WHAT WAS KNOWN? Underreporting of neonatal admissions and mortality is common in many countries, particularly for neonates <1000g, leading to underestimation of in-patient neonatal mortality rates (iNMRs). This has important implications for comparing between hospitals or over time, evaluation of interventions, as well as planning resource allocation and tracking progress towards SDG 3.2 for newborn survival. WHAT WAS DONE THAT IS NEW? Based on context-specific data, a simulation-based approach was used to develop birthweight-specific adjustment functions to account for underreporting of admissions and in-patient neonatal deaths. Various levels of underreporting were then introduced, and adjustment models were re-fitted to estimate the original simulated values. The approach was extended to adjust for underreporting of admissions and deaths in 65 hospitals partnering with NEST360 in four countries (Kenya, Malawi, Nigeria, and Tanzania). Adjustment curves were developed using data from 26 hospitals with plausible mortality rates (≥700 deaths per 1000 live births for neonates <1000g) to create robust birthweight-specific adjustment functions. These functions were then applied across data from all 65 hospitals to adjust for underreporting in a dataset of 172,809 baseline in-patient neonatal mortality admissions. WHAT WAS FOUND? Applying birthweight-specific adjustment functions to simulated data demonstrated the statistical approach to be robust in adjusting for underreporting, since adjusted neonatal iNMRs closely matched the original simulated values ("truth") even at varying levels of underreporting. Using a dataset of 172,809 admissions from 65 hospitals partnering with NEST360, unadjusted iNMRs were 121 deaths per 1000 admissions in Nigeria, 128 per 1000 in Tanzania, 132 per 1000 in Malawi, and 135 per 1000 in Kenya. Birthweight-specific adjustment functions were developed based on 26 hospitals with plausible mortality rates (≥700 deaths per 1000 live births for neonates <1000g). After applying adjustment curves, the iNMRs increased to 162 deaths per 1000 admissions in Nigeria, 183 per 1000 in Tanzania, 174 per 1000 in Malawi, and 172 per 1000 in Kenya. As expected, adjusted iNMRs were higher and reduced inter-hospital variability. WHAT NEXT? This adjustment method may be useful more widely, including in LMIC national routine health data, which is now the main source of neonatal data, given recent defunding of Demographic Health Surveys. Share learning to improve capture of all admissions and deaths in routine data systems, such as increased communication that all live-born babies are to be registered, irrespective of gestational age or weight, regular data audits, and educating/mentoring to promote accurate and complete reporting. Underreporting of neonatal admissions and deaths – particularly among < 1000 g newborns – compromises the plausibility of in-patient neonatal mortality rate (iNMR) estimates. This limits progress tracking, since 2.3 million neonatal deaths occur annually, and 65 countries are projected to miss the Sustainable Development Goal (SDG) 3.2 target of fewer than 12 deaths per 1000 live births by 2030. Reliable iNMR estimates are essential for national and hospital-level monitoring. This study assessed birthweight-specific adjustment curves developed using simulated data, and extended the approach to routine data from 172,809 neonatal admissions across four African countries in the NEST360 network. Simulated data were generated using birthweight intervals of 500 g from 500 to 5000 g, with 1000 values per category representing 1000 hospitals. Admissions were drawn from a negative binomial distribution and mortality rates from a beta distribution based on published birthweight-specific iNMRs. Adjustment functions were developed using data from 500 hospitals without underreporting and tested on 500 with induced underreporting. This approach was then extended to real data from 65 NEST360 partnering hospitals. The adjustment functions were derived from 26 hospitals with plausible reporting (iNMR ≥ 700 per 1000 for neonates < 1000 g). In simulated data, adjusted iNMRs closely matched original values, with median differences ranging from − 4 to 9 deaths per 1000 across birthweight categories. In NEST360 dataset, unadjusted iNMRs were 121 (range 13–272) in Nigeria, 128 (60–214) in Tanzania, 132 (42–234) in Malawi, and 135 (60–250) in Kenya per 1000 admissions. After adjustment, estimates increased to 162 (127–333), 183 (128–233), 174 (120–268), and 172 (123–261), respectively. Variability across hospitals decreased, with standard deviation reducing from 13 to 5 deaths per 1000. Birthweight specific adjustment functions provide a practical and scalable approach to improving the plausibility of iNMR estimates where underreporting is common. These methods can be integrated into routine systems (such as Electronic Medical Record Systems and DHIS2) where key data are available, with modest computational demands. Their use can strengthen mortality surveillance and support more reliable policy and planning, while contributing to progress toward SDG 3.2, contingent on continued improvements in data quality and system capacity.

