Publications by authors named "Elizabeth M Molyneux"

63 Publications

Preterm care during the COVID-19 pandemic: A comparative risk analysis of neonatal deaths averted by kangaroo mother care versus mortality due to SARS-CoV-2 infection.

EClinicalMedicine 2021 Mar 15;33:100733. Epub 2021 Feb 15.

Maternal, Adolescent, Reproductive and Child Health Centre, London School of Hygiene and Tropical Medicine (LSHTM), Keppel Street, London WC1E 7HT, United Kingdom.

Background: COVID-19 is disrupting health services for mothers and newborns, particularly in low- and middle-income countries (LMIC). Preterm newborns are particularly vulnerable. We undertook analyses of the benefits of kangaroo mother care (KMC) on survival among neonates weighing ≤2000 g compared with the risk of SARS-CoV-2 acquired from infected mothers/caregivers.

Methods: We modelled two scenarios over 12 months. Scenario 1 compared the survival benefits of KMC with universal coverage (99%) and mortality risk due to COVID-19. Scenario 2 estimated incremental deaths from reduced coverage and complete disruption of KMC. Projections were based on the most recent data for 127 LMICs (~90% of global births), with results aggregated into five regions.

Findings: Our worst-case scenario (100% transmission) could result in 1,950 neonatal deaths from COVID-19. Conversely, 125,680 neonatal lives could be saved with universal KMC coverage. Hence, the benefit of KMC is 65-fold higher than the mortality risk of COVID-19. If recent evidence of 10% transmission was applied, the ratio would be 630-fold. We estimated a 50% reduction in KMC coverage could result in 12,570 incremental deaths and full disruption could result in 25,140 incremental deaths, representing a 2·3-4·6% increase in neonatal mortality across the 127 countries.

Interpretation: The survival benefit of KMC far outweighs the small risk of death due to COVID-19. Preterm newborns are at risk, especially in LMICs where the consequences of disruptions are substantial. Policymakers and healthcare professionals need to protect services and ensure clearer messaging to keep mothers and newborns together, even if the mother is SARS-CoV-2-positive.

Funding: Eunice Kennedy Shriver National Institute of Child Health & Human Development; Bill & Melinda Gates Foundation; Elma Philanthropies; Wellcome Trust; and Joint Global Health Trials scheme of Department of Health and Social Care, Department for International Development, Medical Research Council, and Wellcome Trust.
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http://dx.doi.org/10.1016/j.eclinm.2021.100733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955179PMC
March 2021

Early doxorubicin cardiotoxicity in Malawian children admitted to Queen Elizabeth Central Hospital, Malawi.

Pediatr Blood Cancer 2021 Mar 15:e29003. Epub 2021 Mar 15.

College of Medicine, Queen Elizabeth Central Hospital, Blantyre, Malawi.

Background: Doxorubicin is known to cause chemotherapy-induced cardiotoxicity. In resource-poor settings, monitoring for cardiotoxicity is not routinely done, and its incidence is unknown. The aim of this study was to determine the proportion of children who developed doxorubicin-induced cardiotoxicity within 1 year of having received treatment at paediatric oncology ward.

Methods: Children aged 3 months to 18 years with cancer were prospectively enrolled and followed up between January 2016 to June 2019. Transthoracic echocardiogram was done at baseline, 1 month, 6 months and a year after completion of therapy. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) of ≥10% to a final value of <50%. An overall incidence risk of developing cardiotoxicity was estimated. A one-way analysis of variance (ANOVA) was conducted to compare baseline LVEF with follow-up measurements.

Findings: Ninety-one children were enrolled, 74% (68/91) were male, and 67% (62/91) were aged 5 months to 14 years. Most patients received a doxorubicin cumulative dose between 100 and 200 mg/m and no cardiotoxicity was observed during the study period. However, of 77 children with at least one follow up, five children 6.54% (95% CI: 2.1-14.5) experienced LVEF reduction of >10%, though not to a final value of <50%. No deterioration of systolic function was found among 20 children who completed follow-up (F = 2.43, p-value = .07).

Interpretation: In this cohort of patients, most received a low cumulative doxorubicin dose and only 22% were available for evaluation at study end; no cardiotoxic events associated with doxorubicin administration were observed after 12 months.
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http://dx.doi.org/10.1002/pbc.29003DOI Listing
March 2021

"So sometimes, it looks like it's a neglected ward": Health worker perspectives on implementing kangaroo mother care in southern Malawi.

PLoS One 2020 17;15(12):e0243770. Epub 2020 Dec 17.

Department of Health Systems and Policy, School of Public Health and Family Medicine, College of Medicine, University of Malawi, Blantyre, Malawi.

Introduction: Kangaroo mother care (KMC) involves continuous skin-to-skin contact of baby on mother's chest to provide warmth, frequent breastfeeding, recognizing danger signs of illness, and early discharge. Though KMC is safe, effective and recommended by the World Health Organization, implementation remains limited in practice. The objective of this study is to understand barriers and facilitators to KMC practice at tertiary and secondary health facilities in southern Malawi from the perspective of health workers.

Methods: This study is part of the "Integrating a neonatal healthcare package for Malawi" project in the Innovating for Maternal and Child Health in Africa initiative. In-depth interviews were conducted between May-Aug 2019 with a purposively drawn sample of service providers and supervisors working in newborn health at a large tertiary hospital and three district-level hospitals in southern Malawi. Data were analyzed using a thematic approach using NVivo 12 software (QSR International, Melbourne, Australia).

