Neonatal Paenibacilliosis: Paenibacillus Infection as a Novel Cause of Sepsis in Term Neonates With High Risk of Sequelae in Uganda.

BACKGROUND: Paenibacillus thiaminolyticus may be an underdiagnosed cause of neonatal sepsis. METHODS: We prospectively enrolled a cohort of 800 full-term neonates presenting with a clinical diagnosis of sepsis at 2 Ugandan hospitals. Quantitative polymerase chain reaction specific to P. thiaminolyticus and to the Paenibacillus genus were performed on the blood and cerebrospinal fluid (CSF) of 631 neonates who had both specimen types available. Neonates with Paenibacillus genus or species detected in either specimen type were considered to potentially have paenibacilliosis, (37/631, 6%). We described antenatal, perinatal, and neonatal characteristics, presenting signs, and 12-month developmental outcomes for neonates with paenibacilliosis versus clinical sepsis due to other causes. RESULTS: Median age at presentation was 3 days (interquartile range 1, 7). Fever (92%), irritability (84%), and clinical signs of seizures (51%) were common. Eleven (30%) had an adverse outcome: 5 (14%) neonates died during the first year of life; 5 of 32 (16%) survivors developed postinfectious hydrocephalus (PIH) and 1 (3%) additional survivor had neurodevelopmental impairment without hydrocephalus. CONCLUSIONS: Paenibacillus species was identified in 6% of neonates with signs of sepsis who presented to 2 Ugandan referral hospitals; 70% were P. thiaminolyticus. Improved diagnostics for neonatal sepsis are urgently needed. Optimal antibiotic treatment for this infection is unknown but ampicillin and vancomycin will be ineffective in many cases. These results highlight the need to consider local pathogen prevalence and the possibility of unusual pathogens when determining antibiotic choice for neonatal sepsis.

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.

Cytomegalovirus infections in infants in Uganda: Newborn-mother pairs, neonates with sepsis, and infants with hydrocephalus.

OBJECTIVES: To estimate the prevalence of cytomegalovirus (CMV) infections among newborn-mother pairs, neonates with sepsis, and infants with hydrocephalus in Uganda. DESIGN AND METHODS: Three populations-newborn-mother pairs, neonates with sepsis, and infants (≤3 months) with nonpostinfectious (NPIH) or postinfectious (PIH) hydrocephalus-were evaluated for CMV infection at 3 medical centers in Uganda. Quantitative PCR (qPCR) was used to characterize the prevalence of CMV. RESULTS: The overall CMV prevalence in 2498 samples across all groups was 9%. In newborn-mother pairs, there was a 3% prevalence of cord blood CMV positivity and 33% prevalence of maternal vaginal shedding. In neonates with clinical sepsis, there was a 2% CMV prevalence. Maternal HIV seropositivity (adjusted odds ratio [aOR] 25.20; 95% confidence interval [CI] 4.43-134.26; p = 0.0001), residence in eastern Uganda (aOR 11.06; 95% CI 2.30-76.18; p = 0.003), maternal age <25 years (aOR 4.54; 95% CI 1.40-19.29; p = 0.02), and increasing neonatal age (aOR 1.08 for each day older; 95% CI 1.00-1.16; p = 0.05), were associated risk factors for CMV in neonates with clinical sepsis. We found a 2-fold higher maternal vaginal shedding in eastern (45%) vs western (22%) Uganda during parturition (n = 22/49 vs 11/50, the Fisher exact test; p = 0.02). In infants with PIH, the prevalence in blood was 24% and in infants with NPIH, it was 20%. CMV was present in the cerebrospinal fluid (CSF) of 13% of infants with PIH compared with 0.5% of infants with NPIH (n = 26/205 vs 1/194, p < 0.0001). CONCLUSIONS: Our findings highlight that congenital and postnatal CMV prevalence is substantial in this African setting, and the long-term consequences are uncharacterized.

