Paenibacillus spp infection among infants with postinfectious hydrocephalus in Uganda: an observational case-control study.

BACKGROUND: Paenibacillus thiaminolyticus is a cause of postinfectious hydrocephalus among Ugandan infants. To determine whether Paenibacillus spp is a pathogen in neonatal sepsis, meningitis, and postinfectious hydrocephalus, we aimed to complete three separate studies of Ugandan infants. The first study was on peripartum prevalence of Paenibacillus in mother-newborn pairs. The second study assessed Paenibacillus in blood and cerebrospinal fluid (CSF) from neonates with sepsis. The third study assessed Paenibacillus in CSF from infants with hydrocephalus. METHODS: In this observational study, we recruited mother-newborn pairs with and without maternal fever (mother-newborn cohort), neonates (aged ≤28 days) with sepsis (sepsis cohort), and infants (aged ≤90 days) with hydrocephalus with and without a history of neonatal sepsis and meningitis (hydrocephalus cohort) from three hospitals in Uganda between Jan 13, 2016 and Oct 2, 2019. We collected maternal blood, vaginal swabs, and placental samples and the cord from the mother-newborn pairs, and blood and CSF from neonates and infants. Bacterial content of infant CSF was characterised by 16S rDNA sequencing. We analysed all samples using quantitative PCR (qPCR) targeting either the Paenibacillus genus or Paenibacillus thiaminolyticus spp. We collected cranial ultrasound and computed tomography images in the subset of participants represented in more than one cohort. FINDINGS: No Paenibacillus spp were detected in vaginal, maternal blood, placental, or cord blood specimens from the mother-newborn cohort by qPCR. Paenibacillus spp was detected in 6% (37 of 631 neonates) in the sepsis cohort and, of these, 14% (5 of 37 neonates) developed postinfectious hydrocephalus. Paenibacillus was the most enriched bacterial genera in postinfectious hydrocephalus CSF (91 [44%] of 209 patients) from the hydrocephalus cohort, with 16S showing 94% accuracy when validated by qPCR. Imaging showed progression from Paenibacillus spp-related meningitis to postinfectious hydrocephalus over 1-3 months. Patients with postinfectious hydrocephalus with Paenibacillus spp infections were geographically clustered. INTERPRETATION: Paenibacillus spp causes neonatal sepsis and meningitis in Uganda and is the dominant cause of subsequent postinfectious hydrocephalus. There was no evidence of transplacental transmission, and geographical evidence was consistent with an environmental source of neonatal infection. Further work is needed to identify routes of infection and optimise treatment of neonatal Paenibacillus spp infection to lessen the burden of morbidity and mortality. FUNDING: National Institutes of Health and Boston Children's Hospital Office of Faculty Development.

Improving Infant Hydrocephalus Outcomes in Uganda: A Longitudinal Prospective Study Protocol for Predicting Developmental Outcomes and Identifying Patients at Risk for Early Treatment Failure after ETV/CPC.

Infant hydrocephalus poses a severe global health burden; 80% of cases occur in the developing world where patients have limited access to neurosurgical care. Surgical treatment combining endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC), first practiced at CURE Children's Hospital of Uganda (CCHU), is as effective as standard ventriculoperitoneal shunt (VPS) placement while requiring fewer resources and less post-operative care. Although treatment focuses on controlling ventricle size, this has little association with treatment failure or long-term outcome. This study aims to monitor the progression of hydrocephalus and treatment response, and investigate the association between cerebral physiology, brain growth, and neurodevelopmental outcomes following surgery. We will enroll 300 infants admitted to CCHU for treatment. All patients will receive pre/post-operative measurements of cerebral tissue oxygenation (SO2), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen consumption (CMRO2) using frequency-domain near-infrared combined with diffuse correlation spectroscopies (FDNIRS-DCS). Infants will also receive brain imaging, to monitor tissue/ventricle volume, and neurodevelopmental assessments until two years of age. This study will provide a foundation for implementing cerebral physiological monitoring to establish evidence-based guidelines for hydrocephalus treatment. This paper outlines the protocol, clinical workflow, data management, and analysis plan of this international, multi-center trial.