Findings: A total of 27 nurses, clinical officers, paediatricians and district health management officials were interviewed. Staff attitudes, inadequate resources and reliance on families emerged as key themes. Health workers from Malawi described KMC practice positively as a low-cost, low-technology solution appropriate for resource-constrained health settings. However, staff perceptions that KMC babies were clinically stable was associated with lower prioritization in care and poor monitoring practices. Neglect of the KMC ward by medical staff, inadequate staffing and reliance on caregivers for supplies were associated with women self-discharging early.

Conclusion: Though routine uptake of KMC was policy for stable low birthweight and preterm infants in the four hospitals, there were gaps in monitoring and maintenance of practice. While conceptualized as a low-cost intervention, sustainable implementation requires investments in technologies, staffing and hospital provisioning of basic supplies such as food, bedding, and KMC wraps. Strengthening hospital capacities to support KMC is needed as part of a continuum of care for premature infants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243770PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746165PMC
January 2021

Scaling up newborn care technologies from tertiary- to secondary-level hospitals in Malawi: an implementation case study of health professional perspectives on bubble CPAP.

Implement Sci Commun 2020 Nov 4;1(1):100. Epub 2020 Nov 4.

School of Public Health and Family Medicine, Department of Health Systems and Policy, College of Medicine, University of Malawi, Blantyre, Malawi.

Background: While Malawi has achieved success in reducing overall under-five mortality, reduction of neonatal mortality remains a persistent challenge. There has, therefore, been a push to strengthen the capacity for quality newborn care at district hospitals through the implementation of innovative neonatal technologies such as bubble continuous positive airway pressure (CPAP). This study investigates tertiary- versus secondary-level hospital differences in capacities for bubble CPAP use and implications for implementation policies.

Methods: A secondary analysis of interviews was conducted with 46 health workers at one tertiary hospital and three secondary hospitals in rural Southern Malawi. Grounded theory was utilized to explore the emerging themes according to health worker cadres (nurse, clinician, district health management) and facility level (tertiary- and secondary-level facilities), which were managed using NVivo 12 (QSR International, Melbourne, Australia).

Results: We identified frequent CPAP use and the availability of neonatal nurses, physicians, and reliable electricity as facilitators for CPAP use at the tertiary hospital. Barriers at the tertiary hospital included initiation eligibility disagreements between clinicians and nurses and insufficient availability of the CPAP machines. At secondary-level hospitals, the use was supported by decision-making and initiation by nurses, involving caretakers to assist in monitoring and reliable availability of CPAP machines. Bubble CPAP was hindered by unreliable electricity, staffing shortages and rotation policies, and poor systems of accountability.

Conclusion: While this study looked at the implementation of bubble CPAP in Malawi, the findings may be applicable for scaling up other novel neonatal technologies in low-resource settings. Implementation policies must consider staffing and management structures at different health services levels for effective scale-up.
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http://dx.doi.org/10.1186/s43058-020-00092-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640662PMC
November 2020

Health workers' views on factors affecting caregiver engagement with bubble CPAP.

BMC Pediatr 2020 04 23;20(1):180. Epub 2020 Apr 23.

Department of Pediatrics and Child Health, College of Medicine, University of Malawi, Blantyre, Malawi.

Background: Severe respiratory distress is a leading cause of mortality among neonates in Malawi. Despite evidence on the safety, cost effectiveness and efficacy of bubble continuous positive airway pressure (CPAP) in managing the condition, its use in Malawian health facilities is limited and little is known about caregivers' engagement with perspectives of bubble CPAP. The purpose of this study was to explore caregiver perspectives for bubble CPAP at both central and district hospitals and key factors that enable effective caregiver engagement in Malawi.

Methods: This was a descriptive qualitative study employing secondary analysis of 46 health care worker in-depth interviews. We interviewed the health workers about their thoughts on caregiver perspectives regarding use of bubble CPAP. We implemented the study at a tertiary facility and three district hospitals in southern Malawi. This was a part of a larger study to understand barriers and facilitators to implementing neonatal innovations in resource-constrained hospitals. Interviews were thematically analysed in NVivo 12 software (QSR International, Melbourne, Australia). Health workers were purposively selected to include nurses, clinicians and district health management involved in the use of bubble CPAP.

Results: Emerging issues included caregiver fears around bubble CPAP equipment as potentially harmful to their new-borns and how inadequate information provided to caregivers exacerbated knowledge gaps and was associated with refusal of care. However, good communication between health care providers and caregivers was associated with acceptance of care. Caregivers' decision-making was influenced by relatives and peer advocates were helpful in supporting caregivers and alleviating fears or misconceptions about bubble CPAP.

Conclusions: Since caregivers turn to relatives and peers for support, there is need to ensure that both relatives and peers are counselled on bubble CPAP for improved understanding and uptake. Health workers need to provide simplified, accurate, up-to-date information on the intervention as per caregivers' level of understanding. Notably, contextualised comprehensible information will help alleviate caregivers' fear and anxieties about bubble CPAP.
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http://dx.doi.org/10.1186/s12887-020-02088-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179004PMC
April 2020

Rethinking management of neonates at risk of sepsis.

