INTRODUCTION: Malnutrition contributes to 45% of all childhood deaths globally, but these modelled estimates lack direct measurements in countries with high malnutrition and under-5 mortality rates. We investigated malnutrition's role in infant and child deaths in the Child Health and Mortality Prevention Surveillance (CHAMPS) network. METHODS: We analysed CHAMPS data from seven sites (Bangladesh, Ethiopia, Kenya, Mali, Mozambique, Sierra Leone and South Africa) collected between 2016 and 2023. An expert panel assessed each death to determine whether malnutrition was an underlying, antecedent or immediate cause or other significant condition. Malnutrition was further classified based on postmortem anthropometry using WHO growth standards for underweight (z-scores for weight-for-age <-2), stunting (length-for-age <-2), and wasting (weight-for-length or MUAC Z-scores <-2). RESULTS: Of 1601 infant and child deaths, malnutrition was considered a causal or significant condition in 632 (39.5%) cases, including 85 (13.4%) with HIV infection. Postmortem measurements indicated 90.1%, 61.2% and 94.1% of these cases were underweight, stunted and wasted, respectively. Most malnutrition-related deaths (n=632) had an infectious cause (89.1%). The adjusted odds of having malnutrition as causal or significant condition were 2.4 (95% CI 1.7 to 3.2) times higher for deaths involving infectious diseases compared with other causes. Common pathogens in the causal pathway for malnutrition-related deaths included Klebsiella pneumoniae (30.4%), Streptococcus pneumoniae (21.5%), Plasmodium falciparum (18.7%) and Escherichia coli/Shigella (17.2%). CONCLUSION: Malnutrition was identified as a causal or significant factor in 39.5% of under-5 deaths in the CHAMPS network, often in combination with infectious diseases. These findings highlight the need for integrated interventions addressing both malnutrition and infectious diseases to effectively reduce under-5 mortality.

The diagnosis of paediatric pulmonary tuberculosis is difficult, especially in young infants who cannot expectorate sputum spontaneously. Breath testing has shown promise in diagnosing respiratory tract infections, but data on paediatric tuberculosis are limited. We performed a prospective cross-sectional study in Kenya in children younger than five years with symptoms of tuberculosis. We analysed exhaled breath with a hand-held battery-powered nose device. For data analysis, machine learning was applied using samples classified as positive (microbiologically confirmed) or negative (unlikely tuberculosis) to assess diagnostic accuracy. Breath analysis was performed in 118 children. The area under the curve of the optimal model was 0.73. At a sensitivity of 86 % (CI 62-96 %), this resulted in a specificity of 42 % (95 % CI 30-55 %). Exhaled breath analysis shows promise as a triage test for TB in young children, although the WHO target product characteristics were not met.

For microbiological confirmation of pediatric pulmonary tuberculosis (PTB), gastric aspirates (GA) are often operationally unfeasible without hospitalization, and the encapsulated orogastric string test is not easily swallowed in young children. The Combined-NasoGastric-Tube-and-String-Test (CNGTST) enables dual collection of GA and string specimens. In a prospective cohort study in Kenya, we examined its feasibility in children under five with presumptive PTB and compared the bacteriological yield of string to GA. Paired GA and string samples were successfully collected in 95.6 % (281/294) of children. Mycobacterium tuberculosis was isolated from 7.0 % (38/541) of GA and 4.3 % (23/541) of string samples, diagnosing 8.2 % (23/281) of children using GA and 5.3 % (15/281) using string. The CNGTST was feasible in nearly all children. Yield from string was two-thirds that of GA despite a half-hour median dwelling time. In settings where the feasibility of hospitalisation for GA is uncertain, the string component can be used to confirm PTB.

Delays in illness recognition, healthcare seeking, and in the provision of appropriate clinical care are common in resource-limited settings. Our objective was to determine the frequency of delays in the "Three Delays-in-Healthcare", and factors associated with delays, among deceased infants and children in seven countries with high childhood mortality. We conducted a retrospective, descriptive study using data from verbal autopsies and medical records for infants and children aged 1-59 months who died between December 2016 and February 2022 in six sites in sub-Saharan Africa and one in South Asia (Bangladesh) and were enrolled in Child Health and Mortality Prevention Surveillance (CHAMPS). Delays in 1) illness recognition in the home/decision to seek care, 2) transportation to healthcare facilities, and 3) the receipt of clinical care in healthcare facilities were categorized according to the "Three Delays-in-Healthcare". Comparisons in factors associated with delays were made using Chi-square testing. Information was available for 1,326 deaths among infants and under 5 children. The majority had at least one identified delay (n = 854, 64%). Waiting >72 hours after illness recognition to seek health care (n = 422, 32%) was the most common delay. Challenges in obtaining transportation occurred infrequently when seeking care (n = 51, 4%). In healthcare facilities, prescribed medications were sometimes unavailable (n = 102, 8%). Deceased children aged 12-59 months experienced more delay than infants aged 1-11 months (68% vs. 61%, P = 0.018). Delays in seeking clinical care were common among deceased infants and children. Additional study to assess the frequency of delays in seeking clinical care and its provision among children who survive is warranted.

