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 characterize 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

Case-control vaccine effectiveness studies: Data collection, analysis and reporting results

The case-control methodology is frequently used to evaluate vaccine effectiveness post-licensure. The results of such studies provide important insight into the level of protection afforded by vaccines in a \u27real world\u27 context, and are commonly used to guide vaccine policy decisions. However, the potential for bias and confounding are important limitations to this method, and the results of a poorly conducted or incorrectly interpreted case-control study can mislead policies. In 2012, a group of experts met to review recent experience with case-control studies evaluating vaccine effectiveness; we summarize the recommendations of that group regarding best practices for data collection, analysis, and presentation of the results of case-control vaccine effectiveness studies. Vaccination status is the primary exposure of interest, but can be challenging to assess accurately and with minimal bias. Investigators should understand factors associated with vaccination as well as the availability of documented vaccination status in the study context; case-control studies may not be a valid method for evaluating vaccine effectiveness in settings where many children lack a documented immunization history. To avoid bias, it is essential to use the same methods and effort gathering vaccination data from cases and controls. Variables that may confound the association between illness and vaccination are also important to capture as completely as possible, and where relevant, adjust for in the analysis according to the analytic plan. In presenting results from case-control vaccine effectiveness studies, investigators should describe enrollment among eligible cases and controls as well as the proportion with no documented vaccine history. Emphasis should be placed on confidence intervals, rather than point estimates, of vaccine effectiveness. Case-control studies are a useful approach for evaluating vaccine effectiveness; however careful attention must be paid to the collection, analysis and presentation of the data in order to best inform evidence-based vaccine policies

Patient and Provider Perspectives on How Trust Influences Maternal Vaccine Acceptance Among Pregnant Women in Kenya

Background Pregnant women and newborns are at high risk for infectious diseases. Altered immunity status during pregnancy and challenges fully vaccinating newborns contribute to this medical reality. Maternal immunization is a strategy to protect pregnant women and their newborns. This study aimed to find out how patient-provider relationships affect maternal vaccine uptake, particularly in the context of a lower middle- income country where limited research in this area exists. Methods We conducted semi-structured, in-depth narrative interviews of both providers and pregnant women from four sites in Kenya: Siaya, Nairobi, Mombasa, and Marsabit. Interviews were conducted in either English or one of the local regional languages. Results We found that patient trust in health care providers (HCPs) is integral to vaccine acceptance among pregnant women in Kenya. The HCP-patient relationship is a fiduciary one, whereby the patients’ trusts is primarily rooted in the provider’s social position as a person who is highly educated in matters of health. Furthermore, patient health education and provider attitudes are crucial for reinstating and fostering that trust, especially in cases where trust was impeded by rumors, community myths and misperceptions, and religious and cultural factors. Conclusion Patient trust in providers is a strong facilitator contributing to vaccine acceptance among pregnant women in Kenya. To maintain and increase immunization trust, providers have a critical role in cultivating a positive environment that allows for favorable interactions and patient health education. This includes educating providers on maternal immunizations and enhancing knowledge of effective risk communication tactics in clinical encounters

Case-control vaccine effectiveness studies: Preparation, design, and enrollment of cases and control

Case-control studies are commonly used to evaluate effectiveness of licensed vaccines after deployment in public health programs. Such studies can provide policy-relevant data on vaccine performance under \u27real world\u27 conditions, contributing to the evidence base to support and sustain introduction of new vaccines. However, case-control studies do not measure the impact of vaccine introduction on disease at a population level, and are subject to bias and confounding, which may lead to inaccurate results that can misinform policy decisions. In 2012, a group of experts met to review recent experience with case-control studies evaluating the effectiveness of several vaccines; here we summarize the recommendations of that group regarding best practices for planning, design and enrollment of cases and controls. Rigorous planning and preparation should focus on understanding the study context including healthcare-seeking and vaccination practices. Case-control vaccine effectiveness studies are best carried out soon after vaccine introduction because high coverage creates strong potential for confounding. Endpoints specific to the vaccine target are preferable to non-specific clinical syndromes since the proportion of non-specific outcomes preventable through vaccination may vary over time and place, leading to potentially confusing results. Controls should be representative of the source population from which cases arise, and are generally recruited from the community or health facilities where cases are enrolled. Matching of controls to cases for potential confounding factors is commonly used, although should be reserved for a limited number of key variables believed to be linked to both vaccination and disease. Case-control vaccine effectiveness studies can provide information useful to guide policy decisions and vaccine development, however rigorous preparation and design is essential

Molecular Characterization of Human Enteroviruses Detected in Children Under Five Years Old in Kenya 2009 - 2015

