The diagnostic potential of urine in paediatric patients undergoing initial treatment for tuberculous meningitis.

Tuberculous meningitis (TBM)-the extrapulmonary form of tuberculosis, is the most severe complication associated with tuberculosis, particularly in infants and children. The gold standard for the diagnosis of TBM requires cerebrospinal fluid (CSF) through lumbar puncture-an invasive sample collection method, and currently available CSF assays are often not sufficient for a definitive TBM diagnosis. Urine is metabolite-rich and relatively unexplored in terms of its potential to diagnose neuroinfectious diseases. We used an untargeted proton magnetic resonance (1H-NMR) metabolomics approach to compare the urine from 32 patients with TBM (stratified into stages 1, 2 and 3) against that from 39 controls in a South African paediatric cohort. Significant spectral bins had to satisfy three of our four strict cut-off quantitative statistical criteria. Five significant biological metabolites were identified-1-methylnicotinamide, 3-hydroxyisovaleric acid, 5-aminolevulinic acid, N-acetylglutamine and methanol-which had no correlation with medication metabolites. ROC analysis revealed that methanol lacked diagnostic sensitivity, but the other four metabolites showed good diagnostic potential. Furthermore, we compared mild (stage 1) TBM and severe (stages 2 and 3) TBM, and our multivariate metabolic model could successfully classify severe but not mild TBM. Our results show that urine can potentially be used to diagnose severe TBM.

"I don't know if you have searched through the scriptures to find a reference on HIV/AIDS. I mean there isn't going to be one, right?": HIV stigma solutions from dialogues between faith leaders and health care workers.

In South African communities, both faith leaders and health care workers play a vital role in supporting the health of community members and people living with HIV in particular. This study describes HIV stigma when faith leaders and health care workers engaged in discourse. The study used a descriptive qualitative inquiry design. Data were gathered between 2015 and 2016 in the areas of Masiphumelele and Gugulethu in Cape Town, South Africa. Three themes emerged: (1) participants identified influences that can increase HIV stigma; (2) participants shared the challenges that they face to reduce HIV stigma; and (3) participants suggested solutions to reduce HIV stigma. Themes discussed include ground-level problems and practical solutions to address HIV stigma in faith communities. Collaboration between faith leaders and health care workers are vital resources in the fight against HIV stigma. Future research and interventions should aim to promote organised collaboration between faith communities and health care structures.

Using telehealth to support community health workers in Uganda during COVID-19: a mixed-method study.

BACKGROUND: At the onset of the COVID-19 pandemic, a local consortium in Uganda set up a telehealth approach that aimed to educate 3,500 Community Health Workers (CHW) in rural areas about COVID-19, help them identify, refer and care for potential COVID-19 cases, and support them in continuing their regular community health work. The aim of this study was to assess the functioning of the telehealth approach that was set up to support CHWs during the COVID-19 pandemic. METHODS: For this mixed-method study, we combined analysis of routine consultation data from the call-center, 24 interviews with key-informants and two surveys of 150 CHWs. Data were analyzed using constant comparative method of analysis. RESULTS: Between March 2020 and June 2021, a total of 35,553 consultations took place via the call center. While the CHWs made extensive use of the call center, they rarely asked for support for potential Covid-19 cases. According to the CHWs, there were no signs that people in their communities were suffering from severe health problems due to COVID-19. People compared the lack of visible symptoms to diseases such as Ebola and were skeptical about the danger of COVID-19. At the same time, people in rural areas were afraid to report relevant symptoms and get tested for fear of being quarantined and stigmatized. The telehealth approach did prove useful for other purposes, such as supporting CHWs with their regular tasks and coordinating the supply of essential products. The health professionals at the call center supported CHWs in diagnosing, referring and treating patients and adhering to infection prevention and control practices. The CHWs felt more informed and less isolated, saying the support from the call center helped them to provide better care and improved the supply of medicine and other essential health products. CONCLUSIONS: The telehealth approach, launched at the start of the COVID-19 pandemic, provided useful support to thousands of CHWs in rural communities in Uganda. The telehealth approach could be quickly set up and scaled up and offers a low cost strategy for providing useful and flexible support to CHWs in rural communities.

Predicting treatment response to vancomycin using bacterial DNA load as a pharmacodynamic marker in premature and very low birth weight neonates: A population PKPD study.

