Hepatic Vitamin A Concentrations and Association with Infectious Causes of Child Death.

OBJECTIVES: To assess postmortem vitamin A (VA) concentrations in children under 5 years of age and evaluate the association between VA deficiency (VAD) and infectious causes of death (CoD). STUDY DESIGN: In this cross-sectional study from the Child Health and Mortality Prevention Surveillance (CHAMPS) Network, liver biopsies collected within 72 hours of death were analyzed from 405 stillbirths and children under 5 years in Kenya and South Africa. Total liver VA (TLVA) concentrations were quantified using ultra-performance liquid chromatography, and cutoffs of ≤0.1 µmol/g, >0.1 to <0.7 µmol/g, ≥0.7 to <1.0 µmol/g, and ≥1.0 µmol/g were used to define VAD, adequate VA status, high VA, and hypervitaminosis A, respectively. CoD were determined by expert panel review. RESULTS: Among 366 liver samples with viable extraction, pooled prevalences of VAD, adequacy, high VA, and hypervitaminosis were 34.2%, 51.1%, 6.0%, and 8.7%, respectively. VAD was more common among neonates compared with stillbirths, infants, or children, and among those with low birthweight (LBW), underweight, or stunting (P < .05). When adjusting for site, age, and sex, there was no significant association of VAD with increased infectious CoD (OR 1.9, 95% confidence interval [CI] 0.9, 3.8, P = .073). In stratified analyses, VA deficient boys, but not girls, had an increased risk of infectious CoD (OR 3.4, 95% CI 1.3, 10.3, P = .013). CONCLUSIONS: Definitive postmortem assessment of VA status identified both VAD and VA excess among children under 5 years of age in Kenya and South Africa. VAD in boys was associated with increased risk of infectious mortality. Our findings may inform a transition from universal VA supplementation (VAS) to targeted strategies in certain countries.

Modeling the impacts of antiviral prophylaxis strategies in mitigating seasonal influenza outbreaks in nursing homes.

BACKGROUND: Antiviral chemoprophylaxis is recommended for use during influenza outbreaks in nursing homes to prevent transmission and severe disease among non-ill residents. Centers for Disease Control and Prevention (CDC) guidance recommends prophylaxis be initiated for all non-ill residents once an influenza outbreak is detected and be continued for at least 14 days and until seven days after the last laboratory-confirmed influenza case is identified. However, not all facilities strictly adhere to this guidance and the impact of such partial adherence is not fully understood. METHODS: We developed a stochastic compartmental framework to model influenza transmission within an average-sized U.S. nursing home. We compared the number of symptomatic illnesses and hospitalizations under varying prophylaxis implementation strategies, in addition to different levels of prophylaxis uptake and adherence by residents and healthcare personnel (HCP). RESULTS: Prophylaxis implemented according to current guidance reduced total symptomatic illnesses and hospitalizations among residents by an average of 12% and 36%, respectively, compared with no prophylaxis. We did not find evidence that alternative implementations of prophylaxis were more effective: compared to full adoption of current guidance, partial adoption resulted in increased symptomatic illnesses and/or hospitalizations, and longer or earlier adoption offered no additional improvements. In addition, increasing uptake and adherence among nursing home residents was effective in reducing resident illnesses and hospitalizations, but increasing HCP uptake had minimal indirect impacts for residents. CONCLUSIONS: The greatest benefits of influenza prophylaxis during nursing home outbreaks will likely be achieved through increasing uptake and adherence among residents and following current CDC guidance.

Serial Interval and Incubation Period Estimates of Monkeypox Virus Infection in 12 Jurisdictions, United States, May-August 2022.

Using data from 12 US health departments, we estimated mean serial interval for monkeypox virus infection to be 8.5 (95% credible interval 7.3-9.9) days for symptom onset, based on 57 case pairs. Mean estimated incubation period was 5.6 (95% credible interval 4.3-7.8) days for symptom onset, based on 35 case pairs.

Rapid review and meta-analysis of serial intervals for SARS-CoV-2 Delta and Omicron variants.

