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A special issue of Children (ISSN 2227-9067). This special issue belongs to the section "Pediatric Infectious Diseases".

Deadline for manuscript submissions: closed (15 September 2021) | Viewed by 50390

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Special Issue Editor

Dr. Anna Nilsson

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Guest Editor

Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, 171 76 Stockholm, Sweden
Interests: pediatric infection; immunity; immunotherapy

Special Issue Information

Dear Colleagues,

Discriminating between bacterial and viral infections in children is still a diagnostic dilemma for the clinician. However, the usage of new methodologies has opened up the possibility of exploring genome-wide expression and transcriptional signatures, uncovering activated pathways consisting of many genes associated with either bacterial or viral infection. As there is diversity in the mechanisms of pathogen recognition by specific receptors, and host responses are altered by different microbes, pathogen specific (virus, bacteria, etc.) transcriptional signatures could be translated into useful clinical biomarkers, and thus used for identification.

For this Special Issue, we invite submissions describing new potential biomarkers that could improve the diagnostics of bacterial versus viral infections in children. We welcome reviews and original articles considering novel approaches as well as identifying gaps in knowledge.

Dr. Anna Nilsson
Guest Editor

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Keywords

Bacterial Infection
Viral Infection
Biomarkers
Pathogen-Recognition
Host Response

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Published Papers (10 papers)

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Research

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13 pages, 1654 KiB

Open AccessArticle

Diagnostic Performance of SARS-CoV-2 Rapid Antigen Test in a Large, German Cohort

by Olivier Mboma, Elmar Rieke, Parviz Ahmad-Nejad, Stefan Wirth and Malik Aydin

Children 2021, 8(8), 682; https://doi.org/10.3390/children8080682 - 8 Aug 2021

Cited by 12 | Viewed by 4240

Abstract

We assessed the performance of a rapid antigen test (RAT) in everyday clinical practice. Between 1 November 2020 until 1 April 2021 all in-patients at the Helios University Hospital Wuppertal, Germany, as well as the accompanying relatives at the Children’s Hospital received a SARS-CoV-2 RAT and a SARS-CoV-2 RT-PCR prior to admission. Out of 3686 patients, 22 (0.6%) subjects were tested positive by RT-PCR and RAT, and 3591 (97.4%) were negative by both methods, showing discordant results: RT-PCR+/RAT− in 58 (1.6%) and RT-PCR−/RAT+ in 15 patients (0.4%). Overall sensitivity and specificity of RAT was 27.5% (95%CI 18.1–38.6%) and 99.6% (95%CI 99.3–99.8%), respectively. The sensitivity was slightly higher in adults (30.4%, 95%CI 18.8–90.9%) than in pediatric subjects (20.8%, 95%CI 7.1–42.2%). False negative RAT had a statistically higher Ct-value (p < 0.001) compared to true positive values, and overall sensitivity increased to 80% [59.3–93.2%] with Ct value < 30. While the sensitivity of the RAT was poor compared with the RT-PCR, the specificity was excellent. However, the sensitivity increased with lower Ct value, and with the right anamnesis the RAT can be a quick and easy approach to distinguish people who are infectious with SARS-CoV-2 from noninfectious people, enabling appropriate triage in clinical practice while waiting for the RT-PCR result. Full article

(This article belongs to the Special Issue Advances in Pediatric Infection and Immunity)

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11 pages, 1824 KiB

Open AccessArticle

Genetic Sequence Variants in TLR4, MBL or IL-1 Receptor Antagonist is not Associated to Increased Risk for Febrile Neutropenia in Children with ALL

by Martina Wahlund, Malin Lindqvist Appell, Ida Hed Myrberg, Anna Berggren and Anna Nilsson

Children 2020, 7(12), 296; https://doi.org/10.3390/children7120296 - 16 Dec 2020

Cited by 4 | Viewed by 2217

Abstract

Sequence variants in genes involved in the immune system have previously been linked to neutropenia as well as infections in cancer patients. Sequence variants in genes coding for TLR4, MBL, and IL-1Ra were investigated in relation to clinical utility of identifying severe episodes of febrile neutropenia (FN) in a cohort of children undergoing treatment for acute lymphoblastic leukemia. The study included 122 children, where data on FN and microbiological findings were retrospectively collected from medical records. Sequence variants in genes coding for MBL, TLR4, and IL-1Ra were identified by pyrosequencing, TaqMan SNP genotyping assay, and gel electrophoresis. A total of 380 episodes of FN were identified and in 139 episodes, there was a microbiological defined infection. Age and treatment intensity were all associated with the risk of developing FN. No sequence variant was associated to increased numbers of FN episodes. Two sequence variants in the TLR4 gene increased the risk of viral infection, whilst sequence variants in the IL-1Ra gene were associated to a decreased risk of bacterial blood-stream infection (BSI). The investigated sequence variants did not associate with increased risk for FN or to severe infections, as to why the clinical utility as a risk-stratification tool is low. Most episodes of FN were classified as fever with unknown origin, emphasizing the need for improved microbial detection methods. Full article

