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Titus Msoka,1 Josephine Rogath,1 Gary Van Guilder,2 Gibson Kapanda,1 Yvo Smulders,3 Marceline Tutu van Furth,3 John Bartlett,4 Michiel van Agtmael2 1Kilimanjaro Christian Medical Centre, Moshi, Tanzania; 2High Altitude Exercise Physiology, Western Colorado University, Gunnison, CO, USA; 3VU University Medical Centre, Amsterdam, the Netherlands; 4Duke University Medical Centre, Durham, NC, USACorrespondence: Titus MsokaKilimanjaro Christian Medical Centre, P.O.Box 3010, Moshi, TanzaniaEmail ftitus2001@yahoo.co.ukPurpose: Cardiovascular disease (CVD) risk assessment is a suitable way to differentiate between high-risk individuals requiring intervention and risk modification, and those at low risk. However, concerns have been raised when adopting a CVD-risk prediction algorithm for HIV-infected patients in sub-Saharan Africa.Patients and Methods: We compared cardiovascular risk profiles between HIV-infected (with and without antiretroviral therapy (ART)) and HIV-uninfected adults as predicted by the American College of Cardiology/American Heart Association (ASCVD) and the Framingham cardiovascular risk score (FRS) algorithms and assessed the concordance of the algorithms in predicting 10-year CVD risk separately in HIV-infected and uninfected groups in a hospital-based cross-sectional study in Tanzania. A cross-sectional hospital-based study including 40 HIV-infected ART-naive, 64 HIV-infected on ART, and 50 HIV-uninfected adults was conducted. Traditional cardiovascular risk factors were determined by standard investigations. The primary outcome was the absolute 10-year CVD risk score based on the two algorithms.Results: Compared to HIV-uninfected, HIV-infected adults were classified at a higher 10-year CVD risk. ASCVD algorithms predicted a higher proportion of high-risk individuals compared to FRS in both HIV-infected and uninfected groups. The concordance between ASCVD and FRS-lipid algorithms was reasonable for both HIV-infected and uninfected groups though relatively higher in the HIV-uninfected group.Conclusion: HIV-infected individuals have a higher 10-year cardiovascular risk compared to HIV-uninfected persons. The concordance between ASCVD and FRS-lipid algorithms is reasonable in both HIV-uninfected and infected persons in Tanzania. Development of an HIV-specific algorithm is needed to accurately predict CVD risk in this population at high-risk.Keywords: atherosclerotic cardiovascular disease risk score, Framingham risk score, antiretroviral therapy, Kilimanjaro Christian Medical Center, Moshi

Of all tuberculosis (TB) cases, 1% affects the central nervous system (CNS), with a mortality rate of up to 60%. Our aim is to fill the 'key gap' in TBM research by analyzing brain specimens in a unique historical cohort of 84 patients, focusing on granuloma formation. We describe three different types: non-necrotizing, necrotizing gummatous, and necrotizing abscess type granuloma. Our hypothesis is that these different types of granuloma are developmental stages of the same pathological process. All types were present in each patient and were mainly localized in the leptomeninges. Intra-parenchymal granulomas were less abundant than the leptomeningeal ones and mainly located close to the cerebrospinal fluid (subpial and subependymal). We found that most of the intraparenchymal granulomas are an extension of leptomeningeal lesions which is the opposite of the classical Rich focus theory. We present a 3D-model to facilitate further understanding of the topographic relation of granulomas with leptomeninges, brain parenchyma and blood vessels. We describe innate and adaptive immune responses during granuloma formation including the cytokine profiles. We emphasize the presence of leptomeningeal B-cell aggregates as tertiary lymphoid structures. Our study forms a basis for further research in neuroinflammation and infectious diseases of the CNS, especially TB.

Background: Human parechoviruses are a major cause of CNS infection in neonates and young children. They have been implicated in neurological sequelae and neurodevelopmental delay. However, the magnitude of this effect has not been systematically reviewed or assessed with meta-analyses. We investigated short-term, medium-term, and long-term neurological sequelae and neurodevelopmental delay in neonates and young children after parechovirus-CNS-infection. Methods: In this systematic review and meta-analyses of studies, we searched PubMed, Embase, and PsycInfo, from the inception of the database until March 18, 2019, for reviews, systematic reviews, cohort studies, case series, and case control studies reporting on neurological or neurodevelopmental outcomes of children 3 months or younger with parechovirus infection of the CNS. Studies that were published after Dec 31, 2007, assessed children younger than 16 years, detailed parechoviruses infection of the CNS (confirmed by PCR), and followed up on neurological and neurodevelopmental outcomes were included. Studies published before Dec 31, 2007, were excluded. The predefined primary outcomes were the proportions of children with neurological sequelae, impairment in auditory or visual functions, or gross motor function delay. The proportion of children in whom neurological or neurodevelopmental outcomes were reported was pooled in meta-analyses. For each outcome variable we calculated the pooled proportion with 95% CI. The proportion of children in whom neurological or neurodevelopmental outcomes were reported was extracted by one author and checked by another. Two authors independently assessed the methodological quality of the studies. Findings: 20 studies were eligible for quantitative synthesis. The meta-analyses showed an increasing proportion of children with neurological sequelae over time: 5% during short-term follow-up (pooled proportion 0·05 [95% CI 0·03–0·08], I2=0·00%; p=0·83) increasing to 27% during long-term follow-up (0·27 [0·17–0·40], I2=52·74%; p=0·026). The proportion of children with suspected neurodevelopmental delay was 9% or more during long-term follow-up. High heterogeneity and methodological issues in the included studies mean that the results should be interpreted with caution. Interpretation: This systematic review suggests the importance of long follow-up, preferably up to preschool or school age (5–6 years), of children with parechovirus infection of the CNS. Although not clinically severe, we found an increasing proportion of neonates and young children with CNS infection had associated neurological sequelae and neurodevelopmental delay over time. We recommend the use of standardised methods to assess neurological and neurodevelopmental functions of these children and to compare results with age-matched reference groups. Funding: No funding was received for this study.