BACKGROUND: The serial interval is the period of time between symptom onset in the primary case and symptom onset in the secondary case. Understanding the serial interval is important for determining transmission dynamics of infectious diseases like COVID-19, including the reproduction number and secondary attack rates, which could influence control measures. Early meta-analyses of COVID-19 reported serial intervals of 5.2 days (95% CI: 4.9-5.5) for the original wild-type variant and 5.2 days (95% CI: 4.87-5.47) for Alpha variant. The serial interval has been shown to decrease over the course of an epidemic for other respiratory diseases, which may be due to accumulating viral mutations and implementation of more effective nonpharmaceutical interventions. We therefore aggregated the literature to estimate serial intervals for Delta and Omicron variants. METHODS: This study followed Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A systematic literature search was conducted of PubMed, Scopus, Cochrane Library, ScienceDirect, and preprint server medRxiv for articles published from April 4, 2021, through May 23, 2023. Search terms were: ("serial interval" or "generation time"), ("Omicron" or "Delta"), and ("SARS-CoV-2" or "COVID-19"). Meta-analyses were done for Delta and Omicron variants using a restricted maximum-likelihood estimator model with a random effect for each study. Pooled average estimates and 95% confidence intervals (95% CI) are reported. RESULTS: There were 46,648 primary/secondary case pairs included for the meta-analysis of Delta and 18,324 for Omicron. Mean serial interval for included studies ranged from 2.3-5.8 days for Delta and 2.1-4.8 days for Omicron. The pooled mean serial interval for Delta was 3.9 days (95% CI: 3.4-4.3) (20 studies) and Omicron was 3.2 days (95% CI: 2.9-3.5) (20 studies). Mean estimated serial interval for BA.1 was 3.3 days (95% CI: 2.8-3.7) (11 studies), BA.2 was 2.9 days (95% CI: 2.7-3.1) (six studies), and BA.5 was 2.3 days (95% CI: 1.6-3.1) (three studies). CONCLUSIONS: Serial interval estimates for Delta and Omicron were shorter than ancestral SARS-CoV-2 variants. More recent Omicron subvariants had even shorter serial intervals suggesting serial intervals may be shortening over time. This suggests more rapid transmission from one generation of cases to the next, consistent with the observed faster growth dynamic of these variants compared to their ancestors. Additional changes to the serial interval may occur as SARS-CoV-2 continues to circulate and evolve. Changes to population immunity (due to infection and/or vaccination) may further modify it.

Household hardships and responses to COVID-19 pandemic-related shocks in Eastern Ethiopia.

BACKGROUND: COVID-19 resulted in enormous disruption to life around the world. To quell disease spread, governments implemented lockdowns that likely created hardships for households. To improve knowledge of consequences, we examine how the pandemic period was associated with household hardships and assess factors associated with these hardships. METHODS: We conducted a cross-sectional study using quasi-Poisson regression to examine factors associated with household hardships. Data were collected between August and September of 2021 from a random sample of 880 households living within a Health and Demographic Surveillance System (HDSS) located in the Harari Region and the District of Kersa, both in Eastern Ethiopia. RESULTS: Having a head of household with no education, residing in a rural area, larger household size, lower income and/or wealth, and community responses to COVID-19, including lockdowns and travel restrictions, were independently associated with experiencing household hardships. CONCLUSIONS: Our results identify characteristics of groups at-risk for household hardships during the pandemic; these findings may inform efforts to mitigate the consequences of COVID-19 and future disease outbreaks.

Using simulated infectious disease outbreaks to inform site selection and sample size for individually randomized vaccine trials during an ongoing epidemic.