Background: While positive blood cultures are the gold standard for late-onset sepsis (LOS) diagnosis in premature and very low birth weight (VLBW) newborns, these results can take days, and early markers of possible treatment efficacy are lacking. The objective of the present study was to investigate whether the response to vancomycin could be quantified using bacterial DNA loads (BDLs) determined by real-time quantitative polymerase chain reaction (RT-qPCR). Methods: VLBW and premature neonates with suspected LOS were included in a prospective observational study. Serial blood samples were collected to measure BDL and vancomycin concentrations. BDLs were measured with RT-qPCR, whereas vancomycin concentrations were measured by LC-MS/MS. Population pharmacokinetic-pharmacodynamic modeling was performed with NONMEM. Results: Twenty-eight patients with LOS treated with vancomycin were included. A one-compartment model with post-menstrual age (PMA) and weight as covariates was used to describe the time PK profile of vancomycin concentrations. In 16 of these patients, time profiles of BDL could be described with a pharmacodynamic turnover model. The relationship between vancomycin concentration and first-order BDL elimination was described with a linear-effect model. Slope S increased with increasing PMA. In 12 patients, no decrease in BDL over time was observed, which corresponded with clinical non-response. Discussion: BDLs determined through RT-qPCR were adequately described with the developed population PKPD model, and treatment response to vancomycin using BDL in LOS can be assessed as early as 8 h after treatment initiation.

Bacterial meningitis in Africa.

Bacterial meningitis differs globally, and the incidence and case fatality rates vary by region, country, pathogen, and age group; being a life-threatening disease with a high case fatality rate and long-term complications in low-income countries. Africa has the most significant prevalence of bacterial meningitis illness, and the outbreaks typically vary with the season and the geographic location, with a high incidence in the meningitis belt of the sub-Saharan area from Senegal to Ethiopia. Streptococcus pneumoniae (pneumococcus) and Neisseria meningitidis (meningococcus) are the main etiological agents of bacterial meningitis in adults and children above the age of one. Streptococcus agalactiae (group B Streptococcus), Escherichia coli, and Staphylococcus aureus are neonatal meningitis's most common causal agents. Despite efforts to vaccinate against the most common causes of bacterial neuro-infections, bacterial meningitis remains a significant cause of mortality and morbidity in Africa, with children below 5 years bearing the heaviest disease burden. The factors attributed to this continued high disease burden include poor infrastructure, continued war, instability, and difficulty in diagnosis of bacterial neuro-infections leading to delay in treatment and hence high morbidity. Despite having the highest disease burden, there is a paucity of African data on bacterial meningitis. In this article, we discuss the common etiologies of bacterial neuroinfectious diseases, diagnosis and the interplay between microorganisms and the immune system, and the value of neuroimmune changes in diagnostics and therapeutics.

Neurodevelopmental outcomes of newborns and infants with parechovirus and enterovirus central nervous infection: a 5-year longitudinal study.

Though parechovirus (PeV) and enterovirus (EV) are common causes of central nervous system (CNS) infection in childhood, little is known about their long-term neurologic/neurodevelopmental complications. We investigated, longitudinally over a 5-year period, motor neurodevelopment in term-born newborns and infants with RT-qPCR-confirmed PeV- or EV-CNS infection. Motor neurodevelopment was assessed with standardized tests: Alberta Infant Motor Scale (AIMS), Bayley Scales of Infant and Toddler Development version-3 (Bayley-3-NL), and Movement Assessment Battery for Children version-2 (M-ABC-2-NL) at 6, 12, 24, and 60 months post-infection. Results of children with PeV-CNS infection were compared with those of peers with EV-CNS infection and with Dutch norm references. In the multivariate analyses adjustments were made for age at onset, gender, maternal education, and time from CNS infection Sixty of 172 eligible children aged ≤ 3 months were included. Children with PeV-CNS infection had consistently lower, non-significant mean gross motor function (GMF) Z-scores, compared with peers with EV-CNS infection and population norm-referenced GMF. Their GMF improved between 6 and 24 months and decreased at 5 years. Their fine motor function (FMF) scores fell within the population norm reference. CONCLUSION: These results suggest that the impact of PeV-A3-CNS infection on gross motor neurodevelopment in young children might manifest later in life. They highlight the importance of longitudinal neurodevelopmental assessments of children with PeV-A3-CNS infection up to school age. WHAT IS KNOWN: • Human parechovirus (PeV) is a major cause of central nervous system infection (CNS infection) in newborns and infants. • There is interest in the neurological and neurodevelopmental outcome of newborns and infants with PeV-A3-CNS infection. WHAT IS NEW: • This prospective study compares the motor neurodevelopment of term-born newborns and infants with PeV-A3-CNS infection with those with EV-CNS infection and with norm references. • The results support the importance of follow-up of newborns and infants with PeV-A3-CNS infection to detect subtle neurodevelopmental delay and start early interventions.

