevated levels of IL-1Ra, IL-6, and TNF-αdecreased within 3 days of antibiotic therapy to levels observed in control subjects. The results show IL-1Ra as a potential useful biomarker of community-acquired bacterial infection.

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1213. A TRAIL/IP-10/CRP Signature Distinguishes between Viral and Bacterial Infection in Chronic Obstructive Pulmonary Disease Patients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1398 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S628-S628

Author(s):

Meital Paz ◽

Salim Halabi ◽

Shachaf Shiber ◽

Ami Neuberger ◽

Neta Petersiel ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Bacterial Infection ◽

Bacterial Infections ◽

Viral Infections ◽

Expert Panel ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Antibiotic Overuse ◽

Copd Patients ◽

History Of

Abstract Background Challenges in determining the etiology of acute exacerbations of chronic obstructive pulmonary disease (COPD) lead to significant overuse of antibiotics. A new host-response assay that integrates the levels of three proteins (TRAIL, IP-10, and CRP) was shown to exhibit high performance in distinguishing between bacterial and viral disease in two double-blind pediatric validation studies. Here we sought to evaluate its ability to differentiate bacterial from viral infection in adult COPD patients with suspicion of lower respiratory tract infection (LRTI). Methods The study population included 492 febrile adult patients prospectively recruited in “Observer”, an EU Horizon 2020 funded study (grant #684589). Patient etiology was determined by majority expert panel based on clinical, laboratory, multiplex PCR, radiological and follow-up data. We compared the expert panel diagnosis with the assay that gives three possible outcomes: viral, bacterial (including viral with bacterial coinfection) or equivocal. Results 45 out 492 adult patients prospectively recruited with suspicion of LRTI had a medical history of COPD. Of these, 20 cases were assigned as suspected viral infections and 19 as suspected bacterial infections (Figure 1). Antibiotics were prescribed to 19/19 bacterial infections and 16/20 viral infections. The assay correctly classified 19/19 bacterial infections and 12/20 viral infections, with 2 viral cases classified by the assay as bacterial and 6 receiving an equivocal outcome. These data support the assay’s potential to reduce antibiotic overuse from 16/20=80% to 8/20=40% (P=0.01). FIgure 1: Flow through of COPD patients in prospective performance validation study “Observer” Conclusion A new TRAIL/IP-10/CRP signature has potential to significantly reduce antibiotic overuse for patients with suspected LRTI and a history of COPD without missing bacterial infection. Disclosures Meital Paz, MD, MeMed Ltd. (Employee) Noa Avni, PhD, MeMed (Employee) Michal Stein, MeMed Ltd. (Employee) Liran Shani, MD, MeMed Ltd. (Employee) Tanya Gottlieb, PhD, MeMed (Employee) Kfir Oved, MD, PhD, MeMed (Employee) Eran Eden, PhD, MeMed (Employee)

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Antiviral metabolite 3'-Deoxy-3',4'-didehydro-cytidine is detectable in serum and identifies acute viral infections including COVID-19

10.1101/2021.07.23.21260740 ◽

2021 ◽

Author(s):

Ravi Mehta ◽

Elena Chekmeneva ◽

Heather Jackson ◽

Caroline Sands ◽

Ewurabena Mills ◽

...

Keyword(s):

Bacterial Infections ◽

Viral Infections ◽

Characteristic Curve ◽

Case Identification ◽

Inflammatory Conditions ◽

Disease Diagnostics ◽

Infectious Disease Diagnostics ◽

Diagnostic Role ◽

Highly Correlated ◽

First Time

There is a critical need for improved infectious disease diagnostics to enable rapid case identification in a viral pandemic and support targeted antimicrobial prescribing. Here we use high-resolution liquid chromatography coupled with mass spectrometry to compare the admission serum metabolome of patients attending hospital with a range of viral infections, including SARS-CoV-2, to those with bacterial infections, non-infected inflammatory conditions and healthy controls. We demonstrate for the first time that 3'-Deoxy-3',4'-didehydro-cytidine (ddhC), a free base of the only known human antiviral small molecule ddhC-triphosphate (ddhCTP), is detectable in serum. ddhC acts as an accurate biomarker for viral infections, generating an area under the receiver operating characteristic curve of 0.954 (95% confidence interval 0.923-0.986) when comparing viral to non-viral cases. Gene expression of viperin, the enzyme responsible for ddhCTP synthesis, is highly correlated with ddhC, providing a biological mechanism for its increase during viral infection. These findings underline a key future diagnostic role of ddhC in the context of pandemic preparedness and antimicrobial stewardship.

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Elevated Serum C1q Levels in Children With Sepsis

Frontiers in Pediatrics ◽

10.3389/fped.2021.619899 ◽

2021 ◽

Vol 9 ◽

Author(s):

Huan Li ◽

Juanjuan Chen ◽

Yuanhui Hu ◽

Xin Cai ◽

Pingan Zhang

Keyword(s):

Bacterial Infections ◽

Viral Infections ◽

Laboratory Data ◽

Elevated Serum ◽

Reference Value ◽

Serum Levels ◽

Critical Group ◽

Control Group ◽

Healthy Children ◽

Complement C1q

Objective: To analyze the serum complement C1q levels in children with sepsis, and explore the suggestive effect of serum C1q levels on the condition of children with sepsis.Methods: The clinical and laboratory data of children with sepsis (n = 95) and healthy children (n = 71) in Renmin Hospital of Wuhan University from January 2019 to October 2019 were collected, and each index of the two groups was compared. Then we divided children with sepsis into three subgroups based on the Pediatric Critical Illness Score (PCIS): non-critical group, critical group, and extremely critical group. The serum C1q and PCT levels of the three subgroups were analyzed, and the correlation analysis was carried out between the levels of serum C1q and PCT levels as well as PCIS among children with sepsis. Finally, we analyzed the serum C1q levels of septic children infected by different pathogens.Results: The serum C1q levels of children with sepsis were significantly higher than those of healthy children (median 198.4 vs. 186.2 mg/L, P < 0.001). In the analysis of subgroups, the serum C1q levels of non-critical group, critical group, and extremely critical group septic children were 182.80 (166.75, 195.85) mg/L, 219.90 (209.10, 246.40) mg/L and 249.95 (239.10, 272.25) mg/L, respectively, which were correlated with the severity of the disease. At the same time, we also found that serum C1q in children with sepsis was positively correlated with PCT levels (r = 0.5982, P < 0.001), and negatively correlated with PCIS score (r = −0.6607, P < 0.001). The serum C1q levels of septic children with bacterial infections, mycoplasma infections, viral infections, and co-infection were higher than those of the control group (P < 0.05).Conclusion: The serum levels of C1q in children with sepsis were increased and related to the severity of sepsis, suggesting that C1q may be involved in the occurrence and development of sepsis, which had reference value for the preliminary diagnosis and severity classification of sepsis.

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