Lancet 2019 Jul;394(10195):279-281

Department of Pediatrics, University of British Columbia and Children's and Women's Health Centres, Vancouver, BC V6H3V4, Canada.

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http://dx.doi.org/10.1016/S0140-6736(19)31627-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675455PMC
July 2019

Lessons learned from a multicentre clinical trial in Africa.

Nat Rev Clin Oncol 2019 04;16(4):211-212

Department of Paediatrics, College of Medicine, Blantyre, Malawi.

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http://dx.doi.org/10.1038/s41571-018-0121-0DOI Listing
April 2019

Peripheral blood RNA gene expression in children with pneumococcal meningitis: a prospective case-control study.

BMJ Paediatr Open 2017 31;1(1):e000092. Epub 2017 Aug 31.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi.

Introduction: Invasive pneumococcal disease (IPD), caused by is a leading cause of pneumonia, meningitis and septicaemia worldwide, with increased morbidity and mortality in HIV-infected children.

Objectives: We aimed to compare peripheral blood expression profiles between HIV-infected and uninfected children with pneumococcal meningitis and controls, and between survivors and non-survivors, in order to provide insight into the host inflammatory response leading to poorer outcomes.

Design And Setting: Prospective case-control observational study in a tertiary hospital in Malawi.

Participants: Children aged 2 months to 16 years with pneumococcal meningitis or pneumonia.

Methods: We used the human genome HGU133A Affymetrix array to explore differences in gene expression between cases with pneumococcal meningitis (n=12) and controls, and between HIV-infected and uninfected cases, and validated gene expression profiles for 34 genes using real-time quantitative PCR (RT-qPCR) in an independent set of cases with IPD (n=229) and controls (n=13). Pathway analysis was used to explore genes differentially expressed.

Results: Irrespective of underlying HIV infection, cases showed significant upregulation compared with controls of the following: S100 calcium-binding protein A12 (S100A12); vanin-1 (VNN1); arginase, liver (ARG1); matrix metallopeptidase 9 (MMP9); annexin A3 (ANXA3); interleukin 1 receptor, type II (IL1R2); CD177 molecule (CD177); endocytic adaptor protein (NUMB) and S100 calcium-binding protein A9 (S100A9), cytoskeleton-associated protein 4 (CKAP4); and glycogenin 1 (GYG1). RT-qPCR confirmed differential expression in keeping with microarray results. There was no differential gene expression in HIV-infected compared with HIV-uninfected cases, but there was significant upregulation of folate receptor 3 (FOLR3), S100A12 in survivors compared with non-survivors.

Conclusion: Children with IPD demonstrated increased expression in genes regulating immune activation, oxidative stress, leucocyte adhesion and migration, arginine metabolism, and glucocorticoid receptor signalling.
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http://dx.doi.org/10.1136/bmjpo-2017-000092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862186PMC
August 2017

Setting up and running a paediatric emergency department in a hospital in Malawi: 15 years on.

BMJ Paediatr Open 2017 21;1(1):e000014. Epub 2017 Jun 21.

Emergency Department, Macclesfield Hospital, Macclesfield, UK.

Paediatric emergency care is not recognised as a specialty in many countries in Africa but is being practised increasingly. Setting up a paediatric emergency care unit takes time and often involves trial and error. Here we describe the start of the paediatric emergency department in Blantyre, Malawi, a low-income country and how it has continued to evolve over 15 years, in the hope that our experience will inform and assist others who are already developing their own emergency unit or wishing to do so.
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http://dx.doi.org/10.1136/bmjpo-2017-000014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842997PMC
June 2017

Challenges and Priorities for Pediatric Critical Care Clinician-Researchers in Low- and Middle-Income Countries.

Front Pediatr 2017 22;5:277. Epub 2017 Dec 22.

Division of Pediatric Critical Care Medicine, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States.

Introduction: There is need for more data on critical care outcomes and interventions from low- and middle-income countries (LMIC). Global research collaborations could help improve health-care delivery for critically ill children in LMIC where child mortality rates remain high.

Materials And Methods: To inform the role of collaborative research in health-care delivery for critically ill children in LMIC, an anonymous online survey of pediatric critical care (PCC) physicians from LMIC was conducted to assess priorities, major challenges, and potential solutions to PCC research. A convenience sample of 56 clinician-researchers taking care of critically ill children in LMIC was targeted. In addition, the survey was made available on a Latin American PCC website. Descriptive statistics were used for data analysis.

Results: The majority of the 47 survey respondents worked at urban, public teaching hospitals in LMIC. Respondents stated their primary PCC research motivations were to improve clinical care and establish guidelines to standardize care. Top challenges to conducting research were lack of funding, high clinical workload, and limited research support staff. Respondent-proposed solutions to these challenges included increasing research funding options for LMIC, better access to mentors from high-income countries, research training and networks, and higher quality medical record documentation.

Conclusion: LMIC clinician-researchers must be better empowered and resourced to lead and influence the local and global health research agenda for critically ill children. Increased funding options, access to training and mentorship in research methodology, and improved data collection systems for LMIC PCC researchers were recognized as key needs for success.
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http://dx.doi.org/10.3389/fped.2017.00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744187PMC
December 2017

Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: A prospective observational study.

PLoS Negl Trop Dis 2017 12 7;11(12):e0006027. Epub 2017 Dec 7.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi.

