Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease.

BACKGROUND: Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease severity in adult COVID-19 is associated to the presence of anti-cytokine autoantibodies (ACAAs) against type I interferons. Similarly, ACAAs may be implicated in KD and MIS-C. Therefore, we explored the immunological response, presence of ACAAs and disease correlates in both disorders. METHODS: Eighteen inflammatory plasma protein levels and seven ACAAs were measured in KD (n = 216) and MIS-C (n = 56) longitudinally by Luminex and/or ELISA. Levels (up to 1 year post-onset) of these proteins were related to clinical data and compared with healthy paediatric controls. FINDINGS: ACAAs were found in both patient groups. The presence of ACAAs lagged behind the inflammatory plasma proteins and peaked in the subacute phase. ACAAs were mostly directed against IFN-γ (>80%) and were partially neutralising at best. KD presented with a higher variety of ACAAs than MIS-C. Increased levels of anti-IL-17A (P = 0·02) and anti-IL-22 (P = 0·01) were inversely associated with ICU admission in MIS-C. Except for CXCL10 in MIS-C (P = 0·002), inflammatory plasma proteins were elevated in both KD and MIS-C. Endothelial angiopoietin-2 levels were associated with coronary artery aneurysms in KD (P = 0·02); and sCD25 (P = 0·009), angiopoietin-2 (P = 0·001), soluble IL-33-receptor (ST2, P = 0·01) and CXCL10 (P = 0·02) with ICU admission in MIS-C. INTERPRETATION: Markers of endothelial activation (E-selectin, angiopoietin-2), and innate and adaptive immune responses (macrophages [CD163, G-CSF], neutrophils [lipocalin-2], and T cells [IFN-γ, CXCL10, IL-6, IL-17]), are upregulated in KD and MIS-C. ACAAs were detected in both diseases and, although only partly neutralising, their transient presence and increased levels in non-ICU patients may suggest a dampening role on inflammation. FUNDING: The Kawasaki study is funded by the Dutch foundation Fonds Kind & Handicap and an anonymous donor. The sponsors had no role in the study design, analysis, or decision for publication.

Inflammatory responses in SARS-CoV-2 associated Multisystem Inflammatory Syndrome and Kawasaki Disease in children: An observational study.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and clinical symptoms that can resemble Kawasaki Disease (KD). We hypothesized that MIS-C and KD might have commonalities as well as unique inflammatory responses and studied these responses in both diseases. In total, fourteen children with MIS-C (n=8) and KD (n=6) were included in the period of March-June 2020. Clinical and routine blood parameters, cardiac follow-up, SARS-CoV-2-specific antibodies and CD4+ T-cell responses, and cytokine-profiles were determined in both groups. In contrast to KD patients, all MIS-C patients had positive Spike protein-specific CD3+CD4+ T-cell responses. MIS-C and KD patients displayed marked hyper-inflammation with high expression of serum cytokines, including the drug-targetable interleukin (IL)-6 and IFN-γ associated chemokines CXCL9, 10 and 11, which decreased at follow-up. No statistical differences were observed between groups. Clinical outcomes were all favourable without cardiac sequelae at 6 months follow-up. In conclusion, MIS-C and KD-patients both displayed cytokine-associated hyper-inflammation with several high levels of drug-targetable cytokines.

Setting the global research agenda for community-based HIV service delivery through the faith sector.