   Introduction:  Human enterovirus (HEVs) infection is common, with an extensive array of clinical displays ranging from asymptomatic to life-threatening. Presentation include nonspecific febrile illness often accompanied by muscle pain, sore throat, abdominal discomfort, rash, headache, encephalitis, aseptic meningitis and acute flaccid paralysis [2]. Objectives: The study objective was to investigate the natural selection and genetic variability of HEVs and to identify HEV serotypes in circulation among children below 5 years old with diarrhea in an informal settlement(Kibera) in Kenya. Methodology: Specimens (n=628) from a prospective cohort study assessing the incidence and etiology of diarrhea from 2009-2015 were analyzed. Enteric Taqman array cards (TAC) were used for initial screening where two hundred and nine (78%) tested positive for HEVs. Of these specimens, 72 (42%) had a cycle threshold (Ct) ≤30 and were tested by conventional PCR targeting the 3’ regions of the viral protein 1 (VP1) gene. A total of 48 (67%) underwent sequencing; 11 (23%) of which yielded nucleotide sequences. Phylogenetic analyses clustered the Kenyan serotypes to HEVs groups C, B and A. Evaluation of the VP1 amino acid sequences revealed numerous amino acid substitutions in relation to reference strains, which were confirmed to be due to natural selection by negative or positive selection. Conclusion: The Heterogeneous nature of stool samples is known to influence disparities in viral nucleic acid yields. TAC detected 209 of which 171 (82%) were confirmed positive for HEVs by real-time reverse transcription polymerase chain reaction (RRT-PCR), targeting the 5’ NTR regions. Therefore, the results may not be a representative of all circulating HEVs in the study area. Since this was a retrospective study of previously collected samples, it is possible that some HEVs strains may have failed to amplify

Under treatment of pneumonia among children under 5 years of age in a malaria-endemic area: population-based surveillance study conducted in Manhica district- rural, Mozambique

BACKGROUND: Integrated Management of Childhood Illness (IMCI) guidelines were developed to decrease morbidity and mortality, yet implementation varies across settings. Factors associated with poor adherence are not well understood. METHODS: We used data from Manhica District Hospital outpatient department and five peripheral health centers to examine pneumonia management for children <5 years old from January 2008 to June 2011. Episodes of IMCI-defined pneumonia (cough or difficult breathing plus tachypnea), severe pneumonia (pneumonia plus chest wall in-drawing), and/or clinician-diagnosed pneumonia (based on discharge diagnosis) were included. RESULTS: Among severe pneumonia episodes, 96.2% (2,918/3,032) attended in the outpatient department and 70.0% (291/416) attended in health centers were appropriately referred to the emergency department. Age<1 year, malnutrition and various physical exam findings were associated with referral. For non-severe pneumonia episodes, antibiotics were prescribed in 45.7% (16,094/35,224). Factors associated with antibiotic prescription included age <1 year, abnormal auscultatory findings, and clinical diagnosis of pneumonia; diagnosis of malaria or gastroenteritis and pallor were negatively associated with antibiotic prescription. CONCLUSION: Adherence to recommended management of severe pneumonia was high in a hospital outpatient department, but suboptimal in health centers. Antibiotics were prescribed in fewer than half of non-severe pneumonia episodes, and diagnosis of malaria was the strongest risk factor for incorrect management

Population impact and effectiveness of sequential 13-valent pneumococcal conjugate and monovalent rotavirus vaccine introduction on infant mortality: prospective birth cohort studies from Malawi

Background Pneumococcal conjugate vaccine (PCV) and rotavirus vaccine (RV) are key tools for reducing common causes of infant mortality. However, measurement of population-level mortality impact is lacking from sub-Saharan Africa. We evaluated mortality impact and vaccine effectiveness (VE) of PCV13 introduced in November 2011, with subsequent RV1 roll-out in October 2012, in Malawi. Methods We conducted two independent community-based birth cohort studies. Study 1, in northern Malawi (40000population), evaluated population impact using change-point analysis and negative-binomial regression of non-traumatic 14–51-week infant mortality preintroduction (1 January 2004 to 31 September 2011) and postintroduction (1 October 2011 to 1 July 2019), and against three-dose coverage. Study 2, in central Malawi (465 000 population), was recruited from 24 November 2011 to 1 June 2015. In the absence of preintroduction data, individual three-dose versus zero-dose VE was estimated using individual-level Cox survival models. In both cohorts, infants were followed with household visits to ascertain vaccination, socioeconomic and survival status. Verbal autopsies were conducted for deaths. Results Study 1 included 20 291 live births and 216 infant deaths. Mortality decreased by 28.6% (95% CI: 15.3 to 39.8) post-PCV13 introduction. A change point was identified in November 2012. Study 2 registered 50 731 live births, with 454 deaths. Infant mortality decreased from 17 to 10/1000 live births during the study period. Adjusted VE was 44.6% overall (95% CI: 23.0 to 59.1) and 48.3% (95% CI: −5.9 to 74.1) against combined acute respiratory infection, meningitis and sepsis-associated mortality. Conclusion These data provide population-level evidence of infant mortality reduction following sequential PCV13 and RV1 introduction into an established immunisation programme in Malawi. These data support increasing coverage of vaccine programmes in high-burden settings

Impact of monovalent rotavirus vaccine on diarrhoea-associated post-neonatal infant mortality in rural communities in Malawi: a population-based birth cohort study

