Admissions to a Low-Resource Neonatal Unit in Malawi Using a Mobile App and Dashboard: A 1-Year Digital Perinatal Outcome Audit

Introduction: Understanding the extent and cause of high neonatal deaths rates in Sub-Saharan Africa is a challenge, especially in the presence of poor-quality and inaccurate data. The NeoTree digital data capture and quality improvement system has been live at Kamuzu Central Hospital, Neonatal Unit, Malawi, since April 2019. Objective: To describe patterns of admissions and outcomes in babies admitted to a Malawian neonatal unit over a 1-year period via a prototype data dashboard. Methods: Data were collected prospectively at the point of care, using the NeoTree app, which includes digital admission and outcome forms containing embedded clinical decision and management support and education in newborn care according to evidence-based guidelines. Data were exported and visualised using Microsoft Power BI. Descriptive and inferential analysis statistics were executed using R. Results: Data collected via NeoTree were 100% for all mandatory fields and, on average, 96% complete across all fields. Coverage of admissions, discharges, and deaths was 97, 99, and 91%, respectively, when compared with the ward logbook. A total of 2,732 neonates were admitted and 2,413 (88.3%) had an electronic outcome recorded: 1,899 (78.7%) were discharged alive, 12 (0.5%) were referred to another hospital, 10 (0.4%) absconded, and 492 (20%) babies died. The overall case fatality rate (CFR) was 204/1,000 admissions. Babies who were premature, low birth weight, out born, or hypothermic on admission, and had significantly higher CFR. Lead causes of death were prematurity with respiratory distress (n = 252, 51%), neonatal sepsis (n = 116, 23%), and neonatal encephalopathy (n = 80, 16%). The most common perceived modifiable factors in death were inadequate monitoring of vital signs and suboptimal management of sepsis. Two hundred and two (8.1%) neonates were HIV exposed, of whom a third [59 (29.2%)] did not receive prophylactic nevirapine, hence vulnerable to vertical infection. Conclusion: A digital data capture and quality improvement system was successfully deployed in a low resource neonatal unit with high (1 in 5) mortality rates providing and visualising reliable, timely, and complete data describing patterns, risk factors, and modifiable causes of newborn mortality. Key targets for quality improvement were identified. Future research will explore the impact of the NeoTree on quality of care and newborn survival

Indirect impacts of the COVID-19 pandemic at two tertiary neonatal units in Zimbabwe and Malawi: an interrupted time series analysis.

OBJECTIVES: To examine indirect impacts of the COVID-19 pandemic on neonatal care in low-income and middle-income countries. DESIGN: Interrupted time series analysis. SETTING: Two tertiary neonatal units in Harare, Zimbabwe and Lilongwe, Malawi. PARTICIPANTS: We included a total of 6800 neonates who were admitted to either neonatal unit from 1 June 2019 to 25 September 2020 (Zimbabwe: 3450; Malawi: 3350). We applied no specific exclusion criteria. INTERVENTIONS: The first cases of COVID-19 in each country (Zimbabwe: 20 March 2020; Malawi: 3 April 2020). PRIMARY OUTCOME MEASURES: Changes in the number of admissions, gestational age and birth weight, source of admission referrals, prevalence of neonatal encephalopathy, and overall mortality before and after the first cases of COVID-19. RESULTS: Admission numbers in Zimbabwe did not initially change after the first case of COVID-19 but fell by 48% during a nurses' strike (relative risk (RR) 0.52, 95% CI 0.41 to 0.66, p0.05). CONCLUSIONS: The indirect impacts of COVID-19 are context-specific. While our study provides vital evidence to inform health providers and policy-makers, national data are required to ascertain the true impacts of the pandemic on newborn health

The Treatment of Possible Severe Infection in Infants: An Open Randomized Safety Trial of Parenteral Benzylpenicillin and Gentamicin Versus Ceftriaxone in Infants <60 days of Age in Malawi