Much of the morbidity and mortality caused by tuberculous meningitis (TBM) is mediated by a dysregulated immune response. Effective host-directed therapy is therefore critical to improve survival and clinical outcomes. Currently only one host-directed therapy (HDT), corticosteroids, is proven to improve mortality. However, there is no evidence that corticosteroids reduce morbidity and the mechanism of action for mortality reduction is uncertain. Further, it has no proven benefit in HIV co-infected individuals. One promising host-directed therapy approach is to restrict the immunopathology arising from tumour necrosis factor (TNF)-α excess is via TNF-α inhibitors. There are accumulating data on the role of thalidomide, anti-TNF-α monoclonal antibodies (infliximab, adalimumab) and the soluble TNF-α receptor (etanercept) in TBM treatment. Thalidomide was developed nearly seventy years ago and has been a highly controversial drug. Birth defects and toxic adverse effects have limited its use but an improved understanding of its immunological mechanism of action suggest that it may have a crucial role in regulating the destructive host response seen in inflammatory conditions such as TBM. Observational studies at our institution found low dosage adjunctive thalidomide safe in treating tuberculous mass lesions and blindness related to optochiasmatic arachnoiditis, with good clinical and radiological response. In this review, we discuss possible mechanisms of action for thalidomide, based on our clinico-radiologic experience and post-mortem histopathological work. We also propose a rationale for its use in the treatment of certain TBM-related complications.

Most cases of hemolytic uremic syndrome (HUS) are caused by infection with enterohemorrhagic Escherichia coli (EHEC). Genetic defects causing uncontrolled complement activation are associated with the more severe atypical HUS (aHUS). Non-EHEC infections can trigger the disease, however, complement defects predisposing to such infections have not yet been studied. We describe a 2-month-old patient infected with different Gram-negative bacterial species resulting in aHUS. Serum analysis revealed slow complement activation kinetics. Rare variant R229C was found in complement inhibitor vitronectin. Recombinant mutated vitronectin showed enhanced complement inhibition in vitro and may have been a predisposing factor for infection. Our work indicates that genetic changes in aHUS can not only result in uncontrolled complement activation but also increase vulnerability to infections contributing to aHUS.

Aims We performed a systematic review and meta-analysis on the effect of HIV infection and antiretroviral therapy (ART) on carotid intima-media thickness (cIMT) to elucidate the role of HIV infection and ART. Also, an analysis on the role of ethnicity and gender on cIMT in HIV-infected populations was performed. Main methods We searched the PubMed, Web of Science, the WHO websites and International AIDS Society for published observational studies were conducted by two independent reviewers for studies comparing HIV-infected antiretroviral-experienced patients and/or inexperienced with healthy controls on cIMT. The primary outcome was the standardized mean difference (SMD) of cIMT. Findings Twenty studies (five cohort, 15 cross-sectional, and two both cohort and cross-sectional studies) were identified comprising 7948 subjects (4656 HIV-infected; 3292 controls). In cohort studies, the standardized mean 1-year change in cIMT between HIV-infected patients and uninfected controls was not significantly different (0.16 mm/yr; 95% CI, −0.16, 0.49; p = 0.326). In 17 cross-sectional studies, the SMD in cIMT was significantly higher in HIV-infected than uninfected persons (0.27 mm; 95% CI, 0.04, 0.49; p = 0.027). HIV-infected patients on ART exhibited significantly higher SMD in cIMT compared to those not on ART (0.75 mm; 95% CI, 0.30, 1.19; p = 0.001). No confounding effect of gender and ethnicity could be established using meta-regression p > 0.05. Significance HIV infection itself and ART appear to influence the progression of cIMT and hence may be risk factors for cardiovascular events. No firm conclusions could be drawn on the effect of ethnic/race and gender differences on cIMT in HIV-infected populations.

Adherence to antiretroviral therapy (ART) remains a challenge for HIV-infected children. In this cross-sectional study, we used structured interview-administered questionnaires and medical records to measure adherence levels and factors associated with adherence and viral suppression. We included 195 South African children aged 2.1–12.9 on ART. Adherence levels ranged between 20.5% (pill count) and 89.1% (self-report). Boys were less adherent according to self-report, girls were less adherent according to pill count. Caregivers ensured medication was taken when the condition directly affected daily life. Well-functioning families and families with high SES provide a context supportive of adherence. Non-disclosure and difficulties administering medication negatively affected adherence and viral suppression. This study shows challenging levels of adherence impacting directly on viral suppression in a South African paediatric HIV program. Gender roles, non-disclosure and difficulty administering medication may undermine adherence and should be taken into account for clinical guidelines, policy design and inform strategies.

Contains fulltext : 196232.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To evaluate a paediatric treatment-support intervention for home-based treatment of HIV infection or tuberculous meningitis (TBM). METHODS: A randomised-controlled study comparing local standard care (controls) with standard care plus intervention (combining adherence education, reinforcement and monitoring) in children aged 0-14 years. We recorded adherence measures (self-report, pill-count, drug-assays for isoniazid and rifampicin in urine and pyrazinamide in saliva), difficulties administering medication and PedsQLquestionnaires for health-related quality-of-life (HRQoL) and family impact. RESULTS: In the HIV group (6-months follow-up, n = 195), more children had above-median HRQoL-scores in the intervention group than in the control group (P = 0.009). Problems reported administering medication declined between baseline and follow-up for controls (P = 0.043). Disclosure of HIV status to the child increased between baseline and follow-up in both groups (intervention P < 0.001; control P = 0.031). In the TBM group (3-months follow-up, n = 43), all adherence measures remained high for both intervention and controls, except for rifampicin which declined between baseline and follow-up in the intervention group (P = 0.031). The intervention group maintained above median HRQoL-scores between baseline and follow-up, when the number of children with above-median HRQoL-scores decreased in the controls (P = 0.063). More children in the intervention group had above-median family impact-scores than controls (P = 0.040). CONCLUSIONS: The low-cost, culturally friendly treatment-support intervention had beneficial effects on health-related quality of life, family impact, caregiver disclosure of HIV status to the child, increased caregiver reporting of medication non-adherence and caregiver reporting of difficulties administering medication. Treatment adherence was not significantly affected in either HIV or TBM group.

