Implication of the 2014 World Health Organization Integrated Management of Childhood Illness Pneumonia Guidelines with and without pulse oximetry use in Malawi: A retrospective cohort study [version 2; peer review: 2 approved]

Background: Under-5 pneumonia mortality remains high in low-income countries. In 2014 the World Health Organization (WHO) advised that children with chest indrawing pneumonia, but without danger signs or peripheral oxygen saturation (SpO 2) < 90% be treated in the community, rather than hospitalized. In Malawi there is limited pulse oximetry availability. Methods: Secondary analysis of 13,413 under-5 pneumonia cases in Malawi. Pneumonia associated case fatality ratios (CFR) were calculated by disease severity under the assumptions of the 2005 and 2014 WHO Integrated Management of Childhood Illness (IMCI) guidelines, with and without pulse oximetry. We investigated if pulse oximetry readings were missing not at random (MNAR). Results: The CFR of patients classified as having non-severe pneumonia per the 2014 IMCI guidelines doubled under the assumption that pulse oximetry was not available (1.5% without pulse oximetry vs 0.7% with pulse oximetry, P<0.001). When 2014 IMCI guidelines were applied with pulse oximetry and a SpO 2 < 90% as the threshold for referral and/or admission, the number of cases meeting hospitalization criteria decreased by 70.3%. Unrecorded pulse oximetry readings were MNAR with an adjusted odds for mortality of 4.9 (3.8, 6.3), similar to that of a SpO 2 < 90%. Although fewer girls were hospitalized, female sex was an independent mortality risk factor. Conclusions: In Malawi, implementation of the 2014 WHO IMCI pneumonia guidelines, without pulse oximetry, will miss high risk cases. Alternatively, implementation of pulse oximetry may result in a large reduction in hospitalization rates without significantly increasing non-severe pneumonia associated CFR if the inability to obtain a pulse oximetry reading is considered a WHO danger sign

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

Effects of an exercise programme with people living with HIV: Research in a disadvantaged setting

This study aimed to analyse the physical health effects of a community based 10-week physical activity programme with people living with HIV. It was developed, implemented and evaluated in a disadvantaged community in South Africa. A pre-post research design was chosen. Major recruitment and adherence challenges resulted in a small sample. Among the 23 participants who took part in both baseline and final testing, compliant participants (n = 12) were compared to non-compliant participants (n = 11). Immunological (CD4, viral load), anthropometric (height, weight, skinfolds and waist to hip ratio), muscular strength (h1RM) and cardiopulmonary fitness (time on treadmill) parameters were measured. The compliant and non-compliant groups were not different at baseline. Muscular strength was the parameter most influenced by compliance with the physical activity programme (F = 4.516, p = 0.047). Weight loss and improvement in cardiopulmonary fitness were restricted by the duration of the programme, compliance and influencing factors (e.g. nutrition, medication). The increase in strength is significant and meaningful in the context, as the participants goals were to look healthy and strong to avoid HIV related stigma. The improvements in appearance were a motivational factor, especially since the changes were made visible in a short time. Practical implications for health promotion are described. More research contextualised in disadvantaged settings is needed.DHE

Antibiotic treatment failure in children aged 1 to 59 months with World Health Organization-defined severe pneumonia in Malawi: A CPAP IMPACT trial secondary analysis

Background Pneumonia is a leading cause of mortality in children <5 years globally. Early identification of hospitalized children with pneumonia who may fail antibiotics could improve outcomes. We conducted a secondary analysis from the Malawi CPAP IMPACT trial evaluating risk factors for antibiotic failure among children hospitalized with pneumonia. Methods Participants were 1–59 months old with World Health Organization-defined severe pneumonia and hypoxemia, severe malnutrition, and/or HIV exposure/infection. All participants received intravenous antibiotics per standard care. First-line antibiotics were benzylpenicillin and gentamicin for five days. Study staff assessed patients for first-line antibiotic failure daily between days 3–6. When identified, patients failing antibiotics were switched to second-line ceftriaxone. Analyses excluded children receiving ceftriaxone and/or deceased by hospital day two. We compared characteristics between patients with and without treatment failure and fit multivariable logistic regression models to evaluate associations between treatment failure and admission characteristics. Results From June 2015–March 2018, 644 children were enrolled and 538 analyzed. Antibiotic failure was identified in 251 (46.7%) participants, and 19/251 (7.6%) died. Treatment failure occurred more frequently with severe malnutrition (50.2% (126/251) vs 28.2% (81/287), p<0.001) and amongst those dwelling 10km from a health facility (22.3% (56/251) vs 15.3% (44/287), p = 0.026). Severe malnutrition occurred more frequently among children living 10km from a health facility than those living <10km (49.0% (49/100) vs 35.7% (275/ 428), p = 0.014). Children with severe malnutrition (adjusted odds ratio (aOR) 2.2 (95% CI 1.52, 3.24), p<0.001) and pre-hospital antibiotics ((aOR 1.47, 95% CI 1.01, 2.14), p = 0.043) had an elevated aOR for antibiotic treatment failure. Conclusion Severe malnutrition and pre-hospital antibiotic use predicted antibiotic treatment failure in this high-risk severe pneumonia pediatric population in Malawi. Our findings suggest addressing complex sociomedical conditions like severe malnutrition and improving pneumonia etiology diagnostics will be key for better targeting interventions to improve childhood pneumonia outcomes