BACKGROUND: Novel strategies are needed to make vaccine efficacy trials more robust given uncertain epidemiology of infectious disease outbreaks, such as arboviruses like Zika. Spatially resolved mathematical and statistical models can help investigators identify sites at highest risk of future transmission and prioritize these for inclusion in trials. Models can also characterize uncertainty in whether transmission will occur at a site, and how nearby or connected sites may have correlated outcomes. A structure is needed for how trials can use models to address key design questions, including how to prioritize sites, the optimal number of sites, and how to allocate participants across sites. METHODS: We illustrate the added value of models using the motivating example of Zika vaccine trial planning during the 2015-2017 Zika epidemic. We used a stochastic, spatially resolved, transmission model (the Global Epidemic and Mobility model) to simulate epidemics and site-level incidence at 100 high-risk sites in the Americas. We considered several strategies for prioritizing sites (average site-level incidence of infection across epidemics, median incidence, probability of exceeding 1% incidence), selecting the number of sites, and allocating sample size across sites (equal enrollment, proportional to average incidence, proportional to rank). To evaluate each design, we stochastically simulated trials in each hypothetical epidemic by drawing observed cases from site-level incidence data. RESULTS: When constraining overall trial size, the optimal number of sites represents a balance between prioritizing highest-risk sites and having enough sites to reduce the chance of observing too few endpoints. The optimal number of sites remained roughly constant regardless of the targeted number of events, although it is necessary to increase the sample size to achieve the desired power. Though different ranking strategies returned different site orders, they performed similarly with respect to trial power. Instead of enrolling participants equally from each site, investigators can allocate participants proportional to projected incidence, though this did not provide an advantage in our example because the top sites had similar risk profiles. Sites from the same geographic region may have similar outcomes, so optimal combinations of sites may be geographically dispersed, even when these are not the highest ranked sites. CONCLUSION: Mathematical and statistical models may assist in designing successful vaccination trials by capturing uncertainty and correlation in future transmission. Although many factors affect site selection, such as logistical feasibility, models can help investigators optimize site selection and the number and size of participating sites. Although our study focused on trial design for an emerging arbovirus, a similar approach can be made for any infectious disease with the appropriate model for the particular disease.

Changes in socio-economic status and lipoproteins in Chilean adolescents: a 16-year longitudinal study.

OBJECTIVE: The present longitudinal study assessed whether changes in socio-economic status (SES) from infancy to adolescence were associated with plasma lipoprotein concentrations in adolescence, of which low HDL-cholesterol (HDL-C) and high LDL-cholesterol (LDL-C), TAG and total cholesterol (TC) concentrations are associated with higher cardiovascular risk. DESIGN: SES, assessed using the modified Graffar Index, was calculated at 1, 5, 10 and 16 years. Principal components factor analysis with varimax rotation extracted two orthogonal SES factors, termed 'environmental capital' and 'social capital'. Generalized linear models were used to analyse associations between environmental and social capital at 1 and 16 years and outcomes (HDL-C, LDL-C, TAG, TC) at 16 years, as well as changes in environmental and social capital from 1-5, 5-10, 10-16 and 1-16 years, and outcomes at 16 years. SETTING: Santiago, Chile.ParticipantsWe evaluated 665 participants from the Santiago Longitudinal Study enrolled at infancy in Fe-deficiency anaemia studies and examined every 5 years to age 16 years. RESULTS: Social capital in infancy was associated with higher HDL-C in adolescence. Environmental capital in adolescence was associated with higher LDL-C and TC during adolescence. Changing environmental capital from 1-16 years was associated with higher LDL-C. Changing environmental capital from 1-5 and 1-16 years was associated with higher TC. CONCLUSIONS: Improvements in environmental capital throughout childhood were associated with less healthy LDL-C and TC concentrations in adolescence. We found no evidence of associations between changing environmental capital and HDL-C or TAG, or changing social capital and HDL-C, LDL-C, TAG or TC.

Associations between household environmental factors and immature mosquito abundance in Quetzaltenango, Guatemala.