(This article belongs to the Special Issue Advances in Pediatric Infection and Immunity)

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11 pages, 1301 KiB

Open AccessArticle

Safety and Dose-Dependent Effects of Echinacea for the Treatment of Acute Cold Episodes in Children: A Multicenter, Randomized, Open-Label Clinical Trial

by Ramon Weishaupt, Arnold Bächler, Simon Feldhaus, Günter Lang, Peter Klein and Roland Schoop

Children 2020, 7(12), 292; https://doi.org/10.3390/children7120292 - 15 Dec 2020

Cited by 12 | Viewed by 8818

Abstract

Background: Due to the frequency and severity of cold symptoms in children, and the risk of associated complications, effective treatments are urgently needed. Here we evaluated the safety profile and treatment benefits of Echinacea in children with acute cold and flu symptoms. Methods: A total of 79 children (4–12 years) were randomized to a treatment regimen of three or five times daily Echinaforce Junior tablets (total of 1200 or 2000 mg Echinacea extract, EFJ) for the prospective treatment of upcoming cold and flu episodes at first signs. Parents recorded respiratory symptoms daily during episodes in their child and physicians and parents subjectively rated tolerability. Results: EFJ was used to treat 130 cold episodes in 68 children and was very well tolerated by more than 96% positive physician’s ratings. EFJ-treated cold episodes lasted 7.5 days on average, with nine out of 10 episodes being fully resolved after 10 days. Five EFJ tablets daily reduced the average episode duration by up to 1.7 days (p < 0.02) in comparison to three EFJ tablets daily regimen. Effective symptom resolution finally contributed to a low antibiotic prescription rate in this study of 4.6%. Conclusions: EFJ tablets present a valuable option for the treatment of acute cold episodes in children showing a wide safety margin and increased therapeutic benefits at five tablets daily. Full article

(This article belongs to the Special Issue Advances in Pediatric Infection and Immunity)

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11 pages, 408 KiB

Open AccessArticle

The Impact of Moderate-Dose Acetylsalicylic Acid in the Reduction of Inflammatory Cytokine and Prevention of Complication in Acute Phase of Kawasaki Disease: The Benefit of Moderate-Dose Acetylsalicylic Acid

by Jung Eun Kwon, Da Eun Roh and Yeo Hyang Kim

Children 2020, 7(10), 185; https://doi.org/10.3390/children7100185 - 16 Oct 2020

Cited by 7 | Viewed by 3071

Abstract

Background: Acetylsalicylic acid (ASA) is part of the recommended treatment of Kawasaki disease (KD). Controversies remain regarding the optimal dose of ASA. We aimed to evaluate the impact of different doses of ASA on inflammation control while minimizing adverse effects in the acute phase treatment of KD. Methods: The enrolled 323 patients with KD were divided into three groups according to ASA dose: moderate-dose (30–50 mg/kg/day), high-dose (80–100 mg/kg/day), and non-ASA. Results: High-dose ASA group showed a significantly shorter duration of fever from the start of treatment to remission than other groups. Baseline level and delta score of interleukin (IL)-1, IL-6, IL-10, tumor necrosis factor-α, and transforming growth factor β were not statistically different among the groups. The number of patients who received additional treatments in the non-ASA group was more than other groups. Coronary artery dilatation was not significantly different among the groups. One patient with high-dose ASA was diagnosed with Reye syndrome. Conclusion: Different doses of ASA did not show any differences in changes of inflammatory bio-makers and cytokines. However, high-dose ASA showed occurrence of Reye syndrome, and non-ASA showed intravenous immunoglobulin refractoriness. We suggest that moderate-dose ASA may be beneficial for the treatment of patients in the acute phase of KD. Full article

(This article belongs to the Special Issue Advances in Pediatric Infection and Immunity)

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Review

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16 pages, 379 KiB

Open AccessReview

Acute Infectious Gastroenteritis: The Causative Agents, Omics-Based Detection of Antigens and Novel Biomarkers

by Haziqah Hasan, Nor Ashika Nasirudeen, Muhammad Alif Farhan Ruzlan, Muhammad Aiman Mohd Jamil, Noor Akmal Shareela Ismail, Asrul Abdul Wahab and Adli Ali

