Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Postnatal care services in rural Zambia: a qualitative exploration of user, provider, and community perspectives on quality of care.

BACKGROUND: Postnatal care (PNC) is an important set of services offered to the mother and her newborn baby immediately after birth for the first six weeks to prevent maternal and neonatal complications and death. This qualitative study explored user and provider perspectives on quality of PNC services in the selected health facilities within the context of the Maternity Homes Access in Zambia project in the Saving Mothers Giving Life districts in rural Zambia. METHODS: Between October 2018 and February 2019, forty focus group discussions (FGDs) (n = 160 participants) and twelve in-depth interviews (IDIs) were conducted in four districts in Southern and Eastern provinces. FGDs comprised women who delivered within the last year, fathers, community elders, and volunteers. IDIs comprised health workers at facility, district, and provincial levels. Data were analysed using content analysis guided by the international quality of care domains derived from the World Health Organization quality of care framework. Findings were triangulated to understand perceptions. RESULTS: Overall, study participants perceived PNC services to be beneficial. Nevertheless, respondents had mixed feelings on the quality of PNC services and expressed a stark difference in their perception of factors affecting service quality. Service users described challenges arising from ineffective communication about the new PNC guidelines, and non-adherence of service providers to quality standards regarding respect, preservation of dignity and emotional support. Other factors were long waiting hours, small examination rooms providing inadequate privacy, and low levels of confidentiality. In contrast, service providers attributed poor service quality to various health system-related factors including low staffing levels, dysfunctional referral services, low supply of essential medicines, supplies, vaccines and equipment for optimal routine emergency obstetric and newborn care and management of complications. CONCLUSION: These findings highlight important intervention opportunities to improve quality of PNC services in Zambia through better communication and raising awareness on PNC guidelines, respect, preservation of dignity and emotional support to mothers. Interventions should also focus on addressing contextual health system challenges including staffing levels, supply chain for essential medicines and commodities, shortening waiting time, and ensuring functional referral system.

Qualitative assessment of infant sleep practices and other risk factors of sudden infant death syndrome (SIDS) among mothers in Lusaka, Zambia.

BACKGROUND: There is very little information on the beliefs and perceptions of mothers about SIDS and its related risk factors in Africa. To better understand parental decisions about infant sleep practices and other risk factors for SIDS, we conducted focus group discussions (FGDs) with mothers of infants in Lusaka, Zambia. METHODS: FGDs involved 35 purposively sampled mothers aged 18-49 years. FGDs were conducted using a semi-structured interview guide in the local language, Nyanja. These were translated, transcribed verbatim into English, and then coded and analyzed using thematic analysis in NVivo 12. RESULTS: Six FGDs were conducted with 35 mothers in April-May 2021 across two study sites. FGD Participants were generally aware of sudden unexplained infant deaths, with several describing stories of apparent SIDS in the community. The side sleeping position was preferred and perceived to be safer for the infant with most believing the supine position posed an aspiration or choking risk to the infant. Bedsharing was also preferred and perceived to be convenient for breastfeeding and monitoring of the infant. Experienced family members such as grandmothers and mothers-in-law, and health care workers were frequently cited as sources of information on infant sleep position. A heightened awareness of the infant's sleeping environment was suggested as a mechanism to prevent SIDS and smothering. CONCLUSIONS: Decisions about bedsharing and infant sleep position were guided by maternal beliefs and perceptions about what is convenient for breastfeeding and safer for the infant. These concerns are vital to designing tailored interventions to address sleep-related sudden infant losses in Zambia. Public health campaigns with tailored messages that address these concerns are likely to be effective at ensuring optimal uptake of safe sleep recommendations.

Persistent Immune Activation in Human Immunodeficiency Virus-Infected Pregnant Women Starting Combination Antiretroviral Therapy After Conception.