BACKGROUND: Aedes aegypti-borne diseases are becoming major public health problems in tropical and sub-tropical regions. While socioeconomic status has been associated with larval mosquito abundance, the drivers or possible factors mediating this association, such as environmental factors, are yet to be identified. We examined possible associations between proximity to houses and roads and immature mosquito abundance, and assessed whether these factors and mosquito prevention measures mediated any association between household environmental factors and immature mosquito abundance. METHODS: We conducted two cross-sectional household container surveys in February-March and November-December, 2017, in urban and rural areas of Quetzaltenango, Guatemala. We used principal components analysis to identify factors from 12 variables to represent the household environment. One factor which included number of rooms in house, electricity, running water, garbage service, cable, television, telephone, latrine, well, and sewer system, was termed "environmental capital." Environmental capital scores ranged from 0 to 5.5. Risk factors analyzed included environmental capital, and distance from nearest house/structure, paved road, and highway. We used Poisson regression to determine associations between distance to nearest house/structure, roads, and highways, and measures of immature mosquito abundance (total larvae, total pupae, and positive containers). Using cubic spline generalized additive models, we assessed non-linear associations between environmental capital and immature mosquito abundance. We then examined whether fumigation, cleaning containers, and distance from the nearest house, road, and highway mediated the relationship between environmental capital and larvae and pupae abundance. RESULTS: We completed 508 household surveys in February-March, and we revisited 469 households in November-December. Proximity to paved roads and other houses/structures was positively associated with larvae and pupae abundance and mediated the associations between environmental capital and total numbers of larvae/pupae (p ≤ 0.01). Distance to highways was not associated with larval/pupal abundance (p ≥ 0.48). Households with the lowest and highest environmental capital had fewer larvae/pupae than households in the middle range (p < 0.01). CONCLUSIONS: We found evidence that proximity to other houses and paved roads was associated with greater abundance of larvae and pupae. Understanding risk factors such as these can allow for improved targeting of surveillance and vector control measures in areas considered at higher risk for arbovirus transmission.

Nowcasting and forecasting the 2022 U.S. mpox outbreak: Support for public health decision making and lessons learned.

In June of 2022, the U.S. Centers for Disease Control and Prevention (CDC) Mpox Response wanted timely answers to important epidemiological questions which can now be answered more effectively through infectious disease modeling. Infectious disease models have shown to be valuable tools for decision making during outbreaks; however, model complexity often makes communicating the results and limitations of models to decision makers difficult. We performed nowcasting and forecasting for the 2022 mpox outbreak in the United States using the R package EpiNow2. We generated nowcasts/forecasts at the national level, by Census region, and for jurisdictions reporting the greatest number of mpox cases. Modeling results were shared for situational awareness within the CDC Mpox Response and publicly on the CDC website. We retrospectively evaluated forecast predictions at four key phases (early, exponential growth, peak, and decline) during the outbreak using three metrics, the weighted interval score, mean absolute error, and prediction interval coverage. We compared the performance of EpiNow2 with a naïve Bayesian generalized linear model (GLM). The EpiNow2 model had less probabilistic error than the GLM during every outbreak phase except for the early phase. We share our experiences with an existing tool for nowcasting/forecasting and highlight areas of improvement for the development of future tools. We also reflect on lessons learned regarding data quality issues and adapting modeling results for different audiences.

Prevalence of food insecurity amid COVID-19 lockdowns and sociodemographic indicators of household vulnerability in Harar and Kersa, Ethiopia.

BACKGROUND: The COVID-19 pandemic was associated with widespread social disruptions, as governments implemented lockdowns to quell disease spread. To advance knowledge of consequences for households in resource-limited countries, we examine food insecurity during the pandemic period. METHODS: We conducted a cross-sectional study and used logistic regression to examine factors associated with food insecurity. Data were collected between August and September of 2021 through a Health and Demographic Surveillance System (HDSS) using a survey instrument focused on knowledge regarding the spread of COVID-19; food availability; COVID-19 related shocks/coping; under-five child healthcare services; and healthcare services for pregnant women. The study is set in two communities in Eastern Ethiopia, one rural (Kersa) and one urban (Harar), and included a random sample of 880 households. RESULTS: Roughly 16% of households reported not having enough food to eat during the pandemic, an increase of 6% since before the pandemic. After adjusting for other variables, households were more likely to report food insecurity if they were living in an urban area, were a larger household, had a family member lose employment, reported an increase in food prices, or were food insecure before the pandemic. Households were less likely to report food insecurity if they were wealthier or had higher household income. CONCLUSIONS: After taking individual and household level sociodemographic characteristics into consideration, households in urban areas were at higher risk for food insecurity. These findings suggest a need for expanding food assistance programs to more urban areas to help mitigate the impact of lockdowns on more vulnerable households.

A systematic review and meta-analysis on the effectiveness of bivalent mRNA booster vaccines against Omicron variants.