Nontyphoidal Salmonellae commonly cause invasive disease in African children that is often fatal. The clinical diagnosis of these infections is hampered by the absence of a clear clinical syndrome. Drug resistance means that empirical antibiotic therapy is often ineffective and currently no vaccine is available. The study objective was to identify risk factors for mortality among children presenting to hospital with invasive Salmonella disease in Africa. We conducted a prospective study enrolling consecutive children with microbiologically-confirmed invasive Salmonella disease admitted to Queen Elizabeth Central Hospital, Blantyre, in 2006. Data on clinical presentation, co-morbidities and outcome were used to identify children at risk of inpatient mortality through logistic-regression modeling. Over one calendar year, 263 consecutive children presented with invasive Salmonella disease. Median age was 16 months (range 0-15 years) and 52/256 children (20%; 95%CI 15-25%) died. Nontyphoidal serovars caused 248/263 (94%) of cases. 211/259 (81%) of isolates were multi-drug resistant. 251/263 children presented with bacteremia, 6 with meningitis and 6 with both. Respiratory symptoms were present in 184/240 (77%; 95%CI 71-82%), 123/240 (51%; 95%CI 45-58%) had gastrointestinal symptoms and 101/240 (42%; 95%CI 36-49%) had an overlapping clinical syndrome. Presentation at <7 months (OR 10.0; 95%CI 2.8-35.1), dyspnea (OR 4.2; 95%CI 1.5-12.0) and HIV infection (OR 3.3; 95%CI 1.1-10.2) were independent risk factors for inpatient mortality. Invasive Salmonella disease in Malawi is characterized by high mortality and prevalence of multi-drug resistant isolates, along with non-specific presentation. Young infants, children with dyspnea and HIV-infected children bear a disproportionate burden of the Salmonella-associated mortality in Malawi. Strategies to improve prevention, diagnosis and management of invasive Salmonella disease should be targeted at these children.
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http://dx.doi.org/10.1371/journal.pntd.0006027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745124PMC
December 2017

Triple therapy of vincristine, bleomycin and etoposide for children with Kaposi sarcoma: Results of a study in Malawian children.

Pediatr Blood Cancer 2018 Feb 8;65(2). Epub 2017 Oct 8.

Queen Elizabeth Central Hospital, College of Medicine, Blantyre, Malawi.

Background: Kaposi sarcoma (KS) is the most common paediatric cancer in human immunodeficiency virus (HIV) endemic countries of sub-Saharan Africa, but there is little research on management and outcomes.

Methods: Children with KS at Queen Elizabeth Central Hospital, Blantyre, Malawi treated between August 2012 and March 2015 with six courses of vincristine, bleomycin and etoposide combination chemotherapy, including antiretroviral therapy (ART) if HIV infected, were studied and outcomes compared with previously reported results.

Findings: Fifty-six children were included; 38 (68%) were male; and 48 (86%) were HIV positive, of whom 36 (77%) were on ART at diagnosis. Median age at diagnosis was 8 years (interquartile range [IQR] 3-12) and median follow-up was 16.9 months (IQR 3.4-36.4). Quality of life improved in 45 (80%) children; the median Lansky Score increased from 80% pre-treatment to 100% post-treatment. Eighteen (32%) children had complete response to treatment. At 12 months, overall survival was 71% (95% confidence interval [CI] 56-82) and event-free survival (event = death, loss to follow-up or relapse) was 50% (95% CI 36-63). At 1 year, the risk of loss to follow-up was 13.4%. In a previous, same-site, randomized controlled study of vincristine monotherapy, vincristine and bleomycin, or oral etoposide, oral etoposide monotherapy had the best outcome with survival at 12 month of 66% (95% CI 46-80) and event-free survival of 52% (95% CI 33-68); however, loss to follow-up was not reported.

Conclusion: Overall survival, event-free survival and quality of life appear to have improved with this three-agent combination chemotherapy; however larger, randomized studies are needed to determine optimal management.
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http://dx.doi.org/10.1002/pbc.26841DOI Listing
February 2018

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.

Pediatr Infect Dis J 2017 Dec;36(12):e328-e333

From the *Department of Pediatrics, College of Medicine, †Department of Pediatrics, Queen Elizabeth Central Hospital, and ‡John Hopkins Research Unit College of Medicine, Blantyre, Malawi; §Department of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom; ¶Malawi Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi; and ‖Division of Infection & Immunity, University College London, London, United Kingdom.

Background: The World Health Organization recommends benzylpenicillin and gentamicin as antimicrobial treatment for infants with sepsis in low-income settings, and ceftriaxone or cefotaxime as an alternative. In a meta-analysis from 13 low-income settings, Staphylococcus aureus, Klebsiella spp. and Escherichia 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 with 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: Three-hundred forty-eight infants were included in analyses. Outcome in the benzylpenicillin and gentamicin and ceftriaxone groups was similar; deaths were 13.7% and 16.5% and sequelae were 14.5% and 11.2%, respectively. More infants in the penicillin/gentamicin group required phototherapy: 15% versus 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.
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http://dx.doi.org/10.1097/INF.0000000000001576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466153PMC
December 2017

Paediatric emergencies in sub-Saharan Africa.

Afr J Emerg Med 2017 7;7(Suppl):S1-S2. Epub 2017 Dec 7.