BACKGROUND: While leading AIDS organizations expect faith and health collaborations to play a crucial role in organizing and scaling up community-based HIV services, it is unclear how this can be realized. Little primary research has been conducted into which strategies for collaboration and service provision are most effective, efficient, scalable and sustainable. Seeking to align research with urgent needs, enhance coordination and increase the likelihood that results are used, this study aimed to set an inclusive global research agenda that reflects priority research questions from key stakeholders at the intersection of HIV healthcare and faith. METHODS: In order to develop this global research agenda, we drew from document analyses, focus group discussions, interviews with purposively selected key informants from all continents (policy-makers, healthcare providers, faith leaders, academics and HIV activists), an online questionnaire, and expert meetings at several global conferences. We carried out focus group discussions and interviews with faith leaders in South Africa. Other stakeholder focus groups and interviews were carried out online or in person in France, Switzerland, the Netherlands and South Africa, and virtual questionnaires were distributed to stakeholders worldwide. Respondents were purposively sampled. RESULTS: We interviewed 53 participants, and 110 stakeholders responded to the online questionnaire. The participants worked in 54 countries, with the majority having research experience (84%), experience with policy processes (73%) and/or experience as a healthcare provider (60%) and identifying as religious (79%). From interviews (N = 53) and questionnaires (N = 110), we identified 10 research themes: addressing sexuality, stigma, supporting specific populations, counselling and disclosure, agenda-setting, mobilizing and organizing funding, evaluating faith-health collaborations, advantage of faith initiatives, gender roles, and education. Respondents emphasized the need for more primary research and prioritized two themes: improving the engagement of faith communities in addressing sexuality and tackling stigma. CONCLUSIONS: A wide range of respondents participated in developing the research agenda. To align research to the prioritized themes and ensure that results are used, it is essential to further engage key users, funders, researchers and other stakeholders, strengthen the capacity for locally embedded research and research uptake and contextualize priorities to diverse religious traditions, key populations and local circumstances.

Bacterial Genotyping of Central Nervous System Tuberculosis in South Africa: Heterogenic Mycobacterium tuberculosis Infection and Predominance of Lineage 4.

Tuberculous meningitis (TBM), the most severe extrapulmonary manifestation of tuberculosis, is caused by the pathogen Mycobacterium tuberculosis The M. tuberculosis complex includes seven lineages, all described to harbor a unique geographical dissemination pattern and clinical presentation. In this study, we set out to determine whether a certain M. tuberculosis lineage demonstrated tropism to cause TBM in patients from Cape Town, South Africa. DNA was extracted from formalin-fixed paraffin-embedded central nervous system (CNS) tissue from a unique neuropathological cohort of 83 TBM patients, collected between 1975 and 2012. M. tuberculosis lineages 1, 2, 3, and 4 were determined using an allele-specific PCR and Sanger sequencing. Of the 83 patient specimens tested, bacterial characterization could be performed on 46 specimens (55%). M. tuberculosis lineage 4 was present in 26 patient specimens (56%), and non-lineage 4 was identified in 10 cases (22%). Moreover, genomic heterogeneity was detected in the CNS specimens of 7 adults and 3 children. We could show that infection of the CNS is not restricted to a single M. tuberculosis lineage and that even young children with rapid progression of disease can harbor more than one M. tuberculosis lineage in the CNS.

Study protocol: The Dutch 20|30 Postmeningitis study: a cross-sectional follow-up of two historical childhood bacterial meningitis cohorts on long-term outcomes.

BACKGROUND: Bacterial meningitis (BM) is a serious, life-threatening infectious disease of the central nervous system that often occurs in young children. The most common severe to moderate sequelae following BM are sensorineural hearing loss, neuromotor disabilities and mental retardation, while subtle sequelae include academic and behavioral disabilities. It is largely unknown whether these more subtle sequelae persist into adolescence and adulthood. Therefore, this study will investigate the very long-term effects of childhood BM in later life. Better understanding of long-term effects and early identification of adverse outcomes after BM are essential for more timely interventions. Additionally, certain single nucleotide polymorphisms (SNPs) are associated with disease severity and might predict adverse sequelae. These include SNPs in genes encoding for pathogen recognition and immune response upon infection. Accordingly, a secondary objective of this study is to investigate the role of genetic variation in BM and use any insights to predict short- and long-term outcomes. METHODS: In the Dutch 20|30 Postmeningitis study, adolescents and young adults (n = 947) from two historical cohorts with a prior episode of BM during childhood will be enrolled into a cross-sectional follow-up investigation using mainly questionnaires that examine executive and behavioral functioning, health-related quality of life, subjective hearing, mood and sleeping disorders, academic performance, and economic self-sufficiency. The results will be compared to normative data by one-sample t-tests. Multivariable regression analysis will be used to assess for any associations with causative pathogens and severity of BM. Participants that complete the questionnaires will be approached to provide a swab for buccal DNA and subsequent sequencing analyses. Logistic regression models will be used to predict sequelae. DISCUSSION: The unique follow-up duration of this cohort will enable us to gain insights into the possible very long-term adverse effects of childhood BM and how these might impact on quality of life. The investigation of host genetic factors will contribute to the development of prediction models which will serve as prognostic tools to identify children who are at high risk of adverse outcome after BM. TRIAL REGISTRATION: Dutch Trial Register NTR-6891. Retrospectively registered 28 December 2017.