This study evaluated the impact of human immunodeficiency virus (HIV) and combination antiretroviral therapy (cART) on immune activation during pregnancy in a Zambian cohort of HIV-exposed but uninfected children followed up from birth. Activated CD8+ T cells (CD38+ and HLA-DR+) were compared among HIV-uninfected (n = 95), cART experienced HIV-infected (n = 111), and cART-naive HIV-infected (n = 21) pregnant women. Immune activation was highest among HIV-infected/cART-naive women but decreased during pregnancy. Immune activation HIV-infected women who started cART during pregnancy was reduced but not to levels similar to those in HIV-uninfected women. The effects of elevated maternal immune activation in pregnancy on subsequent infant health and immunity remain to be determined.

Assessing infant sleep practices and other risk factors of SIDS in Zambia: a cross-sectional survey of mothers in Lusaka, Zambia.

BACKGROUND: Having infants sleep with their parents and sleeping face down or on their sides are the two most proximate and modifiable risk factors for sudden infant death syndrome (SIDS). Little is known about the burden of SIDS or the prevalence of these risk factors in Africa. Our primary objective was to determine the prevalence of modifiable risk factors of SIDS in Lusaka, Zambia. METHODS: We conducted cross-sectional surveys with recent mothers of infants aged < 1 year across two busy urban clinic sites in Lusaka, Zambia. We used log-binomial regression analysis to identify factors predictive of bedsharing and prone sleeping. RESULTS: Surveys were conducted with 478 mothers between April-May 2021. The sleep-related risk factors, bedsharing and side sleeping, were widely prevalent. 89.5% of respondents indicated that they share a bed with the infant during sleep, 73.0% preferred putting their baby on its side, and 19.9% preferred the prone position. Only 6.7% of respondents described using the safer, supine position. Age of infant was the only factor which was predictive of prone sleeping. Infants > 2 months old were twice as likely to be put to sleep in a prone position compared to infants aged less than 2 months old. Mothers reported that they rarely (24.1%) received advice from medical caregivers to use the supine position. Maternal use of alcohol (12.0%) and tobacco (0.8%) during pregnancy were uncommon. CONCLUSIONS: Bedsharing and placing the infant to sleep on the side were commonly reported among the mothers we interviewed. Whether this represents an opportunity to reduce SIDS in Zambia is unclear since accurate data on the burden of SIDS in Zambia is not available. There is a need for increased awareness of SIDS and more prospective data collection on its burden and related risk factors in these African populations.

A Tale of 2 Pneumos: The Impact of Human Immunodeficiency Virus Exposure or Infection Status on Pediatric Nasopharyngeal Carriage of Streptococcus pneumoniae and Pneumocystis jiroveci: A Nested Case Control Analysis From the Pneumonia Etiology Research In Child Health Study.

BACKGROUND: The majority of pediatric human immunodeficiency virus (HIV) cases in Africa reflect maternal-to-child transmission. HIV exposed but uninfected (HEU) children have increased rates of morbidity and mortality when compared to HIV unexposed and uninfected (HUU) children. The mechanisms behind these unexpected trends are only partially understood but could be explained by the differences in the immune response to infections triggered by an altered immune system state. METHODS: Using quantitative reverse transcription polymerase chain reaction, we compared the nasopharyngeal carriage prevalence and density of Streptococcus pneumoniae (SP) and Pneumocystis jirovecii (PJ) between children living with HIV and HEU or HUU cases (pneumonia) and controls (without pneumonia). RESULTS: The cohort included 1154 children (555 cases and 599 matched controls). The SP carriage prevalence rates were similar between cases and controls. Among SP carriers with pneumonia, carriage density was increased among children living with HIV, versus HEU or HUU children (15.8, 4.7, and 3.6 × 105 copies/mL, respectively). The rate of PJ carriage was significantly higher among children living with HIV than among HEU and HUU children (31%, 15%, and 10%, respectively; P < .05), as was carriage density (63.9, 20.9, and 4.8 × 103 copies/mL, respectively; P < .05). CONCLUSIONS: Carriage prevalences and densities for SP and PJ show different kinetics in terms of their relationship with HIV exposure and clinical status, particularly for Pneumocystis jirovecii. This supports the theory that the increased morbidity and mortality observed among HEU children may reflect deficits not just in humoral immunity but in cell-mediated immunity as well.

Histopathological Evaluation of Deceased Persons in Lusaka, Zambia With or Without Coronavirus Disease 2019 (COVID-19) Infection: Results Obtained From Minimally Invasive Tissue Sampling.