Dept of Child Health, School of Medicine and Dentistry, University of Ghana, Accra, Ghana.

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http://dx.doi.org/10.1016/j.afjem.2017.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246871PMC
December 2017

Cytokine Profiles during Invasive Nontyphoidal Salmonella Disease Predict Outcome in African Children.

Clin Vaccine Immunol 2016 07 5;23(7):601-9. Epub 2016 Jul 5.

School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom

Nontyphoidal Salmonella is a leading cause of sepsis in African children. Cytokine responses are central to the pathophysiology of sepsis and predict sepsis outcome in other settings. In this study, we investigated cytokine responses to invasive nontyphoidal Salmonella (iNTS) disease in Malawian children. We determined serum concentrations of 48 cytokines with multiplexed immunoassays in Malawian children during acute iNTS disease (n = 111) and in convalescence (n = 77). Principal component analysis and logistic regression were used to identify cytokine signatures of acute iNTS disease. We further investigated whether these responses are altered by HIV coinfection or severe malnutrition and whether cytokine responses predict inpatient mortality. Cytokine changes in acute iNTS disease were associated with two distinct cytokine signatures. The first is characterized by increased concentrations of mediators known to be associated with macrophage function, and the second is characterized by raised pro- and anti-inflammatory cytokines typical of responses reported in sepsis secondary to diverse pathogens. These cytokine responses were largely unaltered by either severe malnutrition or HIV coinfection. Children with fatal disease had a distinctive cytokine profile, characterized by raised mediators known to be associated with neutrophil function. In conclusion, cytokine responses to acute iNTS infection in Malawian children are reflective of both the cytokine storm typical of sepsis secondary to diverse pathogens and the intramacrophage replicative niche of NTS. The cytokine profile predictive of fatal disease supports a key role of neutrophils in the pathogenesis of NTS sepsis.
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http://dx.doi.org/10.1128/CVI.00128-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933780PMC
July 2016

Kaposi sarcoma in HIV-seronegative children presenting to the paediatric oncology ward in The Queen Elizabeth Central Hospital, Blantyre, Malawi during 2002-2014.

Trop Doct 2016 Jul 29;46(3):138-42. Epub 2015 Nov 29.

Consultant Paediatrician, College of Medicine, Blantyre, Malawi.

One of the most common malignancies in HIV-endemic, resource-poor countries is Kaposi sarcoma (KS). It is an AIDS-defining disease and as Malawi's incidence and prevalence of HIV is high, KS is now the most common cancer in adult male Malawians and the second most common in women and children. Most attention has focused on HIV-seropositive adults as their number far outweighs those of children. This audit concerns the presentation and outcome of HIV-seronegative children with KS who presented in a 12-year period (2002-2014) to The Queen Elizabeth Central Hospital. Twenty (10.5%) of the 191 children with KS presenting to the paediatric oncology ward during 2002-2014 were HIV-seronegative. They were usually younger than seropositive children and 62% had severe anaemia. The main presenting complaints in the HIV-seronegative group were woody oedema, commonly of a limb, and lymphadenopathy. Woody oedema was common in children with or without HIV infection. Seronegative children with KS were less likely to have oral KS than HIV infected children. Of 11 children who completed courses of chemotherapy, seven (63%) had complete cure sustained over a 1-year follow-up period. KS is potentially curable in this group of children. Chemotherapy regimens are equally effective in HIV-seropositive and HIV-seronegative children. The presentation of HIV-seronegative children with KS differs from adults and HIV-seropositive children. Further research is necessary to determine possible triggers for developing KS in HIV-seronegative children.
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http://dx.doi.org/10.1177/0049475515614738DOI Listing
July 2016

The effects of malnutrition on cardiac function in African children.

Arch Dis Child 2016 Feb 9;101(2):166-71. Epub 2015 Nov 9.

Department of Paediatrics, University of Malawi College of Medicine, Blantyre, Malawi.

Objective: Cardiac dysfunction may contribute to high mortality in severely malnourished children. Our objective was to assess the effect of malnutrition on cardiac function in hospitalised African children.

Design: Prospective cross-sectional study.

Setting: Public referral hospital in Blantyre, Malawi.

Patients: We enrolled 272 stable, hospitalised children ages 6-59 months, with and without WHO-defined severe acute malnutrition.

Main Outcome Measures: Cardiac index, heart rate, mean arterial pressure, stroke volume index and systemic vascular resistance index were measured by the ultrasound cardiac output monitor (USCOM, New South Wales, Australia). We used linear regression with generalised estimating equations controlling for age, sex and anaemia.

Results: Our primary outcome, cardiac index, was similar between those with and without severe malnutrition: difference=0.22 L/min/m(2) (95% CI -0.08 to 0.51). No difference was found in heart rate or stroke volume index. However, mean arterial pressure and systemic vascular resistance index were lower in children with severe malnutrition: difference=-8.6 mm Hg (95% CI -12.7 to -4.6) and difference=-200 dyne s/cm(5)/m(2) (95% CI -320 to -80), respectively.

Conclusions: In this largest study to date, we found no significant difference in cardiac function between hospitalised children with and without severe acute malnutrition. Further study is needed to determine if cardiac function is diminished in unstable malnourished children.
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http://dx.doi.org/10.1136/archdischild-2015-309188DOI Listing
February 2016

Outcomes of Patients with Respiratory Distress Treated with Bubble CPAP on a Pediatric Ward in Malawi.

