Availability and use of personal protective equipment in low- and middle-income countries during the COVID-19 pandemic.

BACKGROUND: Availability and appropriate use of personal protective equipment (PPE) is of particular importance in Low and Middle-Income countries (LMICs) where disease outbreaks other than COVID-19 are frequent and health workers are scarce. This study assesses the availability of necessary PPE items during the COVID-19 pandemic at health facilities in seven LMICs. METHODS: Data were collected using a rapid-cycle survey among 1554 health facilities in seven LMICs via phone-based surveys between August 2020 and December 2021. We gathered data on the availability of World Health Organization (WHO)-recommended PPE items and the use of items when examining patients suspected to be infected with COVID-19. We further investigated the implementation of service adaptation measures in a severe shortage of PPE. RESULTS: There were major deficiencies in PPE availability at health facilities. Almost 3 out of 10 health facilities reported a stock-out of medical masks on the survey day. Forty-six percent of facilities did not have respirator masks, and 16% did not have any gloves. We show that only 43% of health facilities had sufficient PPE to comply with WHO guidelines. Even when all items were available, healthcare workers treating COVID-19 suspected patients were reported to wear all the recommended equipment in only 61% of health facilities. We did not find a statistically significant difference in implementing service adaptation measures between facilities experiencing a severe shortage or not. CONCLUSION: After more than a year into the COVID-19 pandemic, the overall availability of PPE remained low in our sample of low and middle-income countries. Although essential, the availability of PPE did not guarantee the proper use of the equipment. The lack of PPE availability and improper use of available PPE enable preventable COVID-19 transmission in health facilities, leading to greater morbidity and mortality and risking the continuity of service delivery by healthcare workers.

Vaccine hesitancy among healthcare workers in low- and middle-income countries during the COVID-19 pandemic: Results from facility surveys across six countries.

BACKGROUND: Vaccine hesitancy remains a critical barrier in mitigating the effects of the ongoing COVID-19 pandemic. The willingness of health care workers (HCWs) to be vaccinated, and, in turn, recommend the COVID-19 vaccine for their patient population is an important strategy. This study aims to understand the uptake of COVID-19 vaccines and the reasoning for vaccine hesitancy among facility-based health care workers (HCWs) in LMICs. METHODS: We conducted nationally representative phone-based rapid-cycle surveys across facilities in six LMICs to better understand COVID-19 vaccine hesitancy. We gathered data on vaccine uptake among facility managers, their perceptions of vaccine uptake and hesitancy among the HCWs operating in their facilities, and their perception of vaccine hesitancy among the patient population served by the facility. RESULTS: 1,148 unique public health facilities participated in the study, with vaccines being almost universally offered to facility-based respondents across five out of six countries. Among facility respondents who have been offered the vaccine, more than 9 in 10 survey respondents had already been vaccinated at the time of data collection. Vaccine uptake among other HCWs at the facility was similarly high. Over 90% of facilities in Bangladesh, Liberia, Malawi, and Nigeria reported that all or most staff had already received the COVID-19 vaccine when the survey was conducted. Concerns about side effects predominantly drive vaccine hesitancy in both HCWs and the patient population. CONCLUSION: Our findings indicate that the opportunity to get vaccinated in participating public facilities is almost universal. We find vaccine hesitancy among facility-based HCWs, as reported by respondents, to be very low. This suggests that a potentially effective effort to increase vaccine uptake equitably would be to channel promotional activities through health facilities and HCWs.However, reasons for hesitancy, even if limited, are far from uniform across countries, highlighting the need for audience-specific messaging.

Cross-sectional health centre and community-based evaluation of the impact of pneumococcal and malaria vaccination on antibiotic prescription and usage, febrile illness and antimicrobial resistance in young children in Malawi: the IVAR study protocol.