Religion has substantial - positive and negative - influence on South Africa's HIV context. This qualitative study explored possibilities for positive church engagement in paediatric HIV care in a rural district in Limpopo Province, South Africa. Opinions, attitudes and experiences of various stakeholders including religious leaders, healthcare workers and people infected/affected with/by HIV were investigated through participant observation, semi-structured interviews and focus group discussions. During the research the original focus on paediatric HIV care shifted to HIV care in general in reaction to participant responses. Participants identified three main barriers to positive church engagement in HIV care: (a) stigma and disclosure; (b) sexual associations with HIV and (c) religious beliefs and practices. All participant groups appreciated the opportunity and relevance of strengthening church involvement in HIV care. Opportunities for positive church engagement in HIV care that participants identified included: (a) comprehensive and holistic HIV care when churches and clinics collaborate; (b) the wide social reach of churches and (c) the safety and acceptance in churches. Findings indicate that despite barriers great potential exists for increased positive church engagement in HIV care in rural South Africa. Recommendations include increased medical knowledge and dialogue on HIV/AIDS within church settings, and increased collaboration between churches and the medical sector.

Background Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; pInterpretation Mortality in children admitted to hospital for sepsis or severe focal infections is low in Europe. The disease burden is mainly in children younger than 5 years and is largely due to vaccine-preventable meningococcal and pneumococcal infections. Despite the availability and application of clinical procedures for microbiological diagnosis, the causative organism remained unidentified in approximately 50% of patients.

Background Rapid and accurate diagnosis of neonatal sepsis is highly warranted because of high associated morbidity and mortality. The aim of this study was to evaluate the performance of a novel multiplex PCR assay for diagnosis of late-onset sepsis and to investigate the value of bacterial DNA load (BDL) determination as a measure of infection severity. Methods This cross-sectional study was conducted in a neonatal intensive care unit. Preterm and/or very low birth weight infants suspected for late-onset sepsis were included. Upon suspicion of sepsis, a whole blood sample was drawn for multiplex PCR to detect the eight most common bacteria causing neonatal sepsis, as well as for blood culture. BDL was determined in episodes with a positive multiplex PCR. Results In total, 91 episodes of suspected sepsis were investigated, and PCR was positive in 53 (58%) and blood culture in 60 (66%) episodes, yielding no significant difference in detection rate (p = 0.17). Multiplex PCR showed a sensitivity of 77%, specificity of 81%, positive predictive value of 87%, and negative predictive value of 68% compared with blood culture. Episodes with discordant results of PCR and blood culture included mainly detection of coagulase-negative staphylococci (CoNS). C-reactive protein (CRP) level and immature to total neutrophil (I/T) ratio were lower in these episodes, indicating less severe disease or even contamination. Median BDL was high (4.1 log10 cfu Eq/ml) with a wide range, and was it higher in episodes with a positive blood culture than in those with a negative blood culture (4.5 versus 2.5 log10 cfu Eq/ml; p < 0.0001). For CoNS infection episodes BDL and CRP were positively associated (p = 0.004), and for Staphylococcus aureus infection episodes there was a positive association between BDL and I/T ratio (p = 0.049). Conclusions Multiplex PCR provides a powerful assay to enhance rapid identification of the causative pathogen in late-onset sepsis. BDL measurement may be a useful indicator of severity of infection. Electronic supplementary material The online version of this article (10.1186/s13054-018-2010-4) contains supplementary material, which is available to authorized users.

Background: Effective combined antiretroviral therapy (cART) has improved life expectancy among people living with HIV-1 infection. Treated HIV-1infection increases the prevalence of metabolic syndrome (MS). Despite sub-Saharan Africa having among the highest rates of HIV-1 infection, the effects of MS in HIV-1-infected individuals on cardiovascular risk is poorly explored. The aim of the study was to assess whether MS and/or HIV-1 treatment correlates with large elastic artery stiffness in HIV-1-infected patients treated with first-line cART. Methods: The study sample comprised of 102 subjects free of cardiovascular disease and major risk factors divided into two groups based on HIV-1 infection, treatment, and MS status: HIV-1 + /cART + /MS + (n = 12); HIV-1 + /cART - /MS + (n = 16); HIV-1 - / MS + (n = 10); HIV-1 + /cART + /MS - (n = 42); HIV-1 + /cART - /MS - (n = 32); HIV-1 - / MS - (n = 39). MS was established according the International Diabetes Federation definition. Large artery stiffness was measured using applanation tonometry to assess aortic pulse wave velocity (aPWV) and aortic augmentation index at heart rate of 75 bpm (AIx@HR75). cART included lamivudine/zidovudine and nevirapine or efavirenz. Results: The prevalence of MS in the HIV-1-infected patients was 28%. There were no significant differences in aPWV in the non-MS groups. However, in subjects with MS, aPWV was significantly higher in the HIV-1 cART patients (9.0 ± 1.9 m/s) compared with both controls (7.5 ± 1.8 m/s; P = 0.018) and untreated HIV-1 patients (7.7 ± 1.3 m/s; P = 0.023), and these differences remained after adjustment for blood pressure and sex. Aortic PWV was significantly elevated (P = 0.009) in HIV-1 cART patients with MS compared to their counterparts without MS. Untreated HIV-1 patients with MS also demonstrated increased aPWV compared to their counterparts without MS (P = 0.05). Aortic AIx@HR75 was, on average, ~ 5% higher in HIV-1 cART patients with MS (28.3 ± 62% compared with untreated HIV-1 patients with MS (23.5 ± 9%; P = 0.075). Sub-group multivariate analysis identified MS as an independent predictor of increased aPWV in HIV-1 cART patients. Conclusions: Our study established that presence of MS in HIV-1 patients on treatment was associated with increased aPWV and hence increased arterial stiffness in sub-Saharan African HIV-1 patients on first-line cART.

Epidemiological evidence supports vitamin D deficiency as a risk factor for tuberculosis. Differences in solar ultraviolet B (UV-B) exposure, the major source of vitamin D, might therefore partially explain global variation in tuberculosis incidence.In a global country-based ecological study, we explored the correlation between vitamin D-proxies, such as solar UV-B exposure, and other relevant variables with tuberculosis incidence, averaged over the period 2004–2013.Across 154 countries, annual solar UV-B exposure was associated with tuberculosis incidence. Tuberculosis incidence in countries in the highest quartile of UV-B exposure was 78% (95% CI 57–88%, pversuslowest quartile 29% lower incidence; p=0.057).The potential preventive applications of vitamin D supplementation in high-risk groups for tuberculosis merits further investigation.

