The prevalence and incidence of HIV in the ART era (2006-2016) in North West Tanzania.

BACKGROUND: Sub-Saharan countries bear a disproportionate percentage of HIV infections and HIV-related deaths despite the efforts to strengthen HIV prevention and treatments services, including ART. It is important to demonstrate how these services have contributed to reducing the epidemic using available population data. METHODS: We estimated the prevalence and incidence rates from a cohort running over 23 years in Magu District, Mwanza Region-North West Tanzania. Adults 15 years and over who were residents of the Kisesa observational HIV cohort study between 2006 and 2016 were eligible for inclusion. Survival analysis was used to calculate person-time at risk, incidence rates and 95% confidence intervals (CIs). Cox regression models were used for the risk factor analyses disaggregated by sex and age group. RESULTS: The HIV prevalence in the sero-surveys decreased from 7.2% in 2006/07 to 6.6% in 2016, with a notable decrease of over 50% for both men and women aged 15-24 years. The incidence rate for HIV was estimated to be 5.5 (95% CI 4.6-6.6) per 1,000 person-years in women compared to 4.6 (95% CI 3.5-5.8) in men, with a decrease over time. Despite the availability of ART services, the uptake is still small. CONCLUSIONS: New infections are still occurring, with high HIV incidence in individuals aged below 45 years. With new guidelines and the 95-95-95 UNAIDS target, prevalence and incidence must be adequately assessed. In addition, there is a need for additional efforts to assess the impact of HIV/AIDS prevention programmes and intervention services, especially in these areas where resources are limited.

Added value of an open narrative in verbal autopsies: a mixed-methods evaluation from Malawi.

Background: The WHO standardised verbal autopsy (VA) instrument includes closed questions, ascertaining signs and symptoms of illness preceding death, and an optional open narrative. As VA analyses increasingly use automated algorithms, inclusion of narratives should be justified. We evaluated the role of open narratives on VA processes, data quality and respondent's emotional stress. Methods: A mixed-methods analysis was conducted using VA data for child deaths (0-59 months), between April 2013 and November 2016 in Mchinji district, Malawi. Deaths were prospectively randomised to receive closed questions only or open narrative followed by closed questions. On concluding the VA, interviewers self-completed questions on respondents' emotional stress. Logistic regression was used to determine associations with visible emotional distress during VAs. A group discussion with interviewers was conducted at the project end, to understand field experiences and explore future recommendations; data were coded using deductive themes. Results: 2509 VAs were included, with 49.8% (n=1341) randomised to open narratives. Narratives lasted a median of 7 minuntes (range: 1-113). Interviewers described improved rapport and felt narratives improved data quality, although there was no difference in the proportion of deaths with an indeterminate cause using an automated algorithm (5.3% vs 6.1%). The majority of respondents did not display visible emotional stress (81%). Those with a narrative had higher, but not statistically significant, odds of emotional distress (adjusted OR: 1.20; 95% CI: 0.98 to 1.47). Factors associated with emotional stress were: infant deaths versus neonates; deaths at a health centre or en-route to hospital versus home; and higher socioeconomic status. Non-parental respondents and increased time between death and interview were associated with lower odds of emotional distress. Conclusion: Conducting an open narrative may help build rapport, something valued by the interviewers. However, additional time and emotional burdens should be further justified, with quality and utility of narratives promoted through standardised recommendations.

Predictive value of pulse oximetry for mortality in infants and children presenting to primary care with clinical pneumonia in rural Malawi: A data linkage study.