Background acute lower respiratory infections (ALRIs) are the leading global cause of post-neonatal death in children younger than 5 years. The impact, cost, and cost-effectiveness of routine pulse oximetry and oxygen on ALRI outcomes at scale remain unquantified. Methods We evaluate the impact and cost-effectiveness of scaling up pulse oximetry and oxygen on childhood ALRI outcomes in Malawi using a new and detailed individual-based model, together with a comprehensive costing assessment for 2024 that includes both capital and operational expenditures. We model 15 scenarios ranging from no pulse oximetry or oxygen (null scenario) to high coverage (90% pulse oximetry usage and 80% oxygen availability) across the health system. Cost-effectiveness results are presented in incremental cost-effectiveness ratios (ICERs) and incremental net health benefits (INHBs) using a Malawi-specific cost-effectiveness threshold of US$80 per disability-adjusted life-year (DALY) averted. Findings The cost-effective strategy is the full scale-up of pulse oximetry to 90% usage rate and oxygen to 80% availability. This combination results in 72% (95% CI 72-72) of hypoxaemic ALRI cases accessing oxygen, averting 71 000 (68 100-74 000) DALYs per year of implementation and 28% (27-29) of potential ALRI deaths, at an ICER of US$35 (33-36) per DALY averted and $924 (887-963) per death averted. The INHB is 40 200 (37 300-43 100) net DALYs averted. Interpretation Pulse oximetry and oxygen are complementary cost-effective interventions in Malawi, where health expenditure is low, and should be scaled up in parallel. Copyright (c) 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

INTRODUCTION:Access to oral antivirals like nirmatrelvir/ritonavir to treat COVID-19 remains largely unavailable across Africa. Ghana, Malawi, Rwanda and Zambia, all members of the COVID Treatment QuickStart Consortium, leveraged existing infrastructure to rapidly commence COVID-19 test-and-treat programs. We describe the individual-level impact within the cascade of care. METHODS:A retrospective cohort study was conducted in 36 facilities across four countries that captured data on SARS-CoV-2 positive individuals who were screened for treatment. Treatment criteria included being high-risk for severe COVID-19 disease progression, presenting within five days of symptom onset, and having mild-to-moderate COVID-19 disease severity; treatment eligibility was ultimately determined by trained healthcare workers. RESULTS:From 1941 participants, 50.2% were determined eligible while 65.2% were prescribed nirmatrelvir/ritonavir. Among those prescribed, 1265 (73.2%) received follow-up, among whom 99.4% confirmed treatment initiation and 97.6% completed the five-day treatment course. Two serious adverse events were reported, but neither was attributed to nirmatrelvir/ritonavir. CONCLUSIONS:These data are the first to suggest COVID-19 oral antiviral treatment can be quickly, efficiently and safely deployed in lower- and middle-income countries, in parallel with implementation research. Programs rapidly integrated their COVID-19 response into existing health service infrastructure, allowing for decentralization and demonstrating that introducing newly developed diagnostics and treatment in government health systems is feasible in lower-resourced settings during health emergencies. Equitable and timely access to diagnostics and treatments is crucial to combat emerging global disease threats and achieve global health equity.