BACKGROUND: A global shift to bivalent mRNA vaccines is ongoing to counterbalance the diminishing effectiveness of the original monovalent vaccines due to the evolution of SARS-CoV-2 variants, yet substantial variation in the bivalent vaccine effectiveness (VE) exists across studies and a complete picture is lacking. METHODS: We searched papers evaluating absolute or relative effectiveness of SARS-CoV-2 BA.1 type or BA.4/5 type bivalent mRNA vaccines on eight publication databases published from September 1st, 2022, to November 8th, 2023. Pooled VE against Omicron-associated infection and severe events (hospitalization and/or death) was estimated in reference to unvaccinated, ≥2 original monovalent doses, and ≥ 3 original monovalent doses. RESULTS: From 630 citations identified, 28 studies were included, involving 55,393,303 individuals. Bivalent boosters demonstrated higher effectiveness against symptomatic or any infection for all ages combined, with an absolute VE of 53.5 % (95 % CI: -22.2-82.3 %) when compared to unvaccinated and relative VE of 30.8 % (95 % CI: 22.5-38.2 %) and 28.4 % (95 % CI: 10.2-42.9 %) when compared to ≥ 2 and ≥ 3 original monovalent doses, respectively. The corresponding VE estimates for adults ≥ 60 years old were 22.5 % (95 % CI: 16.8-39.8 %), 31.4 % (95 % CI: 27.7-35.0 %), and 30.6 % (95 % CI: -13.2-57.5 %). Pooled bivalent VE estimates against severe events were higher, 72.9 % (95 % CI: 60.5-82.4 %), 57.6 % (95 % CI: 42.4-68.8 %), and 62.1 % (95 % CI: 54.6-68.3 %) for all ages, and 72.0 % (95 % CI: 51.4-83.9 %), 63.4 % (95 % CI: 41.0-77.3 %), and 60.7 % (95 % CI: 52.4-67.6 %) for adults ≥ 60 years old, compared to unvaccinated, ≥2 original monovalent doses, and ≥ 3 original monovalent doses, respectively. CONCLUSIONS: The bivalent boosters demonstrated superior protection against severe outcomes than the original monovalent boosters across age groups, highlighting the critical need for improving vaccine coverage, especially among the vulnerable older subpopulation.

Sentinel Enhanced Dengue Surveillance System - Puerto Rico, 2012-2022.