Background HIV-1 infection in northern populations is associated with increased large artery stiffness, both in the absence and presence of combination antiretroviral treatment (cART). It is unclear if similar changes occur in sub-Sahara African HIV-infected persons. The study aimed to determine whether HIV-1 infection with and without cART is associated with large artery stiffness in a cohort of HIV-1-infected patients in Tanzania. Methods In this cross-sectional study, 146 subjects were recruited: 40 uninfected controls, 51 HIV-1-infected untreated persons, and 55 on cART for at least 12 months. Patients were screened for history of hepatic, renal, haematological or cardiovascular disease, diabetes, dyslipoproteinaemia, and hypertension. Following screening, 4 untreated and 21 cART HIV-1 patients were excluded; leaving 47 HIV-1-infected untreated and 34 cART patients to be studied. cART included first line treatment: lamivudine/zidovudine with nevirapine or efavirenz. Large artery stiffness was assessed using applanation tonometry via pulse wave analysis to determine aortic pulse wave velocity (aPWV) and augmentation index corrected to a heart rate of 75 bpm (AIx@HR75). Results Aortic PWV was higher (p = 0.017) in the HIV-1-infected patients on cART (aPWV: 8.2 ± 1.8 m/s) vs. untreated patients (7.3 ± 1.5 m/s) and independent of blood pressure differences. AIx@HR75 was significantly increased in cART HIV-1 (29 ± 8%) vs. untreated HIV-1 patients (23 ± 10%; p = 0.038) and controls (23 ± 10%; p = 0.032). Duration of HIV-1 and cART were independent predictors of arterial stiffening in HIV-1 patients. Conclusions The surrogate markers for arterial stiffness suggest an increased cardiovascular risk in sub-Saharan African HIV-1 patients on first line therapy.

Tuberculous meningitis (TBM) is a severe manifestation of tuberculosis, presenting with high morbidity and mortality in children. Existing diagnostic methods for TBM are invasive and time-consuming and the need for highly sensitive and selective diagnosis remains high on the TBM agenda. Our aim was to exploit metabolomics as an approach to identify metabolites as potential diagnostic predictors for children with TBM through a non-invasive means. Urine samples selected for this study were from three paediatric groups: patients with confirmed TBM (n = 12), patients clinically suspected with TBM but later confirmed to be negative (n = 19) and age-matched controls (n = 29). Metabolomics data were generated through gas chromatography–mass spectrometry analysis and important metabolites were identified according to standard statistical procedures used for metabolomics data. A global metabolite profile that characterized TBM was developed from the data, reflecting the host and microbial responses. Nine different logistic regression models were fitted to selected metabolites for the best combination as predictors for TBM. Four metabolites—methylcitric, 2-ketoglutaric, quinolinic and 4-hydroxyhippuric acids—showed excellent diagnostic ability and provided prognostic insight into our TBM patients. This study is the first to illustrate holistically the metabolic complexity of TBM and provided proof-of-concept that a biosignature of urinary metabolites can be defined for non-invasive diagnosis and prognosis of paediatric TBM patients. The biosignature should be developed and validated through future prospective studies to generate a medical algorithm for diagnosis in the initial stages of the disease and for monitoring of treatment strategies.

Background Effective combined antiretroviral therapy (cART) has improved life expectancy among people living with HIV-1 infection. Treated HIV-1infection increases the prevalence of metabolic syndrome (MS). Despite sub-Saharan Africa having among the highest rates of HIV-1 infection, the effects of MS in HIV-1-infected individuals on cardiovascular risk is poorly explored. The aim of the study was to assess whether MS and/or HIV-1 treatment correlates with large elastic artery stiffness in HIV-1-infected patients treated with first-line cART. Methods The study sample comprised of 102 subjects free of cardiovascular disease and major risk factors divided into two groups based on HIV-1 infection, treatment, and MS status: HIV-1+/cART+/MS+ (n = 12); HIV-1+/cART−/MS+ (n = 16); HIV-1−/ MS+ (n = 10); HIV-1+/cART+/MS− (n = 42); HIV-1+/cART−/MS− (n = 32); HIV-1−/ MS− (n = 39). MS was established according the International Diabetes Federation definition. Large artery stiffness was measured using applanation tonometry to assess aortic pulse wave velocity (aPWV) and aortic augmentation index at heart rate of 75 bpm (AIx@HR75). cART included lamivudine/zidovudine and nevirapine or efavirenz. Results The prevalence of MS in the HIV-1-infected patients was 28%. There were no significant differences in aPWV in the non-MS groups. However, in subjects with MS, aPWV was significantly higher in the HIV-1 cART patients (9.0 ± 1.9 m/s) compared with both controls (7.5 ± 1.8 m/s; P = 0.018) and untreated HIV-1 patients (7.7 ± 1.3 m/s; P = 0.023), and these differences remained after adjustment for blood pressure and sex. Aortic PWV was significantly elevated (P = 0.009) in HIV-1 cART patients with MS compared to their counterparts without MS. Untreated HIV-1 patients with MS also demonstrated increased aPWV compared to their counterparts without MS (P = 0.05). Aortic AIx@HR75 was, on average, ~ 5% higher in HIV-1 cART patients with MS (28.3 ± 62% compared with untreated HIV-1 patients with MS (23.5 ± 9%; P = 0.075). Sub-group multivariate analysis identified MS as an independent predictor of increased aPWV in HIV-1 cART patients. Conclusions Our study established that presence of MS in HIV-1 patients on treatment was associated with increased aPWV and hence increased arterial stiffness in sub-Saharan African HIV-1 patients on first-line cART.

Objective To assess the effect of a prospective screening strategy for the early diagnosis of celiac disease (CD) in children with Down syndrome (DS). Study design Blood samples were taken from 155 children with DS. Buccal swabs were also taken from 9 of these children for determination of human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 positivity. Independently, immunoglobulin A anti-endomysium-(EMA) and anti-tissue transglutaminase antibodies (TGA) were tested. An intestinal biopsy was performed to confirm the diagnosis of CD. Results Sixty-three children (40.6%) had test results that were positive for HLA-DQ2 or HLA-DQ8. Results of HLA DQ-typing of DNA isolated from blood and buccal swabs were identical. Eight of the children in whom test results were positive for HLA-DQ2/8 also had positive test results for EMA and TGA. CD was confirmed in 7 of these children with an intestinal biopsy, and in 1 child, CD was suggested with improvement on a gluten-free diet. Conclusions We found a prevalence of CD in children with DS of 5.2% (10 times higher than the general Dutch population). We recommend HLA-DQ2/8 typing from buccal swabs in the first year of life and initiating serologic screening of children with DS in whom test results are positive for HLA-DQ2 or DQ8 at age 3 years. Early knowledge of negative HLA-DQ2/8 status can reassure most parents that their children do not have a CD risk.