BACKGROUND: Malaria is a leading cause of childhood mortality worldwide. However, accurate estimates of malaria prevalence and causality among patients who die at the country level are lacking due to the limited specificity of diagnostic tools used to attribute etiologies. Accurate estimates are crucial for prioritizing interventions and resources aimed at reducing malaria-related mortality. METHODS: Seven Child Health and Mortality Prevention Surveillance (CHAMPS) Network sites collected comprehensive data on stillbirths and children <5 years, using minimally invasive tissue sampling (MITS). A DeCoDe (Determination of Cause of Death) panel employed standardized protocols for assigning underlying, intermediate, and immediate causes of death, integrating sociodemographic, clinical, laboratory (including extensive microbiology, histopathology, and malaria testing), and verbal autopsy data. Analyses were conducted to ascertain the strength of evidence for cause of death (CoD), describe factors associated with malaria-related deaths, estimate malaria-specific mortality, and assess the proportion of preventable deaths. FINDINGS: Between December 3, 2016, and December 31, 2022, 2673 deaths underwent MITS and had a CoD attributed from four CHAMPS sites with at least 1 malaria-attributed death. No malaria-attributable deaths were documented among 891 stillbirths or 924 neonatal deaths, therefore this analysis concentrates on the remaining 858 deaths among children aged 1-59 months. Malaria was in the causal chain for 42.9% (126/294) of deaths from Sierra Leone, 31.4% (96/306) in Kenya, 18.2% (36/198) in Mozambique, 6.7% (4/60) in Mali, and 0.3% (1/292) in South Africa. Compared to non-malaria related deaths, malaria-related deaths skewed towards older infants and children (p<0.001), with 71.0% among ages 12-59 months. Malaria was the sole infecting pathogen in 184 (70.2%) of malaria-attributed deaths, whereas bacterial and viral co-infections were identified in the causal pathway in 24·0% and 12.2% of cases, respectively. Malnutrition was found at a similar level in the causal pathway of both malaria (26.7%) and non-malaria (30.7%, p=0.256) deaths. Less than two-thirds (164/262; 62.6%) of malaria deaths had received antimalarials prior to death. Nearly all (98·9%) malaria-related deaths were deemed preventable. INTERPRETATION: Malaria remains a significant cause of childhood mortality in the CHAMPS malaria-endemic sites. The high bacterial co-infection prevalence among malaria deaths underscores the potential benefits of antibiotics for severe malaria patients. Compared to non-malaria deaths, many of malaria-attributed deaths are preventable through accessible malaria control measures. FUNDING: This work was supported by the Bill & Melinda Gates Foundation [OPP1126780].

BACKGROUND: Adverse childhood experiences (ACEs) have been shown to have negative, lasting effects on health including increasing the likelihood of engaging in sexual risk behaviors. OBJECTIVE: This study aimed to identify associations between exposures to ACEs and sexual risk behaviors and HIV service utilization among young people. PARTICIPANTS AND SETTING: A sample of 8023 sexually active young people (19-24 year olds) from five sub-Saharan African countries participated Violence Against Children and Youth Surveys (VACS). METHODS: Descriptive analysis of demographic variables, individual ACEs, cumulative ACEs, sexual risk behaviors, HIV testing, antiretroviral treatment (ART) and Antenatal Care (ANC) attendance were completed. Bivariate and multivariable logistic regression analyses were conducted to assess the associations between both individual and cumulative ACEs, sexual HIV risk behaviors, and service utilization while controlling for important covariates such as demographic, having ever been pregnant, had an STI, and used contraception. RESULTS: Exposure to three or more ACEs was higher among males (26.1 %) compared to females (21.3 %); p = 0.003. The most prominent sexual risk behavior for females was having sexual partners who were at least 5 years older (45.7 % compared to males 3.7 %; p < 0.0001) whereas in males it was no or infrequent condom use (45.3 % compared to females 30.1 %; p < 0.0001). Males and females exposed to childhood sexual violence had seven and four times the odds of engaging in transactional sex (aOR = 7.34, 95 % CI: [3.5-15.0]) and (aOR =3.75, 95 % CI: [2.3-6.2], respectively. Females exposed to three or more ACEs were four times more likely to engage in transactional sex (aOR = 4.85, 95 %, CI: [1.6-14.4]) compared to those who did not experience any ACEs. Males exposed to three or more ACEs were two times more likely to engage in early sexual debut (aOR = 2.2, 95 % CI: [1.3-3.4]),]) compared to those who did not experience any ACEs. Females who had witnessed IPV or violence in the community had significantly higher odds of getting tested for HIV (aOR = 2.16, 95 % CI: [1.63-2.87]) and (aOR = 1.36, 95 % CI: [1.03-1.81]), respectively. CONCLUSIONS: This study demonstrated that experiencing ACEs during childhood is associated with higher HIV risk behaviors in sub-Saharan Africa (SSA) with unique differences between males and females.

Guatemala implemented wastewater-based poliovirus surveillance in 2018, and three genetically unrelated vaccine-derived polioviruses (VDPVs) were detected in 2019. The Ministry of Health (MoH) response included event investigation through institutional and community retrospective case searches for acute flaccid paralysis (AFP) during 2018-2020 and a bivalent oral polio/measles, mumps, and rubella vaccination campaign in September 2019. This response was reviewed by an international expert team in July 2021. During the campaign, 93% of children 6 months <7 years of age received a polio-containing vaccine dose. No AFP cases were detected in the community search; institutional retrospective searches found 37% of unreported AFP cases in 2018‒2020. No additional VDPV was isolated from wastewater. No evidence of circulating VDPV was found; the 3 isolated VDPVs were classified as ambiguous VDPVs by the international team of experts. These detections highlight risk for poliomyelitis reemergence in countries with low polio vaccine coverage.