BACKGROUND:Hypoxaemia predicts mortality at all levels of care, and appropriate management can reduce preventable deaths. However, pulse oximetry and oxygen therapy remain inaccessible in many primary care health facilities. We aimed to develop and validate a simple risk score comprising commonly evaluated clinical features to predict hypoxaemia in 2-59-month-old children with pneumonia. METHODS:Data from seven studies conducted in five countries from the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) dataset were included. Readily available clinical features and demographic variables were used to develop a multivariable logistic regression model to predict hypoxemia (oxygen saturation <90%) at presentation to care. The adjusted log coefficients were transformed to derive the PREPARE hypoxemia risk score and its diagnostic value was assessed in a held-out, temporal validation dataset. The model and risk score were analysed by evaluating the area under the receiver operating characteristic curve (AUC), sensitivity and specificity. RESULTS:We included 14 509 children in the analysis; 9.8% (n=2515) were hypoxemic at presentation. The multivariable regression model to predict hypoxemia included age, sex, respiratory distress (nasal flaring, grunting and/or head nodding), lower chest indrawing, respiratory rate, body temperature and weight-for-age z-score. The model showed fair discrimination (AUC 0.70, 95% CI 0.67 to 0.73) and calibration in the validation dataset. The simplified PREPARE hypoxaemia risk score includes five variables: age, respiratory distress, lower chest indrawing, respiratory rate and weight-for-age z-score. CONCLUSION:The PREPARE hypoxemia risk score, comprising five easily available characteristics, has the potential to be used to identify hypoxemia in children with pneumonia with a fair degree of certainty for use in health facilities without pulse oximetry. Its implementation would require careful consideration to limit the burden of inappropriate referrals on patients and the health system. Further external validation in community settings in low- and middle-income countries is required.

Sub-Saharan Africa had a significant burden of infections and deaths from COVID-19. However, throughout the pandemic, the region experienced delays and more limited access to diagnostics and treatment than high-income countries. From late 2022 to 2023, nirmatrelvir/ritonavir was introduced in four sub-Saharan African countries (Ghana, Malawi, Rwanda and Zambia) in a test and treat (T&T) model. This manuscript aims to understand the perspectives of key stakeholders, Ministry of Health, public sector personnel and health care workers on the recommendations for improvement and strengthening of national COVID-19 T&T programs deployed in the four study countries. We conducted in-depth, semi-structured interviews with individuals from two key stakeholder groups: Ministry of Health or public sector personnel involved in developing and/or implementation of COVID-19 T&T policy (purposive sampling) and healthcare workers involved in administering COVID-19 testing and/or treatment at study sites (convenience sampling). Sample size was driven by information power; our target sample size was ten to 12 interviews per stakeholder group per country. We conducted a descriptive qualitative study to explore recommendations for improvement and strengthening of national COVID-19 T&T programs using the Consolidated Framework for Implementation Research to guide qualitative data collection and analysis. Four key themes were identified by key stakeholders as critical to scaling up COVID-19 T&T programs across all study countries: increasing community education, engagement and awareness of COVID-19 and the T&T program; adjusting the T&T program to ensure program integration, decentralization and sustainability; expansion of SARS-COV-2 testing and ensuring availability of testing kits and oral antivirals through reliable national supply chains; and ensuring ongoing training and support for healthcare workers on the COVID-19 T&T program. Our finding, that recommendations were largely common across countries, suggest that a unifying framework for introducing new drugs through T&T programs during future pandemics in Sub-Saharan countries may be possible, particularly when implementation strategies can be customized to fit local contexts. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial Clinicaltrials.gov [NCT06360783][1] ### Clinical Protocols ### Funding Statement This work was supported by Open Society Foundations, the Conrad N. Hilton Foundation, and Pfizer. The donors have no role in the design or analysis of this implementation research study. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Duke University Institutional Review Board (Pro00111388), The study was also approved by local institutional review boards in each country: the Ghana Health Services Ethics Review Committee (017/11/22), the National Health Sciences Research Committee, Malawi (#23/03/4025), the Rwanda National Research Ethics Committee (105/RNEC/2023) and the Institutional Review Board ERES Converge (Zambia) (23-Jan-023). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes NA [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT06360783&atom=%2Fmedrxiv%2Fearly%2F2025%2F03%2F25%2F2025.03.24.25324159.atom