BACKGROUND: The World Health Organization recommends benzylpenicillin and gentamicin as antimicrobial treatment of infants with sepsis in low income settings (LICs), and ceftriaxone or cefotaxime as an alternative. In a meta-analysis from 13 LICs, Staphylococcus aureus, Klebsiella spp. and E.coli accounted for 55% of infants with sepsis. In a review of bacterial meningitis, resistance to third generation cephalosporins was > 50% of all isolates, and 44% of Gram-negative isolates were gentamicin resistant. However, ceftriaxone may cause neonatal jaundice and gentamicin may cause deafness. Therefore, we compared parenteral benzylpenicillin plus gentamicin to ceftriaxone as first line treatment, assessing outcome and adverse events. METHODS:: This was an open randomized trial carried out in the Queen Elizabeth Central Hospital, Blantyre, Malawi from 2010 to 2013. Infants < 60 days of age with possible severe sepsis received either benzylpenicillin and gentamicin or ceftriaxone. Adverse events and outcomes were recorded until 6 months post discharge. RESULTS:: 348 infants were included in analyses. Outcome in the benzylpenicillin and gentamicin or ceftriaxone groups was similar; deaths were 13.7% and 16.5% and sequelae 14.5% and 11.2% respectively. More infants in the penicillin/gentamicin group required phototherapy: 15% v 5%, p=0.03. Thirteen (6%) survivors had bilateral hearing loss. There was no difference between the treatment groups. By 6 months post discharge 11 more infants had died and 17 more children were found to have sequelae. CONCLUSIONS:: Ceftriaxone and gentamicin are safe for infants in our setting. Infants should receive long term follow up as many poor outcomes occurred after hospital discharge

Changes in moderately low birthweight infant feeding, care, and health outcomes before compared to during the COVID-19 pandemic in Malawi

Background: The coronavirus disease 2019 (COVID-19) and the measures taken to minimise its spread have significantly impacted mother- and infant-related healthcare. We describe the changes in newborn feeding, lactation support, and growth outcomes before compared to during the COVID-19 pandemic among moderately low birthweight infants (LBW) (1.5 to <2.5kg) in Malawi. Methods: The data presented here are part of the Low Birthweight Infant Feeding Exploration (LIFE) study, a formative, multisite, mixed methods observational cohort study. In this analysis, we included infants born at two public hospitals in Lilongwe, Malawi between 18 October 2019 and 29 July 2020. We categorised births as "pre-COVID-19 period" (before 1 April 2020) and "during COVID-19 period" (on or after 2 April 2020) and used descriptive statistics and mixed effects models to examine differences in birth complications, lactation support, feeding, and growth outcomes between the two time periods. Results: We included 300 infants and their mothers (n = 273) in the analysis. Most infants (n = 240) were born during the pre-COVID-19 period; 60 were born during the pandemic period. The latter group had a lower prevalence of uncomplicated births (35.8%) compared to pre-pandemic period group (16.7%) (P = 0.004). Fewer mothers reported early initiation of breastfeeding in the pandemic period (27.2%) compared to the pre-pandemic period (14.6%) (P = 0.053), along with significantly less breastfeeding support, particularly in view of discussion of proper latching (44.9% during COVID-19 vs 72.7% pre-COVID-19; P < 0.001) and physical support with positioning (14.3% vs 45.5% pre-COVID-19 P < 0.001). At 10 weeks of age, the prevalence of stunting was 51.0% pre-COVID-19 vs 45.1% during COVID-19 (P = 0.46), the prevalence of underweight was 22.5% pre-COVID-19 vs 30.4% during COVID-19 (P = 0.27), and the prevalence of wasting was 0% pre-COVID-19 vs 2.5% during COVID-19 (P = 0.27). Conclusions: Our findings highlight the continued need to optimise early initiation of breastfeeding and lactation support for infants during COVID-19 and future pandemics. More studies are needed to evaluate the long-term outcomes of moderately LBW born during the COVID-19 pandemic (including growth outcomes) and determine the impact of restrictive measures on access to lactation support and promotion of early initiation of breastfeeding

Protocol for an intervention development and pilot implementation evaluation study of an e-health solution to improve newborn care quality and survival in two low-resource settings, Malawi and Zimbabwe: Neotree.