Children 2021, 8(12), 1112; https://doi.org/10.3390/children8121112 - 2 Dec 2021

Cited by 9 | Viewed by 10397

Abstract

Acute infectious gastroenteritis (AGE) is among the leading causes of mortality in children less than 5 years of age worldwide. There are many causative agents that lead to this infection, with rotavirus being the commonest pathogen in the past decade. However, this trend is now being progressively replaced by another agent, which is the norovirus. Apart from the viruses, bacteria such as Salmonella and Escherichia coli and parasites such as Entamoeba histolytica also contribute to AGE. These agents can be recognised by their respective biological markers, which are mainly the specific antigens or genes to determine the causative pathogen. In conjunction to that, omics technologies are currently providing crucial insights into the diagnosis of acute infectious gastroenteritis at the molecular level. Recent advancement in omics technologies could be an important tool to further elucidate the potential causative agents for AGE. This review will explore the current available biomarkers and antigens available for the diagnosis and management of the different causative agents of AGE. Despite the high-priced multi-omics approaches, the idea for utilization of these technologies is to allow more robust discovery of novel antigens and biomarkers related to management AGE, which eventually can be developed using easier and cheaper detection methods for future clinical setting. Thus, prediction of prognosis, virulence and drug susceptibility for active infections can be obtained. Case management, risk prediction for hospital-acquired infections, outbreak detection, and antimicrobial accountability are aimed for further improvement by integrating these capabilities into a new clinical workflow. Full article

(This article belongs to the Special Issue Advances in Pediatric Infection and Immunity)

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10 pages, 279 KiB

Open AccessReview

Novel Biomarkers Differentiating Viral from Bacterial Infection in Febrile Children: Future Perspectives for Management in Clinical Praxis

by Samuel Rhedin, Kristina Elfving and Anna Berggren

Children 2021, 8(11), 1070; https://doi.org/10.3390/children8111070 - 20 Nov 2021

Cited by 13 | Viewed by 4695

Abstract

Differentiating viral from bacterial infections in febrile children is challenging and often leads to an unnecessary use of antibiotics. There is a great need for more accurate diagnostic tools. New molecular methods have improved the particular diagnostics of viral respiratory tract infections, but defining etiology can still be challenging, as certain viruses are frequently detected in asymptomatic children. For the detection of bacterial infections, time consuming cultures with limited sensitivity are still the gold standard. As a response to infection, the immune system elicits a cascade of events, which aims to eliminate the invading pathogen. Recent studies have focused on these host–pathogen interactions to identify pathogen-specific biomarkers (gene expression profiles), or “pathogen signatures”, as potential future diagnostic tools. Other studies have assessed combinations of traditional bacterial and viral biomarkers (C-reactive protein, interleukins, myxovirus resistance protein A, procalcitonin, tumor necrosis factor-related apoptosis-inducing ligand) to establish etiology. In this review we discuss the performance of such novel diagnostics and their potential role in clinical praxis. In conclusion, there are several promising novel biomarkers in the pipeline, but well-designed randomized controlled trials are needed to evaluate the safety of using these novel biomarkers to guide clinical decisions. Full article

(This article belongs to the Special Issue Advances in Pediatric Infection and Immunity)

13 pages, 297 KiB

Open AccessReview

Update on Viral Infections Involving the Central Nervous System in Pediatric Patients

by Giovanni Autore, Luca Bernardi, Serafina Perrone and Susanna Esposito

Children 2021, 8(9), 782; https://doi.org/10.3390/children8090782 - 6 Sep 2021

Cited by 8 | Viewed by 4602

Abstract

Infections of the central nervous system (CNS) are mainly caused by viruses, and these infections can be life-threatening in pediatric patients. Although the prognosis of CNS infections is often favorable, mortality and long-term sequelae can occur. The aims of this narrative review were to describe the specific microbiological and clinical features of the most frequent pathogens and to provide an update on the diagnostic approaches and treatment strategies for viral CNS infections in children. A literature analysis showed that the most common pathogens worldwide are enteroviruses, arboviruses, parechoviruses, and herpesviruses, with variable prevalence rates in different countries. Lumbar puncture (LP) should be performed as soon as possible when CNS infection is suspected, and cerebrospinal fluid (CSF) samples should always be sent for polymerase chain reaction (PCR) analysis. Due to the lack of specific therapies, the management of viral CNS infections is mainly based on supportive care, and empiric treatment against herpes simplex virus (HSV) infection should be started as soon as possible. Some researchers have questioned the role of acyclovir as an empiric antiviral in older children due to the low incidence of HSV infection in this population and observed that HSV encephalitis may be clinically recognizable beyond neonatal age. However, the real benefit-risk ratio of selective approaches is unclear, and further studies are needed to define appropriate indications for empiric acyclovir. Research is needed to find specific therapies for emerging pathogens. Moreover, the appropriate timing of monitoring neurological development, performing neuroimaging evaluations and investigating the effectiveness of rehabilitation during follow-up should be evaluated with long-term studies. Full article