BACKGROUND: Most childhood deaths globally are considered preventable through high-quality clinical care, which includes adherence to clinical care recommendations. Our objective was to describe adherence to World Health Organization recommendations for the management of leading causes of death among children. METHODS: We conducted a retrospective, descriptive study examining clinical data for children aged 1-59 months who were hospitalized and died in a Child Health and Mortality Prevention Surveillance (CHAMPS) catchment, December 2016-June 2021. Catchment areas included: Baliakandi and Faridpur, Bangladesh; Kersa, Haramaya, and Harar, Ethiopia; Kisumu and Siaya, Kenya; Bamako, Mali; Manhiça and Quelimane, Mozambique; Makeni, Sierra Leone; Soweto, South Africa. We reviewed medical records of those who died from lower respiratory tract infections, sepsis, malnutrition, malaria, and diarrheal diseases to determine the proportion who received recommended treatments and compared adherence by hospitalization duration. FINDINGS: CHAMPS enrolled 460 hospitalized children who died from the leading causes (median age 12 months, 53.0% male). Median hospital admission was 31 h. There were 51.0% (n = 127/249) of children who died from lower respiratory tract infections received supplemental oxygen. Administration of intravenous fluids for sepsis (15.9%, n = 36/226) and supplemental feeds for malnutrition (14.0%, n = 18/129) were uncommon. There were 51.4% (n = 55/107) of those who died from malaria received antimalarials. Of the 80 children who died from diarrheal diseases, 76.2% received intravenous fluids. Those admitted for ≥24 h more commonly received antibiotics for lower respiratory tract infections and sepsis, supplemental feeds for malnutrition, and intravenous fluids for sepsis than those admitted <24 h. INTERPRETATION: Provision of recommended clinical care for leading causes of death among young children was suboptimal. Further studies are needed to understand the reasons for deficits in clinical care recommendation adherence. FUNDING: Bill & Melinda Gates Foundation.

Gender-based violence (GBV) is a complex issue deeply rooted in social structures, making its eradication challenging. GBV increases the risk of HIV transmission and is a barrier to HIV testing, care, and treatment. Quality clinical services for GBV, which includes the provision of HIV postexposure prophylaxis (PEP), vary, and service delivery data are lacking. We describe GBV clinical service delivery in 15 countries supported by the President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Centers for Disease Control and Prevention. Through a descriptive statistical analysis of PEPFAR Monitoring, Evaluation, and Reporting (MER) data, we found a 252% increase in individuals receiving GBV clinical services, from 158,691 in 2017 to 558,251 in 2021. PEP completion was lowest (15%) among 15-19-year-olds. Understanding GBV service delivery is important for policy makers, program managers, and providers to guide interventions to improve the quality of service delivery and contribute to HIV epidemic control.

Diagnosis of tuberculosis (TB) among young children (<5 years) is challenging due to the paucibacillary nature of clinical disease and clinical similarities to other childhood diseases. We used machine learning to develop accurate prediction models of microbial confirmation with simply defined and easily obtainable clinical, demographic, and radiologic factors. We evaluated eleven supervised machine learning models (using stepwise regression, regularized regression, decision tree, and support vector machine approaches) to predict microbial confirmation in young children (<5 years) using samples from invasive (reference-standard) or noninvasive procedure. Models were trained and tested using data from a large prospective cohort of young children with symptoms suggestive of TB in Kenya. Model performance was evaluated using areas under the receiver operating curve (AUROC) and precision-recall curve (AUPRC), accuracy metrics. (i.e., sensitivity, specificity), F-beta scores, Cohen's Kappa, and Matthew's Correlation Coefficient. Among 262 included children, 29 (11%) were microbially confirmed using any sampling technique. Models were accurate at predicting microbial confirmation in samples obtained from invasive procedures (AUROC range: 0.84-0.90) and from noninvasive procedures (AUROC range: 0.83-0.89). History of household contact with a confirmed case of TB, immunological evidence of TB infection, and a chest x-ray consistent with TB disease were consistently influential across models. Our results suggest machine learning can accurately predict microbial confirmation of M. tuberculosis in young children using simply defined features and increase the bacteriologic yield in diagnostic cohorts. These findings may facilitate clinical decision making and guide clinical research into novel biomarkers of TB disease in young children.

BACKGROUND: Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres. METHODS: For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings. FINDINGS: Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms. INTERPRETATION: We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance. FUNDING: WHO, US National Institutes of Health.

The CDC is unwavering in our commitment to provide the highest quality laboratory diagnostic services for parasitic diseases. We clearly hear, understand, and concur with the concerns expressed in the accompanying editorial and appreciate the challenges the pause in testing for parasitic diseases presents for health-care providers, particularly those treating people at elevated risk for parasitic diseases. | | We also recognize the crucial role that our agency plays in ensuring those at risk receive equitable services for infections, including those that are generally known to all Americans as well as neglected diseases that are unfamiliar to most Americans. More broadly, the CDC works to protect the global community from parasitic diseases through three main priorities: reducing parasitic disease-related death, illness, and disability in the United States; reducing the global burden of malaria; and eliminating targeted neglected tropical diseases. Our Parasitic Diseases Laboratory is, in many ways, the foundation of this work and serves as a critical resource and often a laboratory of last resort for challenging diagnoses of unfamiliar pathogens when state and private laboratories do not have the relevant testing capacity. Our laboratory experts develop and improve tools and approaches to detect, prevent, and control disease; provide diagnostic assistance and expertise to public health laboratories; and conduct diagnostic tests for parasitic diseases.