Preoperative risk and postoperative outcome from subdural fluid collections in African infants with postinfectious hydrocephalus.

OBJECTIVE: This study investigated the incidence of postoperative subdural collections in a cohort of African infants with postinfectious hydrocephalus. The authors sought to identify preoperative factors associated with increased risk of development of subdural collections and to characterize associations between subdural collections and postoperative outcomes. METHODS: The study was a post hoc analysis of a randomized controlled trial at a single center in Mbale, Uganda, involving infants (age < 180 days) with postinfectious hydrocephalus randomized to receive either an endoscopic third ventriculostomy plus choroid plexus cauterization or a ventriculoperitoneal shunt. Patients underwent assessment with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III; sometimes referred to as BSID-III) and CT scans preoperatively and then at 6, 12, and 24 months postoperatively. Volumes of brain, CSF, and subdural fluid were calculated, and z-scores from the median were determined from normative curves for CSF accumulation and brain growth. Linear and logistic regression models were used to characterize the association between preoperative CSF volume and the postoperative presence and size of subdural collection 6 and 12 months after surgery. Linear regression and smoothing spline ANOVA were used to describe the relationship between subdural fluid volume and cognitive scores. Causal mediation analysis distinguished between the direct and indirect effects of the presence of a subdural collection on cognitive scores. RESULTS: Subdural collections were more common in shunt-treated patients and those with larger preoperative CSF volumes. Subdural fluid volumes were linearly related to preoperative CSF volumes. In terms of outcomes, the Bayley-III cognitive score was linearly related to subdural fluid volume. The distribution of cognitive scores was significantly different for patients with and those without subdural collections from 11 to 24 months of age. The presence of a subdural collection was associated with lower cognitive scores and smaller brain volume 12 months after surgery. Causal mediation analysis demonstrated evidence supporting both a direct (76%) and indirect (24%) effect (through brain volume) of subdural collections on cognitive scores. CONCLUSIONS: Larger preoperative CSF volume and shunt surgery were found to be risk factors for postoperative subdural collection. The size and presence of a subdural collection were negatively associated with cognitive outcomes and brain volume 12 months after surgery. These results have suggested that preoperative CSF volumes could be used for risk stratification for treatment decision-making and that future clinical trials of alternative shunt technologies to reduce overdrainage should be considered.

Immune activation during Paenibacillus brain infection in African infants with frequent cytomegalovirus co-infection.

Inflammation during neonatal brain infections leads to significant secondary sequelae such as hydrocephalus, which often follows neonatal sepsis in the developing world. In 100 African hydrocephalic infants we identified the biological pathways that account for this response. The dominant bacterial pathogen was a Paenibacillus species, with frequent cytomegalovirus co-infection. A proteogenomic strategy was employed to confirm host immune response to Paenibacillus and to define the interplay within the host immune response network. Immune activation emphasized neuroinflammation, oxidative stress reaction, and extracellular matrix organization. The innate immune system response included neutrophil activity, signaling via IL-4, IL-12, IL-13, interferon, and Jak/STAT pathways. Platelet-activating factors and factors involved with microbe recognition such as Class I MHC antigen-presenting complex were also increased. Evidence suggests that dysregulated neuroinflammation propagates inflammatory hydrocephalus, and these pathways are potential targets for adjunctive treatments to reduce the hazards of neuroinflammation and risk of hydrocephalus following neonatal sepsis.

Paenibacillus infection with frequent viral coinfection contributes to postinfectious hydrocephalus in Ugandan infants.

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.

The impact of African-trained neurosurgeons on sub-Saharan Africa.