Abstract Background The emergence of COVID-19 precipitated containment policies (e.g., lockdowns, school closures, etc.). These policies disrupted healthcare, potentially eroding gains for Sustainable Development Goals including for neonatal mortality. Our analysis aimed to evaluate indirect effects of COVID-19 containment policies on neonatal admissions and mortality in 67 neonatal units across Kenya, Malawi, Nigeria, and Tanzania between January 2019 and December 2021. Methods The Oxford Stringency Index was applied to quantify COVID-19 policy stringency over time for Kenya, Malawi, Nigeria, and Tanzania. Stringency increased markedly between March and April 2020 for these four countries (although less so in Tanzania), therefore defining the point of interruption. We used March as the primary interruption month, with April for sensitivity analysis. Additional sensitivity analysis excluded data for March and April 2020, modelled the index as a continuous exposure, and examined models for each country. To evaluate changes in neonatal admissions and mortality based on this interruption period, a mixed effects segmented regression was applied. The unit of analysis was the neonatal unit (n = 67), with a total of 266,741 neonatal admissions (January 2019 to December 2021). Results Admission to neonatal units decreased by 15% overall from February to March 2020, with half of the 67 neonatal units showing a decline in admissions. Of the 34 neonatal units with a decline in admissions, 19 (28%) had a significant decrease of ≥ 20%. The month-to-month decrease in admissions was approximately 2% on average from March 2020 to December 2021. Despite the decline in admissions, we found no significant changes in overall inpatient neonatal mortality. The three sensitivity analyses provided consistent findings. Conclusion COVID-19 containment measures had an impact on neonatal admissions, but no significant change in overall inpatient neonatal mortality was detected. Additional qualitative research in these facilities has explored possible reasons. Strengthening healthcare systems to endure unexpected events, such as pandemics, is critical in continuing progress towards achieving Sustainable Development Goals, including reducing neonatal deaths to less than 12 per 1000 live births by 2030.

Objectives We aimed to assess the prevalence, presentation and referral patterns of children with acute illness attending primary health centres (PHCs) in a low-resource setting.Design, setting and participants We conducted a secondary analysis of ASPIRE. Children presenting at eight PHCs in urban Blantyre district in southern Malawi with both recorded clinician and mHealth (non-clinician) triage data were included, and patient records from different data collection points along the patient healthcare seeking pathway were consolidated and analysed.Results Between April 2017 and September 2018, a total of 204 924 children were triaged, of whom 155 931 had both recorded clinician and mHealth triage data. The most common presenting symptoms at PHCs were fever (0.3%), cough (0.2%) and difficulty breathing (0.2%). The most common signs associated with referral for under-5 children were trauma (26.7%) and temperature (7.4%). The proportion of emergency and priority clinician triage were highest among young infants <2 months (0.2% and 81.4%, respectively). Of the 3004 referrals (1.9%), 1644 successfully reached the referral facility (54.7%). Additionally, 372 children were sent home from PHC who subsequently self-referred to the referral facility (18.7%).Conclusions Fever and respiratory symptoms were the most common presenting symptoms, and trauma was the most common reason for referral. Rates of referral were low, and of successful referral were moderate. Self-referrals constituted a substantial proportion of attendance at the referral facility. Reducing gaps in care and addressing dropouts as well as self-referrals along the referral pathway could improve child health outcomes.