Cost-effectiveness of home-based vs. in-hospital treatment of paediatric tuberculous meningitis.

SETTING: Cape Town, South Africa, 2014. OBJECTIVE: To assess the societal costs and cost-effectiveness of home-based vs. in-hospital treatment of paediatric tuberculous meningitis. DESIGN: This was an economic evaluation from a societal perspective using probabilistic analysis. Health care, informal care, lost productivity costs and costs in other sectors, health-related quality of life (HRQoL) and family impact were assessed during interviews with care givers, children, medical staff and management. RESULTS: Societal costs for home-based treatment were USD3857, and USD28 043 for in-hospital treatment. Home-based vs. in-hospital treatment HRQoL scores were 90.9% vs. 84.5%, while family impact scores were 94.8% vs. 73.1%. The point estimate of the incremental cost-effectiveness ratio indicated that improving HRQoL and family impact by 1% was associated with a saving of respectively USD3726 and USD1140 for home-based vs. in-hospital treatment. The probability that home-based treatment was less expensive and more effective than in-hospital treatment was 96.3% for HRQoL and 100% for family impact. CONCLUSION: Societal costs of home-based treatment were lower than for in-hospital treatment. Children treated at home had a better HRQoL and family impact scores. Home-based treatment was a cost-effective alternative to in-hospital treatment of drug-susceptible tuberculous meningitis.

Diagnostic accuracy of a uniform research case definition for TBM in children: a prospective study.

BACKGROUND: Bacteriological confirmation of tuberculous meningitis (TBM) is problematic, and rarely guides initial clinical management. A uniform TBM case definition has been proposed for research purposes. METHODS: We prospectively enrolled patients aged 3 months to 13 years with meningitis confirmed using cerebrospinal fluid analysis at Tygerberg Hospital, Cape Town, South Africa. Criteria that differentiated TBM from other causes were explored and the accuracy of a probable TBM score assessed by comparing bacteriologically confirmed cases to 'non-TBM' controls. RESULTS: Of 139 meningitis patients, 79 were diagnosed with TBM (35 bacteriologically confirmed), 10 with bacterial meningitis and 50 with viral meningitis. Among those with bacteriologically confirmed TBM, 15 were Mycobacterium tuberculosis culture-positive and 20 were culture-negative but positive on GenoType(®) MTBDRplus or Xpert(®) MTB/RIF; 18 were positive on only a single commercial nucleic acid amplification test. A probable TBM score provided a sensitivity of 74% (95%CI 57-88) and a specificity of 97% (95%CI 86-99) compared to bacteriologically confirmed TBM. CONCLUSION: A probable TBM score demonstrated excellent specificity compared to bacteriological confirmation. However, 26% of children with TBM would be missed due to the limited accuracy of the case definition. Further prospective testing of an algorithm-based approach to TBM is advisable before recommendation for general clinical practice.

Enterovirus and parechovirus infection in children: a brief overview.

UNLABELLED: Enterovirus and parechovirus are a frequent cause of infection in children. This review is an overview of what is known from enterovirus and parechovirus infection in children and contains information about the epidemiology, pathogenesis, clinical presentation, diagnosis, treatment, and prognosis of enterovirus and parechovirus infection in children. CONCLUSIONS: EV and HPeV infections are a frequent cause of infection in childhood. The clinical presentation is diverse. RT-qPCR is the best way to detect an EV or HPeV. Cerebrospinal fluid, blood and feces have the highest sensitivity for detecting an EV or HPeV. There is no treatment for EV and HPeV infections. Two vaccines against EV 71 are just licensed in China and will be available on the private market. Little is known about the prognosis of EV and HPeV infections. WHAT IS KNOWN: •EV and HPeV are a frequent cause of infection in children. What is new: •This review gives a brief overview over EV and HPeV infection in children.