INTRODUCTION: Vaccination is a potentially critical component of efforts to arrest development and dissemination of antimicrobial resistance (AMR), though little is known about vaccination impact within low-income and middle-income countries. This study will evaluate the impact of vaccination on reducing carriage prevalence of resistant Streptococcus pneumoniae and extended spectrum beta-lactamase-producing Escherichia coli and Klebsiella species. We will leverage two large ongoing cluster-randomised vaccine evaluations in Malawi assessing; first, adding a booster dose to the 13-valent pneumococcal conjugate vaccine (PCV13) schedule, and second, introduction of the RTS,S/AS01 malaria vaccine. METHODS AND ANALYSIS: Six cross-sectional surveys will be implemented within primary healthcare centres (n=3000 users of outpatient facilities per survey) and their local communities (n=700 healthy children per survey): three surveys in Blantyre district (PCV13 component) and three surveys in Mangochi district (RTS,S/AS01 component). We will evaluate antibiotic prescription practices and AMR carriage in children ≤3 years. For the PCV13 component, surveys will be conducted 9, 18 and 33 months following a 3+0 to 2+1 schedule change. For the RTS,S/AS01 component, surveys will be conducted 32, 44 and 56 months post-RTS,S/AS01 introduction. Six health centres in each study component will be randomly selected for study inclusion. Between intervention arms, the primary outcome will be the difference in penicillin non-susceptibility prevalence among S. pneumoniae nasopharyngeal carriage isolates in healthy children. The study is powered to detect an absolute change of 13 percentage points (ie, 35% vs 22% penicillin non-susceptibility). ETHICS AND DISSEMINATION: This study has been approved by the Kamuzu University of Health Sciences (Ref: P01-21-3249), University College London (Ref: 18331/002) and University of Liverpool (Ref: 9908) Research Ethics Committees. Parental/caregiver verbal or written informed consent will be obtained prior to inclusion or recruitment in the health centre-based and community-based activities, respectively. Results will be disseminated via the Malawi Ministry of Health, WHO, peer-reviewed publications and conference presentations.

The use of innovative approaches to strengthen health system resilience during the COVID-19 pandemic: case studies from selected Commonwealth countries.

This article is part of the Research Topic 'Health Systems Recovery in the Context of COVID-19 and Protracted Conflict'. The COVID-19 pandemic has exposed the vulnerabilities and limitations of many health systems and underscored the need for strengthening health system resilience to make and sustain progress toward Universal Health Coverage (UHC), global health security and healthier populations in tandem. In response to the COVID-19 pandemic, Commonwealth countries have been practicing a combination of innovative integrated approaches and actions to build health systems resilience. This includes utilizing digital tools, improvements in all-hazard emergency risk management, developing multisectoral partnerships, strengthening surveillance and community engagement. These interventions have been instrumental in strengthening national COVID-19 responses and can contribute to the evidence-base for increasing country investment into health systems resilience, particularly as we look toward COVID-19 recovery. This paper gives perspectives of five Commonwealth countries and their overall responses to the pandemic, highlighting practical firsthand experiences in the field. The countries included in this paper are Guyana, Malawi, Rwanda, Sri Lanka, and Tanzania. Given the diversity within the Commonwealth both in terms of geographical location and state of development, this publication can serve as a useful reference for countries as they prepare their health systems to better absorb the shocks that may emerge in future emergencies.

In-hospital mortality risk stratification in children aged under 5 years with pneumonia with or without pulse oximetry: A secondary analysis of the Pneumonia REsearch Partnership to Assess WHO REcommendations (PREPARE) dataset.

OBJECTIVES: We determined the pulse oximetry benefit in pediatric pneumonia mortality risk stratification and chest-indrawing pneumonia in-hospital mortality risk factors. METHODS: We report the characteristics and in-hospital pneumonia-related mortality of children aged 2-59 months who were included in the Pneumonia Research Partnership to Assess WHO Recommendations dataset. We developed multivariable logistic regression models of chest-indrawing pneumonia to identify mortality risk factors. RESULTS: Among 285,839 children, 164,244 (57.5%) from hospital-based studies were included. Pneumonia case fatality risk (CFR) without pulse oximetry measurement was higher than with measurement (5.8%, 95% confidence interval [CI] 5.6-5.9% vs 2.1%, 95% CI 1.9-2.4%). One in five children with chest-indrawing pneumonia was hypoxemic (19.7%, 95% CI 19.0-20.4%), and the hypoxemic CFR was 10.3% (95% CI 9.1-11.5%). Other mortality risk factors were younger age (either 2-5 months [adjusted odds ratio (aOR) 9.94, 95% CI 6.67-14.84] or 6-11 months [aOR 2.67, 95% CI 1.71-4.16]), moderate malnutrition (aOR 2.41, 95% CI 1.87-3.09), and female sex (aOR 1.82, 95% CI 1.43-2.32). CONCLUSION: Children with a pulse oximetry measurement had a lower CFR. Many children hospitalized with chest-indrawing pneumonia were hypoxemic and one in 10 died. Young age and moderate malnutrition were risk factors for in-hospital chest-indrawing pneumonia-related mortality. Pulse oximetry should be integrated in pneumonia hospital care for children under 5 years.

