Clinical and economic inpatient burden of respiratory syncytial virus (RSV) infections in children < 2 years of age in Germany, 2014-2019: a retrospective health claims analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause for severe lower respiratory tract infections (LRTI) in children < 2 years of age in Germany - though little is known about the clinical and economic burden of RSV in children with and without risk factors per month of life. METHODS: In a retrospective health claims analysis, we identified RSV inpatient cases between 2014 and 2019. We assessed incidence rates, mortality rate, healthcare resource utilization, associated direct costs per case and excess costs for 30, 90 and 365 days after hospital admission matched to a control group. The outcomes are reported separately for the first and second year of life (i.e., for infants and toddlers) and were stratified by month of life, preterm and risk status (i.e., presence of underlying disease: chronic respiratory or cardiac disease, immunosuppression, neurological diseases, diabetes, conditions originating in the perinatal period). RESULTS: RSV-attributable hospital incidence rate was higher in infants (30.25/1,000) than toddlers (14.52/1,000), highest in the first three months of life (44.21/1,000), in infants born preterm (64.76/1,000) or with any underlying disease (54.85/1,000). Mortality rate was also higher for infants (0.08/1,000) than toddlers (0.04/1,000). Mean 30-day excess costs ranged from 2,953 € for infants born full-term at no risk, hospitalized for 5 days, to 6,694 € for infants born extremely premature, hospitalized for 7 days. CONCLUSION: In Germany, the clinical and economic burden of RSV is substantial, especially in the most vulnerable population, that is, very young infants, those born premature and/or those with an underlying disease.

High burden of acute respiratory tract infections leading to hospitalization at German pediatric hospitals: fall/winter 2022-2023.

PURPOSE: Given reduced immunity levels for seasonally occurring respiratory infections and the experience of an unusually early, severe wave of RSV infections during 2021, a preexisting clinician-led reporting system (CLRS) was updated to prospectively monitor the anticipated high burden of respiratory infections (ARI) in German pediatric hospitals during fall/winter 2022-2023. METHODS: From September 13, 2022 through March 31, 2023, children hospitalized with ARI as a primary diagnosis were monitored via a national CLRS established by the German Society for Pediatric Infectious Diseases (DGPI). Once a week, the CLRS collected overall number of new hospital admissions, ARI-related admissions according to pathogen (SARS-CoV-2, RSV, influenza, and other), plus number of patients admitted to ICU with ARI as a primary diagnosis. RESULTS: With a high participation among children's hospitals across Germany (22.8%), 76 centers submitted 1,053 survey reports. ARI-related hospital admissions showed a steep rise starting in late September 2022 and reached their highpoint in early December 2022 (50.1% of all admissions). In parallel, the average number of newly admitted patients (aNA) with RSV (3.6) peaked, as did those with influenza (2.1) one week later. The average highpoint of ARI patients on ICU (aICU) (2.9) was reached shortly thereafter. Again, RSV (1.6) und influenza (1.2) were predominant pathogens. CONCLUSION: In fall/winter 2022-2023, German hospitals reported a sharp increase in patients with ARIs. While RSV and influenza represented the greatest proportion of ARI, SARS-CoV-2 played a less significant role. Systematic, dynamic collection of ARI data is critical for assessing real burdens on the health care system.

The severity of respiratory syncytial virus infection in children during the SARS-CoV-2/COVID-19 pandemic: A nationwide study of 11,915 cases in Germany.

