Paenibacillusinfection with frequent viral coinfection contributes to postinfectious hydrocephalus in Ugandan infants

Abstract

Postinfectious hydrocephalus (PIH), which often follows neonatal sepsis, is the most common cause of pediatric hydrocephalus worldwide, yet the microbial pathogens underlying this disease remain to be elucidated. Characterization of the microbial agents causing PIH would enable a shift from surgical palliation of cerebrospinal fluid (CSF) accumulation to prevention of the disease. Here, we examined blood and CSF samples collected from 100 consecutive infant cases of PIH and control cases comprising infants with non-postinfectious hydrocephalus in Uganda. Genomic sequencing of samples was undertaken to test for bacterial, fungal, and parasitic DNA; DNA and RNA sequencing was used to identify viruses; and bacterial culture recovery was used to identify potential causative organisms. We found that infection with the bacterium Paenibacillus, together with frequent cytomegalovirus (CMV) coinfection, was associated with PIH in our infant cohort. Assembly of the genome of a facultative anaerobic bacterial isolate recovered from cultures of CSF samples from PIH cases identified a strain of Paenibacillus thiaminolyticus. This strain, designated Mbale, was lethal when injected into mice in contrast to the benign reference Paenibacillus strain. These findings show that an unbiased pan-microbial approach enabled characterization of Paenibacillus in CSF samples from PIH cases, and point toward a pathway of more optimal treatment and prevention for PIH and other proximate neonatal infections.

Poisson Kalman filter for disease surveillance

“…Another critical factor in sepsis and hydrocephalus cases is environmental variables such as rainfall [30], which suggests that a full spatiotemporal model will be necessary to more fully represent these dynamics. Recent findings [17] demonstrate that more than one infection (co-infection) can be found in some of these infants (perhaps even a mixture of noncommunicable bacteria and communicable viruses), demonstrating that a mixed linear and nonlinear model would be required to represent such co-infections. A spatiotemporal model would allow the optimal control to consider multiple methods of control and determine ideal locations and times to apply each.…”

“…III and IV show how to apply the Poisson Kalman filter to track the model from example data from two endemic diseases affecting childhood health in Africa: neonatal sepsis (NS) and postinfectious hydrocephalus (PIH). Although many of these infections are noncommunicable, acquired during birth or from the environment afterward, there is new evidence supporting a role for communicable viruses [17]. In this work we show how the use of the PKF and EPKF fills the need for a computational framework that embodies the interdependent dynamics of NS and PIH.…”

“…The most common brain disorder in childhood is hydrocephalus, and the largest single cause of hydrocephalus in the world is as a sequela of NS [21], accounting for an estimated 160 000 yearly cases of postinfectious hydrocephalus in infancy [22]. The microbial agents responsible for this enormous loss of human life have been poorly characterized [23], although next-generation molecular methods show promise to improve the identification of causal agents [17]. Both NS and PIH occur disproportionately in the developing world, and most of the PIH cases will die in childhood without adequate treatment, substantially compounding the effective mortality due to NS and its tremendous burdens on societies [24,25].…”

“…In order to broaden the applicability of the PKF we now show that it also offers improvements for these nonlinear models by using a standard approach to extend the Kalman equations to nonlinear dynamics. Moreover, because there are potential mechanisms for contagious infections contributing to NS [17], modeling these infections requires a nonlinear system. As in the classical SIR model, we assume that the contagious spread will be simultaneously proportional to the both the number of susceptible cases and the number of infected and so we model the number of contagious cases at time k as βS k I k , where β is infectivity.…”

Brain growth and neurodevelopment after surgical treatment of infant post-infectious hydrocephalus in sub-Saharan Africa

“…Whether children with post-infectious hydrocephalus and apparently culture-negative ventricular CSF may harbour an occult, indolent bacterial or viral (e.g. cytomegalovirus)infection at the time of initial hydrocephalus treatment is a current area of investigation 27. Certainly, the prevalence of unrelated diseases known to impact childhood survival in our patient population, such as malaria and malnutrition, may also hinder brain growth and development, especially when gauged against norms for infants in high-income countries.…”