Serious bacterial infections among Ugandan neonates: Aetiology, clinical findings and one year outcomes

Title: Serious bacterial infections among Ugandan neonates: Aetiology, clinical findings and one year outcomes. Author: K L Burgoine Background: Globally, serious bacterial infections, such as sepsis, pneumonia and meningitis, are a leading cause of neonatal mortality. In sub-Saharan Africa (SSA) there are believed to be up to 2.6 million cases of pSBI every year, leading to an estimated 250,000 deaths. Diagnosis is challenging since signs and symptoms are often non-specific and laboratory facilities are limited. In low-resource settings, the diagnosis of a possible serious bacterial infection (pSBI) relies on clinical algorithms. Cranial ultrasound (cUS) is a relatively cheap, safe and portable method of assessing the neonatal brain that could be used to detect findings indicative of CNS involvement. There are also limited data on the outcomes of pSBI survivors. This is one of the first studies in SSA to assess the role of cUS in the evaluation of infants with pSBI and the early developmental outcome of infants admitted with pSBI. Aims: In term neonates presenting with pSBI to a neonatal unit in eastern Uganda: • Describe the clinical presentation, aetiology and neonatal outcomes • Describe findings on cUS scans at presentation and correlate the imaging findings with presentation, CSF analysis and neonatal mortality • Compare cUS findings to a cohort of similar aged well term neonates. • Describe findings on serial cUS scans up to 28 days • Evaluate mortality, growth and developmental impairment up to 12 months of age and compare it to the contemporaneous control cohort • Investigate the risk factors that contribute to poor early childhood outcome in term-born infants that experienced a possible severe bacterial infection (pSBI) during the neonatal period. Methods: Over a 1-year period, any term neonates presenting to the neonatal unit at Mbale Regional Referral Hospital who met the definition of pSBI were screened for inclusion. We described the microbiological aetiology using blood and CSF culture, the presenting clinical features and the neonatal outcomes. Each neonate had a standard cUS examination performed. The images were interpreted systematically by one of two experts blinded to the clinical details. A contemporaneous cohort of well term neonates were recruited. They underwent the same clinical and cUS examination. We followed-up surviving infants at 2, 6 and 12 months of age to evaluate survival, growth and development. The Bayley Scales of Infant Development-3rd edition (BSID-III) was used and developmental impairment was defined as a scaled-score <-1SD below the mean. Poor outcome was defined as either death, hydrocephalus, post-neonatal seizures or developmental impairment at 12 months of age. Results: 214 neonates with pSBI were recruited. Definite or possible pathogens were identified in 5.6% (12/214) of blood cultures. The most common pathogens isolated were Staphylococcus Aureus, Klebsiella and Escherichia coli. Potential pathogens were isolated in 0% (0/189) of CSF cultures. The overall neonatal mortality was 9.3% (20/214). The neonatal mortality from neonatal meningitis was 22.2% (6/27). Early cUS scans were available for 196/214 (91.6%) neonates with pSBI. There was no observed association between cUS findings at presentation and neonatal mortality. Moderate and severe cortical and/or white matter (WM) echogenicities were significantly associated with abnormal CSF analysis. The presence of signs suggestive of encephalopathy or meningism were associated with abnormal cortical, WM, and basal ganglia and thalami (BGT) echogenicity, ventricular dilatation and bright ventricular lining. At 12 months 164/187 survivors of pSBI were available for assessment; 4/187 infants had died during the post-neonatal period. Developmental impairment was evident across all domains of the BSID-III and the rates of impairment ranged from 7.9% to 14.6%. 24/44 control infants were available for assessment and none of these infants were impaired in any of the 5 domains. The raw scores and the scaled scores for all five neurocognitive domains were significantly lower for survivors of pSBI compared to control infants. Survivors of neonatal meningitis, had the highest rates of developmental impairment, being 24%, 35% and 24% in cognitive, language and motor domains respectively. Survivors of neonatal meningitis had a 12 to 18-fold increased risk of developmental impairment across all domains. By 12 months of age 30.5% (54/177) of infants had a poor outcome. After adjustment for sex, age and weight, the following factors increased the risk of poor outcome: age <48 hours at presentation, respiratory distress (aOR 2.7, 95%CI 1.2-6.2), neonatal seizures (aOR 13.0 (5.2-32.4)), opisthotonus (aOR 9.5 (3.5-27.0)), hypotonia (aOR 3.0 (1.1-8.3)) and raised CSF protein (aOR 9.5 (2.3-38.6)). cUS findings at presentation, significantly associated with poor outcome were abnormal cortex (aOR 6.9 (2.0-23.5)), abnormal white matter (aOR 2.0 (1.0-3.9)), abnormal basal ganglia (aOR 13.6 (2.7-68.2)) and abnormal thalami (aOR 5.28 (1.8-15.2)). Conclusion: It is clear that serious bacterial infections during the neonatal period, even without meningitis, may have a substantial public health and economic burden in SSA. Presentation before 48 hours of age, lower weight, several readily recognisable clinical signs as well as raised CSF protein and cortical, white matter, and central grey matter abnormalities seen on cUS, were all significant predictors of poor outcome. These risk factors will enable us to better consider which infants need more intensive follow-up, early intervention and support. Improving our understanding of the specific aetiologies associated with mortality, developmental impairment and post-infectious hydrocephalus, is now necessary to inform prevention strategies and treatment approaches