J Trop Pediatr 2015 Dec 11;61(6):421-7. Epub 2015 Sep 11.

Paediatric Department, College of Medicine, Blantyre 3, Malawi.

Objective: To describe the outcomes of infants and young children with respiratory distress when treated with a novel, low-cost, stand-alone bubble Continuous Positive Airway Pressure (bCPAP) system in a resource-limited setting.

Methods: A non-randomized, convenience sample study in a pediatric unit in Blantyre, Malawi, 2013. Patients weighing ≤10 kg with respiratory distress were eligible. We compared outcomes for patients with bronchiolitis, pneumonia and Pneumocystis jiroveci pneumonia (PJP) after treatment with bCPAP.

Results: Seventy percent of patients treated with bCPAP survived. Outcomes were best for patients with bronchiolitis and worst for those with PJP. Most survivors (80%) showed improvement within 24 h. All treating physicians found bCPAP useful, leading to a change in practice.

Conclusions: Bubble CPAP was most beneficial to patients with bronchiolitis. Children, who were going to get well, tended to get well quickly. Physicians believed the bCPAP system provided a higher level of care than nasal oxygen.
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http://dx.doi.org/10.1093/tropej/fmv052DOI Listing
December 2015

New technologies for essential newborn care in under-resourced areas: what is needed and how to deliver it.

Paediatr Int Child Health 2015 Aug 8;35(3):192-205. Epub 2015 Jun 8.

Globally, the largest contributors to neonatal mortality are preterm birth, intrapartum complications and infection. Many of these deaths could be prevented by providing temperature stability, respiratory support, hydration and nutrition; preventing and treating infections; and diagnosing and treating neonatal jaundice and hypoglycaemia. Most neonatal health-care technologies which help to accomplish these tasks are designed for high-income countries and are either unavailable or unsuitable in low-resource settings, preventing many neonates from receiving the gold standard of care. There is an urgent need for neonatal health-care technologies which are low-cost, robust, simple to use and maintain, affordable and able to operate from various power supplies. Several technologies have been designed to meet these requirements or are currently under development; however, unmet technology needs remain. The distribution of an integrated set of technologies, rather than separate components, is essential for effective implementation and a substantial impact on neonatal health. Close collaboration between stakeholders at all stages of the development process and an increased focus on implementation research are necessary for effective and sustainable implementation.
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http://dx.doi.org/10.1179/2046905515Y.0000000034DOI Listing
August 2015

Improving the outcome of bacterial meningitis in newborn infants in Africa: reflections on recent progress.

Curr Opin Infect Dis 2015 Jun;28(3):215-20

Department of Paediatrics, College of Medicine and Queen Elizabeth Central Hospital, Blantyre, Malawi.

Purpose Of Review: There has been a reduction in overall under fives mortality (UFM) but neonatal mortality has not fallen at the same rate as for older children. Bacterial meningitis remains a common, often unrecognized and devastating illness in many African newborns with high mortality and morbidity. Further progress in reducing UFM has to focus on quality of care for neonates. Recent efforts to improve diagnosis, treatment and outcome are reviewed.

Recent Findings: Diagnosis is often unsupported by laboratory tests and efforts have been made to improve the clinical diagnosis of bacterial meningitis. Simpler, robust bedside tests are being devised. The cause of bacterial meningitis is changing and first-line antimicrobial therapy and adjuvant therapies are evaluated. Programmes to reduce risk factors and prevent neonatal infections are identified.

Summary: Neonatal care needs to improve in first referral hospitals with simple, low-cost, validated measures provided as bundles of care for both mother and child. First-line antibiotic therapy must be reconsidered in the light of increased infections by multiresistant and Gram-negative bacteria. Studies are needed for effective and safe lengths of antimicrobial therapy, the role of adjuvant therapy and the best anticonvulsants to use.
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http://dx.doi.org/10.1097/QCO.0000000000000162DOI Listing
June 2015

Paediatric oncology: Collaborating in Africa-small steps to sustainable success.

Nat Rev Clin Oncol 2014 Dec 28;11(12):691-2. Epub 2014 Oct 28.

Department of Paediatrics, College of Medicine, Blantyre, Private Bag 360, Chichiri 3, Blantyre, Malawi.

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http://dx.doi.org/10.1038/nrclinonc.2014.189DOI Listing
December 2014

Bacterial meningitis in Malawian adults, adolescents, and children during the era of antiretroviral scale-up and Haemophilus influenzae type b vaccination, 2000-2012.

Clin Infect Dis 2014 May 4;58(10):e137-45. Epub 2014 Feb 4.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.

Background: We documented bacterial meningitis trends among adults and children presenting to a large teaching hospital in Malawi during introduction of Haemophilus influenzae type b (Hib) vaccination and the rollout of antiretroviral therapy (ART).

Methods: We analyzed data from 51 000 consecutive cerebrospinal fluid (CSF) samples obtained from adults, adolescents, and children with suspected meningitis admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi, between 2000 and 2012.