Assembling a global database of child pneumonia studies to inform WHO pneumonia management algorithm: Methodology and applications.

Background: The existing World Health Organization (WHO) pneumonia case management guidelines rely on clinical symptoms and signs for identifying, classifying, and treating pneumonia in children up to 5 years old. We aimed to collate an individual patient-level data set from large, high-quality pre-existing studies on pneumonia in children to identify a set of signs and symptoms with greater validity in the diagnosis, prognosis, and possible treatment of childhood pneumonia for the improvement of current pneumonia case management guidelines. Methods: Using data from a published systematic review and expert knowledge, we identified studies meeting our eligibility criteria and invited investigators to share individual-level patient data. We collected data on demographic information, general medical history, and current illness episode, including history, clinical presentation, chest radiograph findings when available, treatment, and outcome. Data were gathered separately from hospital-based and community-based cases. We performed a narrative synthesis to describe the final data set. Results: Forty-one separate data sets were included in the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) database, 26 of which were hospital-based and 15 were community-based. The PREPARE database includes 285 839 children with pneumonia (244 323 in the hospital and 41 516 in the community), with detailed descriptions of clinical presentation, clinical progression, and outcome. Of 9185 pneumonia-related deaths, 6836 (74%) occurred in children <1 year of age and 1317 (14%) in children aged 1-2 years. Of the 285 839 episodes, 280 998 occurred in children 0-59 months old, of which 129 584 (46%) were 2-11 months of age and 152 730 (54%) were males. Conclusions: This data set could identify an improved specific, sensitive set of criteria for diagnosing clinical pneumonia and help identify sick children in need of referral to a higher level of care or a change of therapy. Field studies could be designed based on insights from PREPARE analyses to validate a potential revised pneumonia algorithm. The PREPARE methodology can also act as a model for disease database assembly.

Risk factors for pneumococcal carriage in adults living with HIV on antiretroviral therapy in the infant pneumococcal vaccine era in Malawi.

OBJECTIVE: Adults living with HIV (ALWHIV) on antiretroviral therapy (ART) are at high risk of pneumococcal carriage and disease. To help evaluate carriage risk in African ALWHIV at least 4 years after infant pneumococcal conjugate vaccination introduction in 2011, we assessed association between pneumococcal carriage and potential risk factors. METHODS: Nasopharyngeal swabs were collected from adults aged 18-40 years attending an ART clinic during rolling, cross-sectional surveys in Blantyre, Malawi between 2015 and 2019. We fitted generalized additive models to estimate the risk of sex, social economic status (SES), living with a child less than 5 years, and ART duration on carriage. RESULTS: Of 2067 adults, median age was 33 years (range 28-37), 1427 (69.0%) were women, 1087 (61.4%) were in low-middle socioeconomic-status (SES), 910 (44.0%) were living with a child less than 5 years, and median ART duration was 3 years (range 0.004-17). We estimated 38.2 and 60.6% reductions in overall and vaccine-serotype carriage prevalence. Overall carriage was associated with low SES, living with a child less than 5 years and shorter duration on ART. By contrast, vaccine-type carriage was associated with living without a child less than 5 years and male sex. CONCLUSION: Despite temporal reductions in overall and vaccine-serotype carriage, there is evidence of incomplete vaccine-serotype indirect protection. A targeted-vaccination campaign should be considered for ALWHIV, along with other public health measures to further reduce vaccine-serotype carriage and therefore disease.