Caffeine for the care of preterm infants in sub-Saharan Africa: a missed opportunity?

In 2019, 2.4 million neonates (infants <28 days of age) died globally. Of these, over 80% were preterm infants (<37 weeks gestation), with the majority born in low-income and middle-income countries.1 Complications of preterm birth, largely from respiratory distress syndrome due to surfactant deficiency, pneumonia or apnoea of prematurity (AOP), are now the leading cause of under 5 mortality globally.1 These conditions are frequently fatal in the absence of effective ventilatory support which is commonplace in neonatal units across sub-Saharan Africa. Although the global neonatal mortality rate (NMR) has halved over the past three decades, significant regional disparities remain. These correlate with World Bank and International Monetary Fund estimates of the proportion of the population living on less than US$1.90 a day, with the majority of poorer countries being in sub-Saharan Africa.1 2 As the region with the highest NMR of 27 per 1000 live births, it is estimated that a baby born in in sub-Saharan Africa is 10 times more likely to die than one born in a high income country.1 Countries in sub-Saharan Africa are unlikely to meet the global target of no more than 12 newborn deaths per 1000 live births by 2030.3 In 2017, 75 countries (almost half from sub-Saharan Africa) signed up to the ‘Every Newborn Action Plan’ that has strategic global and national actions and milestones to address gaps in maternal and newborn care.4 This ambitious commitment requires evidence-based interventions5 and innovative strategies to improve neonatal survival and longer-term outcomes

Perceptions, beliefs, and current practices regarding neonatal skin care and emollient use in eastern Uganda: a qualitative study

Background The skin is a major route of infection in the neonatal period, especially in low birthweight (LBW) infants. Appropriate and safe neonatal skin care practices are required to reduce this risk. The perceptions and beliefs of mothers and other caregivers towards various neonatal skin care practices in our setting have been documented. Data from Asia suggests that the application of emollient to the skin of LBW infants can promote growth, reduce serious neonatal infections, and potentially reduce mortality. This is the first study to explore the acceptability of emollients and massage as part of neonatal skin care in a low-resource setting in sub-Saharan Africa (SSA) that is representative of the majority of government health facilities in Uganda and many in SSA. Objective To explore perceptions, beliefs, and current practices regarding neonatal skin care and emollient use in eastern Uganda. Methods We conducted a qualitative study consisting of three focus group discussions (30 participants), eight in-depth interviews with mothers/caregivers of preterm and term neonates and 12 key informant interviews with midwives, doctors and community health workers involved in neonatal care, to explore the perceptions and practices surrounding neonatal skin care and emollient use. Data collected were transcribed and analyzed using thematic content analysis. Results Mothers perceived that skin care began in utero. Skincare practices depended on the place of delivery; for deliveries in a health facility the skincare practices were mainly based on the health worker’s advice. Vernix caseosa was often washed off due to its perceived undesirability and was attributed to sexual intercourse in the last trimester. Despite their deleterious attributes found in previous studies, petrolatum-based oils, petrolatum-based jellies and talcum baby powders were the most commonly reported items used in neonatal skin care. In our population, there was high acceptability of emollient therapy use; however, neonatal massage was treated with scepticism as mothers feared damaging the vulnerable neonate. Mothers suggested massage and emollient application be undertaken by health workers, if it becomes an intervention. Conclusions In eastern Uganda, the perceptions and beliefs of mothers/caregivers toward neonatal skincare influenced their practices of which some could potentially be beneficial, and others harmful. Emollient use would be easily accepted if adequate sensitisation is conducted and using the gatekeepers such as health workers