(This article belongs to the Special Issue Advances in Pediatric Infection and Immunity)

9 pages, 975 KiB

Open AccessReview

Early Microbial–Immune Interactions and Innate Immune Training of the Respiratory System during Health and Disease

by Gustavo Nino, Carlos E. Rodriguez-Martinez and Maria J. Gutierrez

Children 2021, 8(5), 413; https://doi.org/10.3390/children8050413 - 19 May 2021

Cited by 14 | Viewed by 4862

Abstract

Over the past two decades, several studies have positioned early-life microbial exposure as a key factor for protection or susceptibility to respiratory diseases. Birth cohorts have identified a strong link between neonatal bacterial colonization of the nasal airway and gut with the risk for respiratory infections and childhood asthma. Translational studies have provided companion mechanistic insights on how viral and bacterial exposures in early life affect immune development at the respiratory mucosal barrier. In this review, we summarize and discuss our current understanding of how early microbial–immune interactions occur during infancy, with a particular focus on the emergent paradigm of “innate immune training”. Future human-based studies including newborns and infants are needed to inform the timing and key pathways implicated in the development, maturation, and innate training of the airway immune response, and how early microbiota and virus exposures modulate these processes in the respiratory system during health and disease. Full article

(This article belongs to the Special Issue Advances in Pediatric Infection and Immunity)

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10 pages, 3917 KiB

Open AccessCase Report

The Risk of Nonsteroidal Anti-Inflammatory Drugs in Pediatric Medicine: Listen Carefully to Children with Pain

by Olivier Mboma, Stefan Wirth and Malik Aydin

Children 2021, 8(11), 1048; https://doi.org/10.3390/children8111048 - 13 Nov 2021

Cited by 5 | Viewed by 3965

Abstract

Over the last decades, the use of over-the-counter analgesics in the general population has increased in Germany. Ibuprofen is one of the most commonly used nonsteroidal anti-inflammatory drug (NSAID) and is frequently prescribed to children as an analgesic and/or antipyretic. Besides having a well-established safety and efficacy profile when used in appropriate doses, cases of NSAID-induced acute kidney injury (AKI) have been described in the pediatric population, particularly in the context of dehydration and in combination with other drugs. The ingestion of more than 400 mg/kg is associated with severe or life-threatening toxicity. This report is about two previously healthy adolescents, who developed AKI after taking high daily dose of ibuprofen as a pain reliever without any appropriate medical supervision. With these case reports, in addition to the side effect profiles of this analgesic, we would also like to present a certain therapeutic recommendation that we applied in these patients, and furthermore appeal to pediatricians to strictly set the indications for ibuprofen intake. Full article

(This article belongs to the Special Issue Advances in Pediatric Infection and Immunity)

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10 pages, 1320 KiB

Open AccessBrief Report

Human Species D Adenoviruses Isolated from Diarrheal Feces Show Low Infection Rates in Primary Nasal Epithelial Cells

by Malik Aydin, Sebastian Schellhorn, Stefan Wirth, Wenli Zhang and Anja Ehrhardt

Children 2021, 8(7), 563; https://doi.org/10.3390/children8070563 - 30 Jun 2021

Cited by 2 | Viewed by 2337

Abstract

The importance of adenovirus (Ad) research is significantly increasing with respect to virotherapy for vaccine development, tumor, and gene therapy. Due to the different species and subtypes of this virus, the characterization of the biological significance of especially rare Ad is necessary. Previously, rare Ad types 70, 73, and 74 were originally isolated from fecal samples of immunocompromised patients and they represent recombinants of other Ad types. Here we investigated transduction experiments of these reporter gene tagged Ad types in primary cells exemplified by subject-derived primary nasal epithelial cells (NAEPCs). To analyze the transduction rates, we performed flow cytometry, quantitative polymerase chain reaction (PCR), and cytokine analyses 25 h post-infection. We found that, in contrast to Ad type 5 (as a positive control), the transduction rates of NAEPCs with Ad types 70, 73, and 74 were interestingly low. The major Ad receptor (coxsackievirus-adenovirus receptor and CD46) expression levels showed no significant change after infection with Ad types 70, 73 and 74. Moreover, Interleukin 6 (IL-6) was not released after in vitro Ad transduction. Due to the high risk of developing life-threatening complications in immunocompromised patients by these human species D Ads, even more attention needs to be investigated into the development of diagnostic and therapeutic concepts to prevent and treat those opportunistic infections in susceptible patients. Full article

(This article belongs to the Special Issue Advances in Pediatric Infection and Immunity)

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