Aim: After bacterial meningitis, about one-third of children develops academic and/or behavioural limitations. The aim of our study was to search for structural differences in the brain, with a special focus on the hippocampus, between childhood survivors of bacterial meningitis with and without academic and/or behavioural limitations and healthy siblings. Patients and methods: A selection of a cohort, compiled in an earlier performed retrospective study, was used in this case-control study. Magnetic Resonance Imaging scans of the brain were performed in 43 post-meningitis children, of whom 18 had learning and/or behavioural limitations and 25 had no problems, and 18 controls. Voxel-based morphometry investigated the brain for structural changes. Hippocampal volume and lateral ventricle width were measured. Results: No structural differences between the groups, in any area of the brain, were found. There were no significant differences in hippocampal volume or lateral ventricle width. The group with limitations had three children with a right hippocampal volume smaller than two standard deviations below the mean of the control group. Conclusion: Despite hippocampus lesions found in experimental studies, we found no anatomical differences of the brain or hippocampus related to bacterial meningitis in children, nor to the academic and/or behavioural limitations seen after bacterial meningitis.

Objective: To determine the prevalence, neonatal characteristics, and first-year mortality in Down syndrome (DS) among children in the Netherlands. Study design: The number of DS births registered by the Dutch Paediatric Surveillance Unit (DPSU) in 2003 was compared with total live births (reference population) and perinatal registrations. Results: The prevalence of DS was 16 per 10,000 live births. Compared with the reference population, the 182 children with trisomy 21 had a gestational age of 38 weeks versus 39.1 weeks (P < .001), a birth weight of 3119 g versus 3525 g in males (P < .001) and 2901 g versus 3389 g in females (P < .001), and mothers with a parity of ≥4.17% versus 5% (P < .001) and a mean age of 33.6 years versus 31 years (P < .001) and 33% (n = 54) ≥36 years). The mean age of DS diagnosis was 10.2 days in nonhospital deliveries and 1.8 days in hospital deliveries (P < .001). Children with DS were less often breast-fed (P < .05), and 86% (n = 156) were hospitalized after birth. Neonatal and infant mortality were higher in DS, 1.65% versus 0.36% (P < .02) and 4% versus 0.48% (P < 0.001), respectively. Conclusions: The prevalence of DS in the Netherlands exceeds previously reported levels and is influenced by the mother's age. Neonatal and infant DS mortality have declined, but still exceed those in the reference population. © 2008 Mosby, Inc. All rights reserved.

Background The defining feature of the cerebrospinal fluid (CSF) collected from infants and children with tuberculous meningitis (TBM), derived from an earlier untargeted nuclear magnetic resonance (NMR) metabolomics study, was highly elevated lactic acid. Undetermined was the contribution from host response (L-lactic acid) or of microbial origin (D-lactic acid), which was set out to be determined in this study. Methods In this follow-up study, we used targeted ultra-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (UPLC–ESI–MS/MS) to determine the ratio of the L and D enantiomers of lactic acid in these CSF samples. Results Here we report for the first time that the lactic acid observed in the CSF of confirmed TBM cases was in the L-form and solely a response from the host to the infection, with no contribution from any bacteria. The significance of elevated lactic acid in TBM appears to be that it is a crucial energy substrate, used preferentially over glucose by microglia, and exhibits neuroprotective capabilities. Conclusion These results provide experimental evidence to support our conceptual astrocyte–microglia lactate shuttle model formulated from our previous NMR-based metabolomics study — highlighting the fact that lactic acid plays an important role in neuroinflammatory diseases such as TBM. Furthermore, this study reinforces our belief that the determination of enantiomers of metabolites corresponding to infectious diseases is of critical importance in substantiating the clinical significance of disease markers. Electronic supplementary material The online version of this article (doi:10.1186/s12879-016-1597-9) contains supplementary material, which is available to authorized users.

Recently, a prediction rule for developing neurological sequelae after childhood bacterial meningitis was developed on a small derivation set. Before implementing in practice a prediction rule must first be tested in new patients (external validation). Our aim was to study the external validity of this rule and, if necessary, to update the rule. The prediction rule was tested on newly available data (validation set) by assessing the rule's calibration and discrimination. We updated the prediction rule by adding extra predictors and re-estimating the regression coefficients of the original predictors in the combined datasets. The rule showed poor agreement between predicted risks and observed frequencies. The ROC area was 0.65 (95% CI 0.57-0.72), which was statistically significantly lower than in the derivation set (0.87 (0.78-0.96)), p-value

The objectives of this study were to describe health-related quality of life of postmeningitic children and to examine the association between academic and/or behavioral limitations and health-related quality of life. One hundred and eighty-two children (mean age 9.7 years; range 5.3-14.2) were selected randomly from a cohort of 674 school-age children who recovered from non-Haemophilus influenzae type B bacterial meningitis. These children had neither meningitis with 'complex onset', nor prior cognitive or behavioral problems, nor severe disease sequelae. On average 7.4 years after meningitis, they were evaluated using an 'Academic Achievement Test' and their parents filled in the Child Behavior Checklist, the Child Health Questionnaire, and the Health Utilities Index. The long-term incidence of academic and/or behavioral limitations was 32%. Overall health-related quality of life of the postmeningitic children was decreased in comparison with that of a reference population of schoolchildren. The group of postmeningitic children with academic and/or behavioral limitations showed the most marked decrease in quality of life, especially concerning psychosocial health, cognition and family life. The negative effects on quality of life were not significantly influenced by age, gender, causative pathogen, presence of minor neurological impairment, or presence of hearing impairment. In conclusion, health-related quality of life of postmeningitic children is decreased, particularly of those with academic and/or behavioral limitations.