Impact of secondary and tertiary neonatal interventions on neonatal mortality in a low- resource limited setting hospital in Uganda: a retrospective study.

OBJECTIVE: To assess the impact of secondary and tertiary level neonatal interventions on neonatal mortality over a period of 11 years. DESIGN: Interrupted time series analysis. SETTING: Nsambya Hospital, Uganda. INTERVENTIONS: Neonatal secondary interventions (phase I, 2007-2014) and tertiary level interventions (phase II, 2015-2020). PARTICIPANTS: Neonates. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome: neonatal mortality. SECONDARY OUTCOME: case fatality rate (CFR) for prematurity, neonatal sepsis and asphyxia. RESULTS: During the study period, a total of 25 316 neonates were admitted, of which 1853 (7.3%) died. The average inpatient mortality reduced from 8.2% during phase I to 5.7% during phase II (p=0.001). The CFR for prematurity reduced from 16.2% to 9.2% (p=0.001). There was a trend in reduction for the CFR of perinatal asphyxia from 14.9% to 13.0% (p=0.34). The CFR for sepsis had a more than a twofold increase (3%-6.8% p=0.001) between phase I and phase II. CONCLUSION: Implementation of secondary and tertiary neonatal care in resource-limited settings is feasible. This study shows that these interventions can significantly reduce the neonatal mortality, with the largest impact seen in the reduction of deaths from perinatal asphyxia and prematurity. An increase in sepsis related deaths was observed, suggesting emphasis on infection control is key

A cluster randomised trial to evaluate the effectiveness of household alcohol-based hand rub for the prevention of sepsis, diarrhoea, and pneumonia in Ugandan infants (the BabyGel trial): a study protocol

Background: Infections are one of the leading causes of death in the neonatal period. This trial aims to evaluate if the provision of alcohol-based hand rub (ABHR) to pregnant women for postnatal household use prevents severe infections (including sepsis, diarrhoea, pneumonia, or death) among infants during the first three postnatal months. Methods: Through a cluster-randomised trial in eastern Uganda, 72 clusters are randomised in a 2-arm design with rural villages as units of randomisation. We estimate to include a total of 5932 pregnant women at 34 weeks of gestation. All women and infants in the study are receiving standard antenatal and postnatal care. Women in the intervention group additionally receive six litres of ABHR and training on its use. Research midwives conduct follow-up visits at participants’ homes on days 1, 7, 28, 42, and 90 after birth and telephone calls on days 14, 48, and 60 to assess the mother and infant for study outcomes. Primary analyses will be by intention to treat. Discussion: This study will provide evidence on the effectiveness of a locally available and low-cost intervention in preventing neonatal sepsis and early infant infections. If ABHR is found effective, it could be implemented by adding it to birthing kits. Trial registration: Pan African Clinical Trial Registry, PACTR202004705649428. Registered 1 April 2020, https://pactr.samrc.ac.za/

Early Childhood Outcomes After Neonatal Encephalopathy in Uganda: A Cohort Study.