PURPOSE: Respiratory syncytial virus (RSV) infection is a major cause of childhood hospitalization. The COVID-19 pandemic has disrupted the usual seasonal pattern of RSV, resulting in high activity during the off-season. This study aims to evaluate the effects of the pandemic on the severity of RSV infections. METHODS: Data from 11,915 children hospitalized due to RSV infection between 2016 and 2022 were analyzed. The hospitalized patients were categorized into two groups, from January 2016 to February 2020 (PreCoV19 group) and from March 2020 to December 2022 (CoV19 group). The hospitalization duration, intensive care unit (ICU) admissions, length of stay at ICU, mechanical ventilation requirement and duration, Elixhauser comorbidity index scores, and in-hospital mortality were analyzed. RESULTS: Children in the PreCoV19 group had a mean age of 0.4 ± 0.7, whereas those in the CoV19 group had a mean age of 0.6 ± 1.0 years. Children during the pandemic had significantly shorter hospital stays (4.3 ± 2.6 days) compared to children of the pre-pandemic period (4.9 ± 3.3 days). Although ICU admission rates did not change, the duration of ICU stays decreased in the CoV19 group. Moreover, the in-hospital mortality did not differ between the groups. A multivariable analysis showed that younger age, regardless of the pandemic period, was associated with prolonged hospital stays, higher ICU admission rates, and an increased requirement for mechanical ventilation. CONCLUSION: Our findings highlight significant changes of the clinical characteristics of RSV infections during the pandemic, with implications for clinical management and public health strategies.

Clinical recommendations for the inpatient management of lower respiratory tract infections in children and adolescents with severe neurological impairment in Germany.

Children and adolescents with severe neurological impairment (SNI) require specialized care due to their complex medical needs. In particular, these patients are often affected by severe and recurrent lower respiratory tract infections (LRTIs). These infections, including viral and bacterial etiology, pose a significant risk to these patients, often resulting in respiratory insufficiency and long-term impairments. Using expert consensus, we developed clinical recommendations on the management of LRTIs in children and adolescents with SNI. These recommendations emphasize comprehensive multidisciplinary care and antibiotic stewardship. Initial treatment should involve symptomatic care, including hydration, antipyretics, oxygen therapy, and respiratory support. In bacterial LRTIs, antibiotic therapy is initiated based on the severity of the infection, with aminopenicillin plus a beta-lactamase inhibitor recommended for community-acquired LRTIs and piperacillin-tazobactam for patients with chronic lung disease or tracheostomy. Ongoing management includes regular evaluations, adjustments to antibiotic therapy based on pathogen identification, and optimization of supportive care. Implementation of these recommendations aims to improve the diagnosis and treatment of LRTIs in children and adolescents with SNI. What is Known: • Children and adolescents with severe neurological impairment are particularly affected by severe and recurrent lower respiratory tract infections (LRTIs). • The indication and choice of antibiotic therapy for bacterial LRTI is often difficult because there are no evidence-based treatment recommendations for this heterogeneous but vulnerable patient population; the frequent overuse of broad-spectrum or reserve antibiotics in this patient population increases selection pressure for multidrug-resistant pathogens. What is New: • The proposed recommendations provide a crucial framework for focused diagnostics and treatment of LRTIs in children and adolescents with severe neurological impairment. • Along with recommendations for comprehensive and multidisciplinary therapy and antibiotic stewardship, ethical and palliative care aspects are taken into account.

Association of viral load with TRAIL, IP-10, CRP biomarker signature and disease severity in children with respiratory tract infection or fever without source: A prospective, multicentre cohort study.

BACKGROUND: To investigate the association of viral load (VL) with (i) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein-10, C-reactive protein, and a combinatorial score (BV score), and (ii) clinical severity. STUDY DESIGN: In this prospective, multicentre cohort substudy, children with respiratory tract infection or fever without source were enrolled. VL for influenza virus, rhinovirus, respiratory syncytial virus, and adenovirus was measured from nasopharyngeal swabs. The reference standard diagnosis was established based on expert panel adjudication. RESULTS: Of 1140 recruited patients, 333 had a virus monodetection. VL for the aggregated data set correlated with TRAIL and IP-10 levels, with the length of oxygen therapy, and inversely with the BV score. At a single viral level, only the influenza VL yielded a correlation with TRAIL, IP-10 levels, and the BV score. Children with a viral reference standard diagnosis had significantly higher VL than those with bacterial infection (p = 0.0005). Low TRAIL (incidence rate ratio [IRR] 0.6, 95% confidence interval [CI] 0.39-0.91) and young age (IRR 0.62, 95% CI 0.49-0.79) were associated with a longer hospital stay, while young age (IRR 0.33, 95% CI 0.18-0.61), low TRAIL (IRR 0.25, 95% CI 0.08-0.76), and high VL (IRR 1.16, 95% CI 1.00-1.33) were predictive of longer oxygen therapy. CONCLUSION: These findings indicate that VL correlates with biomarkers and may serve as a complementary tool pertaining to disease severity.