BACKGROUND: Pediatric tuberculosis (TB) remains a critical public health concern, yet bacteriologic confirmation of TB in children is challenging. Clinical, demographic, and radiological factors associated with a positive Mycobacterium tuberculosis specimen in young children (5years) are poorly understood. METHODS: We conducted a prospective cohort study of young children with presumptive TB and examined clinical, demographic, and radiologic factors associated with invasive and noninvasive specimen collection techniques (gastric aspirate, induced sputum, nasopharyngeal aspirate, stool, and string test); up to 2 samples were taken per child, per technique. We estimated associations between these factors and a positive specimen for each technique using generalized estimating equations (GEEs) and logistic regression. RESULTS: A median (range) of 544 (507-566) samples were obtained for each specimen collection technique from 300 enrolled children; bacteriologic yield was low across all collection techniques (range, 1%-7% from Xpert MTB/RIF or culture), except for lymph node fine needle aspiration (29%) taken for children with cervical lymphadenopathy. Factors associated with positive M. tuberculosis samples across all techniques included prolonged lethargy (median [range] adjusted odds ratio [aOR], 8.1 [3.9-10.1]), history of exposure with a TB case (median [range] aOR, 6.1 [2.9-9.0]), immunologic evidence of M. tuberculosis infection (median [range] aOR, 4.6 [3.7-9.2]), large airway compression (median [range] aOR, 6.7 [4.7-9.5]), and hilar/mediastinal density (median [range] aOR, 2.9 [1.7-3.2]). CONCLUSIONS: Identifying factors that lead to a positive M. tuberculosis specimen in very young children can inform clinical management and increase the efficiency of diagnostic testing in children being assessed for TB.

INTRODUCTION: The high burden of stillbirths and neonatal deaths is driving global initiatives to improve birth outcomes. Discerning stillbirths from neonatal deaths can be difficult in some settings, yet this distinction is critical for understanding causes of perinatal deaths and improving resuscitation practices for live born babies. METHODS: We evaluated data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network to compare the accuracy of determining stillbirths versus neonatal deaths from different data sources and to evaluate evidence of resuscitation at delivery in accordance with World Health Organization (WHO) guidelines. CHAMPS works to identify causes of stillbirth and death in children <5 years of age in Bangladesh and 6 countries in sub-Saharan Africa. Using CHAMPS data, we compared the final classification of a case as a stillbirth or neonatal death as certified by the CHAMPS Determining Cause of Death (DeCoDe) panel to both the initial report of the case by the family member or healthcare worker at CHAMPS enrollment and the birth outcome as stillbirth or livebirth documented in the maternal health record. RESULTS: Of 1967 deaths ultimately classified as stillbirth, only 28 (1.4%) were initially reported as livebirths. Of 845 cases classified as very early neonatal death, 33 (4%) were initially reported as stillbirth. Of 367 cases with post-mortem examination showing delivery weight >1000g and no maceration, the maternal clinical record documented that resuscitation was not performed in 161 cases (44%), performed in 14 (3%), and unknown or data missing for 192 (52%). CONCLUSION: This analysis found that CHAMPS cases assigned as stillbirth or neonatal death after DeCoDe expert panel review were generally consistent with the initial report of the case as a stillbirth or neonatal death. Our findings suggest that more frequent use of resuscitation at delivery and improvements in documentation around events at birth could help improve perinatal outcomes.

BACKGROUND: Tuberculosis (TB) is a leading cause of illness and death in children globally. Improved bacteriologic and clinical diagnostic approaches in children are urgently needed. METHODS: In a prospective cohort study, a consecutive series of young (<5 years) children presenting with symptoms suggestive of TB and parenchymal abnormality on chest radiograph in inpatient and outpatient settings in Kisumu County, Kenya from October 2013 to August 2015 were evaluated at baseline and over 6 months. Up to 14 specimens per child were tested for the Mycobacterium tuberculosis complex by fluorescence microscopy, Xpert MTB/RIF and mycobacterial culture. Using detailed clinical characterization, cases were retrospectively classified according to standardized research case definitions and the sensitivity and specificity of microbiological tests on different specimen types were determined. RESULTS: Among 300 young children enrolled, 266 had sufficient information to be classified according to the research clinical case definition. Of these, 36% (96/266) had TB disease; 32% (31/96) with bacteriologically confirmed intrathoracic TB. Compared to culture, the sensitivity of a single Xpert test ranged from 60 to 67% and specificity from 97.5 to 100% for different specimen types. CONCLUSIONS: Despite extensive specimen collection and laboratory testing, TB could not be bacteriologically confirmed in almost two-thirds of children with intrathoracic TB classified by research clinical case definitions. Improved diagnostic tests are needed to identify children with TB and to exclude other potential causes of illness.