Prospective assessment of clinical symptoms associated with enterovirus and parechovirus genotypes in a multicenter study in Dutch children.

BACKGROUND: Human non-polio enterovirus (EV) and human parechovirus (HPeV) are important pathogens of viral infection and aseptic meningitis in children. The aim of this study is to prospectively compare the incidence, clinical signs, blood and cerebrospinal fluid in EV and HPeV infected children. OBJECTIVES: To compare the clinical symptoms and laboratory data of children with different EV and HPeV genotypes. STUDY DESIGN: This study is part of a multicenter prospective cohort study. Children were included in 3 different hospitals in The Netherlands from 2008 to 2011. RESULTS: Of 285 included patients, 140 (49%) had EV and 44 (15%) HPeV infection. Of children with EV infection 9 (6%) had EV-A, 109 (78%) EV-B, 12 (9%) had a non-type able EV and in 10 (7%) no genotyping was performed. Of children with HPeV infection, 24 (55%) had HPeV-3, 6 (14%) HPeV-1, 2 (5%) HPeV-4 and 1 (2%) HPeV-6. Meningitis was more frequent in EV than in HPeV infected children (54% vs. 36%, p=0.046), and in EV-B than EV-A infected children (60 vs. 33%). In contrast gastroenteritis was more frequent in HPeV than EV infected children (30% vs. 15%, p=0.030), and significantly more in HPeV-1 than HPeV-3 infected children (p<0.001). CONCLUSIONS: EV infection is more often associated with meningitis and HPeV infection more often with a gastro-enteritis. EV genotype B infection is more often associated with meningitis than EV genotype A infection. HPeV-1 infection was more often associated with gastroenteritis than HPeV-3 infection.

The diagnostic value of cerebrospinal fluid chemistry results in childhood tuberculous meningitis.

PURPOSE: Cerebrospinal fluid (CSF) hypoglycorrhachia and elevated protein is well-described in bacterial meningitis, but evidence for its differential diagnostic value in tuberculous meningitis (TBM) is lacking. We aimed to assess the diagnostic utility of CSF glucose, CSF to serum glucose ratio and CSF protein in children with suspected TBM. METHODS: We describe CSF glucose and protein values as well as CSF to serum glucose ratios in a prospective evaluation of TBM suspects seen at Tygerberg Children's Hospital, Cape Town, South Africa, from January 1985 to January 2014. RESULTS: Of 615 TBM suspects, 88 (14%) had microbiologically confirmed TBM, 381 (62%) 'probable' TBM and 146 (24%) 'non-TBM'. Mean absolute CSF glucose concentration was significantly lower in the microbiologically confirmed (1.87 ± 1.15 mmol/L) and 'probable' TBM (1.82 ± 1.19 mmol/L) groups compared to non-TBM (3.66 ± 0.88 mmol/L). A CSF glucose concentration of <2.2 mmol/L diagnosed TBM with sensitivity 0.68 and specificity 0.96. Sensitivity using a CSF to serum glucose ratio of <0.5 was 0.90. Mean CSF protein was significantly elevated in the microbiologically confirmed TBM (1.91 ± 1.44 g/L) and 'probable' TBM (2.01 ± 1.49 g/L) groups compared to the non-TBM (0.31 ± 0.31 g/L). A CSF protein >1 g/L diagnosed TBM with sensitivity 0.78 and specificity 0.94. CONCLUSION: Absolute CSF glucose values of <2.2 mmol/L and protein values of >1 g/L differentiated between TBM and non-bacterial meningitis with good specificity, although sensitivity was poor. A CSF to serum glucose ratio is more informative than the absolute value.

Chest radiograph findings in children with tuberculous meningitis.