BACKGROUND: The mortality impact of pulse oximetry use during infant and childhood pneumonia management at the primary healthcare level in low-income countries is unknown. We sought to determine mortality outcomes of infants and children diagnosed and referred using clinical guidelines with or without pulse oximetry in Malawi. METHODS AND FINDINGS: We conducted a data linkage study of prospective health facility and community case and mortality data. We matched prospectively collected community health worker (CHW) and health centre (HC) outpatient data to prospectively collected hospital and community-based mortality surveillance outcome data, including episodes followed up to and deaths within 30 days of pneumonia diagnosis amongst children 0-59 months old. All data were collected in Lilongwe and Mchinji districts, Malawi, from January 2012 to June 2014. We determined differences in mortality rates using <90% and <93% oxygen saturation (SpO2) thresholds and World Health Organization (WHO) and Malawi clinical guidelines for referral. We used unadjusted and adjusted (for age, sex, respiratory rate, and, in analyses of HC data only, Weight for Age Z-score [WAZ]) regression to account for interaction between SpO2 threshold (pulse oximetry) and clinical guidelines, clustering by child, and CHW or HC catchment area. We matched CHW and HC outpatient data to hospital inpatient records to explore roles of pulse oximetry and clinical guidelines on hospital attendance after referral. From 7,358 CHW and 6,546 HC pneumonia episodes, we linked 417 CHW and 695 HC pneumonia episodes to 30-day mortality outcomes: 16 (3.8%) CHW and 13 (1.9%) HC patients died. SpO2 thresholds of <90% and <93% identified 1 (6%) of the 16 CHW deaths that were unidentified by integrated community case management (iCCM) WHO referral protocol and 3 (23%) and 4 (31%) of the 13 HC deaths, respectively, that were unidentified by the integrated management of childhood illness (IMCI) WHO protocol. Malawi IMCI referral protocol, which differs from WHO protocol at the HC level and includes chest indrawing, identified all but one of these deaths. SpO2 < 90% predicted death independently of WHO danger signs compared with SpO2 ≥ 90%: HC Risk Ratio (RR), 9.37 (95% CI: 2.17-40.4, p = 0.003); CHW RR, 6.85 (1.15-40.9, p = 0.035). SpO2 < 93% was also predictive versus SpO2 ≥ 93% at HC level: RR, 6.68 (1.52-29.4, p = 0.012). Hospital referrals and outpatient episodes with referral decision indications were associated with mortality. A substantial proportion of those referred were not found admitted in the inpatients within 7 days of referral advice. All 12 deaths in 73 hospitalised children occurred within 24 hours of arrival in the hospital, which highlights delay in appropriate care seeking. The main limitation of our study was our ability to only match 6% of CHW episodes and 11% of HC episodes to mortality outcome data. CONCLUSIONS: Pulse oximetry identified fatal pneumonia episodes at HCs in Malawi that would otherwise have been missed by WHO referral guidelines alone. Our findings suggest that pulse oximetry could be beneficial in supplementing clinical signs to identify children with pneumonia at high risk of mortality in the outpatient setting in health centres for referral to a hospital for appropriate management.

Population impact and effectiveness of sequential 13-valent pneumococcal conjugate and monovalent rotavirus vaccine introduction on infant mortality: prospective birth cohort studies from Malawi.

BACKGROUND: Pneumococcal conjugate vaccine (PCV) and rotavirus vaccine (RV) are key tools for reducing common causes of infant mortality. However, measurement of population-level mortality impact is lacking from sub-Saharan Africa. We evaluated mortality impact and vaccine effectiveness (VE) of PCV13 introduced in November 2011, with subsequent RV1 roll-out in October 2012, in Malawi. METHODS: We conducted two independent community-based birth cohort studies. Study 1, in northern Malawi (40000population), evaluated population impact using change-point analysis and negative-binomial regression of non-traumatic 14-51-week infant mortality preintroduction (1 January 2004 to 31 September 2011) and postintroduction (1 October 2011 to 1 July 2019), and against three-dose coverage. Study 2, in central Malawi (465 000 population), was recruited from 24 November 2011 to 1 June 2015. In the absence of preintroduction data, individual three-dose versus zero-dose VE was estimated using individual-level Cox survival models. In both cohorts, infants were followed with household visits to ascertain vaccination, socioeconomic and survival status. Verbal autopsies were conducted for deaths. RESULTS: Study 1 included 20 291 live births and 216 infant deaths. Mortality decreased by 28.6% (95% CI: 15.3 to 39.8) post-PCV13 introduction. A change point was identified in November 2012. Study 2 registered 50 731 live births, with 454 deaths. Infant mortality decreased from 17 to 10/1000 live births during the study period. Adjusted VE was 44.6% overall (95% CI: 23.0 to 59.1) and 48.3% (95% CI: -5.9 to 74.1) against combined acute respiratory infection, meningitis and sepsis-associated mortality. CONCLUSION: These data provide population-level evidence of infant mortality reduction following sequential PCV13 and RV1 introduction into an established immunisation programme in Malawi. These data support increasing coverage of vaccine programmes in high-burden settings.