Results: There was a significant decline in the total number of CSF isolates over 12 years (incident rate ratio [IRR], 0.93; 95% CI, .92-.94; P < .001). This decline was entirely in children aged <5 years (IRR, 0.87; 95% CI, .85-.88; P < .001) and coincided with the introduction of Hib vaccination. The number of adult isolates has remained unchanged (IRR, 0.99; 95% CI, .97-1.0; P = .135) despite rapid scale-up of ART provision. In children aged <5 years, Streptococcus pneumoniae, nontyphoidal salmonellae (NTS), and Hib were the most frequently isolated pathogens, and have declined over this time period. Streptococcus pneumoniae was the most frequently isolated pathogen in older children and adults. Estimated incidence of bacterial meningitis in 2012 was 20 per 100,000 cases in children aged <14 years, 6 per 100,000 adolescents, and 10 per 100,000 adults.

Conclusions: Rates of bacterial meningitis have declined in children, but not adults, coinciding with the introduction of Hib vaccination. The highly successful rollout of ART has not yet resulted in a reduction in the incidence in adults where the burden remains high. Long-term surveillance of bacterial meningitis outside of the epidemic "meningitis belt" in Africa is essential.
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http://dx.doi.org/10.1093/cid/ciu057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001285PMC
May 2014

Relationship between Plasmodium falciparum malaria prevalence, genetic diversity and endemic Burkitt lymphoma in Malawi.

Sci Rep 2014 Jan 17;4:3741. Epub 2014 Jan 17.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.

Endemic Burkitt lymphoma (eBL) has been linked to Plasmodium falciparum (Pf) malaria infection, but the contribution of infection with multiple Pf genotypes is uncertain. We studied 303 eBL (cases) and 274 non eBL-related cancers (controls) in Malawi using a sensitive and specific molecular-barcode array of 24 independently segregating Pf single nucleotide polymorphisms. Cases had a higher Pf malaria prevalence than controls (64.7% versus 45.3%; odds ratio [OR] 2.1, 95% confidence interval (CI): 1.5 to 3.1). Cases and controls were similar in terms of Pf density (4.9 versus 4.5 log copies, p = 0.28) and having ≥3 non-clonal calls (OR 2.7, 95% CI: 0.7-9.9, P = 0.14). However, cases were more likely to have a higher Pf genetic diversity score (153.9 versus 133.1, p = 0.036), which measures a combination of clonal and non-clonal calls, than controls. Further work is needed to evaluate the possible role of Pf genetic diversity in the pathogenesis of endemic BL.
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http://dx.doi.org/10.1038/srep03741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894552PMC
January 2014

Bacterial meningitis in Malawian infants <2 months of age: etiology and susceptibility to World Health Organization first-line antibiotics.

Pediatr Infect Dis J 2014 Jun;33(6):560-5

From the *Department of Paediatrics, University of Malawi College of Medicine, Blantyre, Malawi; †Centre for Immunity, Infection and Evolution, Edinburgh, United Kingdom; ‡Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi; §Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom; ¶Emergency Department, Townsville Hospital, Douglas, Queensland, Australia; ‖Centre for Inflammation Research, University of Edinburgh, Edinburgh; and **Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

Background: Neonatal meningitis is an important cause of morbidity in sub-Saharan Africa and requires urgent empiric treatment with parenteral administered antibiotics. Here we describe the etiology, antimicrobial susceptibility and suitability of the World Health Organization first-line recommended antibiotics (penicillin and gentamicin) for bacterial meningitis in young infants in Malawi.

Methods: We reviewed all cerebrospinal fluid samples received from infants ≤2 months of age with clinically suspected meningitis between January 1, 2002, and December 31, 2008, at the Queen Elizabeth Central Hospital in Blantyre, Malawi.

Results: We identified 259 culture-positive isolates from 259 infants ≤2 months of age. Sixty isolates were from neonates ≤7 days old, in whom the most common pathogens were Group B Streptococcus (27/60; 45.0%), Streptococcus pneumoniae (13/60; 21.7%) and nontyphoidal Salmonella enterica (7/60; 11.7%). One hundred and ninety one isolates were from young infants who were >7 days and ≤2 months of age. In this group, the most common isolates were S. pneumoniae (80/191; 41.9%), Group B Streptococcus (38/191; 19.9%) and nontyphoidal Salmonella enterica (34/191; 17.8%). More isolates were susceptible to ceftriaxone than to the combination of penicillin and gentamicin (218/220; 99.1% vs. 202/220; 91.8%, Fisher's exact test P = 0.006). In particular, Gram-negative isolates were significantly more susceptible to ceftriaxone than to gentamicin (72/74; 97.3% vs. 63/74; 85.1%, Fisher's exact test P = 0.020). Penicillin and gentamicin provided less coverage for Gram-negative than Gram-positive isolates (74/86; 86.0% vs. 155/163; 95.1%, χ = 6.24, P = 0.012).

Conclusions: In view of these results, the World Health Organization recommendations for empiric penicillin and gentamicin for suspected neonatal meningitis should be reevaluated.
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http://dx.doi.org/10.1097/INF.0000000000000210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025590PMC
June 2014

Glycerol and acetaminophen as adjuvant therapy did not affect the outcome of bacterial meningitis in Malawian children.

Pediatr Infect Dis J 2014 Feb;33(2):214-6

From the *Department of Pediatrics and Child Health, College of Medicine, Malawi; †Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; ‡National Institute for Health and Welfare; and §Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.