Healthcare utilization and maternal and child mortality during the COVID-19 pandemic in 18 low- and middle-income countries: An interrupted time-series analysis with mathematical modeling of administrative data.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has had wide-reaching direct and indirect impacts on population health. In low- and middle-income countries, these impacts can halt progress toward reducing maternal and child mortality. This study estimates changes in health services utilization during the pandemic and the associated consequences for maternal, neonatal, and child mortality. METHODS AND FINDINGS: Data on service utilization from January 2018 to June 2021 were extracted from health management information systems of 18 low- and lower-middle-income countries (Afghanistan, Bangladesh, Cameroon, Democratic Republic of the Congo (DRC), Ethiopia, Ghana, Guinea, Haiti, Kenya, Liberia, Madagascar, Malawi, Mali, Nigeria, Senegal, Sierra Leone, Somalia, and Uganda). An interrupted time-series design was used to estimate the percent change in the volumes of outpatient consultations and maternal and child health services delivered during the pandemic compared to projected volumes based on prepandemic trends. The Lives Saved Tool mathematical model was used to project the impact of the service utilization disruptions on child and maternal mortality. In addition, the estimated monthly disruptions were also correlated to the monthly number of COVID-19 deaths officially reported, time since the start of the pandemic, and relative severity of mobility restrictions. Across the 18 countries, we estimate an average decline in OPD volume of 13.1% and average declines of 2.6% to 4.6% for maternal and child services. We projected that decreases in essential health service utilization between March 2020 and June 2021 were associated with 113,962 excess deaths (110,686 children under 5, and 3,276 mothers), representing 3.6% and 1.5% increases in child and maternal mortality, respectively. This excess mortality is associated with the decline in utilization of the essential health services included in the analysis, but the utilization shortfalls vary substantially between countries, health services, and over time. The largest disruptions, associated with 27.5% of the excess deaths, occurred during the second quarter of 2020, regardless of whether countries reported the highest rate of COVID-19-related mortality during the same months. There is a significant relationship between the magnitude of service disruptions and the stringency of mobility restrictions. The study is limited by the extent to which administrative data, which varies in quality across countries, can accurately capture the changes in service coverage in the population. CONCLUSIONS: Declines in healthcare utilization during the COVID-19 pandemic amplified the pandemic's harmful impacts on health outcomes and threaten to reverse gains in reducing maternal and child mortality. As efforts and resource allocation toward prevention and treatment of COVID-19 continue, essential health services must be maintained, particularly in low- and middle-income countries.

Derivation and validation of a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality in 20 countries.

INTRODUCTION: Existing risk assessment tools to identify children at risk of hospitalised pneumonia-related mortality have shown suboptimal discriminatory value during external validation. Our objective was to derive and validate a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality across various settings. METHODS: We used primary, baseline, patient-level data from 11 studies, including children evaluated for pneumonia in 20 low-income and middle-income countries. Patients with complete data were included in a logistic regression model to assess the association of candidate variables with the outcome hospitalised pneumonia-related mortality. Adjusted log coefficients were calculated for each candidate variable and assigned weighted points to derive the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) risk assessment tool. We used bootstrapped selection with 200 repetitions to internally validate the PREPARE risk assessment tool. RESULTS: A total of 27 388 children were included in the analysis (mean age 14.0 months, pneumonia-related case fatality ratio 3.1%). The PREPARE risk assessment tool included patient age, sex, weight-for-age z-score, body temperature, respiratory rate, unconsciousness or decreased level of consciousness, convulsions, cyanosis and hypoxaemia at baseline. The PREPARE risk assessment tool had good discriminatory value when internally validated (area under the curve 0.83, 95% CI 0.81 to 0.84). CONCLUSIONS: The PREPARE risk assessment tool had good discriminatory ability for identifying children at risk of hospitalised pneumonia-related mortality in a large, geographically diverse dataset. After external validation, this tool may be implemented in various settings to identify children at risk of hospitalised pneumonia-related mortality.

Clinical pneumonia in the hospitalised child in Malawi in the post-pneumococcal conjugate vaccine era: a prospective hospital-based observational study.