INTRODUCTION: Every year 2.4 million deaths occur worldwide in babies younger than 28 days. Approximately 70% of these deaths occur in low-resource settings because of failure to implement evidence-based interventions. Digital health technologies may offer an implementation solution. Since 2014, we have worked in Bangladesh, Malawi, Zimbabwe and the UK to develop and pilot Neotree: an android app with accompanying data visualisation, linkage and export. Its low-cost hardware and state-of-the-art software are used to improve bedside postnatal care and to provide insights into population health trends, to impact wider policy and practice. METHODS AND ANALYSIS: This is a mixed methods (1) intervention codevelopment and optimisation and (2) pilot implementation evaluation (including economic evaluation) study. Neotree will be implemented in two hospitals in Zimbabwe, and one in Malawi. Over the 2-year study period clinical and demographic newborn data will be collected via Neotree, in addition to behavioural science informed qualitative and quantitative implementation evaluation and measures of cost, newborn care quality and usability. Neotree clinical decision support algorithms will be optimised according to best available evidence and clinical validation studies. ETHICS AND DISSEMINATION: This is a Wellcome Trust funded project (215742_Z_19_Z). Research ethics approvals have been obtained: Malawi College of Medicine Research and Ethics Committee (P.01/20/2909; P.02/19/2613); UCL (17123/001, 6681/001, 5019/004); Medical Research Council Zimbabwe (MRCZ/A/2570), BRTI and JREC institutional review boards (AP155/2020; JREC/327/19), Sally Mugabe Hospital Ethics Committee (071119/64; 250418/48). Results will be disseminated via academic publications and public and policy engagement activities. In this study, the care for an estimated 15 000 babies across three sites will be impacted. TRIAL REGISTRATION NUMBER: NCT0512707; Pre-results

Neighbourhood prevalence-to-notification ratios for adult bacteriologically-confirmed tuberculosis reveals hotspots of underdiagnosis in Blantyre, Malawi

Funding: This work was supported by two grants from Wellcome Trust (ELC grant number WT200901/Z/16/Z) and (PM grant number 200901/Z/16/Z). JRC was funded by UK Medical Research Council (MRC) programme grant MC_UU_00004/07. PJD was supported by a fellowship from the MRC (MR/P022081/1); this UK funded award was part of the EDCTP2 programme supported by the European Union. RMB was funded by Wellcome Trust (203905/16/Z). KCH was supported by the European Research Council (757699) and UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). TC was supported by US NIH R01 R01AI147854.Local information is needed to guide targeted interventions for respiratory infections such as tuberculosis (TB). Case notification rates (CNRs) are readily available, but systematically underestimate true disease burden in neighbourhoods with high diagnostic access barriers. We explored a novel approach, adjusting CNRs for under-notification (P:N ratio) using neighbourhood-level predictors of TB prevalence-to-notification ratios. We analysed data from 1) a citywide routine TB surveillance system including geolocation, confirmatory mycobacteriology, and clinical and demographic characteristics of all registering TB patients in Blantyre, Malawi during 2015–19, and 2) an adult TB prevalence survey done in 2019. In the prevalence survey, consenting adults from randomly selected households in 72 neighbourhoods had symptom-plus-chest X-ray screening, confirmed with sputum smear microscopy, Xpert MTB/Rif and culture. Bayesian multilevel models were used to estimate adjusted neighbourhood prevalence-to-notification ratios, based on summarised posterior draws from fitted adult bacteriologically-confirmed TB CNRs and prevalence. From 2015–19, adult bacteriologically-confirmed CNRs were 131 (479/371,834), 134 (539/415,226), 114 (519/463,707), 56 (283/517,860) and 46 (258/578,377) per 100,000 adults per annum, and 2019 bacteriologically-confirmed prevalence was 215 (29/13,490) per 100,000 adults. Lower educational achievement by household head and neighbourhood distance to TB clinic was negatively associated with CNRs. The mean neighbourhood P:N ratio was 4.49 (95% credible interval [CrI]: 0.98–11.91), consistent with underdiagnosis of TB, and was most pronounced in informal peri-urban neighbourhoods. Here we have demonstrated a method for the identification of neighbourhoods with high levels of under-diagnosis of TB without the requirement for a prevalence survey; this is important since prevalence surveys are expensive and logistically challenging. If confirmed, this approach may support more efficient and effective targeting of intensified TB and HIV case-finding interventions aiming to accelerate elimination of urban TB.Peer reviewe

World Health Organization Danger Signs to predict bacterial sepsis in young infants: A pragmatic cohort study