Spinning disk-remote focusing microscopy.

Fast confocal imaging was achieved by combining remote focusing with differential spinning disk optical sectioning to rapidly acquire images of live samples at cellular resolution. Axial and lateral full width half maxima less than 5 µm and 490 nm respectively are demonstrated over 130 µm axial range with a 256 × 128 µm field of view. A water-index calibration slide was used to achieve an alignment that minimises image volume distortion. Application to live biological samples was demonstrated by acquiring image volumes over a 24 µm axial range at 1 volume/s, allowing for the detection of calcium-based neuronal activity in Platynereis dumerilii larvae.

Care-seeking patterns amongst suspected paediatric pneumonia deaths in rural Malawi.

Background: Pneumonia remains a leading cause of paediatric deaths. To understand contextual challenges in care pathways, we explored patterns in care-seeking amongst children who died of pneumonia in Malawi. Methods: We conducted a mixed-methods analysis of verbal autopsies (VA) amongst deaths in children aged 1-59 months from 10/2011 to 06/2016 in Mchinji district, Malawi. Suspected pneumonia deaths were defined as: 1. caregiver reported cough and fast breathing in the 2-weeks prior to death; or, 2. the caregiver specifically stated the child died of pneumonia; or 3. cause of death assigned as 'acute respiratory infection' using InterVA-4. Data were extracted from free-text narratives based on domains in the 'Pathways to Survival' framework, and described using proportions. Qualitative analysis used a framework approach, with pre-specified themes. Results: We analysed 171 suspected pneumonia deaths. In total, 86% of children were taken to a healthcare facility during their final illness episode, and 44% sought care more than once.  Of children who went to hospital (n=119), 70% were admitted, and 25% received oxygen. Half of the children died within a healthcare setting (43% hospital, 5% health centre and 2% private clinics), 64 (37%) at home, and 22 (13%) in transit. Challenges in delayed care, transport and quality of care (including oxygen), were reported. Conclusions: Healthcare was frequently sought for children who died of suspected pneumonia, however several missed opportunities for care were seen. Sustained investment in timely appropriate care seeking, quick transportation to hospital and improved case management at all levels of the system is needed.

Cascade of care for HIV-seroconverters in rural Tanzania: a longitudinal study.

We examined the HIV care cascade in a community-based cohort study in Kisesa, Magu, Tanzania. We analyzed the proportion achieving each stage of the cascade - Seroconversion, Awareness of HIV status, Enrollment in Care and Antiretroviral therapy (ART) initiation - and estimated the median and interquartile range for the time for progression to the next stage. Modified Poisson regression was used to estimate prevalence risk ratios for enrollment in care and initiation of ART. From 2006 to 2017, 175 HIV-seroconverters were identified. 140 (80%) knew their HIV status, of whom 97 (69.3%) were enrolled in HIV care, and 87 (49.7%) had initiated ART. Time from seroconversion to awareness of HIV status was 731.3 [475.5-1345.8] days. Time from awareness to enrollment was 7 [0-64] days, and from enrollment to ART initiation was 19 [3-248] days. There were no demographic differences in enrollment in care or ART initiation. Efforts have been focusing on shortening time from seroconversion to diagnosis, mostly by increasing the number of testing clinics available. We recommend increased systematic testing to reduce time from seroconversion to awareness of status, and by doing so speed up enrollment into care. Interventions that increase enrollment are likely to have the most impact in achieving UNAIDS targets.