BACKGROUND: Although much has been learned about the pathophysiology of coronavirus disease 2019 (COVID-19) infections, pathology data from patients who have died of COVID-19 in low- and middle-income country settings remain sparse. We integrated minimally invasive tissue sampling (MITS) into an ongoing postmortem surveillance study of COVID-19 in deceased individuals of all ages in Lusaka, Zambia. METHODS: We enrolled deceased subjects from the University Teaching Hospital Morgue in Lusaka, Zambia within 48 hours of death. We collected clinical and demographic information, a nasopharyngeal swab, and core tissue biopsies from the lung, liver, and kidneys for pathologic analysis. Individuals were considered eligible for MITS if they had a respiratory syndrome prior to death or a COVID-19+ polymerase chain reaction (PCR) nasopharyngeal swab specimen. Samples were retested using quantitative reverse transcriptase PCR. RESULTS: From June to September 2020 we performed MITS on 29 deceased individuals. PCR results were available for 28/29 (96.5%) cases. Three had a COVID-19+ diagnosis antemortem, and 5 more were identified postmortem using the recommended cycle threshold cut-point <40. When expanding the PCR threshold to 40 ≤ cycle threshold (Ct) ≤ 45, we identified 1 additional case. Most cases were male and occurred in the community The median age at death was 47 years (range 40-64). Human immunodeficiency virus (HIV)/AIDS, tuberculosis, and diabetes were more common among the COVID-19+ cases. Diffuse alveolar damage and interstitial pneumonitis were common among COVID-19+ cases; nonspecific findings of hepatic steatosis and acute kidney injury were also prevalent in the COVID-19+ group. Vascular thrombi were rarely detected. CONCLUSIONS: Lung abnormalities typical of viral pneumonias were common among deceased COVID-19+ individuals, as were nonspecific findings in the liver and kidneys. Pulmonary vascular thrombi were rarely detected, which could be a limitation of the MITS technique. Nonetheless, MITS offers a valuable alternative to open autopsy for understanding pathological changes due to COVID-19.

Risk Factors for Respiratory Syncytial Virus-Associated Community Deaths in Zambian Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of infant deaths. Its epidemiology in low- and middle-income countries is poorly understood. Risk factors associated with RSV-associated infant deaths that occur in community settings are incompletely known. METHODS: Community deaths for infants aged 4 days to 6 months were identified during a 3-year postmortem RSV prevalence study at the main city morgue in Lusaka, Zambia, where 80% of deaths are registered. This analysis focuses on the subset of deaths for which an abbreviated verbal autopsy was available and intended to sort deaths into respiratory or nonrespiratory causes by clinical adjudication. Posterior nasopharyngeal swab samples were collected within 48 hours of death and tested for RSV using quantitative reverse-transcription polymerase chain reaction. Associations between potential risk factors were determined as relative risks with 95% confidence intervals (CIs). RESULTS: We prospectively enrolled 798 community infant deaths with verbal autopsies and RSV laboratory results, of which 62 results were positive. The mean age of the infants was 10 weeks, and 41.4% of them were male. Of all deaths, 44% were attributed to respiratory causes. RSV was detected in 7.8% of the community infants and was significantly associated with respiratory deaths (risk ratio, 4.0 [95% CI, 2.2-7.1]). Compared with older infants, those aged 0-8 weeks had a 2.83 (95% CI, 1.30-6.15) increased risk of dying with RSV. The risk of RSV for the 0-8-week age group increased to 5.24 (1.56-33.14) with adjustment for demographics, parental education, and geography. RSV deaths were increased with domiciliary overcrowding and were concentrated in poor and dense neighborhoods in Lusaka (risk ratio, 2.00 [95% CI, 1.22-3.27]). CONCLUSION: RSV is a significant contributor to community respiratory deaths in this population, particularly in the first 3 months of life and in the more poor and dense parts of Lusaka.