Problem/Condition: Dengue is the most prevalent mosquitoborne viral illness worldwide and is endemic in Puerto Rico. Dengue's clinical spectrum can range from mild, undifferentiated febrile illness to hemorrhagic manifestations, shock, multiorgan failure, and death in severe cases. The disease presentation is nonspecific; therefore, various other illnesses (e.g., arboviral and respiratory pathogens) can cause similar clinical symptoms. Enhanced surveillance is necessary to determine disease prevalence, to characterize the epidemiology of severe disease, and to evaluate diagnostic and treatment practices to improve patient outcomes. The Sentinel Enhanced Dengue Surveillance System (SEDSS) was established to monitor trends of dengue and dengue-like acute febrile illnesses (AFIs), characterize the clinical course of disease, and serve as an early warning system for viral infections with epidemic potential. Reporting Period: May 2012-December 2022. Description of System: SEDSS conducts enhanced surveillance for dengue and other relevant AFIs in Puerto Rico. This report includes aggregated data collected from May 2012 through December 2022. SEDSS was launched in May 2012 with patients with AFIs from five health care facilities enrolled. The facilities included two emergency departments in tertiary acute care hospitals in the San Juan-Caguas-Guaynabo metropolitan area and Ponce, two secondary acute care hospitals in Carolina and Guayama, and one outpatient acute care clinic in Ponce. Patients arriving at any SEDSS site were eligible for enrollment if they reported having fever within the past 7 days. During the Zika epidemic (June 2016-June 2018), patients were eligible for enrollment if they had either rash and conjunctivitis, rash and arthralgia, or fever. Eligibility was expanded in April 2020 to include reported cough or shortness of breath within the past 14 days. Blood, urine, nasopharyngeal, and oropharyngeal specimens were collected at enrollment from all participants who consented. Diagnostic testing for dengue virus (DENV) serotypes 1-4, chikungunya virus, Zika virus, influenza A and B viruses, SARS-CoV-2, and five other respiratory viruses was performed by the CDC laboratory in San Juan. Results: During May 2012-December 2022, a total of 43,608 participants with diagnosed AFI were enrolled in SEDSS; a majority of participants (45.0%) were from Ponce. During the surveillance period, there were 1,432 confirmed or probable cases of dengue, 2,293 confirmed or probable cases of chikungunya, and 1,918 confirmed or probable cases of Zika. The epidemic curves of the three arboviruses indicate dengue is endemic; outbreaks of chikungunya and Zika were sporadic, with case counts peaking in late 2014 and 2016, respectively. The majority of commonly identified respiratory pathogens were influenza A virus (3,756), SARS-CoV-2 (1,586), human adenovirus (1,550), respiratory syncytial virus (1,489), influenza B virus (1,430), and human parainfluenza virus type 1 or 3 (1,401). A total of 5,502 participants had confirmed or probable arbovirus infection, 11,922 had confirmed respiratory virus infection, and 26,503 had AFI without any of the arboviruses or respiratory viruses examined. Interpretation: Dengue is endemic in Puerto Rico; however, incidence rates varied widely during the reporting period, with the last notable outbreak occurring during 2012-2013. DENV-1 was the predominant virus during the surveillance period; sporadic cases of DENV-4 also were reported. Puerto Rico experienced large outbreaks of chikungunya that peaked in 2014 and of Zika that peaked in 2016; few cases of both viruses have been reported since. Influenza A and respiratory syncytial virus seasonality patterns are distinct, with respiratory syncytial virus incidence typically reaching its annual peak a few weeks before influenza A. The emergence of SARS-CoV-2 led to a reduction in the circulation of other acute respiratory viruses. Public Health Action: SEDSS is the only site-based enhanced surveillance system designed to gather information on AFI cases in Puerto Rico. This report illustrates that SEDSS can be adapted to detect dengue, Zika, chikungunya, COVID-19, and influenza outbreaks, along with other seasonal acute respiratory viruses, underscoring the importance of recognizing signs and symptoms of relevant diseases and understanding transmission dynamics among these viruses. This report also describes fluctuations in disease incidence, highlighting the value of active surveillance, testing for a panel of acute respiratory viruses, and the importance of flexible and responsive surveillance systems in addressing evolving public health challenges. Various vector control strategies and vaccines are being considered or implemented in Puerto Rico, and data from ongoing trials and SEDSS might be integrated to better understand epidemiologic factors underlying transmission and risk mitigation approaches. Data from SEDSS might guide sampling strategies and implementation of future trials to prevent arbovirus transmission, particularly during the expansion of SEDSS throughout the island to improve geographic representation.

Comparison of the Sensitivity and Specificity of Commercial Anti-Dengue Virus IgG Tests to Identify Persons Eligible for Dengue Vaccination.

The Advisory Committee on Immunization Practices (ACIP) recommended that dengue pre-vaccination screening tests for Dengvaxia administration have at least 98% specificity and 75% sensitivity. This study evaluates the performance of commercial anti-DENV IgG tests to identify tests that could be used for pre-vaccination screening. First, for 7 tests, we evaluated sensitivity and specificity in early convalescent dengue virus (DENV) infection, using 44 samples collected 7-30 days after symptom onset and confirmed by RT-PCR. Next, for the 5 best performing tests and two additional tests (with and without an external test reader) that became available later, we evaluated performance to detect past dengue infection among a panel of 44 specimens collected in 2018-2019 from healthy 9-16-year-old children from Puerto Rico. Finally, a full-scale evaluation was done with the 4 best performing tests using 400 specimens from the same population. We used virus focus reduction neutralization test and an in-house DENV IgG ELISA as reference standards. Of seven tests, five showed ≥75% sensitivity detecting anti-DENV IgG in early convalescent specimens with low cross-reactivity to Zika virus. For the detection of previous DENV infections the tests with the highest performance were the Euroimmun NS1 IgG ELISA (sensitivity 84.5%, specificity 97.1%) and CTK Dengue IgG rapid test R0065C with the test reader (sensitivity 76.2% specificity 98.1%). There are IgG tests available that can be used to accurately classify individuals with previous DENV infection as eligible for dengue vaccination to support safe vaccine implementation.