Background: Rotavirus is a major contributor to child mortality. The effect of rotavirus vaccine on diarrhoea mortality has been estimated in middle-income but not low-income settings, where mortality is high and vaccine effectiveness in reducing admissions to hospital is lower. Empirical population-based mortality studies have not been done in any setting. Malawi introduced monovalent rotavirus vaccine (RV1) in October, 2012. We aimed to investigate the impact and effectiveness of the RV1 vaccine in reducing diarrhoea-associated mortality in infants aged 10–51 weeks. Methods: In this population-based cohort study, we included infants born between Jan 1, 2012, and June 1, 2015, in Mchinji, Central Malawi and analysed data on those surviving 10 weeks. Individual vaccination status was extracted from caregiver-held records or report at home visits at 4 months and 1 year of age. Survival to 1 year was confirmed at home visit, or cause of death ascertained by verbal autopsy. We assessed impact (1 minus mortality rate ratio following vs before vaccine introduction) using Poisson regression. Among vaccine-eligible infants (born from Sept 17, 2012), we assessed effectiveness (1 minus hazard ratio) using Cox regression. Findings: Between Jan 1, 2012, and June 1, 2015, we recruited 48 672 livebirths in Mchinji, among whom 38 518 were vaccine-eligible and 37 570 survived to age 10 weeks. Two-dose versus zero-dose effectiveness analysis included 28 141 infants, of whom 101 had diarrhoea-associated death before 1 year of age. Diarrhoea-associated mortality declined by 31% (95% CI 1–52; p=0·04) after RV1 introduction. Effectiveness against diarrhoea-mortality was 34% (95% CI –28 to 66; p=0·22). Interpretation: RV1 was associated with substantial reduction in diarrhoea-associated deaths among infants in this rural sub-Saharan African setting. These data add considerable weight to evidence showing the impact of rotavirus vaccine programmes. Funding: Wellcome Trust and GlaxoSmithKline Biologicals

Population impact and effectiveness of monovalent rotavirus vaccination in urban Malawian children 3 years after vaccine introduction: ecological and case-control analyses

Background. Rotavirus vaccines have been introduced in many low-income African countries including Malawi in 2012. Despite early evidence of vaccine impact, determining persistence of protection beyond infancy, the utility of the vaccine against specific rotavirus genotypes, and effectiveness in vulnerable subgroups is important. Methods. We compared rotavirus prevalence in diarrheal stool and hospitalization incidence before and following rotavirus vaccine introduction in Malawi. Using case-control analysis, we derived vaccine effectiveness (VE) in the second year of life and for human immunodeficiency virus (HIV)–exposed and stunted children. Results. Rotavirus prevalence declined concurrent with increasing vaccine coverage, and in 2015 was 24% compared with prevaccine mean baseline in 1997–2011 of 32%. Since vaccine introduction, population rotavirus hospitalization incidence declined in infants by 54.2% (95% confidence interval [CI], 32.8–68.8), but did not fall in older children. Comparing 241 rotavirus cases with 692 test-negative controls, VE was 70.6% (95% CI, 33.6%–87.0%) and 31.7% (95% CI, −140.6% to 80.6%) in the first and second year of life, respectively, whereas mean age of rotavirus cases increased from 9.3 to 11.8 months. Despite higher VE against G1P[8] than against other genotypes, no resurgence of nonvaccine genotypes has occurred. VE did not differ significantly by nutritional status (78.1% [95% CI, 5.6%–94.9%] in 257 well-nourished and 27.8% [95% CI, −99.5% to 73.9%] in 205 stunted children; P = .12), or by HIV exposure (60.5% [95% CI, 13.3%–82.0%] in 745 HIV-unexposed and 42.2% [95% CI, −106.9% to 83.8%] in 174 exposed children; P = .91). Conclusions. Rotavirus vaccination in Malawi has resulted in reductions in disease burden in infants &lt;12 months, but not in older children. Despite differences in genotype-specific VE, no genotype has emerged to suggest vaccine escape. VE was not demonstrably affected by HIV exposure or stunting

Multiple introductions and predominance of 3 rotavirus group A genotype G3P[8] in Kilifi, coastal Kenya, 4 years after nationwide vaccine introduction

Globally, rotavirus group A (RVA) remains a major cause of severe childhood diarrhea, despite the use of vaccines in more than 100 countries. RVA sequencing for local outbreaks facilitates investigation into strain composition, origins, spread, and vaccine failure. In 2018, we collected 248 stool samples from children aged less than 13 years admitted with diarrheal illness to Kilifi County Hospital, coastal Kenya. Antigen screening detected RVA in 55 samples (22.2%). Of these, VP7 (G) and VP4 (P) segments were successfully sequenced in 48 (87.3%) and phylogenetic analysis based on the VP7 sequences identified seven genetic clusters with six different GP combinations: G3P[8], G1P[8], G2P[4], G2P[8], G9P[8] and G12P[8]. The G3P[8] strains predominated the season (n = 37, 67.2%) and comprised three distinct G3 genetic clusters that fell within Lineage I and IX (the latter also known as equine-like G3 Lineage). Both the two G3 lineages have been recently detected in several countries. Our study is the first to document African children infected with G3 Lineage IX. These data highlight the global nature of RVA transmission and the importance of increasing global rotavirus vaccine coverage