High burden of RSV hospitalizations in Germany 2021-2022.

BACKGROUND: Public health measures implemented to mitigate the effects of the COVID-19 pandemic disrupted the worldwide transmission of endemic respiratory viruses such as RSV, as well as other typical, seasonal, and viral respiratory pathogens. METHODS: From October 18, 2021 to March 31, 2022, RSV cases admitted to German pediatric hospitals were monitored via a newly established, national, Clinician-Led Reporting System (CLRS) that recorded patient age and type of respiratory support. A subanalysis of the first 4 months of the monitoring period was additionally performed. RESULTS: In October 2021, a total of 471 hospitalized pediatric RSV cases per day were documented by 67 reporting hospitals. By January 2022, this number dropped to three cases at 11 hospitals (median of reporting hospitals: 37 (11%)). During these months, the median of hospitalized children on general wards and intensive care units was 133 and 15, respectively. In the subanalysis conducted to examine the period October to January, an average of 3.6 ± 2.2 patients per hospital per day were hospitalized on general wards (median 4 cases; range 0.3-8 cases), whereas 0.4 ± 2.2 patients were on intensive care units (median 0.3 cases; range 0-0.9 cases), with 11.5% receiving respiratory support. The majority of patients were under 2 years old. CONCLUSION: The overall burden of out-of-season RSV cases was extraordinarily high in Germany in 2021-2022. The newly established CLRS may help evaluate and, therefore, better allocate local and national pediatric care resources.

Antibiotic utilization in hospitalized children under 2 years of age with influenza or respiratory syncytial virus infection - a comparative, retrospective analysis.

BACKGROUND: Infections due to Respiratory Syncytial Virus (RSV) and Influenza virus (FLU) are leading causes of hospitalization in young children. Yet, there is little data on factors associated with antibiotic use in these patients. METHODS: We conducted a retrospective, single-center study of all patients below 2 years of age hospitalized between 2014 and 2018. We compared children with RSV infection to children with FLU infection analyzing clinical characteristics and factors contributing to an increased rate of antimicrobial utilization. RESULTS: RSV infection was diagnosed in 476/573 (83.1%), FLU in 95/573 (16.6%), and RSV-FLU-co-infection in 2/573 (0.3%) patients. Median age was lower for RSV compared to FLU (4 vs. 12 months; p < 0.0001). Children with RSV had longer hospitalization (5 vs. 4 days; p = 0.0023) and needed oxygen more frequently (314/476 vs. 23/95; p < 0.0001) than FLU patients. There was no significant difference in the overall antibiotic utilization between RSV and FLU patients (136/476 vs. 21/95; p = 0.2107). Logistic regression analyses revealed that septic appearance on admission (odds ratio [OR] 8.95, 95% confidence interval [CI] 1.5-54.1), acute otitis media (OR 4.5, 95% CI 2.1-9.4), a longer oxygen therapy (OR 1.40; 95% CI 1.13-1.74) and a higher C-reactive protein (CRP) (OR 1.7, 95% CI 1.5-2.0) were significantly associated with antibiotic use in both groups, but not age or pneumonia. CONCLUSIONS: In our cohort, the rate of antibiotic utilization was comparable between RSV and FLU patients, while for both groups distinct clinical presentation and a high CRP value were associated with higher antibiotic use.

Polar Infection of Echovirus-30 Causes Differential Barrier Affection and Gene Regulation at the Blood-Cerebrospinal Fluid Barrier.