Contraceptive use and discontinuation among women in rural North-West Tanzania.

INTRODUCTION: Existing estimates of contraceptive use in Tanzania rely on cross-sectional or retrospective study designs. This study used a 2-year, retrospective, month-by-month calendar of contraceptive utilization among women aged 15-49 years. METHODS: We estimated the median duration of contraceptive use, factors associated with use, and contraceptive discontinuation rates in sexually active women, using life tables and Cox proportional hazard model. RESULTS: A total of 5416 women contributed to the analysis in the study. Of the 5416 women, 942 (17%) had never had sex, 410 (7.6%) had no sexual partner in the last year. Among the 5416 women, 4064 were sexually active during the period, 814 (21.1%) were pregnant or amenorrheic, 610 (15.0%) were using contraception, and 1203 (29.6%) did not want to get pregnant but were not using contraception. In the 1813 women who wanted to avoid pregnancy, contraceptive use was lower among women over 35 years compared to younger ones (OR = 0.28, 95%CI: 0.19, 0.41), and in HIV positive women (OR = 0.89, 95%CI: 0.60-1.32). On the other hand, use was higher among women who were married/living together compared to unmarried ones (OR = 2.23, 95% CI: 1.54, 3.23). Using a 2-year retrospective contraceptive calendar, 1054 women reported contraceptive use, 15.8% discontinued within 6 months and 30.5% discontinued within 12 months. Higher rates of contraceptive discontinuation were observed among women who used pills (OR = 1.86, 95%CI: 1.25, 2.77) or injections (OR = 2.04, 95%CI: 1.59, 2.61) compared to those who used implants. CONCLUSION: Contraceptive use was significantly associated with age, education and parity, but not with HIV status. HIV status, number of living children and education are not statistically associated with discontinuation of contraceptive use Pills and injections had the highest rates of discontinuation. Wider choice and greater accessibility of long-acting contraceptive methods with better effectiveness and convenience may serve women better. Furthermore, special efforts may be needed to remove barriers to contraceptive use amongst younger women.

Is 'Health for All' synonymous with 'antibiotics for all': changes in antibiotic prescribing in a performance-based financing pilot in Zanzibar.

Universal Health Coverage, to meet the Sustainable Development Goal of 'Health for All', aims to increase the access of preventative and curative care services, particularly to the poor and vulnerable. However, the very provision of curative services by health providers in the primary care setting in low-income countries is considered one of the major drivers of antimicrobial resistance. The Zanzibar Ministry of Health introduced performance-based financing (PBF) in 2 of 10 Health Districts in July 2013. Payments to health facilities and staff were on a fee-for-service basis using 'direct quality indicators'. Results of an evaluation of secondary data of two indicators, 'treatment according to guidelines' and 'antibiotics prescribed according to guidelines' from 31 Primary Health Care Units in the two PBF pilot districts are compared with 28 in non-PBF districts. The proportion of patients treated with an antibiotic not in accordance with treatment guidelines after the introduction of PBF fell to 2%, 6% and 5% in 2014, 2015 and 2016, respectively, compared with an increase from 25% (2013) to 31% (2014) and 22% (2015, 2016) in non-PBF facilities. The key take-home messages from this evaluation are firstly that 'direct quality indicators' to improve the use of treatment guidelines, introduced into a national PBF reform that includes financial incentives and rigorous verification of register entries, have the potential to significantly reduce inappropriate use of antibiotics in high population density settings in Africa. Secondly, for a sustained reduction in the overall proportion of unnecessary antibiotic prescriptions rigorous monitoring of health worker behaviour is required to address changes in prescribing practice. A well-designed and monitored PBF with 'direct quality indicators' has the potential to ensure that 'Health for All', in terms of increased access to primary health services is not synonymous with 'antibiotics for all'.

HIV-seroconversion among HIV-1 serodiscordant married couples in Tanzania: a cohort study.