Tuberculosis meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis and is particularly intense in small children; there is no universally accepted algorithm for the diagnosis and substantiation of TB infection, which can lead to delayed intervention, a high risk factor for morbidity and mortality. In this study a proton magnetic resonance (1H NMR)-based metabolomics analysis and several chemometric methods were applied to data generated from lumber cerebrospinal fluid (CSF) samples from three experimental groups: (1) South African infants and children with confirmed TBM, (2) non-meningitis South African infants and children as controls, and (3) neurological controls from the Netherlands. A total of 16 NMR-derived CSF metabolites were identified, which clearly differentiated between the controls and TBM cases under investigation. The defining metabolites were the combination of perturbed glucose and highly elevated lactate, common to some other neurological disorders. The remaining 14 metabolites of the host’s response to TBM were likewise mainly energy-associated indicators. We subsequently generated a hypothesis expressed as an “astrocyte–microglia lactate shuttle” (AMLS) based on the host’s response, which emerged from the NMR-metabolomics information. Activation of microglia, as implied by the AMLS hypothesis, does not, however, present a uniform process and involves intricate interactions and feedback loops between the microglia, astrocytes and neurons that hamper attempts to construct basic and linear cascades of cause and effect; TBM involves a complex integration of the responses from the various cell types present within the CNS, with microglia and the astrocytes as main players.

An infant with pneumococcal meningitis developed signs of raised intracranial pressure during the progression of the disease, including loss of consciousness, hypertension, bradycardia, and respiratory depression. However, both the emergency computed tomography scan findings and intracranial pressure measured by lumbar puncture were normal. Diffusion-weighted magnetic resonance imaging identified multiple lesions with restricted diffusion suggestive of ischemia in the brainstem, explaining the signs observed in the patient. These lesions could not be identified on T(2)-weighted images at that time.

We present a case of Pott's disease, where the patient presented with neurological impairment due to vertebral granulomatous necrosis, needing immediate decompression and later stabilizing and reconstructive orthopaedic surgery, in order to create awareness for TB in general, especially this forgotten form of spinal tuberculosis.

Infections caused by Mycobacterium haemophilum in immunocompetent patients are unusual. M. haemophilum have been associated with cervicofacial lymphadenitis in children, but inguinal infections have not yet been described. We present a case of an inguinal lymphadenitis caused by M. haemophilum in an immunocompetent girl.

The aim of this study was to determine the prevalence of 25-hydroxyvitamin D (25(OH)D) deficiency in a hospital-based population of both native Dutch and non-Western immigrants and to investigate the influence of immigrant status on the prevalence of vitamin D deficiency. A cross-sectional survey was conducted among 132 patients (1–18 years of age) visiting the paediatric outpatient department. Serum levels of 25(OH)D were measured using high-performance liquid chromatography. Cut-off levels of 30 and 50 nmol/l for serum 25(OH)D were evaluated. One third of the patients had serum 25(OH)D levels below 30 nmol/l, and half of the study population had serum levels below 50 nmol/l. Non-Western immigrants had an increased risk for vitamin D deficiency compared to their native Dutch peers [25(OH)D of

Background Sensorineural hearing loss is the most common sequela in survivors of bacterial meningitis (BM). In the past we developed a validated prediction model to identify children at risk for post-meningitis hearing loss. It is known that host genetic variations, besides clinical factors, contribute to severity and outcome of BM. In this study it was determined whether host genetic risk factors improve the predictive abilities of an existing model regarding hearing loss after childhood BM. Methods Four hundred and seventy-one Dutch Caucasian childhood BM were genotyped for 11 single nucleotide polymorphisms (SNPs) in seven different genes involved in pathogen recognition. Genetic data were added to the original clinical prediction model and performance of new models was compared to the original model by likelihood ratio tests and the area under the curve (AUC) of the receiver operating characteristic curves. Results Addition of TLR9-1237 SNPs and the combination of TLR2 + 2477 and TLR4 + 896 SNPs improved the clinical prediction model, but not significantly (increase of AUC’s from 0.856 to 0.861 and from 0.856 to 0.875 (p = 0.570 and 0.335, respectively). Other SNPs analysed were not linked to hearing loss. Conclusions Although addition of genetic risk factors did not significantly improve the clinical prediction model for post-meningitis hearing loss, AUC’s of the pre-existing model remain high after addition of genetic factors. Future studies should evaluate whether more combinations of SNPs in larger cohorts has an additional value to the existing prediction model for post meningitis hearing loss.

Objective: This study aimed external validation of a formerly developed prediction model identifying children at risk for hearing loss after bacterial meningitis (BM). Independent risk factors included in the model are: duration of symptoms prior to admission, petechiae, cerebral spinal fluid (CSF) glucose level, Streptococcus pneumoniae and ataxia. Validation helps to evaluate whether the model has potential in clinical practice. Study design: 116 Dutch school-age BM survivors were included in the validation cohort and screened for sensorineural hearing loss (>25 dB). Risk factors were obtained from medical records. The model was applied to the validation cohort and its performance was compared with the development cohort. Validation was performed by application of the model on the validation cohort and by assessment of discrimination and goodness of fit. Calibration was evaluated by testing deviations in intercept and slope. Multiple imputation techniques were used to deal with missing values. Results: Risk factors were distributed equally between both cohorts. Discriminative ability (Area Under the Curve, AUC) of the model was 0.84 in the development and 0.78 in the validation cohort. Hosmer-Lemeshow test for goodness of fit was not significant in the validation cohort, implying good fit concerning the similarity of expected and observed cases. There were no significant differences in calibration slope and intercept. Sensitivity and negative predicted value were high, while specificity and positive predicted value were low which is comparable with findings in the development cohort. Conclusions: Performance of the model remained good in the validation cohort. This prediction model might be used as a screening tool and can help to identify those children that need special attention and a long follow-up period or more frequent auditory testing. © 2013 de Jonge et al.

Tuberculous meningitis (TBM) is a prevalent form of central nervous system tuberculosis (CNS-TB) and the most severe common form of bacterial meningitis in infants and children below the age of 13 years, especially in the Western Cape Province of South Africa. Research to identify markers for timely and accurate diagnosis and treatment outcomes remains high on the agenda for TBM, in respect of which the field of metabolomics is as yet largely unexploited. However, the national Department of Science and Technology (DST) recently established several biotechnology platforms at South African institutions, including one for metabolomics hosted at North-West University. We introduce this national platform for nuclear magnetic resonance (NMR) metabolomics by providing an overview of work on TBM. We focus on selected collaborative multidisciplinary approaches to this disease and conclude with the outcomes of an untargeted NMR metabolomics study of cerebrospinal fluid from TBM patients. This study enabled the formulation of a conceptual shuttle representing the unique metabolic plasticity of CNS metabolism towards the energy requirements for the microglia-driven neuroinflammatory responses, of which TBM is one example. From insights generated by this explorative NMR metabolomics investigation, we propose directions for future in-depth research strategies to address this devastating disease. In our view, the timely initiative of the DST, the operational expertise in metabolomics now available and the potential for involving national and international networks in this field of research offers remarkable opportunities for the future of metabolomics in South Africa and for an ever greater understanding of disease mechanisms.