BACKGROUND: HIV testing efficiency could be improved by focusing on high yield populations and identifying types of health facilities where people with undiagnosed HIV infection are more likely to attend. METHODS: A retrospective cohort analysis of data collected during an integrated TB/HIV active case-finding intervention in Western Kenya. Data were analyzed from health facilities' registers on individuals who reported TB-suggestive symptoms between 1 July and 31 December 2018 and who had an HIV test result within one month following symptom screening. We used logistic regression with general estimating equations adjusting for sub-county level data to identify health facility-level predictors of new HIV diagnoses. RESULTS: Of 11,376 adults with presumptive TB identified in 143 health facilities, 1038 (9%) tested HIV positive. The median HIV positivity per health facility was 6% (IQR = 2-15%). Patients with TB symptoms were over three times as likely to have a new HIV diagnosis in private not-for-profit facilities compared to those in government facilities (adjusted odds ratio (aOR) 3.40; 95% CI = 1.96-5.90). Patients tested in hospitals were over two times as likely to have a new HIV diagnosis as those tested in smaller facilities (i.e., health centers and dispensaries) (aOR 2.26; 95% CI = 1.60-3.21). CONCLUSION: Individuals with presumptive TB who attended larger health facilities and private not-for-profit facilities had a higher likelihood of being newly diagnosed with HIV. Strengthening HIV services at these facilities and outreach to populations that use them could help to close the HIV diagnosis gap.

BACKGROUND: Recommended by the World Health Organization as an initial diagnostic test for TB in children, Xpert(®) MTB/RIF is widely implemented in many countries, including Kenya.METHODS: Three hundred HIV-positive and negative children (<5 years) were enrolled in Kisumu County, Kenya, from October 2013 to August 2015. Multiple specimen types were collected from each child and tested using Xpert, liquid culture, and phenotypic drug susceptibility testing (DST). Samples positive for rifampin (RIF) resistance on Xpert were tested using line-probe assay and sequencing.RESULTS: Of 32 children with bacteriologically confirmed TB, 27 had positive Xpert results. Of these, 3/27 (11%, 95% CI 4-28) had RIF resistance detected on Xpert, but not by phenotypic DST, line-probe assay, or sequencing. For these three children, five Xpert tests showed RIF resistance; all five tests had semi-quantitative "very low" results and delay or absence of probe D signal, whereas no Xpert results with higher semi-quantitative results showed RIF resistance. All three children responded well to standard TB treatment.CONCLUSIONS: False RIF resistance may be detected in pediatric specimens. Further study is needed to determine if false RIF resistance is associated with low bacterial load.

BACKGROUND: Lower respiratory tract infections are a leading cause of death in young children, but few studies have collected the specimens needed to define the role of specific causes. The Child Health and Mortality Prevention Surveillance (CHAMPS) platform aims to investigate causes of death in children aged <5 years in high-mortality rate settings, using postmortem minimally invasive tissue sampling and other advanced diagnostic techniques. We examined findings for deaths identified in CHAMPS sites in 7 countries in sub-Saharan Africa and south Asia to evaluate the role of respiratory syncytial virus (RSV). METHODS: We included deaths that occurred between December 2016 and December 2019. Panels determined causes of deaths by reviewing all available data including pathological results from minimally invasive tissue sampling, polymerase chain reaction screening for multiple infectious pathogens in lung tissue, nasopharyngeal swab, blood, and cerebrospinal fluid samples, clinical information from medical records, and verbal autopsies. RESULTS: We evaluated 1213 deaths, including 695 in neonates (aged <28 days), 283 in infants (28 days to <12 months), and 235 in children (12-59 months). RSV was detected in postmortem specimens in 67 of 1213 deaths (5.5%); in 24 deaths (2.0% of total), RSV was determined to be a cause of death, and it contributed to 5 other deaths. Younger infants (28 days to <6 months of age) accounted for half of all deaths attributed to RSV; 6.5% of all deaths in younger infants were attributed to RSV. RSV was the underlying and only cause in 4 deaths; the remainder (n = 20) had a median of 2 (range, 1-5) other conditions in the causal chain. Birth defects (n = 8) and infections with other pathogens (n = 17) were common comorbid conditions. CONCLUSIONS: RSV is an important cause of child deaths, particularly in young infants. These findings add to the substantial body of literature calling for better treatment and prevention options for RSV in high-mortality rate settings.

INTRODUCTION: In low-resource settings, a social autopsy tool has been proposed to measure the effect of delays in access to healthcare on deaths, complementing verbal autopsy questionnaires routinely used to determine cause of death. This study estimates the contribution of various delays in maternal healthcare to subsequent neonatal mortality using a social autopsy case-control design. METHODS: This study was conducted at the Child Health and Mortality Prevention Surveillance (CHAMPS) Sierra Leone site (Makeni City and surrounding rural areas). Cases were neonatal deaths in the catchment area, and controls were sex- and area-matched living neonates. Odds ratios for maternal barriers to care and neonatal death were estimated, and stratified models examined this association by neonatal age and medical complications. RESULTS: Of 53 neonatal deaths, 26.4% of mothers experienced at least one delay during pregnancy or delivery compared to 46.9% of mothers of stillbirths and 18.6% of control mothers. The most commonly reported delay among neonatal deaths was receiving care at the facility (18.9%). Experiencing any barrier was weakly associated (OR 1.68, CI 0.77, 3.67) and a delay in receiving care at the facility was strongly associated (OR 19.15, CI 3.90, 94.19) with neonatal death. DISCUSSION: Delays in healthcare are associated with neonatal death, particularly delays experienced at the healthcare facility. Heterogeneity exists in the prevalence of specific delays, which has implications for local public health policy. The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