Case reduction and cost-effectiveness of the RTS,S/AS01 malaria vaccine alongside bed nets in Lilongwe, Malawi

Background: RTS,S/AS01, the most advanced vaccine against malaria, is now undergoing pilot implementation in Malawi, Ghana, and Kenya where an estimated 360,000 children will be vaccinated each year. In this study we evaluate RTS,S/AS01 alongside bed net use and estimate cost-effectiveness. Methods: RTS,S/AS01 phase III trial and bed net prevalence data were used to determine the effect of vaccination in the urban/periurban and rural areas of Lilongwe, Malawi. Cost data were used to calculate the cost-effectiveness of various interventions over three years. Findings: Since bed nets reduce malaria incidence and homogeneous vaccine efficacy was assumed, participants without bed nets received greater relative benefit from vaccination with RTS,S/AS01 than participants with bed nets. Similarly, since malaria incidence in rural Lilongwe is higher than in urban Lilongwe, the impact and cost-effectiveness of vaccine interventions is increased in rural areas. In rural Lilongwe, we estimated that vaccinating one child without a bed net would prevent 2·59 (1·62 to 3·38) cases of malaria over three years, corresponding to a cost of $10·08 (7·71 to 16·13) per case averted. Alternatively, vaccinating one child with a bed net would prevent 1·59 (0·87 to 2·57) cases, corresponding to$16·43 (10·16 to 30·06) per case averted. Providing RTS,S/AS01 to 30,000 children in rural Lilongwe was estimated to cost $782,400 and to prevent 58,611 (35,778 to 82,932) cases of malaria over a three-year period. Joint interventions providing both vaccination and bed nets (to those without them) were estimated to prevent additional cases of malaria and to be similarly cost-effective, compared to vaccine-only interventions. Interpretation: To maximize malaria prevention, vaccination and bed net distribution programs could be integrated. Funding: Impacts of Environment, Host Genetics and Antigen Diversity on Malaria Vaccine Efficacy (1R01AI137410-01

Environmental modifiers of RTS,S/AS01 malaria vaccine efficacy in Lilongwe, Malawi

Background: RTS,S/AS01 is the first vaccine against malaria to undergo pilot implementation, beginning in 2019 and vaccinating 360,000 children per year in Malawi, Ghana, and Kenya. The four-dose vaccine is given as a primary three-dose series with a fourth dose given approximately 18 months later. The efficacy of RTS,S/AS01 was variable among the 11 sites participating in the 2009-2014 phase III trial (MALARIA-055, NCT00866619), possibly due to differences in transmission intensity. However, a within-site examination of environmental factors related to transmission intensity and their impact on vaccine efficacy has yet to be conducted. Methods: We implemented the phase III RTS,S/AS01 trial at the Malawi site, which enrolled 1578 infants (6-12 weeks) and children (5-17 months) living in the Lilongwe District in Central Malawi and followed them for 3 years between 2009 and 2014. A global positioning system survey and an ecological questionnaire were conducted to collect participant household locations and characteristics, while additional data on background malaria prevalence were obtained from a concurrent Malaria Transmission Intensity (MTI) survey. Negative binomial regression models were used to assess whether the efficacy of the vaccine varied by estimated background malaria prevalence, household roof type, or amount of nearby vegetation. Results: Vaccine efficacy did not significantly vary by estimated malaria prevalence or by roof type. However, increased vegetation cover was associated with an increase in the efficacy of the three-dose primary RTS,S/AS01 series in the 18 months before the fourth dose and a decrease in the efficacy of the primary vaccine series in the second 18 months following, if the fourth dose was not given. Vegetation cover did not alter the efficacy of the fourth dose in a statistically or practically significant manner. Conclusions: Vegetation coverage in this study site might be a proxy for nearness to rivers or branching, shallow wetlands called "dambos"which could serve as breeding sites for mosquitoes. We observed statistically significant modification of the efficacy of RTS,S/AS01 by forest cover, suggesting that initial vaccine efficacy and the importance of the fourth dose varies based on ecological context. Trial registration: Efficacy of GSK Biologicals' Candidate Malaria Vaccine (257049) Against Malaria Disease Caused by P. falciparum Infection in Infants and Children in Africa. NCT00866619 prospectively registered 20 March 2009