OBJECTIVE: Assess characteristics of clinical pneumonia after introduction of pneumococcal conjugate vaccine (PCV), by HIV exposure status, in children hospitalised in a governmental hospital in Malawi. METHODS AND FINDINGS: We evaluated 1139 children ≤5 years old hospitalised with clinical pneumonia: 101 HIV-exposed, uninfected (HEU) and 1038 HIV-unexposed, uninfected (HUU). Median age was 11 months (IQR 6-20), 59% were male, median mid-upper arm circumference (MUAC) was 14 cm (IQR 13-15) and mean weight-for-height z score was -0.7 (±2.5). The highest Respiratory Index of Severity in Children (RISC) scores were allocated to 10.4% of the overall cohort. Only 45.7% had fever, and 37.2% had at least one danger sign at presentation. The most common clinical features were crackles (54.7%), nasal flaring (53.5%) and lower chest wall indrawing (53.2%). Compared with HUU, HEU children were significantly younger (9 months vs 11 months), with lower mean birth weight (2.8 kg vs 3.0 kg) and MUAC (13.6 cm vs 14.0 cm), had higher prevalence of vomiting (32.7% vs 22.0%), tachypnoea (68.4% vs 49.8%) and highest RISC scores (20.0% vs 9.4%). Five children died (0.4%). However, clinical outcomes were similar for both groups. CONCLUSIONS: In this post-PCV setting where prevalence of HIV and malnutrition is high, children hospitalised fulfilling the WHO Integrated Management of Childhood Illness criteria for clinical pneumonia present with heterogeneous features. These vary by HIV exposure status but this does not influence either the frequency of danger signs or mortality. The poor performance of available severity scores in this population and the absence of more specific diagnostics hinder appropriate antimicrobial stewardship and the rational application of other interventions.

External validation of the RISC, RISC-Malawi, and PERCH clinical prediction rules to identify risk of death in children hospitalized with pneumonia.

BACKGROUND: Existing scores to identify children at risk of hospitalized pneumonia-related mortality lack broad external validation. Our objective was to externally validate three such risk scores. METHODS: We applied the Respiratory Index of Severity in Children (RISC) for HIV-negative children, the RISC-Malawi, and the Pneumonia Etiology Research for Child Health (PERCH) scores to hospitalized children in the Pneumonia REsearch Partnerships to Assess WHO REcommendations (PREPARE) data set. The PREPARE data set includes pooled data from 41 studies on pediatric pneumonia from across the world. We calculated test characteristics and the area under the curve (AUC) for each of these clinical prediction rules. RESULTS: The RISC score for HIV-negative children was applied to 3574 children 0-24 months and demonstrated poor discriminatory ability (AUC = 0.66, 95% confidence interval (CI) = 0.58-0.73) in the identification of children at risk of hospitalized pneumonia-related mortality. The RISC-Malawi score had fair discriminatory value (AUC = 0.75, 95% CI = 0.74-0.77) among 17 864 children 2-59 months. The PERCH score was applied to 732 children 1-59 months and also demonstrated poor discriminatory value (AUC = 0.55, 95% CI = 0.37-0.73). CONCLUSIONS: In a large external application of the RISC, RISC-Malawi, and PERCH scores, a substantial number of children were misclassified for their risk of hospitalized pneumonia-related mortality. Although pneumonia risk scores have performed well among the cohorts in which they were derived, their performance diminished when externally applied. A generalizable risk assessment tool with higher sensitivity and specificity to identify children at risk of hospitalized pneumonia-related mortality may be needed. Such a generalizable risk assessment tool would need context-specific validation prior to implementation in that setting.

A pragmatic health centre-based evaluation comparing the effectiveness of a PCV13 schedule change from 3+0 to 2+1 in a high pneumococcal carriage and disease burden setting in Malawi: a study protocol.

INTRODUCTION: Streptococcus pneumoniae (the pneumococcus) is commonly carried as a commensal bacterium in the nasopharynx but can cause life-threatening disease. Transmission occurs by human respiratory droplets and interruption of this process provides herd immunity. A 2017 WHO Consultation on Optimisation of pneumococcal conjugate vaccines (PCV) Impact highlighted a substantial research gap in investigating why the impact of PCV vaccines in low-income countries has been lower than expected. Malawi introduced the 13-valent PCV (PCV13) into the national Expanded Programme of Immunisations in 2011, using a 3+0 (3 primary +0 booster doses) schedule. With evidence of greater impact of a 2+1 (2 primary +1 booster dose) schedule in other settings, including South Africa, Malawi's National Immunisations Technical Advisory Group is seeking evidence of adequate superiority of a 2+1 schedule to inform vaccine policy. METHODS: A pragmatic health centre-based evaluation comparing impact of a PCV13 schedule change from 3+0 to 2+1 in Blantyre district, Malawi. Twenty government health centres will be randomly selected, with ten implementing a 2+1 and 10 to continue with the 3+0 schedule. Health centres implementing 3+0 will serve as the direct comparator in evaluating 2+1 providing superior direct and indirect protection against pneumococcal carriage. Pneumococcal carriage surveys will evaluate carriage prevalence among children 15-24 months, randomised at household level, and schoolgoers 5-10 years of age, randomly selected from school registers. Carriage surveys will be conducted 18 and 33 months following 2+1 implementation. ANALYSIS: The primary endpoint is powered to detect an effect size of 50% reduction in vaccine serotype (VT) carriage among vaccinated children 15-24 months old, expecting a 14% and 7% VT carriage prevalence in the 3+0 and 2+1 arms, respectively. ETHICS AND DISSEMINATION: The study has been approved by the Malawi College of Medicine Research Ethics Committee (COMREC; Ref: P05.19.2680), the University College London Research Ethics Committee (Ref: 8603.002) and the University of Liverpool Research Ethics Committee (Ref: 5439). The results from this study will be actively disseminated through manuscript publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT04078997.