BackgroundGenetic variation in immune response genes is associated with susceptibility and severity of infectious diseases. Toll-like receptor (TLR) 9 polymorphisms are associated with susceptibility to develop meningococcal meningitis (MM). The aim of this study is to compare genotype distributions of twoTLR9polymorphisms between clinical severity variables in MM survivors.MethodsWe used DNA samples of a cohort of 390 children who survived MM. Next, we determined the genotype frequencies ofTLR9-1237 andTLR9+2848 polymorphisms and compared these between thirteen clinical variables associated with prognostic factors predicting adverse outcome of bacterial meningitis in children.ResultsTheTLR9 -1237 TC and CC genotypes were associated with a decreased incidence of a positive blood culture forNeisseria (N.) meningitidis(p = 0.014, odds ratio (OR) 0.5. 95% confidence interval (CI) 0.3 – 0.9). TheTLR9 +2848 AA mutant was associated with a decreased incidence of a positive blood culture forN. meningitidis(p = 0.017, OR 0.6, 95% CI 0.3 – 0.9). Cerebrospinal fluid (CSF) leukocytes per μL were higher in patients carrying theTLR9 -1237 TC or CC genotypes compared to carriers of the TT wild type (WT) (p = 0.024, medians: 2117, interquartile range (IQR) 4987 versus 955, IQR 3938). CSF blood/glucose ratios were lower inTLR9 -1237 TC or CC carriers than in carriers of the TT WT (p = 0.017, medians: 0.20, IQR 0.4 versus 0.35, IQR 0.5). CSF leukocytes/μL were higher in patients carrying theTLR9 +2848 AA mutant compared to carriers of GG or GA (p = 0.0067, medians: 1907, IQR 5221 versus 891, IQR 3952).ConclusionsWe identified TLR9 genotypes associated with protection against meningococcemia and enhanced local inflammatory responses inside the central nervous system, important steps in MM pathogenesis and defense.

Introduction: In-hospital treatment of children with tuberculous meningitis (TBM) is not a feasible option in many resource-poor countries. Home-based treatment has shown to be a viable alternative. Adherence is an important factor determining success of treatment.Objective: Identify possible barriers to adherence of home-based treatment and caretaker perception of the disease.Method: A qualitative study consisting of 11 in-depth semi-structured interviews was performed based on principles of the health belief model.Results: Barriers of adherence identified include poor understanding of the disease and transmission route, difficulty with medication administration and side effects, lack of access to the health-care facility, long waiting times and hidden costs of transportation. Caretakers showed good appreciation of the adverse effects of noncompliance and benefits obtained from taking treatment in the home environment.Conclusion: Improved doctor-patient communication, information brochures, structural changes to hospital settings, provision of financial and peer support all contribute to optimal TBM home-based treatment. © The Author [2011]. Published by Oxford University Press. All rights reserved.

The aim of this study was to assess the prevalence of congenital heart defects (CHDs) and persistent pulmonary hypertension of the neonate (PPHN) in children with Down syndrome (DS) and to assess its impact on neonatal factors. It was a prospective study of a birth cohort of children with DS born between 2003 and 2006 registered by the Dutch Paediatric Surveillance Unit (DPSU). A CHD occurred in 43% of 482 children with trisomy 21. Atrioventricular septal defect was found in 54%, ventricular septal defect in 33.3% and patent ductus arteriosus in 5.8%. The incidence of PPHN in DS was 5.2%, which is significantly higher than the general population (p < 0.001). The reported mortality in newborns with DS was overall 3.3% and was still significant higher in children with a CHD versus no CHD (5.8% versus 1.5%) (p = 0.008). The presence of CHD in children with DS had no influence on their birth weight, mean gestational age and Apgar score. In neonates with DS, we found not only a 43% prevalence of CHD, but also a high incidence of PPHN at 5.2%. Early recognition of the cardiac condition of neonates with DS seems justified.

OBJECTIVES. Respiratory syncytial virus is the single-most important cause of lower respiratory tract infections in children. Preterm birth and congenital heart disease are known risk factors for severe respiratory syncytial virus infections. Although Down syndrome is associated with a high risk of respiratory tract infections, little is known about the incidence of respiratory syncytial virus infections in this group. The aim of our study was to determine the incidence of respiratory syncytial virus lower respiratory tract infection–associated hospitalization among children with Down syndrome.PATIENTS AND METHODS. We performed a retrospective observational study and a prospective nationwide birth-cohort study of children with Down syndrome. The retrospective cohort comprised 176 children with Down syndrome. A birth cohort of 219 children with Down syndrome was prospectively followed until 2 years of age. All 276 siblings of the birth cohort were used as controls.RESULTS. Of the 395 patients with Down syndrome, 180 (45.6%) had a known risk factor for severe respiratory syncytial virus infections; 39 (9.9%) of these were hospitalized for respiratory syncytial virus lower respiratory tract infections. Two control children (0.7%) versus 9 term children with Down syndrome without congenital heart disease (7.6%) were hospitalized for respiratory syncytial virus lower respiratory tract infections. The median duration of hospitalization was 10 days; mechanical ventilation was required for 5 children (12.8%).CONCLUSIONS. This is the first study, to our knowledge, to demonstrate that Down syndrome is a novel independent risk factor for severe respiratory syncytial virus lower respiratory tract infections. These findings should prompt studies to investigate possible mechanisms that underlie severe respiratory syncytial virus lower respiratory tract infections in children with Down syndrome. The effect of respiratory syncytial virus prophylaxis in this specific population needs to be established.

Pericarditis is a rare manifestation of tuberculosis and can be fatal. We describe a 15-year-old girl admitted for a large pericardial effusion. Subxiphoid pericardial biopsy was performed. Biopsy samples were positive for M. tuberculosis DNA by PCR, which confirmed the diagnosis of tuberculous pericarditis.