BACKGROUND: Tuberculous meningitis (TBM) is diagnosed based on a combination of clinical, laboratory and radiological findings, including signs suggestive of tuberculosis (TB) on a standard chest X-ray (CXR). METHODS: We describe the radiological features suggestive of intrathoracic TB in children diagnosed with TBM during a prospective evaluation of TBM suspects seen at Tygerberg Children's Hospital, Cape Town, South Africa. RESULTS: Of 84 children treated for TBM, 31 (37%) had 'definite' TBM, 45 (55%) 'probable' TBM and 8 (9%) 'possible' TBM. In total, 37 (44%) TBM patients had CXR findings suggestive of TB, 9 (11%) with disseminated (miliary) TB. Only 1 in 4.39 children aged ≤3 years with TBM had suggestive CXR findings. The presence of complicated intrathoracic lymph node disease was significantly higher in children aged ≤3 years (OR 21.69, 95%CI 2.73-172.67, P < 0.01). Among 6 human immunodeficiency virus infected children, 3 (50%) had intrathoracic lymphadenopathy. CONCLUSION: The majority of the children with TBM, including the very young, did not have signs suggestive of TB on CXR.

Improved diagnosis of childhood tuberculous meningitis using more than one nucleic acid amplification test.

BACKGROUND: Early treatment is critical to reducing tuberculous meningitis (TBM) related morbidity and mortality. Diagnosis based on cerebrospinal fluid (CSF) culture is impractical due to slow turnaround times, while microscopy has poor sensitivity. Enhanced detection methods are essential to guide early treatment initiation, especially in vulnerable young children. METHODS: We assessed the diagnostic accuracy of the GenoType(®) MTBDRplus and Xpert(®) MTB/RIF assays on CSF collected from paediatric meningitis suspects prospectively enrolled at Tygerberg Hospital, Cape Town, South Africa. Fluorescent auramine-O microscopy, liquid culture for Mycobacterium tuberculosis, GenoType and Xpert assays were performed on all CSF samples. RESULTS: Of 101 meningitis suspects, 55 were diagnosed with TBM and 46 served as non-TBM controls. Using a pre-defined TBM case definition as reference standard, sensitivities and specificities were 4% and 100% for fluorescent microscopy, 22% and 100% for culture, 33% and 98% for GenoType, 26% and 100% for Xpert, 22% and 100% for microscopy and culture combined and 49% and 98% for GenoType and Xpert combined. Culture, GenoType and Xpert combined performed best, with 56% sensitivity and 98% specificity. CONCLUSION: Although commercial nucleic-acid amplification tests performed on CSF revealed incrementally improved diagnostic accuracy, providing rapid microbiological confirmation, they cannot serve as a rule-out test.

Lipoarabinomannan enzyme-linked immunosorbent assay for early diagnosis of childhood tuberculous meningitis.

SETTING: Tuberculous meningitis (TBM) is a severe complication of tuberculosis (TB) predominantly affecting young children. Early initiation of treatment is important to prevent morbidity and mortality associated with TBM, emphasising the importance of early diagnosis. Among the most promising new methods for diagnosing TB are antigen-detection assays based on the detection of lipoarabinomannan (LAM). OBJECTIVE: To evaluate the diagnostic value of a commercial, antigen-capture enzyme-linked immunosorbent assay (ELISA) test based on the detection of LAM in urine for the early diagnosis of TBM in children. METHOD: A cross-sectional study in which urine samples from paediatric patients with suspected TBM attending the Tygerberg Children's Hospital, Cape Town, South Africa, were tested for LAM. RESULTS: Complete data were available for 50 of 56 patients with suspected TBM. TBM was diagnosed in 21 (42%) patients and excluded in 29 (58%). The LAM ELISA had a sensitivity of 4.8% and a specificity of 93.1%. Serial measurements in the first 2 weeks after treatment initiation did not improve test performance. CONCLUSION: We have shown that urinary LAM detection was of little value for the diagnosis of TBM in a cohort of paediatric patients with suspected TBM.

Unsuccessful validation of 2004 model for predicting academic or behavioural limitations after childhood bacterial meningitis.