Disruptions in maternal and child health service utilization during COVID-19: analysis from eight sub-Saharan African countries.

The coronavirus-19 pandemic and its secondary effects threaten the continuity of essential health services delivery, which may lead to worsened population health and a protracted public health crisis. We quantify such disruptions, focusing on maternal and child health, in eight sub-Saharan countries. Service volumes are extracted from administrative systems for 63 954 facilities in eight countries: Cameroon, Democratic Republic of Congo, Liberia, Malawi, Mali, Nigeria, Sierra Leone and Somalia. Using an interrupted time series design and an ordinary least squares regression model with facility-level fixed effects, we analyze data from January 2018 to February 2020 to predict what service utilization levels would have been in March-July 2020 in the absence of the pandemic, accounting for both secular trends and seasonality. Estimates of disruption are derived by comparing the predicted and observed service utilization levels during the pandemic period. All countries experienced service disruptions for at least 1 month, but the magnitude and duration of the disruptions vary. Outpatient consultations and child vaccinations were the most commonly affected services and fell by the largest margins. We estimate a cumulative shortfall of 5 149 491 outpatient consultations and 328 961 third-dose pentavalent vaccinations during the 5 months in these eight countries. Decreases in maternal health service utilization are less generalized, although significant declines in institutional deliveries, antenatal care and postnatal care were detected in some countries. There is a need to better understand the factors determining the magnitude and duration of such disruptions in order to design interventions that would respond to the shortfall in care. Service delivery modifications need to be both highly contextualized and integrated as a core component of future epidemic response and planning.

Impact and effectiveness of 13-valent pneumococcal conjugate vaccine on population incidence of vaccine and non-vaccine serotype invasive pneumococcal disease in Blantyre, Malawi, 2006-18: prospective observational time-series and case-control studies.

BACKGROUND: The population impact of pneumococcal conjugate vaccines (PCVs) depends on direct and indirect protection. Following Malawi's introduction of the 13-valent PCV (PCV13) in 2011, we examined its impact on vaccine and non-vaccine serotype invasive pneumococcal disease among vaccine-eligible-age and vaccine-ineligible-age children and adults. METHODS: We did a prospective observational time-series analysis and a case-control study. We used data from between Jan 1, 2006, and Dec 31, 2018, from laboratory-based surveillance at a government hospital in Malawi. This period included 6 years before and 7 years after introduction of PCV13. By use of negative-binomial regression, we evaluated secular trend-adjusted incidence rate ratio (IRR) in vaccine serotype and non-vaccine serotype invasive pneumococcal disease before and after introduction of PCV. We compared predicted counterfactual incidence in hypothetical absence of vaccine with empirically observed incidence following vaccine introduction. The case-control study assessed vaccine effectiveness, comparing PCV uptake among cases of vaccine-eligible-age invasive pneumococcal disease versus matched community controls. FINDINGS: Surveillance covered 10 281 476 person-years of observation, with 140 498 blood and 63 291 cerebrospinal fluid cultures. A reduction in total (vaccine serotype plus non-vaccine serotype) invasive pneumococcal disease incidence preceded introduction of PCV: 19% (IRR 0·81, 95% CI 0·74 to 0·88, p<0·0001) among infants (<1 year old), 14% (0·86, 0·80 to 0·93, p<0·0001) among children aged 1-4 years, and 8% (0·92, 0·83 to 1·01, p=0·084) among adolescents and adults (≥15 years old). Among children aged 5-14 years there was a 2% increase in total invasive pneumococcal disease (1·02, 0·93 to 1·11, p=0·72). Compared with the counterfactually predicted incidence, incidence of post-PCV13 vaccine serotype invasive pneumococcal disease was 74% (95% CI 70 to 78) lower among children aged 1-4 years and 79% (76 to 83) lower among children aged 5-14 years, but only 38% (37 to 40) lower among infants and 47% (44 to 51) lower among adolescents and adults. Although non-vaccine serotype invasive pneumococcal disease has increased in incidence since 2015, observed incidence remains low. The case-control study (19 cases and 76 controls) showed vaccine effectiveness against vaccine serotype invasive pneumococcal disease of 80·7% (-73·7 to 97·9). INTERPRETATION: In a high-mortality, high-HIV-prevalence setting in Africa, there were significant pre-vaccine reductions in the incidence of invasive pneumococcal disease. 7 years after PCV introduction, although vaccine-attributable impact among vaccine-eligible-age children was significant, indirect effects benefitting unvaccinated infants and adults were not. Policy decisions should consider multiple alternative strategies for reducing disease burden, including targeted vaccination outside infant Expanded Programme of Immunization to benefit vulnerable populations. FUNDING: Bill & Melinda Gates Foundation, Wellcome Trust, and National Institute for Health Research.