Background Each year an estimated 2.3 million newborns die in the first 28 days of life. Most of these deaths are preventable, and high-quality neonatal care is fundamental for surviving and thriving. Service readiness is used to assess the capacity of hospitals to provide care, but current health facility assessment (HFA) tools do not fully evaluate inpatient small and sick newborn care (SSNC). Methods Health systems ingredients for SSNC were identified from international guidelines, notably World Health Organization (WHO), and other standards for SSNC. Existing global and national service readiness tools were identified and mapped against this ingredients list. A novel HFA tool was co-designed according to a priori considerations determined by policymakers from four African governments, including that the HFA be completed in one day and assess readiness across the health system. The tool was reviewed by > 150 global experts, and refined and operationalised in 64 hospitals in Kenya, Malawi, Nigeria, and Tanzania between September 2019 and March 2021. Results Eight hundred and sixty-six key health systems ingredients for service readiness for inpatient SSNC were identified and mapped against four global and eight national tools measuring SSNC service readiness. Tools revealed major content gaps particularly for devices and consumables, care guidelines, and facility infrastructure, with a mean of 13.2% ( n = 866, range 2.2–34.4%) of ingredients included. Two tools covered 32.7% and 34.4% ( n = 866) of ingredients and were used as inputs for the new HFA tool, which included ten modules organised by adapted WHO health system building blocks, including: infrastructure, pharmacy and laboratory, medical devices and supplies, biomedical technician workshop, human resources, information systems, leadership and governance, family-centred care, and infection prevention and control. This HFA tool can be conducted at a hospital by seven assessors in one day and has been used in 64 hospitals in Kenya, Malawi, Nigeria, and Tanzania. Conclusion This HFA tool is available open-access to adapt for use to comprehensively measure service readiness for level-2 SSNC, including respiratory support. The resulting facility-level data enable comparable tracking for Every Newborn Action Plan coverage target four within and between countries, identifying facility and national-level health systems gaps for action.

Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis.

Providing emergency care in low resource settings relies on delivery by lower cadres of health workers (LCHW). We describe the development, implementation and mixed methods evaluation of a mobile health (mHealth) triage algorithm based on the WHO Emergency, Triage, Assessment, and Treatment (ETAT) for primary-level care. We conducted an observational study design of implementation research. Key stakeholders were engaged throughout implementation. Clinicians and LCHW at eight primary health centres in Blantyre district were trained to use an mHealth algorithm for triage. An mHealth patient surveillance system monitored patients from presentation through referral to tertiary and final outcome. A total of 209,174 children were recorded by ETAT between April 2017 and September 2018, and 155,931 had both recorded mHealth and clinician triage outcome data. Concordance between mHealth triage by lower cadres of HCW and clinician assessment was 81·6% (95% CI [81·4, 81·8]) over all outcomes (kappa: 0·535 (95% CI [0·530, 0·539]). Concordance for mHealth emergency triage was 0.31 with kappa 0.42. The most common mHealth recorded emergency sign was breathing difficulty (74·1% 95% CI [70·1, 77·9]) and priority sign was raised temperature (76·2% (95% CI [75·9, 76·6]). A total of 1,644 referrals out of 3,004 (54·7%) successfully reached the tertiary site. Both providers and carers expressed high levels of satisfaction with the mHealth ETAT pathway. An mHealth triage algorithm can be used by LCHWs with moderate concordance with clinician triage. Implementation of ETAT through an mHealth algorithm documented successful referrals from primary to tertiary, but half of referred patients did not reach the tertiary site. Potential harms of such systems, such as cases requiring referral being missed during triage, require further evaluation. The ASPIRE mHealth primary ETAT approach can be used to prioritise acute illness and support future resource planning within both district and national health system.