Echovirus-30 (E-30) is responsible for the extensive global outbreaks of meningitis in children. To gain access to the central nervous system, E-30 first has to cross the epithelial blood-cerebrospinal fluid barrier. Several meningitis causing bacteria preferentially infect human choroid plexus papilloma (HIBCPP) cells in a polar fashion from the basolateral cell side. Here, we investigated the polar infection of HIBCPP cells with E-30. Both apical and basolateral infections caused a significant decrease in the transepithelial electrical resistance of HIBCPP cells. However, to reach the same impact on the barrier properties, the multiplicity of infection of the apical side had to be higher than that of the basolateral infection. Furthermore, the number of infected cells at respective time-points after basolateral infection was significantly higher compared to apical infection. Cytotoxic effects of E-30 on HIBCPP cells during basolateral infection were observed following prolonged infection and appeared more drastically compared to the apical infection. Gene expression profiles determined by massive analysis of cDNA ends revealed distinct regulation of specific genes depending on the side of HIBCPP cells' infection. Altogether, our data highlights the polar effects of E-30 infection in a human in vitro model of the blood-cerebrospinal fluid barrier leading to central nervous system inflammation.

Distinct migratory pattern of naive and effector T cells through the blood-CSF barrier following Echovirus 30 infection.

BACKGROUND: Echovirus 30 (E-30) is one of the most frequently isolated pathogens in aseptic meningitis worldwide. To gain access to the central nervous system (CNS), E-30 and immune cells have to cross one of the two main barriers of the CNS, the epithelial blood-cerebrospinal fluid barrier (BCSFB) or the endothelial blood-brain barrier (BBB). In an in vitro model of the BCSFB, it has been shown that E-30 can infect human immortalized brain choroid plexus papilloma (HIBCPP) cells. METHODS: In this study we investigated the migration of different T cell subpopulations, naive and effector T cells, through HIBCPP cells during E-30 infection. Effects of E-30 infection and the migration process were evaluated via immunofluorescence and flow cytometry analysis, as well as transepithelial resistance and dextran flux measurement. RESULTS: Th1 effector cells and enterovirus-specific effector T cells migrated through HIBCPP cells more efficiently than naive CD4+ T cells following E-30 infection of HIBCPP cells. Among the different naive T cell populations, CD8+ T cells crossed the E-30-infected HIBCPP cell layer in a significantly higher number than CD4+ T cells. A large amount of effector T cells also remained attached to the basolateral side of the HIBCPP cells compared with naive T cells. Analysis of HIBCPP barrier function showed significant alteration after E-30 infection and trans- as well as paracellular migration of T cells independent of the respective subpopulation. Morphologic analysis of migrating T cells revealed that a polarized phenotype was induced by the chemokine CXCL12, but reversed to a round phenotype after E-30 infection. Further characterization of migrating Th1 effector cells revealed a downregulation of surface adhesion proteins such as LFA-1 PSGL-1, CD44, and CD49d. CONCLUSION: Taken together these results suggest that naive CD8+ and Th1 effector cells are highly efficient to migrate through the BCSFB in an inflammatory environment. The T cell phenotype is modified during the migration process through HIBCPP cells.

Infectious causes of peripheral facial nerve palsy in children-a retrospective cohort study with long-term follow-up.

The aim of this study was to analyze the clinical and laboratory characteristics of children with peripheral facial nerve palsy (pFP) with a focus on identifying infectious etiology and long-term outcome. We conducted an ICD-10-based retrospective chart review on children hospitalized with pFP between January 1, 2006, and December 31, 2016. Furthermore, a telephone-based follow-up survey was performed. A total of 158 patients were identified, with a median age of 10.9 years (interquartile range 6.4-13.7). An infectious disease was associated with pFP in 82 patients (51.9%); 73 cases were classified as idiopathic pFP (46.2%). Three cases occurred postoperatively or due to a peripheral tumor. Among the infectious diseases, we identified 33 cases of neuroborreliosis and 12 viral infections of the central nervous system (CNS), caused by the varicella-zoster virus, human herpesvirus 6, herpes simplex virus, enterovirus, and Epstein-Barr virus. Other infections were mainly respiratory tract infections (RTIs; 37 cases). Children with an associated CNS infection had more often headache and nuchal rigidity, a higher cerebrospinal fluid cell count, and a longer length of hospital stay. Long-term follow-up revealed an associated lower risk of relapse in CNS infection-associated pFP. Among all groups, permanent sequelae were associated with female sex, a shorter length of hospitalization, and a lower white blood cell count at presentation. pFP is frequently caused by an CNS infection or is associated with concurrent RTIs, with a potential impact on the short- and long-term clinical course.