Challenges in conducting trials for pediatric tuberculous meningitis: lessons from the field

SETTING: TBM-KIDS is a phase I/II trial enrolling children with tuberculous meningitis (TBM) in three tertiary referral centers in India and Malawi. OBJECTIVE: To describe the challenges encountered in conducting the first randomized clinical trial of antimicrobial agents in pediatric TBM. DESIGN: The sources of the data were primarily monthly trial reports, non-enrollment case report forms, study diaries and registers maintained for recruitment, experiences shared by key team members during regular study calls and comments from site review visits. We reviewed, broadly categorized, and describe in detail the challenges encountered by study teams in trial implementation. RESULTS: Over 17 months, 3371 children with clinical presentations consistent with meningoencephalitis or undergoing lumbar puncture were assessed for eligibility; 21 (<1%) met enrollment criteria. We encountered challenges related to diagnosis, management of sick children, large catchment areas, adverse event attribution, concomitant medications, infrastructure requirements, expensive pediatric formulations with short expiry, and detection of treatment response in a highly variable disease across the age continuum. Training and adaptation of tools for neurocognitive and neurologic function assessment were necessary. Special care was undertaken to explain study participation to distraught caregivers and manage children longitudinally. CONCLUSION: Interventional trials in pediatric TBM are challenging but are critically important for improving the treatment of a disease that disables children physically, cognitively and emotionally. Sharing these challenges may help to address them more effectively as a TB research community and to advance treatments for this at-risk population

Social-ecological, motivational and volitional factors for initiating and maintaining physical activity in the context of HIV

Sport and exercise can have several health benefits for people living with HIV. These benefits can be achieved through different types of physical activity, adapting to disease progression, motivation and social-ecological options. However, physical activity levels and adherence to exercise are generally low in people living with HIV. At the same time, high drop-out rates in intervention studies are prevalent; even though they often entail more favourable conditions than interventions in the natural settings. Thus, in the framework of an intervention study, the present study aims to explore social-ecological, motivational and volitional correlates of South African women living with HIV with regard to physical activity and participation in a sport and exercise health promotion programme. The qualitative data was produced in the framework of a non-randomised pre-post intervention study that evaluated structure, processes and outcomes of a 10-week sport and exercise programme. All 25 participants of the programme were included in this analysis, independent of compliance. Data was produced through questionnaires, participatory group discussions, body image pictures, research diaries and individual semi-structured interviews. All participants lived in a low socioeconomic, disadvantaged setting. Hence, the psychological correlates are contextualised and social-ecological influences on perception and behaviour are discussed. The results show the importance of considering social-cultural and environmental influences on individual motives, perceptions and expectancies, the fear of disclosure and stigmatisation, sport and exercise-specific group dynamics and self-supporting processes. Opportunities and strategies to augment physical activity and participation in sport and exercise programmes in the context of HIV are discussed.Scopu

Asymptomatic Plasmodium falciparum malaria prevalence among adolescents and adults in Malawi, 2015–2016

Malaria remains a significant cause of morbidity and mortality in Malawi, with an estimated 18–19% prevalence of Plasmodium falciparum in children 2–10 years in 2015–2016. While children report the highest rates of clinical disease, adults are thought to be an important reservoir to sustained transmission due to persistent asymptomatic infection. The 2015–2016 Malawi Demographic and Health Survey was a nationally representative household survey which collected dried blood spots from 15,125 asymptomatic individuals ages 15–54 between October 2015 and February 2016. We performed quantitative polymerase chain reaction on 7,393 samples, detecting an overall P. falciparum prevalence of 31.1% (SE = 1.1). Most infections (55.6%) had parasitemias ≤ 10 parasites/µL. While 66.2% of individuals lived in a household that owned a bed net, only 36.6% reported sleeping under a long-lasting insecticide-treated net (LLIN) the previous night. Protective factors included urbanicity, greater wealth, higher education, and lower environmental temperatures. Living in a household with a bed net (prevalence difference 0.02, 95% CI − 0.02 to 0.05) and sleeping under an LLIN (0.01; − 0.02 to 0.04) were not protective against infection. Our findings demonstrate a higher parasite prevalence in adults than published estimates among children. Understanding the prevalence and distribution of asymptomatic infection is essential for targeted interventions

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial

Background. Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. Methods. TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). Results. Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01). Conclusions. In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial. Clinical Trials Registration. NCT02958709