Evaluation of Pneumococcal Serotyping of Nasopharyngeal-Carriage Isolates by Latex Agglutination, Whole-Genome Sequencing (PneumoCaT), and DNA Microarray in a High-Pneumococcal-Carriage-Prevalence Population in Malawi.

Accurate assessment of the serotype distribution associated with pneumococcal colonization and disease is essential for evaluating and formulating pneumococcal vaccines and for informing vaccine policy. For this reason, we evaluated the concordance between pneumococcal serotyping results by latex agglutination, whole-genome sequencing (WGS) with PneumoCaT, and DNA microarray for samples from community carriage surveillance in Blantyre, Malawi. Nasopharyngeal swabs were collected according to WHO recommendations between 2015 and 2017 by using stratified random sampling among study populations. Participants included healthy children 3 to 6 years old (vaccinated with the 13-valent pneumococcal conjugate vaccine [PCV13] as part of the Expanded Program on Immunization [EPI]), healthy children 5 to 10 years old (age-ineligible for PCV13), and HIV-infected adults (18 to 40 years old) on antiretroviral therapy (ART). For phenotypic serotyping, we used a 13-valent latex kit (Statens Serum Institut [SSI], Denmark). For genomic serotyping, we applied the PneumoCaT pipeline to whole-genome sequence libraries. For molecular serotyping by microarray, we used the BUGS Bioscience Senti-SP microarray. A total of 1,347 samples were analyzed. Concordance was 90.7% (95% confidence interval [CI], 89.0 to 92.2%) between latex agglutination and PneumoCaT, 95.2% (95% CI, 93.9 to 96.3%) between latex agglutination and the microarray, and 96.6% (95% CI, 95.5 to 97.5%) between the microarray and PneumoCaT. By detecting additional vaccine serotype (VT) pneumococci carried at low relative abundances (median, 8%), the microarray increased VT detection by 31.5% over that by latex serotyping. To conclude, all three serotyping methods were highly concordant in identifying dominant serotypes. Latex serotyping is accurate in identifying vaccine serotypes and requires the least expertise and resources for field implementation and analysis. However, WGS, which adds population structure, and microarray, which adds multiple-serotype carriage, should be considered at regional reference laboratories for investigating the importance of vaccine serotypes at low relative abundances in transmission and disease.

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.

High residual carriage of vaccine-serotype Streptococcus pneumoniae after introduction of pneumococcal conjugate vaccine in Malawi.

There are concerns that pneumococcal conjugate vaccines (PCVs) in sub-Saharan Africa sub-optimally interrupt Streptococcus pneumoniae vaccine-serotype (VT) carriage and transmission. Here we assess PCV carriage using rolling, prospective nasopharyngeal carriage surveys between 2015 and 2018, 3.6-7.1 years after Malawi's 2011 PCV13 introduction. Carriage decay rate is analysed using non-linear regression. Despite evidence of reduction in VT carriage over the study period, there is high persistent residual carriage. This includes among PCV-vaccinated children 3-5-year-old (16.1% relative reduction from 19.9% to 16.7%); PCV-unvaccinated children 6-8-year-old (40.5% reduction from 26.4% to 15.7%); HIV-infected adults 18-40-years-old on antiretroviral therapy (41.4% reduction from 15.2% to 8.9%). VT carriage prevalence half-life is similar among PCV-vaccinated and PCV-unvaccinated children (3.26 and 3.34 years, respectively). Compared with high-income settings, there is high residual VT carriage 3.6-7.1 years after PCV introduction. Rigorous evaluation of strategies to augment vaccine-induced control of carriage, including alternative schedules and catch-up campaigns, is required.