The diverse cellular responses of the choroid plexus during infection of the central nervous system.

The choroid plexus (CP) is responsible for the production of a large amount of the cerebrospinal fluid (CSF). As a highly vascularized structure, the CP also presents a significant frontier between the blood and the central nervous system (CNS). To seal this border, the epithelium of the CP forms the blood-CSF barrier, one of the most important barriers separating the CNS from the blood. During the course of infectious disease, cells of the CP can experience interactions with intruding pathogens, especially when the CP is used as gateway for entry into the CNS. In return, the CP answers to these encounters with diverse measures. Here, we will review the distinct responses of the CP during infection of the CNS, which include engaging of signal transduction pathways, the regulation of gene expression in the host cells, inflammatory cell response, alterations of the barrier, and, under certain circumstances, cell death. Many of these actions may contribute to stage an immunological response against the pathogen and subsequently help in the clearance of the infection.

Strain-dependent effects of clinical echovirus 30 outbreak isolates at the blood-CSF barrier.

BACKGROUND: Echovirus (E) 30 (E-30) meningitis is characterized by neuroinflammation involving immune cell pleocytosis at the protective barriers of the central nervous system (CNS). In this context, infection of the blood-cerebrospinal fluid barrier (BCSFB), which has been demonstrated to be involved in enteroviral CNS pathogenesis, may affect the tight junction (TJ) and adherens junction (AJ) function and morphology. METHODS: We used an in vitro human choroid plexus epithelial (HIBCPP) cell model to investigate the effect of three clinical outbreak strains (13-311, 13-759, and 14-397) isolated in Germany in 2013, and compared them to E-30 Bastianni. Conducting transepithelial electrical resistance (TEER), paracellular dextran flux measurement, quantitative real-time polymerase chain reaction (qPCR), western blot, and immunofluorescence analysis, we investigated TJ and AJ function and morphology as well as strain-specific E-30 infection patterns. Additionally, transmission electron and focused ion beam microscopy electron microscopy (FIB-SEM) was used to evaluate the mode of leukocyte transmigration. Genome sequencing and phylogenetic analyses were performed to discriminate potential genetic differences among the outbreak strains. RESULTS: We observed a significant strain-dependent decrease in TEER with strains E-30 Bastianni and 13-311, whereas paracellular dextran flux was only affected by E-30 Bastianni. Despite strong similarities among the outbreak strains in replication characteristics and particle distribution, strain 13-311 was the only outbreak isolate revealing comparable disruptive effects on TJ (Zonula Occludens (ZO) 1 and occludin) and AJ (E-cadherin) morphology to E-30 Bastianni. Notwithstanding significant junctional alterations upon E-30 infection, we observed both para- and transcellular leukocyte migration across HIBCPP cells. Complete genome sequencing revealed differences between the strains analyzed, but no explicit correlation with the observed strain-dependent effects on HIBCPP cells was possible. CONCLUSION: The findings revealed distinct E-30 strain-specific effects on barrier integrity and junctional morphology. Despite E-30-induced barrier alterations leukocyte trafficking did not exclusively occur via the paracellular route.

Neutrophil extracellular trap formation in the Streptococcus suis-infected cerebrospinal fluid compartment.