BACKGROUND: Heterosexual transmission is the main driver of the HIV epidemic in Tanzania. Only one estimate of the incidence rate of intra-marital HIV seroconversion in Tanzania has been reported and was derived from data collected between 1991 and 1995. Moreover, little is known about the specific risk factors for intra-marital seroconversion in Tanzania. Improved evidence around factors that increase the risk of HIV transmission to a serodiscordant spouse is needed to develop and improve evidence-based interventions. We sought to investigate the rate of intra-marital HIV seroconversion among HIV sero-discordant couples in Tanzania as well as its associated risk factors. METHODS: We identified all HIV positive individuals in the TAZAMA HIV-serosurvey cohort and followed up their serodiscordant spouse from 2006 to 2016. The rate of seroconversion was analyzed by survival analysis using non-parametric regressions with exponential distribution. RESULTS: We found 105 serodiscordant couples, 14 of which had a seroconverting spouse. The overall HIV-1 incidence rate among spouses of people with HIV-1 infection was 38.0 per 1000 person/years [22.5-64.1]. Notably, the HIV-1 incidence rate among HIV-1 seronegative male spouses was 6.7[0.9-47.5] per 1000 person/years, compared to 59.3 [34.4-102.1] per 1000 person/years among female spouses. Sex of the serodiscordant spouse was the only significant variable, even after adjusting for other variables (Hazard rate = 8.86[1.16-67.70], p = 0.036). CONCLUSIONS: Our study suggests that rates of HIV-1 seroconversion of sero-discordant partners are much higher within marriage than in the general population in Tanzania. The major risk factor for HIV-1 seroconversion is sex of the serodiscordant spouse, with female spouses being at very high risk of acquiring HIV infection. This suggests that future programs that target serodiscordant couples could be a novel and effective means of preventing HIV-1 transmission in Tanzania.

Enrollment in HIV Care and Treatment Clinic and Associated Factors Among HIV Diagnosed Patients in Magu District, Tanzania.

HIV care and treatment clinics (CTC) are important for management of HIV morbidity and mortality, and to reduce HIV transmission. Enrollment in HIV care and treatment clinics remains low in many developing countries. We followed up 632 newly diagnosed HIV patients aged 15 years and above from Magu District, Tanzania. Logistic regression was used to assess factors significantly associated with enrollment for CTC services. Kaplan-Meier plots and log-rank tests were used to evaluate differences in timing uptake of services. Among 632 participants, 214 (33.9%) were enrolled in CTC, and of those enrolled 120 (56.6%) took longer than 3 months to enroll. Those living in more rural villages were less likely to be enrolled than in the villages with semi-urban settings (OR 0.36; 95% CI 0.17-0.76). Moreover, those with age group 35-44 years and with age group 45 years and above were 2 times higher odds compared to those with age group 15-24 years, (OR 2.03; 95% CI 1.05-3.91) and (OR 2.69; 95% CI 1.40-5.18) respectively. Enrollment in the CTC in Tanzania is low. To increase uptake of antiretroviral therapy, it is critical to improve linkage between HIV testing and care services, and to rollout these services into the primary health facilities.

Characterizing a Leak in the HIV Care Cascade: Assessing Linkage Between HIV Testing and Care in Tanzania.

Background: In Tanzania, HIV testing data are reported aggregately for national surveillance, making it difficult to accurately measure the extent to which newly diagnosed persons are entering care, which is a critical step of the HIV care cascade. We assess, at the individual level, linkage of newly diagnosed persons to HIV care. Methods: An expanded two-part referral form was developed to include additional variables and unique identifiers. The expanded form contained a corresponding number for matching the two-parts between testing and care. Data were prospectively collected at 16 health facilities in the Magu District of Tanzania. Results: The records of 1,275 unique people testing HIV positive were identified and included in our analysis. Of these, 1,200 (94.1%) responded on previous testing history, with 184 (15.3%) testing twice or more during the pilot, or having had a previous HIV positive test. Three-quarters (932; 73.1%) of persons were linked to care during the pilot timeframe. Health service provision in the facility carrying out the HIV test was the most important factor for linkage to care; poor linkage occurred in facilities where HIV care was not immediately available. Conclusions: It is critical for persons newly diagnosed with HIV to be linked to care in a timely manner to maximize treatment effectiveness. Our findings show it is feasible to measure linkage to care using routinely collected data arising from an amended national HIV referral form. Our results illustrate the importance of utilizing individual-level data for measuring linkage to care, as repeat testing is common.