In Kenya, HIV prevalence estimates among female sex workers (FSWs) are almost five times higher than among women in the general population. However, only 68% of infected FSWs are aware of their HIV-positive status. We aimed to identify perceived benefits, opportunities, and barriers of HIV self-testing (HIVST) in improving testing coverage among FSWs. Twenty focus group discussions were conducted with 77 service providers, 42 peer educators (PEs) and outreach workers, and 37 FSWs attending drop-in centers (DiCEs) in four regions of Kenya. An additional 8 FSWs with HIV-negative or unknown status-completed in-depth interviews. Data were analyzed thematically. Acceptability of HIVST was high, with cited benefits including confidentiality, convenience, and ease of use. Barriers included absence of counseling, potential for inaccurate results, fear of partner reaction, possible misuse, and fear that HIVST could lead to further stigmatization. PEs and DiCEs were the preferred models for distributing HIVST kits. FSWs wanted kits made available free or at a nominal cost (100 Kenya Shillings or ∼USD 1). Linkage to confirmatory testing, the efficiency of distributing HIVST kits using peers and DiCEs, and the types and content of effective HIVST messaging require further research.

IMPORTANCE: Criterion-standard specimens for tuberculosis diagnosis in young children, gastric aspirate (GA) and induced sputum, are invasive and rarely collected in resource-limited settings. A far less invasive approach to tuberculosis diagnostic testing in children younger than 5 years as sensitive as current reference standards is important to identify. OBJECTIVE: To characterize the sensitivity of preferably minimally invasive specimen and assay combinations relative to maximum observed yield from all specimens and assays combined. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cross-sectional diagnostic study, the reference standard was a panel of up to 2 samples of each of 6 specimen types tested for Mycobacterium tuberculosis complex by Xpert MTB/RIF assay and mycobacteria growth indicator tube culture. Multiple different combinations of specimens and tests were evaluated as index tests. A consecutive series of children was recruited from inpatient and outpatient settings in Kisumu County, Kenya, between October 2013 and August 2015. Participants were children younger than 5 years who had symptoms of tuberculosis (unexplained cough, fever, malnutrition) and parenchymal abnormality on chest radiography or who had cervical lymphadenopathy. Children with 1 or more evaluable specimen for 4 or more primary study specimen types were included in the analysis. Data were analyzed from February 2015 to October 2020. MAIN OUTCOMES AND MEASURES: Cumulative and incremental diagnostic yield of combinations of specimen types and tests relative to the maximum observed yield. RESULTS: Of the 300 enrolled children, the median (interquartile range) age was 2.0 (1.0-3.6) years, and 151 (50.3%) were female. A total of 294 met criteria for analysis. Of 31 participants with confirmed tuberculosis (maximum observed yield), 24 (sensitivity, 77%; interdecile range, 68%-87%) had positive results on up to 2 GA samples and 20 (sensitivity, 64%; interdecile range, 53%-76%) had positive test results on up to 2 induced sputum samples. The yields of 2 nasopharyngeal aspirate (NPA) samples (23 of 31 [sensitivity, 74%; interdecile range, 64%-84%]), of 1 NPA sample and 1 stool sample (22 of 31 [sensitivity, 71%; interdecile range, 60%-81%]), or of 1 NPA sample and 1 urine sample (21.5 of 31 [sensitivity, 69%; interdecile range, 58%-80%]) were similar to reference-standard specimens. Combining up to 2 each of GA and NPA samples had an average yield of 90% (28 of 31). CONCLUSIONS AND RELEVANCE: NPA, in duplicate or in combination with stool or urine specimens, was readily obtainable and had diagnostic yield comparable with reference-standard specimens. This combination could improve tuberculosis diagnosis among children in resource-limited settings. Combining GA and NPA had greater yield than that of the current reference standards and may be useful in certain clinical and research settings.

Rationale: U.S. health departments routinely conduct post-arrival evaluation of immigrants and refugees at risk for tuberculosis (TB), but this important intervention has not been thoroughly studied.Objectives: To assess outcomes of the post-arrival evaluation intervention.Methods: We categorized at-risk immigrants and refugees as having had recent completion of treatment for pulmonary TB disease overseas (including in Mexico and Canada); as having suspected TB disease (chest radiograph/clinical symptoms suggestive of TB) but negative culture results overseas; or as having latent TB infection (LTBI) diagnosed overseas. Among 2.1 million U.S.-bound immigrants and refugees screened for TB overseas during 2013-2016, 90,737 were identified as at risk for TB. We analyzed a national data set of these at-risk immigrants and refugees and calculated rates of TB disease for those who completed post-arrival evaluation.Results: Among 4,225 persons with recent completion of treatment for pulmonary TB disease overseas, 3,005 (71.1%) completed post-arrival evaluation within 1 year of arrival; of these, TB disease was diagnosed in 22 (732 cases/100,000 persons), including 4 sputum culture-positive cases (133 cases/100,000 persons), 13 sputum culture-negative cases (433 cases/100,000 persons), and 5 cases with no reported sputum-culture results (166 cases/100,000 persons). Among 55,938 with suspected TB disease but negative culture results overseas, 37,089 (66.3%) completed post-arrival evaluation; of these, TB disease was diagnosed in 597 (1,610 cases/100,000 persons), including 262 sputum culture-positive cases (706 cases/100,000 persons), 281 sputum culture-negative cases (758 cases/100,000 persons), and 54 cases with no reported sputum-culture results (146 cases/100,000 persons). Among 30,574 with LTBI diagnosed overseas, 18,466 (60.4%) completed post-arrival evaluation; of these, TB disease was diagnosed in 48 (260 cases/100,000 persons), including 11 sputum culture-positive cases (60 cases/100,000 persons), 22 sputum culture-negative cases (119 cases/100,000 persons), and 15 cases with no reported sputum-culture results (81 cases/100,000 persons). Of 21,714 persons for whom treatment for LTBI was recommended at post-arrival evaluation, 14,977 (69.0%) initiated treatment and 8,695 (40.0%) completed treatment.Conclusions: Post-arrival evaluation of at-risk immigrants and refugees can be highly effective. To optimize the yield and impact of this intervention, strategies are needed to improve completion rates of post-arrival evaluation and treatment for LTBI.