Streptococcus suis is an important meningitis-causing pathogen in pigs and humans. Neutrophil extracellular traps (NETs) have been identified as host defense mechanism against different pathogens. Here, NETs were detected in the cerebrospinal fluid (CSF) of S. suis-infected piglets despite the presence of active nucleases. To study NET-formation and NET-degradation after transmigration of S. suis and neutrophils through the choroid plexus epithelial cell barrier, a previously described model of the human blood-CSF barrier was used. NETs and respective entrapment of streptococci were recorded in the "CSF compartment" despite the presence of active nucleases. Comparative analysis of S. suis wildtype and different S. suis nuclease mutants did not reveal significant differences in NET-formation or bacterial survival. Interestingly, transcript expression of the human cathelicidin LL-37, a NET-stabilizing factor, increased after transmigration of neutrophils through the choroid plexus epithelial cell barrier. In good accordance, the porcine cathelicidin PR-39 was significantly increased in CSF of piglets with meningitis. Furthermore, we confirmed that PR-39 is associated with NETs in infected CSF and inhibits neutrophil DNA degradation by bacterial nucleases. In conclusion, neutrophils form NETs after breaching the infected choroid plexus epithelium, and those NETs may be protected by antimicrobial peptides against bacterial nucleases.

Neuroinvasion and Inflammation in Viral Central Nervous System Infections.

Neurotropic viruses can cause devastating central nervous system (CNS) infections, especially in young children and the elderly. The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) have been described as relevant sites of entry for specific viruses as well as for leukocytes, which are recruited during the proinflammatory response in the course of CNS infection. In this review, we illustrate examples of established brain barrier models, in which the specific reaction patterns of different viral families can be analyzed. Furthermore, we highlight the pathogen specific array of cytokines and chemokines involved in immunological responses in viral CNS infections. We discuss in detail the link between specific cytokines and chemokines and leukocyte migration profiles. The thorough understanding of the complex and interrelated inflammatory mechanisms as well as identifying universal mediators promoting CNS inflammation is essential for the development of new diagnostic and treatment strategies.

The choroid plexus may be an underestimated site of tumor invasion to the brain: an in vitro study using neuroblastoma cell lines.

BACKGROUND: The central nervous system (CNS) is protected by several barriers, including the blood-brain (BBB) and blood-cerebrospinal fluid (BCSFB) barriers. Understanding how cancer cells circumvent these protective barriers to invade the CNS is of crucial interest, since brain metastasis during cancer is often a fatal event in both children and adults. However, whereas much effort has been invested in elucidating the process of tumor cell transmigration across the BBB, the role of the BCSFB might still be underestimated considering the significant number of meningeal cancer involvement. Our work aimed to investigate the transmigration of neuroblastoma cells across the BCSFB in vitro. METHODS: We used an inverted model of the human BCSFB presenting proper restrictive features including adequate expression of tight-junction proteins, low permeability to integrity markers, and high trans-epithelial electrical resistance. Two different human neuroblastoma cell lines (SH-SY5Y and IMR-32) were used to study the transmigration process by fluorescent microscopy analysis. RESULTS: The results show that neuroblastoma cells are able to actively cross the tight human in vitro BCSFB model within 24 h. The presence and transmigration of neuroblastoma cancer cells did not affect the barrier integrity within the duration of the experiment. CONCLUSIONS: In conclusion, we presume that the choroid plexus might be an underestimated site of CNS invasion, since neuroblastoma cell lines are able to actively cross a choroid plexus epithelial cell layer. Further studies are warranted to elucidate the molecular mechanisms of tumor cell transmigration in vitro and in vivo.

Background Paper for the update of meningococcal vaccination recommendations in Germany: use of the serogroup B vaccine in persons at increased risk for meningococcal disease.