Association of Respiratory Syncytial Virus Infection and Underlying Risk Factors for Death Among Young Infants Who Died at University Teaching Hospital, Lusaka Zambia.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections and child mortality. While RSV disease burden is highest in low- and middle-income countries, most knowledge about risk factors for fatal RSV disease comes from high-income settings. METHODS: Among infants aged 4 days to <6 months who died at University Teaching Hospital in Lusaka, Zambia, we tested nasopharyngeal swabs obtained postmortem for RSV using reverse transcriptase-quantitative polymerase chain reaction. Through a systematic review of death certificates and hospital records, we identified 10 broad categories of underlying medical conditions associated with infant deaths. We used backward-selection models to calculate adjusted and unadjusted risk ratios (RRs) for the association between each underlying condition and RSV status. RESULTS: From 720 infant deaths, 6% (44) were RSV-positive, 70% were <4 weeks old, and 54% were male. At least 1 underlying condition was found in 85% of infants, while 63% had ≥2. Prematurity/low birth weight (53% [384]) and complications of labor and delivery (32% [230]) were the most common conditions. Congenital cardiac conditions were significantly associated with an increased risk of RSV infection (4%, 32; adjusted RR: 3.57; 95% CI: 1.71-7.44). No other underlying conditions were significantly associated with RSV. CONCLUSIONS: Other than congenital cardiac conditions, we found a lack of association between RSV and underlying risk factors. This differs from high-income settings, where RSV mortality is concentrated among high-risk infants. In this population, birth-related outcomes are the highest mortality risk factors. Improved neonatal care remains crucial in the fight against neonatal mortality.

Global Respiratory Syncytial Virus-Related Infant Community Deaths.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of pediatric death, with >99% of mortality occurring in low- and lower middle-income countries. At least half of RSV-related deaths are estimated to occur in the community, but clinical characteristics of this group of children remain poorly characterized. METHODS: The RSV Global Online Mortality Database (RSV GOLD), a global registry of under-5 children who have died with RSV-related illness, describes clinical characteristics of children dying of RSV through global data sharing. RSV GOLD acts as a collaborative platform for global deaths, including community mortality studies described in this supplement. We aimed to compare the age distribution of infant deaths <6 months occurring in the community with in-hospital. RESULTS: We studied 829 RSV-related deaths <1 year of age from 38 developing countries, including 166 community deaths from 12 countries. There were 629 deaths that occurred <6 months, of which 156 (25%) occurred in the community. Among infants who died before 6 months of age, median age at death in the community (1.5 months; IQR: 0.8-3.3) was lower than in-hospital (2.4 months; IQR: 1.5-4.0; P < .0001). The proportion of neonatal deaths was higher in the community (29%, 46/156) than in-hospital (12%, 57/473, P < 0.0001). CONCLUSIONS: We observed that children in the community die at a younger age. We expect that maternal vaccination or immunoprophylaxis against RSV will have a larger impact on RSV-related mortality in the community than in-hospital. This case series of RSV-related community deaths, made possible through global data sharing, allowed us to assess the potential impact of future RSV vaccines.

Cost and Impact of Dried Blood Spot Versus Plasma Separation Card for Scale-up of Viral Load Testing in Resource-limited Settings.

BACKGROUND: Routine plasma viral load (VL) testing is recommended for monitoring human immunodeficiency virus-infected patients on antiretroviral therapy. In Zambia, VL scale-up is limited due to logistical obstacles around plasma specimen collection, storage, and transport to centralized laboratories. Dried blood spots (DBSs) could circumvent many logistical challenges at the cost of increased misclassification. Recently, plasma separation cards (PSCs) have become available and, though more expensive, have lower total misclassification than DBSs. METHODS: Using a geospatial model created for optimizing VL utilization in Zambia, we estimated the short-term cost of uptake/correct VL result using either DBSs or PSCs to increase VL access on equipment available in-country. Five scenarios were modeled: (1) plasma only (status quo); (2) plasma at high-volume sites, DBS at low-volume sites; (3) plasma at high-volume sites, PSC at low-volume sites; (4) PSC only; (5) DBS only. RESULTS: Scenario 1 resulted in 795 342 correct results due to limited patient access. When allowing for full and partial adoption of dried specimens, access increases by 19%, with scenario 3 producing the greatest number of correct results expected (929 857). The average cost per correct VL result was lowest in the plasma + DBS scenario at $30.90 compared to $31.62 in our plasma + PSC scenario. The cost per correct result of using dried specimens only was dominated in the incremental analysis, due primarily to fewer correct results. CONCLUSIONS: Adopting the partial use of dried specimens will help achieve improved VL access for patients at the lowest cost per correct result.