Disclosing child sexual abuse (CSA) is a necessary first step to access the legal, health, and psycho-social services that survivors and their families need. However, disclosure rates are low: of young women who experienced CSA in Zimbabwe, only 9% disclosed the first incident. The purpose of this qualitative study was to explore and describe perceived barriers to disclosing CSA in Zimbabwe. We conducted focus group discussions with children aged 10-14 years (n = 40) and their parents/caregivers aged 20-62 years (n = 40), participating in an intervention trial in Chitungwiza, Zimbabwe. We found that potential retaliation against survivors and their families is a major barrier to disclosing CSA. These retaliatory acts, which we refer to as "re-victimization," arise from stigma or the victim feeling blamed or doubted and manifest through physical violence, emotional violence, and deprivation of family life and education. Our findings suggest that addressing social and cultural norms related to sex and strengthening legal protection for CSA survivors and their families could encourage CSA disclosure and could help end this violence. Our findings also highlight a need to increase children's awareness of their rights and to create safe systems for disclosure of sexual abuse.

BACKGROUND: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. METHODS: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. FINDINGS: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96.2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per muL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2.48, 95% CI 2.05-3.08) but not after 30 days (1.25, 0.84-2.49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3.15, 95% CI 1.16-8.84). INTERPRETATION: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients. FUNDING: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A.

OBJECTIVE: To compare the prevalence of tuberculosis infection and disease in household contacts of patients with bacteriologically confirmed tuberculosis disease and contacts of non-bacteriologically confirmed disease in western Kenya. METHODS: We enrolled newly diagnosed index patients and their household contacts from March 2014 to June 2016. All contacts were evaluated with a symptom questionnaire, tuberculin skin test (TST), and HIV test. Clinical evaluation and sputum testing were performed for those with symptoms, positive TST result, or HIV infection. RESULTS: We enrolled 1155 contacts of 330 index patients with bacteriologically confirmed tuberculosis and 192 contacts of 55 index patients with non-bacteriologically confirmed tuberculosis. 3.5% of contacts of patients with bacteriologically confirmed tuberculosis were diagnosed with tuberculosis, whereas no contacts of index patients with non-bacteriologically confirmed tuberculosis were. Of those diagnosed with tuberculosis disease, 58.5% reported symptoms, 34.1% reported no symptoms but had positive TST results, and 7.3% had neither symptoms nor positive TST but were HIV-positive. Among 872 contacts with a TST result, 50.9% of contacts of index patients with bacteriologically confirmed tuberculosis and 41.0% of contacts of index patients with non-bacteriologically confirmed tuberculosis had a positive result (prevalence ratio = 1.16, 95% confidence interval 0.92-1.48). CONCLUSION: In a high-burden setting, tuberculosis disease was more prevalent among contacts of patients with bacteriologically confirmed tuberculosis than contacts of patients with non-bacteriologically confirmed disease. TST was feasible to perform and helped to detect cases that would have been missed had only symptomatic contacts been evaluated.

Despite reductions over the past 2 decades, childhood mortality remains high in low- and middle-income countries in sub-Saharan Africa and South Asia. In these settings, children often die at home, without contact with the health system, and are neither accounted for, nor attributed with a cause of death. In addition, when cause of death determinations occur, they often use nonspecific methods. Consequently, findings from models currently utilized to build national and global estimates of causes of death are associated with substantial uncertainty. Higher-quality data would enable stakeholders to effectively target interventions for the leading causes of childhood mortality, a critical component to achieving the Sustainable Development Goals by eliminating preventable perinatal and childhood deaths. The Child Health and Mortality Prevention Surveillance (CHAMPS) Network tracks the causes of under-5 mortality and stillbirths at sites in sub-Saharan Africa and South Asia through comprehensive mortality surveillance, utilizing minimally invasive tissue sampling (MITS), postmortem laboratory and pathology testing, verbal autopsy, and clinical and demographic data. CHAMPS sites have established facility- and community-based mortality notification systems, which aim to report potentially eligible deaths, defined as under-5 deaths and stillbirths within a defined catchment area, within 24-36 hours so that MITS can be conducted quickly after death. Where MITS has been conducted, a final cause of death is determined by an expert review panel. Data on cause of death will be provided to local, national, and global stakeholders to inform strategies to reduce perinatal and childhood mortality in sub-Saharan Africa and South Asia.