Background Every Newborn Action Plan (ENAP) coverage target 4 necessitates national scale-up of Level-2 Small and Sick Newborn Care (SSNC) (with Continuous Positive Airway Pressure (CPAP)) in 80% of districts by 2025. Routine neonatal inpatient data is important for improving quality of care, targeting equity gaps, and enabling data-driven decision-making at individual, district, and national-levels. Existing neonatal inpatient datasets vary in purpose, size, definitions, and collection processes. We describe the co-design and operationalisation of a core inpatient dataset for use to track outcomes and improve quality of care for small and sick newborns in high-mortality settings. Methods A three-step systematic framework was used to review, co-design, and operationalise this novel neonatal inpatient dataset in four countries (Malawi, Kenya, Tanzania, and Nigeria) implementing with the Newborn Essential Solutions and Technologies (NEST360) Alliance. Existing global and national datasets were identified, and variables were mapped according to categories. A priori considerations for variable inclusion were determined by clinicians and policymakers from the four African governments by facilitated group discussions. These included prioritising clinical care and newborn outcomes data, a parsimonious variable list, and electronic data entry. The tool was designed and refined by > 40 implementers and policymakers during a multi-stakeholder workshop and online interactions. Results Identified national and international datasets ( n = 6) contained a median of 89 (IQR:61–154) variables, with many relating to research-specific initiatives. Maternal antenatal/intrapartum history was the largest variable category (21, 23.3%). The Neonatal Inpatient Dataset (NID) includes 60 core variables organised in six categories: (1) birth details/maternal history; (2) admission details/identifiers; (3) clinical complications/observations; (4) interventions/investigations; (5) discharge outcomes; and (6) diagnosis/cause-of-death. Categories were informed through the mapping process. The NID has been implemented at 69 neonatal units in four African countries and links to a facility-level quality improvement (QI) dashboard used in real-time by facility staff. Conclusion The NEST360 NID is a novel, parsimonious tool for use in routine information systems to inform inpatient SSNC quality. Available on the NEST360/United Nations Children's Fund (UNICEF) Implementation Toolkit for SSNC, this adaptable tool enables facility and country-level comparisons to accelerate progress toward ENAP targets. Additional linked modules could include neonatal at-risk follow-up, retinopathy of prematurity, and Level-3 intensive care.

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.

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 (SpO2) < 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 SpO2 < 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 SpO2 < 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.

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

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 (SpO2) < 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 SpO2 < 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 SpO2 < 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.

Background: Pulse oximeters are not routinely available in outpatient clinics in low- and middle-income countries. We derived clinical scores to identify hypoxemic child pneumonia.Methods: This was a retrospective pooled analysis of two outpatient datasets of 3-35 month olds with World Health Organization (WHO)-defined pneumonia in Bangladesh and Malawi. We constructed, internally validated, and compared fit & discrimination of four models predicting SpO(2 )< 93% and <90%: (1) Integrated Management of Childhood Illness guidelines, (2) WHO-composite guidelines, (3) Independent variable least absolute shrinkage and selection operator (LASSO); (4) Composite variable LASSO.Results: 12,712 observations were included. The independent and composite LASSO models discriminated moderately (both C-statistic 0.77) between children with a SpO(2 )< 93% and >= 94%; model predictive capacities remained moderate after adjusting for potential overfitting (C-statistic 0.74 and 0.75). The IMCI and WHO-composite models had poorer discrimination (C-statistic 0.56 and 0.68) and identified 20.6% and 56.8% of SpO(2 )< 93% cases. The highest score stratum of the independent and composite LASSO models identified 46.7% and 49.0% of SpO(2 )< 93% cases. Both LASSO models had similar performance for a SpO(2 )< 90%.Conclusions: In the absence of pulse oximeters, both LASSO models better identified outpatient hypoxemic pneumonia cases than the WHO guidelines. Score external validation and implementation are needed.

Pneumonia remains the leading cause of infectious morbidity and mortality in children; however, research remains chronically under-funded and has been excluded from major global financing mechanisms. 1 Head MG Brown RJ Newell ML Scott JAG Batchelor J Atun R The allocation of US$105 billion in global funding from G20 countries for infectious disease research between 2000 and 2017: a content analysis of investments. Lancet Glob Health. 2020; 8: e1295-e1304 Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar To achieve the Sustainable Development Goals, as set out in the UN 2030 Agenda for Sustainable Development, funding for childhood pneumonia research should be prioritised.

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.