We investigated the benefit of 2 candidate adjunctive therapies in bacterial meningitis: glycerol, which has shown promise in earlier studies, and acetaminophen, which is reportedly beneficial in adult septicemia. In a hospital in Blantyre, Malawi, we enrolled 360 children aged ≥ 2 months with proven bacterial meningitis (36% HIV infected) in a double-blind, randomized, placebo-controlled trial of glycerol and acetaminophen in a 2 × 2 factorial design. Of 4 groups, first group received oral glycerol, second received rectal acetaminophen, third received both therapies and the fourth received placebos only. Adjuvant therapies were given for the first 48 hours of antibiotic therapy. Endpoints were mortality and neurological sequelae. Baseline findings were similar across all groups, except that many children had prior antibiotics in the acetaminophen group and many were anemic in the acetaminophen and glycerol group. Outcomes were similar for all groups. We found no benefit from oral glycerol or rectal acetaminophen in, mostly pneumococcal, meningitis in Malawian children.
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http://dx.doi.org/10.1097/INF.0000000000000122DOI Listing
February 2014

Sexual abuse of children in low-income settings: time for action.

Paediatr Int Child Health 2013 Nov 18;33(4):239-46. Epub 2013 Sep 18.

Queen Elizabeth Central Hospital, Blantyre, Malawi.

In this article, child sexual abuse in low-income settings is reviewed, including the extent of the problem, the way children present, and how they should be managed. Liaising with other agencies, training in all aspects of sexual abuse and creating an environment that is conducive to good care by all groups involved is essential. Technical details of medical examination are not covered as appropriate guidelines are accessible.
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http://dx.doi.org/10.1179/2046905513Y.0000000087DOI Listing
November 2013

Developing a palliative care service for children in the Queen Elizabeth Central Hospital, Blantyre, Malawi.

Arch Dis Child 2013 Sep 29;98(9):698-701. Epub 2013 Jul 29.

The Paediatric Department, Queen Elizabeth Central Hospital, Blantyre, Malawi.

There are too few palliative care services for children in resource poor countries. Health carers are overwhelmed with cases of acute illness that need their urgent attention, and chronically ill children with life-limiting diseases have been sidelined. The HIV epidemic in southern Africa revealed the huge needs in our own hospital, and in 2002, we started a hospital-based paediatric palliative care service. It was the first in Africa. We describe here how it developed and expanded in the ensuing years and how it has affected our staff, the children and their families in our care.
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http://dx.doi.org/10.1136/archdischild-2013-303722DOI Listing
September 2013

Clinical trials to improve childhood cancer care and survival in sub-Saharan Africa.

Nat Rev Clin Oncol 2013 10 30;10(10):599-604. Epub 2013 Jul 30.

Department of Paediatric Oncology, VU University Medical Centre, De Boelelaan 1117, 1018HV Amsterdam, Netherlands.

Over 80% of children with cancer live in low and middle-income countries where survival rates are much lower than high-income countries. Challenges to successful treatment of paediatric cancers in these countries include late presentation, malnutrition, failure to complete treatment and less-intense supportive care leading to increased treatment-related mortality and the need to reduce the intensity of treatment. Clinical trials can contribute to improved care and survival by providing objective information on the number of patients treated, accuracy of diagnosis, causes of treatment failure and the efficacy of specific interventions. Clinical trials can also help to build capacity (salary support and training), improve facilities (equipment) and fund treatment or essential associated costs (social support, nutritional support and follow-up care). In this article, we discuss our experience with clinical trials in Malawi and sub-Saharan Africa with emphasis on the treatment of children with Wilms tumour.
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http://dx.doi.org/10.1038/nrclinonc.2013.137DOI Listing
October 2013

Risk factors for death and severe sequelae in Malawian children with bacterial meningitis, 1997-2010.

Pediatr Infect Dis J 2013 Feb;32(2):e54-61

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Background: Acute bacterial meningitis (ABM) causes significant death and disability in children worldwide, with HIV recognized as an established risk factor for infection and negative outcomes. However, additional major risk factors for death and disability in pediatric ABM remain unclear.

Methods: We conducted a retrospective analysis of case data from 3 departmental studies of ABM involving 1784 children <15 years old who attended Queen Elizabeth Central Hospital in Blantyre, Malawi during 1997 to 2010. Univariate and multivariate logistic regression models were used to estimate the effects of HIV seropositivity, impaired consciousness and causative organism on death and severe sequelae.

Results: Impaired consciousness or coma at the time of admission was strongly associated with death (coma: odds ratio [OR] = 14.4, 95% confidence interval [CI]: 9.42, 22.1) and severe sequelae (Coma: OR = 3.27, 95% CI: 2.02, 5.29) in multivariate logistic regression models. HIV seropositivity was significantly associated with increased odds of death (OR = 1.65, 95% CI: 1.20, 2.26) but not with developing severe sequelae (OR = 0.88, 95% CI: 0.56, 1.38). After adjustment, infection with Salmonella spp. was associated with increased odds of death (OR = 2.11, 95% CI: 1.06, 4.08) and pneumococcal meningitis was associated with increased odds of severe sequelae (OR = 1.84, 95% CI: 1.03, 3.29).

Conclusions: Impaired consciousness and HIV infection increased the odds of death from ABM in Malawian children. Use of pneumococcal conjugate vaccine could greatly reduce the burden of ABM in Malawi.
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http://dx.doi.org/10.1097/INF.0b013e31826faf5aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671939PMC
February 2013