BACKGROUND: Neonatal encephalopathy (NE) is a leading cause of global child mortality. Survivor outcomes in low-resource settings are poorly described. We present early childhood outcomes after NE in Uganda. METHODS: We conducted a prospective cohort study of term-born infants with NE (n = 210) and a comparison group of term non-encephalopathic (non-NE) infants (n = 409), assessing neurodevelopmental impairment (NDI) and growth at 27-30 months. Relationships between early clinical parameters and later outcomes were summarised using risk ratios (RR). FINDINGS: Mortality by 27-30 months was 40·3% after NE and 3·8% in non-NE infants. Impairment-free survival occurred in 41·6% after NE and 98·7% of non-NE infants. Amongst NE survivors, 29·3% had NDI including 19·0% with cerebral palsy (CP), commonly bilateral spastic CP (64%); 10·3% had global developmental delay (GDD) without CP. CP was frequently associated with childhood seizures, vision and hearing loss and mortality. NDI was commonly associated with undernutrition (44·1% Z-score < - 2) and microcephaly (32·4% Z-score < - 2). Motor function scores were reduced in NE survivors without CP/GDD compared to non-NE infants (median difference - 8·2 (95% confidence interval; - 13·0, - 3·7)). Neonatal clinical seizures (RR 4.1(2.0-8.7)), abnormalities on cranial ultrasound, (RR 7.0(3.8-16.3), nasogastric feeding at discharge (RR 3·6(2·1-6·1)), and small head circumference at one year (Z-score < - 2, RR 4·9(2·9-5·6)) increased the risk of NDI. INTERPRETATION: In this sub-Saharan African population, death and neurodevelopmental disability after NE were common. CP was associated with sensorineural impairment, malnutrition, seizures and high mortality by 2 years. Early clinical parameters predicted impairment outcomes

Early cranial ultrasound findings among infants with neonatal encephalopathy in Uganda: an observational study.

BACKGROUND: In sub-Saharan Africa, the timing and nature of brain injury and their relation to mortality in neonatal encephalopathy (NE) are unknown. We evaluated cranial ultrasound (cUS) scans from term Ugandan infants with and without NE for evidence of brain injury. METHODS: Infants were recruited from a national referral hospital in Kampala. Cases (184) had NE and controls (100) were systematically selected unaffected term infants. All had cUS scans <36 h reported blind to NE status. RESULTS: Scans were performed at median age 11.5 (interquartile range (IQR): 5.2-20.2) and 8.4 (IQR: 3.6-13.5) hours, in cases and controls respectively. None had established antepartum injury. Major evolving injury was reported in 21.2% of the cases vs. 1.0% controls (P < 0.001). White matter injury was not significantly associated with bacteremia in encephalopathic infants (odds ratios (OR): 3.06 (95% confidence interval (CI): 0.98-9.60). Major cUS abnormality significantly increased the risk of neonatal death (case fatality 53.9% with brain injury vs. 25.9% without; OR: 3.34 (95% CI: 1.61-6.95)). CONCLUSION: In this low-resource setting, there was no evidence of established antepartum insult, but a high proportion of encephalopathic infants had evidence of major recent and evolving brain injury on early cUS imaging, suggesting prolonged or severe acute exposure to hypoxia-ischemia (HI). Early abnormalities were a significant predictor of death

The Bacterial and Viral Complexity of Postinfectious Hydrocephalus in Uganda

Postinfectious hydrocephalus (PIH), often following neonatal sepsis, is the most common cause of pediatric hydrocephalus world-wide, yet the microbial pathogens remain uncharacterized. Characterization of the microbial agents causing PIH would lead to an emphasis shift from surgical palliation of cerebrospinal fluid (CSF) accumulation to prevention. We examined blood and CSF from 100 consecutive cases of PIH and control cases of non-postinfectious hydrocephalus (NPIH) in infants in Uganda. Genomic testing was undertaken for bacterial, fungal, and parasitic DNA, DNA and RNA sequencing for viral identification, and extensive bacterial culture recovery. We uncovered a major contribution to PIH from Paenibacillus , upon a background of frequent cytomegalovirus (CMV) infection. CMV was only found in CSF in PIH cases. A facultatively anaerobic isolate was recovered. Assembly of the genome revealed a strain of P. thiaminolyticus . In mice, this isolate designated strain Mbale , was lethal in contrast with the benign reference strain. These findings point to the value of an unbiased pan-microbial approach to characterize PIH in settings where the organisms remain unknown, and enables a pathway towards more optimal treatment and prevention of the proximate neonatal infections. One Sentence Summary We have discovered a novel strain of bacteria upon a frequent viral background underlying postinfectious hydrocephalus in Uganda

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