Bacterial sepsis is generally a major concern in ill infants. To help triaging decisions by front-line health workers in these situations, the World Health Organization (WHO) has developed danger signs (DS). The objective of this study was to evaluate the extent to which nine DS predict bacterial sepsis in young infants presenting with suspected sepsis in a low-income country setting. The study pragmatically evaluated nine DS in infants younger than 3 months with suspected sepsis in a regional hospital in Lilongwe, Malawi, between June 2018 and April 2020. Main outcomes were positive blood or cerebrospinal fluid (CSF) cultures for neonatal pathogens, and mortality. Among 401 infants (gestational age [mean ± SD]: 37.1±3.3 weeks, birth weight 2865±785 grams), 41 had positive blood or CSF cultures for a neonatal pathogen. In-hospital mortality occurred in 9.7% of infants overall (N = 39/401), of which 61.5% (24/39) occurred within 48 hours of admission. Mortality was higher in infants with bacterial sepsis compared to other infants (22.0% [9/41] versus 8.3% [30/360]; p = 0.005). All DS were associated with mortality except for temperature instability and tachypnea, whereas none of the DS were significantly associated with bacterial sepsis, except for “unable to feed” (OR 2.25; 95%CI: 1.17–4.44; p = 0.017). The number of DS predicted mortality (OR: 1.75; 95%CI: 1.43–2.17; p<0.001; AUC: 0.756), but was marginally associated with positive cultures with a neonatal pathogen (OR 1.22; 95%CI: 1.00–1.49; p = 0.046; AUC: 0.743). The association between number of DS and mortality remained significant after adjusting for admission weight, the only statistically significant co-variable (OR 1.75 [95% CI: 1.39–2.23]; p<0.001). Considering all positive cultures including potential bacterial contaminants resulted a non-significant association between number of DS and sepsis (OR 1.09 [95% CI: 0.93–1.28]; p = 0.273). In conclusion, this study shows that DS were strongly associated with death, but were marginally associated with culture-positive pathogen sepsis in a regional hospital setting. These data imply that the incidence of bacterial sepsis and attributable mortality in infants in LMIC settings may be inaccurately estimated based on clinical signs alone

Neighbourhood prevalence-to-notification ratios for adult bacteriologically-confirmed tuberculosis reveals hotspots of underdiagnosis in Blantyre, Malawi

Local information is needed to guide targeted interventions for respiratory infections such as tuberculosis (TB). Case notification rates (CNRs) are readily available, but systematically underestimate true disease burden in neighbourhoods with high diagnostic access barriers. We explored a novel approach, adjusting CNRs for under-notification (P:N ratio) using neighbourhood-level predictors of TB prevalence-to-notification ratios. We analysed data from 1) a citywide routine TB surveillance system including geolocation, confirmatory mycobacteriology, and clinical and demographic characteristics of all registering TB patients in Blantyre, Malawi during 2015-19, and 2) an adult TB prevalence survey done in 2019. In the prevalence survey, consenting adults from randomly selected households in 72 neighbourhoods had symptom-plus-chest X-ray screening, confirmed with sputum smear microscopy, Xpert MTB/Rif and culture. Bayesian multilevel models were used to estimate adjusted neighbourhood prevalence-to-notification ratios, based on summarised posterior draws from fitted adult bacteriologically-confirmed TB CNRs and prevalence. From 2015-19, adult bacteriologically-confirmed CNRs were 131 (479/371,834), 134 (539/415,226), 114 (519/463,707), 56 (283/517,860) and 46 (258/578,377) per 100,000 adults per annum, and 2019 bacteriologically-confirmed prevalence was 215 (29/13,490) per 100,000 adults. Lower educational achievement by household head and neighbourhood distance to TB clinic was negatively associated with CNRs. The mean neighbourhood P:N ratio was 4.49 (95% credible interval [CrI]: 0.98-11.91), consistent with underdiagnosis of TB, and was most pronounced in informal peri-urban neighbourhoods. Here we have demonstrated a method for the identification of neighbourhoods with high levels of under-diagnosis of TB without the requirement for a prevalence survey; this is important since prevalence surveys are expensive and logistically challenging. If confirmed, this approach may support more efficient and effective targeting of intensified TB and HIV case-finding interventions aiming to accelerate elimination of urban TB

Prevalence of bacteriologically-confirmed pulmonary tuberculosis in urban Blantyre, Malawi 2019-20: substantial decline compared to 2013-14 national survey