Impact of monovalent rotavirus vaccine on diarrhoea-associated post-neonatal infant mortality in rural communities in Malawi: a population-based birth cohort study.

BACKGROUND: Rotavirus is a major contributor to child mortality. The effect of rotavirus vaccine on diarrhoea mortality has been estimated in middle-income but not low-income settings, where mortality is high and vaccine effectiveness in reducing admissions to hospital is lower. Empirical population-based mortality studies have not been done in any setting. Malawi introduced monovalent rotavirus vaccine (RV1) in October, 2012. We aimed to investigate the impact and effectiveness of the RV1 vaccine in reducing diarrhoea-associated mortality in infants aged 10-51 weeks. METHODS: In this population-based cohort study, we included infants born between Jan 1, 2012, and June 1, 2015, in Mchinji, Central Malawi and analysed data on those surviving 10 weeks. Individual vaccination status was extracted from caregiver-held records or report at home visits at 4 months and 1 year of age. Survival to 1 year was confirmed at home visit, or cause of death ascertained by verbal autopsy. We assessed impact (1 minus mortality rate ratio following vs before vaccine introduction) using Poisson regression. Among vaccine-eligible infants (born from Sept 17, 2012), we assessed effectiveness (1 minus hazard ratio) using Cox regression. FINDINGS: Between Jan 1, 2012, and June 1, 2015, we recruited 48 672 livebirths in Mchinji, among whom 38 518 were vaccine-eligible and 37 570 survived to age 10 weeks. Two-dose versus zero-dose effectiveness analysis included 28 141 infants, of whom 101 had diarrhoea-associated death before 1 year of age. Diarrhoea-associated mortality declined by 31% (95% CI 1-52; p=0·04) after RV1 introduction. Effectiveness against diarrhoea-mortality was 34% (95% CI -28 to 66; p=0·22). INTERPRETATION: RV1 was associated with substantial reduction in diarrhoea-associated deaths among infants in this rural sub-Saharan African setting. These data add considerable weight to evidence showing the impact of rotavirus vaccine programmes. FUNDING: Wellcome Trust and GlaxoSmithKline Biologicals.

Correction: Impact of a Participatory Intervention with Women's Groups on Psychological Distress among Mothers in Rural Bangladesh: Secondary Analysis of a Cluster-Randomised Controlled Trial.

[This corrects the article DOI: 10.1371/journal.pone.0110697.].

Impact of the 13-Valent Pneumococcal Conjugate Vaccine on Clinical and Hypoxemic Childhood Pneumonia over Three Years in Central Malawi: An Observational Study.

BACKGROUND: The pneumococcal conjugate vaccine's (PCV) impact on childhood pneumonia during programmatic conditions in Africa is poorly understood. Following PCV13 introduction in Malawi in November 2011, we evaluated the case burden and rates of childhood pneumonia. METHODS AND FINDINGS: Between January 1, 2012-June 30, 2014 we conducted active pneumonia surveillance in children <5 years at seven hospitals, 18 health centres, and with 38 community health workers in two districts, central Malawi. Eligible children had clinical pneumonia per Malawi guidelines, defined as fast breathing only, chest indrawing +/- fast breathing, or, ≥1 clinical danger sign. Since pulse oximetry was not in the Malawi guidelines, oxygenation <90% defined hypoxemic pneumonia, a distinct category from clinical pneumonia. We quantified the pneumonia case burden and rates in two ways. We compared the period immediately following vaccine introduction (early) to the period with >75% three-dose PCV13 coverage (post). We also used multivariable time-series regression, adjusting for autocorrelation and exploring seasonal variation and alternative model specifications in sensitivity analyses. The early versus post analysis showed an increase in cases and rates of total, fast breathing, and indrawing pneumonia and a decrease in danger sign and hypoxemic pneumonia, and pneumonia mortality. At 76% three-dose PCV13 coverage, versus 0%, the time-series model showed a non-significant increase in total cases (+47%, 95% CI: -13%, +149%, p = 0.154); fast breathing cases increased 135% (+39%, +297%, p = 0.001), however, hypoxemia fell 47% (-5%, -70%, p = 0.031) and hospital deaths decreased 36% (-1%, -58%, p = 0.047) in children <5 years. We observed a shift towards disease without danger signs, as the proportion of cases with danger signs decreased by 65% (-46%, -77%, p<0.0001). These results were generally robust to plausible alternative model specifications. CONCLUSIONS: Thirty months after PCV13 introduction in Malawi, the health system burden and rates of the severest forms of childhood pneumonia, including hypoxemia and death, have markedly decreased.