OBJECTIVE: Sub-Saharan Africa (SSA) represents 17% of the world's land, 14% of the population, and 1% of the gross domestic product. Previous reports have indicated that 81/500 African neurosurgeons (16.2%) worked in SSA-i.e., 1 neurosurgeon per 6 million inhabitants. Over the past decades, efforts have been made to improve neurosurgery availability in SSA. In this study, the authors provide an update by means of the polling of neurosurgeons who trained in North Africa and went back to practice in SSA. METHODS: Neurosurgeons who had full training at the World Federation of Neurosurgical Societies (WFNS) Rabat Training Center (RTC) over the past 16 years were polled with an 18-question survey focused on demographics, practice/case types, and operating room equipment availability. RESULTS: Data collected from all 21 (100%) WFNS RTC graduates showed that all neurosurgeons returned to work to SSA in 12 different countries, 90% working in low-income and 10% in lower-middle-income countries, defined by the World Bank as a Gross National Income per capita of ≤ US$995 and US$996-$3895, respectively. The cumulative population in the geographical areas in which they practice is 267 million, with a total of 102 neurosurgeons reported, resulting in 1 neurosurgeon per 2.62 million inhabitants. Upon return to SSA, WFNS RTC graduates were employed in public/private hospitals (62%), military hospitals (14.3%), academic centers (14.3%), and private practice (9.5%). The majority reported an even split between spine and cranial and between trauma and elective; 71% performed between 50 and more than 100 neurosurgical procedures/year. Equipment available varied across the cohort. A CT scanner was available to 86%, MRI to 38%, surgical microscope to 33%, endoscope to 19.1%, and neuronavigation to 0%. Three (14.3%) neurosurgeons had access to none of the above. CONCLUSIONS: Neurosurgery availability in SSA has significantly improved over the past decade thanks to the dedication of senior African neurosurgeons, organizations, and volunteers who believed in forming the new neurosurgery generation in the same continent where they practice. Challenges include limited resources and the need to continue expanding efforts in local neurosurgery training and continuing medical education. Focus on affordable and low-maintenance technology is needed.

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/)

Subspecialty pediatric neurosurgery training: a skill-based training model for neurosurgeons in low-resourced health systems.

There is inadequate pediatric neurosurgical training to meet the growing burden of disease in low- and middle-income countries (LMIC). Subspecialty expertise in the management of hydrocephalus and spina bifida-two of the most common pediatric neurosurgical conditions-offers a high-yield opportunity to mitigate morbidity and avoid unnecessary death. The CURE Hydrocephalus and Spina Bifida (CHSB) fellowship offers an intensive subspecialty training program designed to equip surgeons from LMIC with the state-of-the-art surgical skills and equipment to most effectively manage common neurosurgical conditions of childhood. Prospective fellows and their home institution undergo a comprehensive evaluation before being accepted for the 8-week training period held at CURE Children's Hospital of Uganda (CCHU) in Mbale, Uganda. The fellowship combines anatomy review, treatment paradigms, a flexible endoscopic simulation lab, daily ward and ICU rounds, radiology rounds, and clinic exposure. The cornerstone of the fellowship is the unique operative experience that includes a high volume of endoscopic third ventriculostomy with choroid plexus cauterization, myelomeningocele closure, and ventriculoperitoneal shunting, among many other procedures performed at CCHU. Upon completion, fellows return to their home institution to establish or rejuvenate a robust pediatric practice as part of a worldwide network of CHSB trainees committed to the care of underserved children. To date, the fellowship has graduated 33 surgeons from 20 different LMIC who are independently performing thousands of hydrocephalus and spina bifida operations each year.

Pancaost syndrome related to hydatid cyst.

Pancoast syndrome remains a rare presentation of pulmonary diseases. Even in endemic area of echinococcosis, lung's hydatid cyst is seldomly revealed by this syndrome. We report a case of a 38 year old male patient who presented to our department with neck and left superior limb pain associated with palmar muscle atrophy and Horner's syndrome. Radiological investigations suggested the diagnosis of hydatid cyst of the left lung apex which was confirmed by surgical excision and pathological examination of the lesion. This case highlights an uncommon etiology of Pancoast syndrome which might mislead physicians in their practice.