Comparison of Predicted Cardiovascular Risk Profiles by Different CVD Risk-Scoring Algorithms between HIV-1-Infected and Uninfected Adults: A Cross-Sectional Study in Tanzania.

PURPOSE: 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.

The effect of HIV infection, antiretroviral therapy on carotid intima-media thickness: A systematic review and meta-analysis.

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.

Correction to: Association of HIV-infection, antiretroviral treatment and metabolic syndrome with large artery stiffness: a cross-sectional study.

Following publication of the original article [1], the authors reported that they have provided the wrong caption.

Human parechovirus meningitis and gross-motor neurodevelopment in young children.

This multicenter prospective cohort study describes the impact of human parechovirus meningitis on gross-motor neurodevelopment of young children. Gross-motor function was measured using Alberta Infant Motor Scale. Of a total of 38 eligible children < 10 months of age at onset, nine cases had clinical evidence of meningitis and polymerase chain reaction positive for human parechovirus in cerebrospinal fluid; 11 had no meningitis and polymerase chain reaction positive for human parechovirus in nasopharyngeal aspirate, blood, urine, or feces; and in 18, no pathogen was identified (reference group).The children with human parechovirus meningitis showed more frequent albeit not statistically significant suspect gross-motor function delay (mean Z-score (standard deviation) - 1.69 (1.05)) than children with human parechovirus infection-elsewhere (- 1.38 (1.51)). The reference group did not fall in the range of suspect gross-motor function delay (- 0.96 (1.07)). Adjustment for age at onset and maternal education did not alter the results.Conclusion: Six months after infection, children with human parechovirus meningitis showed more frequent albeit not statistically significant suspect gross-motor function delay compared to the population norm and other two groups. Longitudinal studies in larger samples and longer follow-up periods are needed to confirm the impact and persistence of human parechovirus meningitis on neurodevelopment in young children. What is Known: • Human parechovirus is progressively becoming a major viral cause of meningitis in children. • There is keen interest in the development of affected infants with human parechovirus meningitis. What is New: • This study describes prospectively gross-motor functional delay in children with both clinical evidence of meningitis and polymerase chain reaction positive for human parechovirus in cerebrospinal fluid. • It shows the importance of screening young children for developmental delay in order to refer those with delay for early intervention to maximize their developmental potential.

Longitudinal Association Between Human Parechovirus Central Nervous System Infection and Gross-Motor Neurodevelopment in Young Children.

BACKGROUND: A paucity of studies investigated the association between human parechovirus (HPeV) central nervous system (CNS) infection and motor and neurocognitive development of children. This study describes the gross-motor function (GMF) in young children during 24 months after HPeV-CNS infection compared with children in whom no pathogen was detected. METHODS: GMF of children was assessed with Alberta Infant Motor Scale, Bayley Scales of Infant and Toddler Development or Movement Assessment Battery for Children. We conducted multivariate analyses and adjusted for age at onset, maternal education and time from infection. RESULTS: Of 91 included children, at onset <24 months of age, 11 had HPeV-CNS infection and in 47 no pathogen was detected. Nineteen children were excluded because of the presence of other infection, preterm birth or genetic disorder, and in 14 children, parents refused to consent for participation. We found no longitudinal association between HPeV-CNS infection and GMF (ß = -0.53; 95% confidence interval: -1.18 to 0.07; P = 0.11). At 6 months, children with HPeV-CNS infection had suspect GMF delay compared with the nonpathogen group (mean difference = 1.12; 95% confidence interval: -1.96 to -0.30; P = 0.03). This difference disappeared during 24-month follow-up and, after adjustment for age at onset, both groups scored within the normal range for age. Maternal education and time from infection did not have any meaningful influence. CONCLUSIONS: We found no longitudinal association between HPeV-CNS infection and GMF during the first 24-month follow-up. Children with HPeV-CNS infection showed a suspect GMF delay at 6-month follow-up. This normalized during 24-month follow-up.

Association of HIV-infection, antiretroviral treatment and metabolic syndrome with large artery stiffness: a cross-sectional study.

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.