Non-treatment of children with community health worker-diagnosed fast-breathing pneumonia in rural Malawi: exploratory subanalysis of a prospective cohort study.

BACKGROUND: Despite recent progress, pneumonia remains the largest infectious killer of children globally. This paper describes outcomes of not treating community-diagnosed fast-breathing pneumonia on patient recovery. METHODS: We conducted an exploratory subanalysis of an observational prospective cohort study in Malawi. We recruited children (2-59 months) diagnosed by community health workers with fast-breathing pneumonia using WHO integrated community case management (iCCM) guidelines. Children were followed at days 5 and 14 with a clinical assessment of recovery. We conducted bivariate and multivariable logistic regression for the association between treatment of fast-breathing pneumonia and recovery, adjusting for potential confounders. RESULTS: We followed up 847 children, of whom 78 (9%) had not been given antibiotics (non-treatment). Non-treatment cases had higher baseline rates of diarrhoea, non-severe hypoxaemia and fever. Non-recovery (persistence or worsening of symptoms) was 13% and 23% at day 5 in those who did receive and those who did not receive co-trimoxazole. Non-recovery, when defined as worsening of symptoms only, at day 5 was 7% in treatment and 10% in non-treatment cases. For both definitions, combined co-trimoxazole and lumefantrine-artemether (LA) treatment trended towards protection (adjusted OR (aOR) 0.28; 95% CI 0.12 to 0.68/aOR 0.29; 95% CI 0.08 to 1.01). CONCLUSION: We found that children who did not receive co-trimoxazole treatment had worse clinical outcomes; malaria co-diagnosis and treatment also play a significant role in non-recovery. Further research into non-treatment of fast-breathing pneumonia, using a pragmatic approach with consideration for malaria co-diagnosis and HIV status is needed to guide refinement of community treatment algorithms in this region.

Can We Predict Oral Antibiotic Treatment Failure in Children with Fast-Breathing Pneumonia Managed at the Community Level? A Prospective Cohort Study in Malawi.

BACKGROUND: Pneumonia is the leading cause of infectious death amongst children globally, with the highest burden in Africa. Early identification of children at risk of treatment failure in the community and prompt referral could lower mortality. A number of clinical markers have been independently associated with oral antibiotic failure in childhood pneumonia. This study aimed to develop a prognostic model for fast-breathing pneumonia treatment failure in sub-Saharan Africa. METHOD: We prospectively followed a cohort of children (2-59 months), diagnosed by community health workers with fast-breathing pneumonia using World Health Organisation (WHO) integrated community case management guidelines. Cases were followed at days 5 and 14 by study data collectors, who assessed a range of pre-determined clinical features for treatment outcome. We built the prognostic model using eight pre-defined parameters, using multivariable logistic regression, validated through bootstrapping. RESULTS: We assessed 1,542 cases of which 769 were included (32% ineligible; 19% defaulted). The treatment failure rate was 15% at day 5 and relapse was 4% at day 14. Concurrent malaria diagnosis (OR: 1.62; 95% CI: 1.06, 2.47) and moderate malnutrition (OR: 1.88; 95% CI: 1.09, 3.26) were associated with treatment failure. The model demonstrated poor calibration and discrimination (c-statistic: 0.56). CONCLUSION: This study suggests that it may be difficult to create a pragmatic community-level prognostic child pneumonia tool based solely on clinical markers and pulse oximetry in an HIV and malaria endemic setting. Further work is needed to identify more accurate and reliable referral algorithms that remain feasible for use by community health workers.