The Predictive Performance of a Pneumonia Severity Score in Human Immunodeficiency Virus-negative Children Presenting to Hospital in 7 Low- and Middle-income Countries.

BACKGROUND: In 2015, pneumonia remained the leading cause of mortality in children aged 1-59 months. METHODS: Data from 1802 human immunodeficiency virus (HIV)-negative children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study with severe or very severe pneumonia during 2011-2014 were used to build a parsimonious multivariable model predicting mortality using backwards stepwise logistic regression. The PERCH severity score, derived from model coefficients, was validated on a second, temporally discrete dataset of a further 1819 cases and compared to other available scores using the C statistic. RESULTS: Predictors of mortality, across 7 low- and middle-income countries, were age <1 year, female sex, ≥3 days of illness prior to presentation to hospital, low weight for height, unresponsiveness, deep breathing, hypoxemia, grunting, and the absence of cough. The model discriminated well between those who died and those who survived (C statistic = 0.84), but the predictive capacity of the PERCH 5-stratum score derived from the coefficients was moderate (C statistic = 0.76). The performance of the Respiratory Index of Severity in Children score was similar (C statistic = 0.76). The number of World Health Organization (WHO) danger signs demonstrated the highest discrimination (C statistic = 0.82; 1.5% died if no danger signs, 10% if 1 danger sign, and 33% if ≥2 danger signs). CONCLUSIONS: The PERCH severity score could be used to interpret geographic variations in pneumonia mortality and etiology. The number of WHO danger signs on presentation to hospital could be the most useful of the currently available tools to aid clinical management of pneumonia.

Healthcare worker perceptions of the implementation context surrounding an infection prevention intervention in a Zambian neonatal intensive care unit.

BACKGROUND: Infants in the neonatal intensive care unit (NICU) are particularly susceptible to healthcare-associated infections (HAIs). NICUs in low- and middle income countries face additional challenges to HAI prevention. There is a need to better understand the role of the implementation context surrounding infection prevention interventions in low- and middle income countries. AIM: The aim of this study was to identify NICU healthcare worker perceptions of an intervention to reduce bloodstream infections in a large Zambian NICU. METHODS: Semi-structured interviews were conducted with NICU staff during a prospective cohort study examining the impact of an infection prevention bundle on bloodstream infections. Interviews were analyzed using an integrated approach, combining inductive theme generation with an application of the Consolidated Framework for Implementation Research (CFIR). RESULTS: Interviews were conducted with 17 NICU staff (5 physicians and 12 nurses). Respondents believed the bundle elements were easy to use, well-designed and facilitated improved performance. Four organizational characteristics that facilitated HAI transmission were identified - (1) lack of NICU admission protocols; (2) physical crowding; (3) understaffing; and (4) equipment shortages. Respondents suggested that NICU resource constraints reflected a societal ethos that devalued the medical care of infants. Despite the challenges, respondents were highly motivated to prevent HAIs and believed this was an achievable goal. They enthusiastically welcomed the bundle but expressed serious concern about sustainability following the study. CONCLUSIONS: By eliciting healthcare worker perceptions about the context surrounding an infection prevention intervention, our study identified key organizational and societal factors to inform implementation strategies to achieve sustained improvement.

Preventing Bloodstream Infections and Death in Zambian Neonates: Impact of a Low-cost Infection Control Bundle.