Tuberculous meningitis (TM) is a severe complication of tuberculosis that mainly occurs during childhood. No murine models are available to study this disease. The purpose of the present study was to develop a murine model to investigate the pathogenesis of TM. Mice were intracerebrally injected with Mycobacterium tuberculosis. Bacilli could be cultured from brain homogenates, and, on histopathological examination, all mice were found to have meningeal cellular infiltration. We found elevated levels of chemoattractants for mononuclear phagocytes and neutrophilic granulocytes. This is the first murine model for TM that can be used for research on the host response to TM, in particular the innate immune response.

Neuropsychological impairments possibly underlying academic and/or behavioural limitations were studied in 149 school-age survivors of bacterial meningitis, 68 with and 81 without academic and/or behavioural limitations. Academic limitations affected mathematics, reading, and writing. Behavioural limitations were inferred from scores in the clinical range on the Child Behaviour Checklist. These children had been selected from a cohort of 674 children (57% males) who had recovered from non-Haemophilus influenzae type B bacterial meningitis and who had a mean age at infection of 2 years 4 months (range 1mo to 9y 5mo). They had neither 'complex onset' meningitis, prior cognitive or behavioural problems, nor severe disease sequelae. They were assessed with standardized assessment methods a mean of 7.8 years (range 4 to 10.4) after meningitis. Children with limitations (32% of the cohort) performed generically poorly on measures of cognitive functioning, speed, and motor steadiness, rather than having impairments in specific neuropsychological domains. The presence of two or more minor neurological signs was more frequent in the group with than in the group without limitations (30% versus 9%); this may explain the relatively poor speed and motor steadiness of the group with limitations.

To determine the role of endogenous interleukin-18 (IL-18) in pneumococcal meningitis, meningitis was induced in IL-18 gene-deficient (IL-18(-/-)) and wild-type (WT) mice by intranasal inoculation of Streptococcus pneumoniae with hyaluronidase. Induction of meningitis resulted in an upregulation of both pro- and mature IL-18 in brain tissue in WT mice. IL-18(-/-) and WT mice were equally susceptible to develop meningitis after intranasal infection, yet IL-18(-/-) mice showed a prolonged survival and a suppressed inflammatory response, as reflected by a less profound inflammatory infiltrate around the meninges and lower concentrations of cytokines and chemokines in brain tissue. These findings suggest that endogenous IL-18 contributes to a detrimental inflammatory response during pneumococcal meningitis and that elimination of IL-18 may improve the outcome of this disease. (C) 2003 Elsevier Science B.V. All rights reserved

Intracisternal injection of the CXC-chemokines KC or macrophage inflammatory protein (MIP)-2 induced a pleocytosis in the cerebrospinal fluid (CSF) of rats in a dose dependent way. MIP-2 was much more potent than KC. The concurrent injection of both chemokines revealed a profound synergistic effect on leukocyte recruitment into CSF. (C) 2002 Elsevier Science B.V. All rights reserved

In 1998, an outbreak of systemic infections caused by Bacillus cereus occurred in the Neonatal Intensive Care Unit of the University Hospital Vrije Universiteit, Amsterdam, The Netherlands. Three neonates developed sepsis with positive blood cultures. One neonate died, and the other two neonates recovered. An environmental survey, a prospective surveillance study of neonates, and a case control study were performed, in combination with molecular typing, in order to identify potential sources and transmission routes of infection. Genotypic fingerprinting by amplified-fragment length polymorphism (AFLP) showed that the three infections were caused by a single clonal type of B. cereus . The same strain was found in trachea aspirate specimens of 35 other neonates. The case control study showed mechanical ventilation with a Sensormedics ventilation machine to be a risk factor for colonization and/or infection (odds ratio, 9.8; 95% confidence interval, 1.1 to 88.2). Prospective surveillance showed that colonization with B. cereus occurred exclusively in the respiratory tract of mechanically ventilated neonates. The epidemic strain of B. cereus was found on the hands of nursing staff and in balloons used for manual ventilation. Sterilization of these balloons ended the outbreak. We conclude that B. cereus can cause outbreaks of severe opportunistic infection in neonates. Typing by AFLP proved very useful in the identification of the outbreak and in the analysis of strains recovered from the environment to trace the cause of the epidemic.

Cutaneous zygomycosis is a rare but severe fungal infection with high risk of dissemination. Early recognition, deep surgical biopsy for diagnosis, aggressive treatment with repeated surgical debridement, and targeted pharmacotherapy are essential and can prevent dissemination and fatal outcome. We present case reports of 2 patients.

Since interleukin-10 (IL-10) controls the production of tumor necrosis factor alpha (TNF-alpha) and this latter cytokine has a deleterious effect on neuronal cells, we determined the levels of both cytokines in cerebrospinal fluid (CSF) from children with bacterial meningitis. High levels of IL-10 (1,164 pg/mL) and TNF-alpha (3,158 pg/mL) were detected in CSF from 10 children with meningitis, but these cytokines were not detectable in CSF from 12 controls. In vitro neutralization of IL-10 demonstrated that endogenously formed IL-10 is important for limiting the production of TNF-alpha by leukocytes. We assume that IL-10 in CSF will decrease the inflammatory reaction associated with meningitis and will result in the development of fewer sequelae because of its inhibitory effect on the production of TNF-alpha.

Background Previously two prediction rules identifying children at risk of hearing loss and academic or behavioral limitations after bacterial meningitis were developed. Streptococcus pneumoniae as causative pathogen was an important risk factor in both. Since 2006 Dutch children receive seven-valent conjugate vaccination against S. pneumoniae. The presumed effect of vaccination was simulated by excluding all children infected by S. pneumoniae with the serotypes included in the vaccine, from both previous collected cohorts (between 1990-1995). Methods Children infected by one of the vaccine serotypes were excluded from both original cohorts (hearing loss: 70 of 628 children; academic or behavioral limitations: 26 of 182 children). All identified risk factors were included in multivariate logistic regression models. The discriminative ability of both new models was calculated. Results The same risk factors as in the original models were significant. The discriminative ability of the original hearing loss model was 0.84 and of the new model 0.87. In the academic or behavioral limitations model it was 0.83 and 0.84 respectively. Conclusion It can be assumed that the prediction rules will also be applicable on a vaccinated population. However, vaccination does not provide 100% coverage and evidence is available that serotype replacement will occur. The impact of vaccination on serotype replacement needs to be investigated, and the prediction rules must be validated externally.