Cause-specific neonatal mortality: analysis of 3772 neonatal deaths in Nepal, Bangladesh, Malawi and India.

OBJECTIVE: Understanding the causes of death is key to tackling the burden of three million annual neonatal deaths. Resource-poor settings lack effective vital registration systems for births, deaths and causes of death. We set out to describe cause-specific neonatal mortality in rural areas of Malawi, Bangladesh, Nepal and rural and urban India using verbal autopsy (VA) data. DESIGN: We prospectively recorded births, neonatal deaths and stillbirths in seven population surveillance sites. VAs were carried out to ascertain cause of death. We applied descriptive epidemiological techniques and the InterVA method to characterise the burden, timing and causes of neonatal mortality at each site. RESULTS: Analysis included 3772 neonatal deaths and 3256 stillbirths. Between 63% and 82% of neonatal deaths occurred in the first week of life, and males were more likely to die than females. Prematurity, birth asphyxia and infections accounted for most neonatal deaths, but important subnational and regional differences were observed. More than one-third of deaths in urban India were attributed to asphyxia, making it the leading cause of death in this setting. CONCLUSIONS: Population-based VA methods can fill information gaps on the burden and causes of neonatal mortality in resource-poor and data-poor settings. Local data should be used to inform and monitor the implementation of interventions to improve newborn health. High rates of home births demand a particular focus on community interventions to improve hygienic delivery and essential newborn care.

Methods and challenges in measuring the impact of national pneumococcal and rotavirus vaccine introduction on morbidity and mortality in Malawi.

BACKGROUND: Pneumonia and gastroenteritis are leading causes of vaccine-preventable childhood morbidity and mortality. Malawi introduced pneumococcal conjugate and rotavirus vaccines to the immunisation programme in 2011 and 2012, respectively. Evaluating their effectiveness is vital to ensure optimal implementation and justify sustained investment. METHODS/DESIGN: A national evaluation platform was established to determine vaccine effectiveness and impact in Malawi. Impact and effectiveness against vaccine-type invasive pneumococcal disease, radiological pneumonia and rotavirus gastroenteritis are investigated using before-after incidence comparisons and case-control designs, respectively. Mortality is assessed using a prospective population cohort. Cost-effectiveness evaluation is nested within the case-control studies. We describe platform characteristics including strengths and weaknesses for conducting vaccine evaluations. DISCUSSION: Integrating data from individual level and ecological methods across multiple sites provides comprehensive information for policymakers on programme impact and vaccine effectiveness including changes in serotype/genotype distribution over time. Challenges to robust vaccine evaluation in real-world conditions include: vaccination ascertainment; pre-existing rapid decline in mortality and pneumococcal disease in the context of non-vaccine interventions; and the maintenance of completeness and quality of reporting at scale and over time. In observational non-randomised designs ascertainment of vaccine status may be biased particularly in infants with fatal outcomes. In the context of multiple population level interventions targeting study endpoints attribution of reduced incidence to vaccine impact may be flawed. Providing evidence from several independent but complementary studies will provide the greatest confidence in assigning impact. Welcome declines in disease incidence and in child mortality make accrual of required sample sizes difficult, necessitating large studies to detect the relatively small but potentially significant contribution of vaccines to mortality prevention. Careful evaluation of vaccine effectiveness and impact in such settings is critical to sustaining support for vaccine programmes. Our evaluation platform covers a large population with a high prevalence of HIV and malnutrition and its findings will be relevant to other settings in sub-Saharan Africa.