Recent evidence shows rapidly changing tuberculosis (TB) epidemiology in Southern and Eastern Africa, with need for subdistrict prevalence estimates to guide targeted interventions. We conducted a pulmonary TB prevalence survey to estimate current TB burden in Blantyre city, Malawi. From May 2019 to March 2020, 115 households in middle/high-density residential Blantyre, were randomly-selected from each of 72 clusters. Consenting eligible participants (household residents ≥ 18 years) were interviewed, including for cough (any duration), and offered HIV testing and chest X-ray; participants with cough and/or abnormal X-ray provided two sputum samples for microscopy, Xpert MTB/Rif and mycobacterial culture. TB disease prevalence and risk factors for prevalent TB were calculated using complete-case analysis, multiple imputation, and inverse probability weighting. Of 20,899 eligible adults, 15,897 (76%) were interviewed, 13,490/15,897 (85%) had X-ray, and 1,120/1,394 (80%) sputum-eligible participants produced at least one specimen, giving 15,318 complete cases (5,895, 38% men). 29/15,318 had bacteriologically-confirmed TB (189 per 100,000 complete-case (cc) / 150 per 100,000 with inverse weighting (iw)). Men had higher burden (cc: 305 [95% CI:144–645] per 100,000) than women (cc: 117 [95% CI:65–211] per 100,000): cc adjusted odds ratio (aOR) 2.70 (1.26–5.78). Other significant risk factors for prevalent TB on complete-case analysis were working age (25–49 years) and previous TB treatment, but not HIV status. Multivariable analysis of imputed data was limited by small numbers, but previous TB and age group 25–49 years remained significantly associated with higher TB prevalence. Pulmonary TB prevalence for Blantyre was considerably lower than the 1,014 per 100,000 for urban Malawi in the 2013–14 national survey, at 150–189 per 100,000 adults, but some groups, notably men, remain disproportionately affected. TB case-finding is still needed for TB elimination in Blantyre, and similar urban centres, but should focus on reaching the highest risk groups, such as older men

Diagnostic accuracy of a three-gene Mycobacterium tuberculosis host response cartridge using fingerstick blood for childhood tuberculosis: a multicentre prospective study in low-income and middle-income countries

BACKGROUND: Childhood tuberculosis remains a major cause of morbidity and mortality in part due to missed diagnosis. Diagnostic methods with enhanced sensitivity using easy-to-obtain specimens are needed. We aimed to assess the diagnostic accuracy of the Cepheid Mycobacterium tuberculosis Host Response prototype cartridge (MTB-HR), a candidate test measuring a three-gene transcriptomic signature from fingerstick blood, in children with presumptive tuberculosis disease. METHODS: RaPaed-TB was a prospective diagnostic accuracy study conducted at four sites in African countries (Malawi, Mozambique, South Africa, and Tanzania) and one site in India. Children younger than 15 years with presumptive pulmonary or extrapulmonary tuberculosis were enrolled between Jan 21, 2019, and June 30, 2021. MTB-HR was performed at baseline and at 1 month in all children and was repeated at 3 months and 6 months in children on tuberculosis treatment. Accuracy was compared with tuberculosis status based on standardised microbiological, radiological, and clinical data. FINDINGS: 5313 potentially eligible children were screened, of whom 975 were eligible. 784 children had MTB-HR test results, of whom 639 had a diagnostic classification and were included in the analysis. MTB-HR differentiated children with culture-confirmed tuberculosis from those with unlikely tuberculosis with a sensitivity of 59·8% (95% CI 50·8–68·4). Using any microbiological confirmation (culture, Xpert MTB/RIF Ultra, or both), sensitivity was 41·6% (34·7–48·7), and using a composite clinical reference standard, sensitivity was 29·6% (25·4–34·2). Specificity for all three reference standards was 90·3% (95% CI 85·5–94·0). Performance was similar in different age groups and by malnutrition status. Among children living with HIV, accuracy against the strict reference standard tended to be lower (sensitivity 50·0%, 15·7–84·3) compared with those without HIV (61·0%, 51·6–69·9), although the difference did not reach statistical significance. Combining baseline MTB-HR result with one Ultra result identified 71·2% of children with microbiologically confirmed tuberculosis. INTERPRETATION: MTB-HR showed promising diagnostic accuracy for culture-confirmed tuberculosis in this large, geographically diverse, paediatric cohort and hard-to-diagnose subgroups. FUNDING: European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Swedish International Development Cooperation Agency, Bundesministerium für Bildung und Forschung; German Center for Infection Research (DZIF)