In December 2013 Bexsero® became available in Germany for vaccination against serogroup B meningococci (MenB). In August 2015 the German Standing Committee on Vaccination (STIKO) endorsed a recommendation for use of this vaccine in persons at increased risk of invasive meningococcal disease (IMD). This background paper summarizes the evidence underlying the recommendation. Bexsero® is based on surface protein antigens expressed by about 80% of circulating serogroup B meningococci in Germany. The paper reviews available data on immunogenicity and safety of Bexsero® in healthy children and adolescents; data in persons with underlying illness and on the effectiveness in preventing clinical outcomes are thus far unavailable.STIKO recommends MenB vaccination for the following persons based on an individual risk assessment: (1) Persons with congenital or acquired immune deficiency or suppression. Among these, persons with terminal complement defects and properdin deficiency, including those under eculizumab therapy, are at highest risk with reported invasive meningococcal disease (IMD) incidences up 10,000-fold higher than in the general population. Persons with asplenia were estimated to have a ~ 20-30-fold increased risk of IMD, while the risk in individuals with other immune defects such as HIV infection or hypogammaglobulinaemia was estimated at no more than 5-10-fold higher than the background risk. (2) Laboratory staff with a risk of exposure to N. meningitidis aerosols, for whom an up to 271-fold increased risk for IMD has been reported. (3) Unvaccinated household (-like) contacts of a MenB IMD index case, who have a roughly 100-200-fold increased IMD risk in the year after the contact despite chemoprophylaxis. Because the risk is highest in the first 3 months and full protective immunity requires more than one dose (particularly in infants and toddlers), MenB vaccine should be administered as soon as possible following identification of the serogroup of the index case.

Neisseria meningitidis elicits a pro-inflammatory response involving IκBζ in a human blood-cerebrospinal fluid barrier model.

BACKGROUND: The human-specific, Gram-negative bacterium Neisseria meningitidis (Nm) is a leading cause of bacterial meningitis worldwide. The blood-cerebrospinal fluid barrier (BCSFB), which is constituted by the epithelial cells of the choroid plexus (CP), has been suggested as one of the potential entry sites of Nm into the CSF and can contribute to the inflammatory response during infectious diseases of the brain. Toll-like receptors (TLRs) are involved in mediating signal transduction caused by the pathogens. METHODS: Using a recently established in vitro model of the human BCSFB based on human malignant CP papilloma (HIBCPP) cells we investigated the cellular response of HIBCPP cells challenged with the meningitis-causing Nm strain, MC58, employing transcriptome and RT-PCR analysis, cytokine bead array, and enzyme-linked immunosorbent assay (ELISA). In comparison, we analyzed the answer to the closely related unencapsulated carrier isolate Nm α14. The presence of TLRs in HIBCPP and their role during signal transduction caused by Nm was studied by RT-PCR and the use of specific agonists and mutant bacteria. RESULTS: We observed a stronger transcriptional response after infection with strain MC58, in particular with its capsule-deficient mutant MC58siaD-, which correlated with bacterial invasion levels. Expression evaluation and Gene Set Enrichment Analysis pointed to a NFκB-mediated pro-inflammatory immune response involving up-regulation of the transcription factor IκBζ. Infected cells secreted significant levels of pro-inflammatory chemokines and cytokines, including, among others, IL8, CXCL1-3, and the IκBζ target gene product IL6. The expression profile of pattern recognition receptors in HIBCPP cells and the response to specific agonists indicates that TLR2/TLR6, rather than TLR4 or TLR2/TLR1, is involved in the cellular reaction following Nm infection. CONCLUSIONS: Our data show that Nm can initiate a pro-inflammatory response in human CP epithelial cells probably involving TLR2/TLR6 signaling and the transcriptional regulator IκBζ.

Multiple aseptic splenic abscesses in a 15 year old patient.

BACKGROUND: Splenic abscesses in children are rare. In recent years aseptic abscesses have been recognized as a new disease entity, especially in adults. CASE PRESENTATION: We present a rare case of a 15 year old girl with aseptic abscesses, in whom antibiotic therapy comprising metronidazole and meropenem was partly beneficial in improving the patient's clinical condition and inflammatory parameters. Eventually corticosteroid therapy led to complete and long lasting resolution of symptoms. Further diagnostic work-up revealed autoimmune thyroiditis, but no signs of inflammatory bowel disease. CONCLUSION: Aseptic splenic abscesses should always prompt clinicians to initiate further diagnostics to determine a potential underlying condition and a regular follow-up. Anaerobic bacteria may play a role in the pathogenesis of the disease and besides corticosteroid treatment antibiotics covering anaerobes may be beneficial.