Post-mortem investigation of deaths due to pneumonia in children aged 1-59 months in sub-Saharan Africa and South Asia from 2016 to 2022: an observational study.

BACKGROUND: The Child Health and Mortality Prevention Surveillance (CHAMPS) Network programme undertakes post-mortem minimally invasive tissue sampling (MITS), together with collection of ante-mortem clinical information, to investigate causes of childhood deaths across multiple countries. We aimed to evaluate the overall contribution of pneumonia in the causal pathway to death and the causative pathogens of fatal pneumonia in children aged 1-59 months enrolled in the CHAMPS Network. METHODS: In this observational study we analysed deaths occurring between Dec 16, 2016, and Dec 31, 2022, in the CHAMPS Network across six countries in sub-Saharan Africa (Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) and one in South Asia (Bangladesh). A standardised approach of MITS was undertaken on decedents within 24-72 h of death. Diagnostic tests included blood culture, multi-organism targeted nucleic acid amplifications tests (NAATs) of blood and lung tissue, and histopathology examination of various organ tissue samples. An interdisciplinary expert panel at each site reviewed case data to attribute the cause of death and pathogenesis thereof on the basis of WHO-recommended reporting standards. FINDINGS: Pneumonia was attributed in the causal pathway of death in 455 (40·6%) of 1120 decedents, with a median age at death of 9 (IQR 4-19) months. Causative pathogens were identified in 377 (82·9%) of 455 pneumonia deaths, and multiple pathogens were implicated in 218 (57·8%) of 377 deaths. 306 (67·3%) of 455 deaths occurred in the community or within 72 h of hospital admission (presumed to be community-acquired pneumonia), with the leading bacterial pathogens being Streptococcus pneumoniae (108 [35·3%]), Klebsiella pneumoniae (78 [25·5%]), and non-typeable Haemophilus influenzae (37 [12·1%]). 149 (32·7%) deaths occurred 72 h or more after hospital admission (presumed to be hospital-acquired pneumonia), with the most common pathogens being K pneumoniae (64 [43·0%]), Acinetobacter baumannii (19 [12·8%]), S pneumoniae (15 [10·1%]), and Pseudomonas aeruginosa (15 [10·1%]). Overall, viruses were implicated in 145 (31·9%) of 455 pneumonia-related deaths, including 54 (11·9%) of 455 attributed to cytomegalovirus and 29 (6·4%) of 455 attributed to respiratory syncytial virus. INTERPRETATION: Pneumonia contributed to 40·6% of all childhood deaths in this analysis. The use of post-mortem MITS enabled biological ascertainment of the cause of death in the majority (82·9%) of childhood deaths attributed to pneumonia, with more than one pathogen being commonly implicated in the same case. The prominent role of K pneumoniae, non-typable H influenzae, and S pneumoniae highlight the need to review empirical management guidelines for management of very severe pneumonia in low-income and middle-income settings, and the need for research into new or improved vaccines against these pathogens. FUNDING: Bill & Melinda Gates Foundation.

Burden of child mortality from malaria in high endemic areas: Results from the CHAMPS network using minimally invasive tissue sampling.

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.

Child deaths caused by Klebsiella pneumoniae in sub-Saharan Africa and south Asia: a secondary analysis of Child Health and Mortality Prevention Surveillance (CHAMPS) data.