OBJECTIVE: To evaluate the utility of a broad and non-specific symptom screen for identifying people with undiagnosed HIV infection. DESIGN: Secondary analysis of operational data collected during implementation of a cluster-randomized trial for tuberculosis case detection. METHODS: As part of the trial, adults reporting cough, fever, night sweats, weight loss, or difficulty breathing of any duration in the past month were identified in health facilities and community-based mobile screening units in western Kenya. Adults reporting any symptom were offered HIV testing. We analysed the HIV testing data from this study, using modified Poisson regression to identify predictors of new HIV diagnoses among adults with symptoms and initially unknown HIV status. RESULTS: We identified 3,818 symptomatic adults, referred 1424 (37%) for testing, of whom 1065 (75%) accepted, and 107 (10%) were newly diagnosed with HIV. The prevalence of new HIV diagnoses was 21% (95% CI: 17-25%) among those tested in health facilities and 5% (95% CI 4-7%) among those tested in mobile units. More men were diagnosed with HIV than women despite fewer men being screened. People who reported 4-5 symptoms were over twice as likely to be diagnosed with HIV compared to those reporting 1-3 symptoms (adjusted prevalence ratio [aPR] in health facilities = 2.58, 95% CI, 1.65-4.05; aPR in mobile units = 2.63, 95% CI, 1.37-5.03). CONCLUSION: We observed a high yield of new HIV diagnoses among adults identified by active application of a broad symptom screen. Integrated tuberculosis and HIV screening using could help close the detection gap for both conditions.

SETTING: Efficient tuberculosis (TB) active case-finding strategies are important in settings with high TB burdens and limited resources, such as those in western Kenya. OBJECTIVE: To guide efforts to optimize screening efficiency, we identified the predictors of TB among people screened in health facilities and communities. DESIGN: During February 2015-June 2016, adults aged >/=15 years reporting any TB symptom were identified in health facilities and community mobile screening units, and evaluated for TB. We assessed the predictors of TB using a modified Poisson regression with generalized estimating equations to account for clustering according to screening site. RESULTS: TB was diagnosed in 484 (20.3%) of 2394 symptomatic adults in health facilities and 39 (3.4%) of 1424 in communities. In health facilities, >10% of symptomatic adults in all demographic groups had TB, and no predictors were associated with a >/=2-fold increased risk. In communities, the independent predictors of TB were male sex (adjusted prevalence ratio [aPR] = 4.26, 95%CI 2.43-7.45), HIV infection (aPR 2.37, 95%CI 1.18-4.77), and household TB contact in the last 2 years (aPR 2.84, 95%CI 1.62-4.96). CONCLUSION: Our findings support the notion of general TB screening in health facilities and evaluation of the adult household contacts of TB patients.

OBJECTIVE: To evaluate the utility of a broad and non-specific symptom screen for identifying people with undiagnosed HIV infection. DESIGN: Secondary analysis of operational data collected during implementation of a cluster-randomized trial for tuberculosis case detection. METHODS: As part of the trial, adults reporting cough, fever, night sweats, weight loss, or difficulty breathing of any duration in the past month were identified in health facilities and community-based mobile screening units in western Kenya. Adults reporting any symptom were offered HIV testing. We analysed the HIV testing data from this study, using modified Poisson regression to identify predictors of new HIV diagnoses among adults with symptoms and initially unknown HIV status. RESULTS: We identified 3,818 symptomatic adults, referred 1424 (37%) for testing, of whom 1065 (75%) accepted, and 107 (10%) were newly diagnosed with HIV. The prevalence of new HIV diagnoses was 21% (95% CI: 17-25%) among those tested in health facilities and 5% (95% CI 4-7%) among those tested in mobile units. More men were diagnosed with HIV than women despite fewer men being screened. People who reported 4-5 symptoms were over twice as likely to be diagnosed with HIV compared to those reporting 1-3 symptoms (adjusted prevalence ratio [aPR] in health facilities = 2.58, 95% CI, 1.65-4.05; aPR in mobile units = 2.63, 95% CI, 1.37-5.03). CONCLUSION: We observed a high yield of new HIV diagnoses among adults identified by active application of a broad symptom screen. Integrated tuberculosis and HIV screening using could help close the detection gap for both conditions.

Setting: Although Kenya has a high burden of tuberculosis (TB), only 46% of cases were diagnosed in 2016. Objective: To identify strategies for increasing attendance at community-based mobile screening units. Design: We analysed operational data from a cluster-randomised trial, which included community-based mobile screening implemented during February 2015-April 2016. Community health volunteers (CHVs) recruited individuals with symptoms from the community, who were offered testing for human immunodeficiency virus (HIV) and sputum collection for Xpert((R)) MTB/RIF testing. We compared attendance across different mobile unit sites using Wilcoxon rank-sum test. Results: A total of 1424 adults with symptoms were screened at 25 mobile unit sites. The median total attendance among sites was 54 (range 6-134, interquartile range [IQR] 24-84). The median yields of TB diagnoses and new HIV diagnoses were respectively 2.4% (range 0.0-16.7, IQR 0.0-5.3) and 2.5% (range 0.0-33.3, IQR 1.2-4.2). Attendance at urban sites was variable; attendance at rural sites where CHVs were paid a daily minimum wage was significantly higher than at rural sites where CHVs were paid a nominal monthly stipend (P < 0.001). Conclusion: Mobile units were most effective and efficient when implemented as a single event with community health workers who are paid a daily wage.