BACKGROUND: Sepsis is a leading cause of neonatal mortality in low-resource settings. As facility-based births become more common, the proportion of neonatal deaths due to hospital-onset sepsis has increased. METHODS: We conducted a prospective cohort study in a neonatal intensive care unit in Zambia where we implemented a multifaceted infection prevention and control (IPC) bundle consisting of IPC training, text message reminders, alcohol hand rub, enhanced environmental cleaning, and weekly bathing of babies ≥1.5 kg with 2% chlorhexidine gluconate. Hospital-associated sepsis, bloodstream infection (BSI), and mortality (>3 days after admission) outcome data were collected for 6 months prior to and 11 months after bundle implementation. RESULTS: Most enrolled neonates had a birth weight ≥1.5 kg (2131/2669 [79.8%]). Hospital-associated mortality was lower during the intervention than baseline period (18.0% vs 23.6%, respectively). Total mortality was lower in the intervention than prior periods. Half of enrolled neonates (50.4%) had suspected sepsis; 40.8% of cultures were positive. Most positive blood cultures yielded a pathogen (409/549 [74.5%]), predominantly Klebsiella pneumoniae (289/409 [70.1%]). The monthly rate and incidence density rate of suspected sepsis were lower in the intervention period for all birth weight categories, except babies weighing <1.0 kg. The rate of BSI with pathogen was also lower in the intervention than baseline period. CONCLUSIONS: A simple IPC bundle can reduce sepsis and death in neonates hospitalized in high-risk, low-resource settings. Further research is needed to validate these findings in similar settings and to identify optimal implementation strategies for improvement and sustainability. CLINICAL TRIALS REGISTRATION: NCT02386592.

Equity dimensions of the availability and quality of reproductive, maternal and neonatal health services in Zambia.

OBJECTIVE: To assess how quality and availability of reproductive, maternal, neonatal (RMNH) services vary by district wealth and urban/rural status in Zambia. METHODS: We conducted a retrospective analysis of data from the Millennium Development Goal Acceleration Initiative baseline assessment of 117 health facilities in 9 districts. Quality was assessed through a composite score of 23 individual RMNH indicators, ranging from 0 to 1. Availability was evaluated by density of providers and facilities. Districts were divided into wealth groups based on the multidimensional poverty index (MPI). Relative inequity was calculated using the concentration index for quality indicators (positive favours rich, negative favours poor). Multivariable linear regression was performed for the dependent variable composite quality indicator using MPI, urban/rural, and facility level of care as independent variables. RESULTS: 13 hospitals, 85 health centres and 19 health posts were included. The RMNH composite quality indicator was 0.64. Availability of facilities and providers was universally low. The concentration index for the composite quality indicator was -0.015 [-0.043, 0.013], suggesting no clustering to favour either rich or poor districts. Rich districts had the highest absolute numbers of health facilities and providers, but lowest numbers per facility per 1 000 000 population. Urban districts had slightly better service quality, but not availability. Using regression analysis, only facility level of care was significantly associated with quality outcome. CONCLUSIONS: Composite quality of RMNH services did not vary by district wealth, but was slightly higher in urban districts. The availability data suggest that the higher population in richer districts outpaces health infrastructure.

Safety of Induced Sputum Collection in Children Hospitalized With Severe or Very Severe Pneumonia.

BACKGROUND.: Induced sputum (IS) may provide diagnostic information about the etiology of pneumonia. The safety of this procedure across a heterogeneous population with severe pneumonia in low- and middle-income countries has not been described. METHODS.: IS specimens were obtained as part a 7-country study of the etiology of severe and very severe pneumonia in hospitalized children <5 years of age. Rigorous clinical monitoring was done before, during, and after the procedure to record oxygen requirement, oxygen saturation, respiratory rate, consciousness level, and other evidence of clinical deterioration. Criteria for IS contraindications were predefined and serious adverse events (SAEs) were reported to ethics committees and a central safety monitor. RESULTS.: A total of 4653 IS procedures were done among 3802 children. Thirteen SAEs were reported in relation to collection of IS, or 0.34% of children with at least 1 IS specimen collected (95% confidence interval, 0.15%-0.53%). A drop in oxygen saturation that required supplemental oxygen was the most common SAE. One child died after feeding was reinitiated 2 hours after undergoing sputum induction; this death was categorized as "possibly related" to the procedure. CONCLUSIONS.: The overall frequency of SAEs was very low, and the nature of most SAEs was manageable, demonstrating a low-risk safety profile for IS collection even among severely ill children in low-income-country settings. Healthcare providers should monitor oxygen saturation and requirements during and after IS collection, and assess patients prior to reinitiating feeding after the IS procedure, to ensure patient safety.