AIM: In 2004, a model identifying children at risk of academic or behavioural limitations after bacterial meningitis (BM) was presented. Risk factors were male gender, low birthweight, lower educational level of the father, Streptococcus pneumoniae, lower cerebrospinal fluid (CSF) leucocyte count, delay between admission and start of antibiotics, dexamethasone <2 days, seizures and prolonged fever. The aim of this study was to validate that prediction model in an independent cohort. METHODS: Academic or behavioural limitations were determined in 93 Dutch school-age BM survivors. Risk factors for limitations were obtained from medical files. Validation was performed by applying the model in the cohort, then assessing discrimination and goodness of fit. Multiple imputation techniques were used to deal with missing values. RESULTS: Although fit of the model appeared good when it came to similarity of expected and observed cases (p-value of the Hosmer-Lemeshow test 0.24-0.57), discrimination was poor. Area under the curve (AUC) of the receiver operated characteristics (ROC) curve of the model was 0.83 (95% CI: 0.77-0.89) in the development cohort and 0.53 (95% CI: 0.41-0.65) in the validation cohort. CONCLUSION: External validation of the model was unsuccessful. It is not suitable for implementation in practice.

Prospective comparison of the detection rates of human enterovirus and parechovirus RT-qPCR and viral culture in different pediatric specimens.

BACKGROUND: Reverse-transcriptase quantitative real-time polymerase chain reaction (RT-qPCR) has become the gold standard for the diagnosis of human enterovirus (EV) and parechovirus (HPeV) infections. The detection rate of RT-qPCR in different pediatric body specimens has not been compared prospectively in a multicentre study. OBJECTIVES: This study compared the diagnostic detection rates of EV and HPeV RT-qPCR and viral culture in different specimens (feces, nasopharynx, blood, urine and cerebrospinal fluid (CSF)) of pediatric patients. STUDY DESIGN: This prospective, multicenter study performed an EV and HPeV RT-qPCR on nasopharynx, blood, urine, feces and CSF specimens and a viral culture on nasopharynx, feces and CSF specimens in symptomatic children<16 years. RESULTS: Of 285 included children EV was detected in 140 (49%) and HPeV in 44 (15%) children. Both EV and HPeV RT-qPCR had a higher sensitivity and negative predictive value than EV and HPeV viral culture, respectively. EV and HPeV RT-qPCR in feces specimen had the highest sensitivity (99.2% and 95.1%) of all specimens. Pooling results of specimens increased the detection rate for both viruses. CONCLUSION: Of all specimens, RT-qPCR in feces had the highest detection rate for both EV and HPeV in symptomatic pediatric patients. An EV was detected in all EV positive patients if a RT-qPCR was performed on both feces and CSF specimens or in both feces and urine specimens. HPeV was detected in all HPeV positive patients if a RT-qPCR was performed on both feces and CSF specimens, feces and nasopharynx specimens or CSF and nasopharynx specimens.

Computational modeling of tuberculous meningitis reveals an important role for tumor necrosis factor-α.

Tuberculosis is a global health issue with annually about 1.5 million deaths and 2 billion infected people worldwide. Extra-pulmonary tuberculosis comprises 13% of all cases of which tuberculous meningitis is the most severe. It has a high mortality and is often diagnosed once irreversible neurological damage has already occurred. Development of diagnostic and treatment strategies requires a thorough understanding of the pathogenesis of tuberculous meningitis. This disease is characterized by the formation of a cerebral granuloma, which is a collection of immune cells that attempt to immunologically restrain, and physically contain bacteria. The cytokine tumor necrosis factor-α is known for its important role in granuloma formation. Because traditional experimental animal studies exploring tuberculous meningitis are difficult and expensive, another approach is needed to begin to address this important and significant disease outcome. Here, we present an in silico model capturing the unique immunological environment of the brain that allows us to study the key mechanisms driving granuloma formation in time. Uncertainty and sensitivity analysis reveals a dose-dependent effect of tumor necrosis factor-α on bacterial load and immune cell numbers thereby influencing the onset of tuberculous meningitis. Insufficient levels result in bacterial overgrowth, whereas high levels lead to uncontrolled inflammation being detrimental to the host. These findings have important implications for the development of immuno-modulating treatment strategies for tuberculous meningitis.

Seasonal variation in the incidence rate of tuberculous meningitis is associated with sunshine hours.