[An infant with meningitis caused by resistant pneumococcus: infection despite vaccination]. / Zuigeling met meningitis door resistente pneumokok: ondanks vaccinatie toch besmetting.

BACKGROUND: Following the introduction of a heptavalent pneumococcal conjugate vaccine (PCV7) in the Netherlands in 2006, the incidence of invasive pneumococcal disease (IPD) declined significantly. Since then a shift towards non-vaccine serotype IPD has been noted. CASE DESCRIPTION: We present the case of multidrug resistant non-vaccine serotype 19A pneumococcal meningitis in a 5-month-old boy. He was admitted to our Paediatric Intensive Care Unit (PICU) with seizures and septic shock. A barbiturate-induced coma was eventually required to control the seizures; shock was combated with intravenous fluids and inotropes. He received a 6-week course of ceftriaxone and vancomycin. At follow-up, one year after discharge, he had unilateral deafness and minor developmental delay. CONCLUSION: Worldwide, pneumococcal serotype 19A is now the most common cause of IPD in children, with an increasing incidence of multidrug resistant strains. This trend has not yet been observed in the Netherlands. This case demonstrates that even following the introduction of PCV7 pneumococcal meningitis can still occur. Prompt recognition of the symptoms is still essential.

Characteristics of pediatric patients with enterovirus meningitis and no cerebral fluid pleocytosis.

UNLABELLED: Human non-polio enterovirus (EV) is the most important cause of aseptic meningitis in children. Only a few studies report the lack of cerobrospinal fluid (CSF) pleocytosis in children with confirmed EV meningitis; however, the characteristics of these children have not been well defined. This paper describes the clinical and laboratory features of EV meningitis in children with no CSF pleocytosis. Clinical, laboratory, and virological data of Dutch patients <16 years diagnosed with EV meningitis, between 2003 and 2008, were analyzed retrospectively. Data of children with and without CSF pleocytosis were compared. A total of 149 children were infected with EV. Patients presented mainly with fever (n = 113), malaise (n = 43), abdominal pain (n = 47), and irritability (n = 61). Of the 60 patients with EV meningitis, 23 had no pleocytosis. Those who lacked CSF pleocytosis were younger [odds ratio (OR) 1.00; 95% confidence interval (CI) 1.000-1.002; p = 0.001], had experienced drowsiness more (OR 9.60; 95% CI 2.24-41.15; p = 0.002), had lower white blood cell counts (OR 0.73; 95% CI 0.61-0.89; p = 0.001), and had higher C-reactive protein (OR 1.13; 95% CI 1.03-1.23; p = 0.006) than those with pleocytosis. CONCLUSION: These findings show that EV meningitis occurs in the absence of CSF pleocytosis, particularly in young infants, meaning that EV meningitis in this age group cannot be solely excluded by the absence of CSF pleocytosis. They also confirm the importance of genome detection in the diagnosis of EV meningitis in young infants.

Recurrent wheeze in children with Down syndrome: is it asthma?

AIM: To compare the prevalence of current wheeze in children with Down syndrome (DS), their siblings, and nonrelated population controls. METHODS: This was a case-control study in which the International Study of Asthma and Allergy in Childhood questionnaire for respiratory symptoms was completed by parents for 130 children with DS, 167 of their siblings, and for 119 age- and sex-matched control subjects from the general population. RESULTS: Both wheeze ever and wheeze during the last 12 months was more commonly reported in DS than in their siblings or controls. The relative risk (RR) of current wheeze in DS was 2.8 (95% CI, 1.42-5.51) compared with siblings, and 2.75 (95% CI, 1.28-5.88) compared with controls. A doctor's diagnosis of asthma was found in 3.1% in children with DS, in 4.2% in siblings and in 6.7% in controls. During 4-years follow-up, the diagnosis of asthma could not be confirmed in the 24 DS children with current wheeze, and atopy was found in none of them. CONCLUSION: Wheeze is common in children with DS. This is likely to be related to the factors specific for DS and probably unrelated to asthma.

Inguinal lymphadenitis caused by mycobacterium haemophilum in an immunocompetent child.

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.

Validating and updating a prediction rule for neurological sequelae after childhood bacterial meningitis.

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<0.01. The updated prediction rule showed adequate performance in the combined data sets; the ROC area was 0.77 (95% CI 0.72-0.82). Further study of the generalizability of this updated rule may stimulate application in clinical practice.

Academic and behavioral limitations and health-related quality of life in school-age survivors of bacterial meningitis.

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.