Limited Utility of Polymerase Chain Reaction in Induced Sputum Specimens for Determining the Causes of Childhood Pneumonia in Resource-Poor Settings: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

BACKGROUND.: Sputum examination can be useful in diagnosing the cause of pneumonia in adults but is less well established in children. We sought to assess the diagnostic utility of polymerase chain reaction (PCR) for detection of respiratory viruses and bacteria in induced sputum (IS) specimens from children hospitalized with severe or very severe pneumonia. METHODS.: Among children aged 1-59 months, we compared organism detection by multiplex PCR in IS and nasopharyngeal/oropharyngeal (NP/OP) specimens. To assess whether organism presence or density in IS specimens was associated with chest radiographic evidence of pneumonia (radiographic pneumonia), we compared prevalence and density in IS specimens from children with radiographic pneumonia and children with suspected pneumonia but without chest radiographic changes or clinical or laboratory findings suggestive of pneumonia (nonpneumonia group). RESULTS.: Among 4232 cases with World Health Organization-defined severe or very severe pneumonia, we identified 1935 (45.7%) with radiographic pneumonia and 573 (13.5%) with nonpneumonia. The organism detection yield was marginally improved with IS specimens (96.2% vs 92.4% for NP/OP specimens for all viruses combined [P = .41]; 96.9% vs 93.3% for all bacteria combined [P = .01]). After accounting for presence in NP/OP specimens, no organism was detected more frequently in the IS specimens from the radiographic pneumonia compared with the nonpneumonia cases. Among high-quality IS specimens, there were no statistically significant differences in organism density, except with cytomegalovirus, for which there was a higher quantity in the IS specimens from cases with radiographic pneumonia compared with the nonpneumonia cases (median cycle threshold value, 27.9 vs 28.5, respectively; P = .01). CONCLUSIONS.: Using advanced molecular methods with IS specimens provided little additional diagnostic information beyond that obtained with NP/OP swab specimens.

The Effect of Antibiotic Exposure and Specimen Volume on the Detection of Bacterial Pathogens in Children With Pneumonia.

BACKGROUND.: Antibiotic exposure and specimen volume are known to affect pathogen detection by culture. Here we assess their effects on bacterial pathogen detection by both culture and polymerase chain reaction (PCR) in children. METHODS.: PERCH (Pneumonia Etiology Research for Child Health) is a case-control study of pneumonia in children aged 1-59 months investigating pathogens in blood, nasopharyngeal/oropharyngeal (NP/OP) swabs, and induced sputum by culture and PCR. Antibiotic exposure was ascertained by serum bioassay, and for cases, by a record of antibiotic treatment prior to specimen collection. Inoculated blood culture bottles were weighed to estimate volume. RESULTS.: Antibiotic exposure ranged by specimen type from 43.5% to 81.7% in 4223 cases and was detected in 2.3% of 4863 controls. Antibiotics were associated with a 45% reduction in blood culture yield and approximately 20% reduction in yield from induced sputum culture. Reduction in yield of Streptococcus pneumoniae from NP culture was approximately 30% in cases and approximately 32% in controls. Several bacteria had significant but marginal reductions (by 5%-7%) in detection by PCR in NP/OP swabs from both cases and controls, with the exception of S. pneumoniae in exposed controls, which was detected 25% less frequently compared to nonexposed controls. Bacterial detection in induced sputum by PCR decreased 7% for exposed compared to nonexposed cases. For every additional 1 mL of blood culture specimen collected, microbial yield increased 0.51% (95% confidence interval, 0.47%-0.54%), from 2% when volume was ≤1 mL to approximately 6% for ≥3 mL. CONCLUSIONS.: Antibiotic exposure and blood culture volume affect detection of bacterial pathogens in children with pneumonia and should be accounted for in studies of etiology and in clinical management.

Sustained effect of couples' HIV counselling and testing on risk reduction among Zambian HIV serodiscordant couples.