Tuberculous meningitis (TBM) is a severe complication of tuberculosis and occurs mainly during early childhood. The incidence rate of TBM varies with season, and serum vitamin D levels, which are dependent on sunlight, might play a role. We studied the association between TBM incidence rate and hours of sunshine in Cape Town, South Africa and found a significant association between the incidence rate of TBM and hours of sunshine 3 months earlier (incidence rate ratio per 100 sunshine hours 0·69, 95% confidence interval 0·54-0·88, P = 0·002). The association supports the hypothesis that vitamin D might play a role in the pathophysiology of TBM. Further prospective studies in which vitamin D status is measured are necessary to determine causality.

Detection of enterovirus RNA in cerebrospinal fluid: comparison of two molecular assays.

Enterovirus (EV) and human parechovirus (HPeV) are a major cause of infection in childhood. A rapid diagnostic test may improve the management of patients with EV and HPeV infection. The aim of this study is to evaluate the performance of the GeneXpert enterovirus assay (GXEA) for detection of EV RNA compared to a user-developed reverse-transcriptase (RT) quantitative real-time PCR (qPCR) in routine clinical practice. Also a RT-qPCR assay for detection of HPeV RNA in different clinical samples was developed and evaluated. Cerebrospinal fluid (CSF) from 232 patients suspected for meningitis was collected and tested for EV and HPeV using RT-qPCR assays. In parallel an aliquot of the samples was tested using the GXEA and viral culture. EV RNA was detected in 22 (19.0%) and 28 (24.1%) of 116 samples using the GXEA and RT-qPCR assay, respectively. EV was isolated from 10 of 116 (8.6%) samples by viral culture. GXEA had a sensitivity, specificity, positive predictive value and negative predictive value of 82.1%, 100%, 100% and 96.2%, respectively. In this study, molecular assays were superior to viral culture for detecting EV RNA in CSF. GXEA showed a high specificity but a lower sensitivity for the detection of EV RNA compared to the RT-qPCR assay.

Genetic variation of innate immune response genes in invasive pneumococcal and meningococcal disease applied to the pathogenesis of meningitis.

The susceptibility, severity and prognosis of infectious diseases depend on the ability of the host immune system to respond to pathogens. Genetic variation of immune response genes is associated with susceptibility to and severity of infectious diseases. Bacterial meningitis (BM) is a serious and life-threatening infectious disease of the central nervous system (CNS). Despite adequate antibiotic treatment and immunization strategies, mortality remains high, especially in developing countries. Streptococcus pneumoniae and Neisseria meningitidis are the two most common causative microorganisms of BM worldwide. The pathogenesis of BM starts with mucosal bacterial colonization, followed by invasion and survival of bacteria in the bloodstream, crossing of the blood-brain barrier, finally causing infection in the CNS, where host defense is less adequate. Host defense to BM starts with a complex cascade of pathogen recognition and subsequent intracellular signaling causing transcription of genes leading to the production of inflammatory mediators. Although this immune reaction is essential for killing microbes, it is also associated with damage to healthy cells and thus adverse disease outcome. This review provides an overview of the pathogenesis of invasive pneumococcal disease and invasive meningococcal disease related to the influence of genetic variation in genes involved in innate immunity, focusing on BM.

[Postmeningitis deafness in young children: action warranted before obliteration of the cochlea]. / Doofheid na bacteriële meningitis bij jonge kinderen: ingrijpen vóór de cochlea is geoblitereerd.

Meningitis may cause inflammation of the cochlea, which may result in deafness and also in rapid obliteration ofthe cochlea with fibrous tissue or even ossification, conditions that obstruct the placement ofa cochlear implant. In the first of two cases of postmeningitis deafness, in a boy aged 6 months and a girl aged 1 year and 9 months, ignorance about the time of audiological follow-up threatened the options for restoration of hearing. In the other case, a long diagnostic programme and an unsuccessful attempt at cochlear implantation caused a long delay in optimal restoration of hearing. Both cases illustrate the difficulties in connection with postmeningitis deafness in relation to the option of a cochlear implant operation. To increase the chances of a successful implantation, the time span between meningitis and audiological and radiological follow-up must be short. Auditory brain stem responses (ABR) and MRI are the keystones of the work-up.