The Epidemiology of Hypoxemic Pneumonia among Young Infants in Malawi.

We describe hypoxemic pneumonia prevalence in outpatient and inpatient settings, in-hospital mortality, and clinical guideline performance for identifying hypoxemia in young infants in Malawi. In this retrospective analysis of a prospective cohort study, we investigate infants younger than 2 months participating in pneumonia surveillance at seven hospitals and 18 outpatient health centers in Malawi between 2011 and 2014. Logistic regression, multiple imputation with chained equations, and pattern mixture modeling were used to determine the association between peripheral capillary oxyhemoglobin saturation (SpO2) levels and hospital mortality. We describe outpatient clinician hospital referral recommendations based on clinical characteristics and SpO2 distributions. Among 1,879 analyzed cases, SpO2 < 90% was more prevalent among outpatient health center cases compared with hospitalized cases (22.6% versus 13.5%, 95% CI: 17.6-28.4% and 12.0-15.3%, respectively). A larger proportion of hospitalized infants had signs of respiratory distress compared with infants at health centers (67.7% versus 56.6%, P < 0.001) and most hospitalized infants were boys (56.7% versus 40.6%, P < 0.001). An SpO2 of 90-92% and < 90% was associated with similarly increased odds of in-hospital mortality (adjusted odds ratio [aOR]: 4.3 and 4.4, 95% CI: 1.7-11.1 and 1.8-10.5, respectively). Unrecorded, or unobtainable, SpO2 was highly associated with mortality (n = 127, aOR: 18.1; 95% CI: 7.6-42.8). Four of 22 (18%) infants at health centers who did not meet clinical referral criteria had an SpO2 ≤ 92%. Clinicians should consider hospital referral in young infants with a SpO2 ≤ 92%. Infants with unobtainable SpO2 readings should be considered a high-risk group, and hospital referral of these cases may be appropriate.

Use of bubble continuous positive airway pressure (bCPAP) in the management of critically ill children in a Malawian paediatric unit: an observational study.

Introduction: In low-resource countries, respiratory failure is associated with a high mortality risk among critically ill children. We evaluated the role of bubble continuous positive airway pressure (bCPAP) in the routine care of critically ill children in Lilongwe, Malawi. Methods: We conducted an observational study between 26 February and 15 April 2014, in an urban paediatric unit with approximately 20 000 admissions/year (in-hospital mortality <5% approximately during this time period). Modified oxygen concentrators or oxygen cylinders provided humidified bCPAP air/oxygen flow. Children up to the age of 59 months with signs of severe respiratory dysfunction were recruited. Survival was defined as survival during the bCPAP-treatment and during a period of 48 hours following the end of the bCPAP-weaning process. Results: 117 children with signs of respiratory failure were included in this study and treated with bCPAP. Median age: 7 months. Malaria rapid diagnostic tests were positive in 25 (21%) cases, 15 (13%) had severe anaemia (Hb < 7.0 g/dL); 55 (47%) children had multiorgan failure (MOF); 22 (19%) children were HIV-infected/exposed. 28 (24%) were severely malnourished. Overall survival was 79/117 (68%); survival was 54/62 (87%) in children with very severe pneumonia (VSPNA) but without MOF. Among the 19 children with VSPNA (single-organ failure (SOF)) and negative HIV tests, all children survived. Survival rates were lower in children with MOF (including shock) (45%) as well as in children with severe malnutrition (36%) and proven HIV infection or exposure (45%). Conclusion: Despite the limitations of this study, the good outcome of children with signs of severe respiratory dysfunction (SOF) suggests that it is feasible to use bCPAP in the hospital management of critically ill children in resource-limited settings. The role of bCPAP and other forms of non-invasive ventilatory support as a part of an improved care package for critically ill children with MOF at tertiary and district hospital level in low-resource countries needs further evaluation. Critically ill children with nutritional deficiencies and/or HIV infection/exposure need further study to determine bCPAP efficacy.