The Incidence of Postoperative Seizures Following Treatment of Postinfectious Hydrocephalus in Ugandan Infants: A Post Hoc Comparison of Endoscopic Treatment vs Shunt Placement in a Randomized Controlled Trial.

BACKGROUND: There are currently no published data directly comparing postoperative seizure incidence following endoscopic third ventriculostomy (ETV), with/without choroid plexus cauterization (CPC), to that for ventriculoperitoneal shunt (VPS) placement. OBJECTIVE: To compare postoperative epilepsy incidence for ETV/CPC and VPS in Ugandan infants treated for postinfectious hydrocephalus (PIH). METHODS: We performed an exploratory post hoc analysis of a randomized trial comparing VPS and ETV/CPC in 100 infants (<6 mo old) presenting with PIH. Minimum follow-up was 2 yr. Variables associated with and the incidence of postoperative epilepsy were compared (intention-to-treat) using a bivariate analysis. Time to first seizure was compared using the Kaplan-Meier method, and the relative risk for the 2 treatments was determined using Mantel-Haenszel hazard ratios. RESULTS: Seizure incidence was not related to age (P = .075), weight (P = .768), sex (P = .151), head circumference (P = .281), time from illness to hydrocephalus onset (P = .973), or hydrocephalus onset to treatment (P = .074). Irritability (P = .027) and vision deficit (P = .04) were preoperative symptoms associated with postoperative seizures. Ten (10%) patients died, and 20 (20%) developed seizures over the follow-up period. Overall seizure incidence was 9.4 per 100 person-years (9.4 and 9.5 for ETV/CPC and VPS, respectively; P = .483), with no significant difference in seizure risk between groups (hazard ratio, 1.02; 95% CI: 0.42, 2.45; P = .966). Mean time to seizure onset was 8.5 mo for ETV/CPC and 11.2 mo for VPS (P = .464). As-treated, per-protocol, and attributable-intervention analyses yielded similar results. CONCLUSION: Postoperative seizure incidence following treatment of PIH was 20% within 2 yr, regardless of treatment modality.

Infection risk for Bactiseal Universal Shunts versus Chhabra shunts in Ugandan infants: a randomized controlled trial.

OBJECTIVE Clinical and economic repercussions of ventricular shunt infections are magnified in low-resource countries. The efficacy of antibiotic-impregnated shunts in this setting is unclear. A previous retrospective cohort study comparing the Bactiseal Universal Shunt (BUS) and the Chhabra shunt provided clinical equipoise; thus, the authors conducted this larger randomized controlled trial in Ugandan children requiring shunt placement for hydrocephalus to determine whether there was, in fact, any advantage of one shunt over the other. METHODS Between April 2013 and September 2016, the authors randomly assigned children younger than 16 years of age without evidence of ventriculitis to either BUS or Chhabra shunt implantation in this single-blind randomized controlled trial. The primary outcome was shunt infection, and secondary outcomes included reoperation and death. The minimum follow-up was 6 months. Time to outcome was assessed using the Kaplan-Meier method. The significance of differences was tested using Wilcoxon rank-sum, chi-square, Fisher's exact, and t-tests. RESULTS Of the 248 patients randomized, the BUS was implanted in 124 and the Chhabra shunt in 124. There were no differences between the groups in terms of age, sex, or hydrocephalus etiology. Within 6 months of follow-up, there were 14 infections (5.6%): 6 BUS (4.8%) and 8 Chhabra (6.5%; p = 0.58). There were 14 deaths (5.6%; 5 BUS [4.0%] vs 9 Chhabra [7.3%], p = 0.27) and 30 reoperations (12.1%; 15 BUS vs 15 Chhabra, p = 1.00). There were no significant differences in the time to primary or secondary outcomes at 6 months' follow-up (p = 0.29 and 0.17, respectively, Wilcoxon rank-sum test). CONCLUSIONS Among Ugandan infants, BUS implantation did not result in a lower incidence of shunt infection or other complications. Any recommendation for a more costly standard of care in low-resource countries must have contextually relevant, evidence-based support. Clinical trial registration no.: PACTR201804003240177 (http://www.pactr.org/)