BACKGROUND: Klebsiella pneumoniae is an important cause of nosocomial and community-acquired pneumonia and sepsis in children, and antibiotic-resistant K pneumoniae is a growing public health threat. We aimed to characterise child mortality associated with this pathogen in seven high-mortality settings. METHODS: We analysed Child Health and Mortality Prevention Surveillance (CHAMPS) data on the causes of deaths in children younger than 5 years and stillbirths in sites located in seven countries across sub-Saharan Africa (Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) and south Asia (Bangladesh) from Dec 9, 2016, to Dec 31, 2021. CHAMPS sites conduct active surveillance for deaths in catchment populations and following reporting of an eligible death or stillbirth seek consent for minimally invasive tissue sampling followed by extensive aetiological testing (microbiological, molecular, and pathological); cases are reviewed by expert panels to assign immediate, intermediate, and underlying causes of death. We reported on susceptibility to antibiotics for which at least 30 isolates had been tested, and excluded data on antibiotics for which susceptibility testing is not recommended for Klebsiella spp due to lack of clinical activity (eg, penicillin and ampicillin). FINDINGS: Among 2352 child deaths with cause of death assigned, 497 (21%, 95% CI 20-23) had K pneumoniae in the causal chain of death; 100 (20%, 17-24) had K pneumoniae as the underlying cause. The frequency of K pneumoniae in the causal chain was highest in children aged 1-11 months (30%, 95% CI 26-34; 144 of 485 deaths) and 12-23 months (28%, 22-34; 63 of 225 deaths); frequency by site ranged from 6% (95% CI 3-11; 11 of 184 deaths) in Bangladesh to 52% (44-61; 71 of 136 deaths) in Ethiopia. K pneumoniae was in the causal chain for 450 (22%, 95% CI 20-24) of 2023 deaths that occurred in health facilities and 47 (14%, 11-19) of 329 deaths in the community. The most common clinical syndromes among deaths with K pneumoniae in the causal chain were sepsis (44%, 95% CI 40-49; 221 of 2352 deaths), sepsis in conjunction with pneumonia (19%, 16-23; 94 of 2352 deaths), and pneumonia (16%, 13-20; 80 of 2352 deaths). Among K pneumoniae isolates tested, 121 (84%) of 144 were resistant to ceftriaxone and 80 (75%) of 106 to gentamicin. INTERPRETATION: K pneumoniae substantially contributed to deaths in the first 2 years of life across multiple high-mortality settings, and resistance to antibiotics used for sepsis treatment was common. Improved strategies are needed to rapidly identify and appropriately treat children who might be infected with this pathogen. These data suggest a potential impact of developing and using effective K pneumoniae vaccines in reducing neonatal, infant, and child deaths globally. FUNDING: Bill & Melinda Gates Foundation.

Identifying delays in healthcare seeking and provision: The Three Delays-in-Healthcare and mortality among infants and children aged 1-59 months.

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.

Effectiveness of SARS-CoV-2 vaccines against Omicron infection and severe events: a systematic review and meta-analysis of test-negative design studies.

Background: A rapidly growing body was observed of literature evaluating the vaccine effectiveness (VE) against Omicron in test-negative design studies. Methods: We systematically searched papers that evaluated VE of SARS-CoV-2 vaccines on PubMed, Web of Science, Cochrane Library, Google Scholar, Embase, Scopus, bioRxiv, and medRxiv published from November 26th, 2021, to June 27th, 2022 (full doses and the first booster), and to January 8th, 2023 (the second booster). The pooled VE against Omicron-associated infection and severe events were estimated. Results: From 2,552 citations identified, 42 articles were included. The first booster provided stronger protection against Omicron than full doses alone, shown by VE estimates of 53.1% (95% CI: 48.0-57.8) vs. 28.6% (95% CI: 18.5-37.4) against infection and 82.5% (95% CI: 77.8-86.2) vs. 57.3% (95% CI: 48.5-64.7) against severe events. The second booster offered strong protection among adults within 60 days of vaccination against infection (VE=53.1%, 95% CI: 48.0-57.8) and severe events (VE=87.3% (95% CI: 75.5-93.4), comparable to the first booster with corresponding VE estimates of 59.9% against infection and 84.8% against severe events. The VE estimates of booster doses against severe events among adults sustained beyond 60 days, 77.6% (95% CI: 69.4-83.6) for first and 85.9% (95% CI: 80.3-89.9) for the second booster. The VE estimates against infection were less sustainable regardless of dose type. Pure mRNA vaccines provided comparable protection to partial mRNA vaccines, but both provided higher protection than non-mRNA vaccines. Conclusions: One or two SARS-CoV-2 booster doses provide considerable protection against Omicron infection and substantial and sustainable protection against Omicron-induced severe clinical outcomes.