BACKGROUND: We present temporal trends in self-reported and biological markers of unprotected sex and sex with concurrent partners in discordant couples receiving couples' voluntary HIV counselling and testing (CVCT). METHODS: Heterosexual Zambian HIV-serodiscordant couples were enrolled into longitudinal follow-up in an open cohort (1994-2012). Multivariable Anderson-Gill models explored predictors of self-report and biological indicators of unprotected sex within (including sperm on a vaginal swab, incident pregnancy or incident linked HIV infection) and outside (including self-report, STI and unlinked HIV infection) the union. Measures of secular trends in baseline measures were also examined. RESULTS: At enrolment of 3049 couples, men were 35 years old on average, women were 29 years, and couples had been together for an average of 7 years. M+F- couples reported an average of 16.6 unprotected sex acts in the 3 months prior to enrolment (pre-CVCT), dropping to 5.3 in the >0-3 month interval, and 2.0 in >6 month intervals (p-trend <0.001). Corresponding values for M-F+ couples were 22.4 unprotected sex acts in the 3 months prior enrolment, dropping to 5.2 in the >0-3 month interval, and 3.1 in >6 month intervals (p-trend <0.001). Significant reductions in self-report and biological markers of outside partners were also noted. Predictors of unprotected sex between study partners after CVCT included prevalent pregnancy (adjusted HR, aHR=1.6-1.9); HIV+ men being circumcised (aHR=1.2); and HIV- women reporting sex with outside partners (aHR=1.3), alcohol (aHR=1.2), injectable (aHR=1.4) or oral (aHR=1.4) contraception use. Fertility intentions were also predictive of unprotected sex (aHR=1.2-1.4). Secular trends indicated steady declines in reported outside partners and STIs. CONCLUSION: Reductions in self-reported unprotected sex after CVCT were substantial and sustained. Reinforced risk-reduction counselling in pregnant couples, couples desiring children and couples with HIV- women having outside partners or using alcohol or injectable or oral contraception are indicated.

Incidence of Severe and Nonsevere Pertussis Among HIV-Exposed and -Unexposed Zambian Infants Through 14 Weeks of Age: Results From the Southern Africa Mother Infant Pertussis Study (SAMIPS), a Longitudinal Birth Cohort Study.

BACKGROUND: Maternal vaccination with tetanus, reduced-dose diphtheria, and acellular pertussis vaccine (Tdap) could be an effective way of mitigating the high residual burden of infant morbidity and mortality caused by Bordetella pertussis To better inform such interventions, we conducted a burden-of-disease study to determine the incidence of severe and nonsevere pertussis among a population of Zambian infants. METHODS: Mother-infant pairs were enrolled at 1 week of life, and then seen at 2- to 3-week intervals through 14 weeks of age. At each visit, nasopharyngeal (NP) swabs were obtained from both, and symptoms were catalogued. Using polymerase chain reaction (PCR) to identify cases, and a severity scoring system to triage these into severe/nonsevere, we calculated disease incidence using person-time at risk as the denominator. RESULTS: From a population of 1981 infants, we identified 10 with clinical pertussis, for an overall incidence of 2.4 cases (95% confidence interval [CI], 1.2-4.2) per 1000 infant-months and a cumulative incidence of 5.2 cases (95% CI, 2.6-9.0) per 1000 infants. Nine of 10 cases occurred within a 3-month window (May-July 2015), with highest incidence between birth and 6 weeks of age (3.5 cases per 1000 infant-months), concentrated among infants prior to vaccination or among those who had only received 1 dose of Diphtheria Tetanus whole cell Pertussis (DTwP). Maternal human immunodeficiency virus (HIV) modestly increased the risk of infant pertussis (risk ratio, 1.8 [95% CI, .5-6.9]). Only 1 of 10 infant cases qualified as having severe pertussis. The rest presented with the mild and nonspecific symptoms of cough, coryza, and/or tachypnea. Notably, cough durations were long, exceeding 30 days in several cases, with PCRs repeatedly positive over time. CONCLUSIONS: Pertussis is circulating freely among this population of Zambian infants but rarely presents with the classical symptoms of paroxysmal cough, whooping, apnea, and cyanosis. Maternal HIV appears to increase the risk, while lack of effective exposure to DTwP increased the risk.