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.

Causes of stillbirth and death among children younger than 5 years in eastern Hararghe, Ethiopia: a population-based post-mortem study.

BACKGROUND: Child mortality is high in Ethiopia, but reliable data on the causes of death are scarce. We aimed to gather data for the contributory causes of stillbirth and child deaths in eastern Ethiopia. METHODS: In this population-based post-mortem study, we established a death-notification system in health facilities and in the community in Kersa (rural), Haramaya (rural) and Harar (urban) in eastern Ethiopia, at a new site of the Child Health and Mortality Prevention Surveillance (CHAMPS) network. We collected ante-mortem data, did verbal autopsies, and collected post-mortem samples via minimally invasive tissue sampling from stillbirths (weighing at least 1000 g or with an estimated gestational age of at least 28 weeks) and children who died younger than 5 years. Children-or their mothers, in the case of stillbirths and deaths in children younger than 6 months-had to have lived in the catchment area for the past 6 months to be included. Molecular, microbiological, and histopathological analyses were done in collected samples. Cause of death was established by an expert panel on the basis of these data and classified as underlying, comorbid, or immediate separately for stillbirths, neonatal deaths (deaths aged 0-27 days), and child deaths (aged 28 days to <5 years). FINDINGS: Between Feb 4, 2019, and Feb 3, 2021, 312 deaths were eligible for inclusion, and the families gave consent in 195 (63%) cases. Cause of death was established in 193 (99%) cases. Among 114 stillbirths, the underlying cause of death was perinatal asphyxia or hypoxia in 60 (53%) and birth defects in 24 (21%). Among 59 neonatal deaths, the most common underlying cause was perinatal asphyxia or hypoxia (17 [29%]) and the most common immediate cause of death was neonatal sepsis, which occurred in 27 (60%). Among 20 deaths in children aged 28 days to 59 months, malnutrition was the leading underlying cause (15 [75%]) and infections were common immediate and comorbid causes. Pathogens were identified in 19 (95%) child deaths, most commonly Klebsiella pneumoniae and Streptococcus pneumoniae. INTERPRETATION: Perinatal asphyxia or hypoxia, infections, and birth defects accounted for most stillbirths and child deaths. Most deaths could have been prevented with feasible interventions, such as improved maternity services, folate supplementation, and improved vaccine uptake. FUNDING: Bill & Melinda Gates Foundation.

Microbiota that affect risk for shigellosis in children in low-income countries.

Pathogens in the gastrointestinal tract exist within a vast population of microbes. We examined associations between pathogens and composition of gut microbiota as they relate to Shigella spp./enteroinvasive Escherichia coli infection. We analyzed 3,035 stool specimens (1,735 nondiarrheal and 1,300 moderate-to-severe diarrheal) from the Global Enteric Multicenter Study for 9 enteropathogens. Diarrheal specimens had a higher number of enteropathogens (diarrheal mean 1.4, nondiarrheal mean 0.95; p<0.0001). Rotavirus showed a negative association with Shigella spp. in cases of diarrhea (odds ratio 0.31, 95% CI 0.17-0.55) and had a large combined effect on moderate-to-severe diarrhea (odds ratio 29, 95% CI 3.8-220). In 4 Lactobacillus taxa identified by 16S rRNA gene sequencing, the association between pathogen and disease was decreased, which is consistent with the possibility that Lactobacillus spp. are protective against Shigella spp.-induced diarrhea. Bacterial diversity of gut microbiota was associated with diarrhea status, not high levels of the Shigella spp. ipaH gene.

A national cholera epidemic with high case fatality rates--Kenya 2009.

BACKGROUND: Cholera remains endemic in sub-Saharan Africa. We characterized the 2009 cholera outbreaks in Kenya and evaluated the response. METHODS: We analyzed surveillance data and estimated case fatality rates (CFRs). Households in 2 districts, East Pokot (224 cases; CFR = 11.7%) and Turkana South (1493 cases; CFR = 1.0%), were surveyed. We randomly selected 15 villages and 8 households per village in each district. Healthcare workers at 27 health facilities (HFs) were surveyed in both districts. RESULTS: In 2009, cholera outbreaks caused a reported 11 425 cases and 264 deaths in Kenya. Data were available from 44 districts for 6893 (60%) cases. District CFRs ranged from 0% to 14.3%. Surveyed household respondents (n = 240) were aware of cholera (97.5%) and oral rehydration solution (ORS) (87.9%). Cholera deaths were reported more frequently from East Pokot (n = 120) than Turkana South (n = 120) households (20.7% vs. 12.3%). The average travel time to a HF was 31 hours in East Pokot compared with 2 hours in Turkana South. Fewer respondents in East Pokot (9.8%) than in Turkana South (33.9%) stated that ORS was available in their village. ORS or intravenous fluid shortages occurred in 20 (76.9%) surveyed HFs. CONCLUSIONS: High CFRs in Kenya are related to healthcare access disparities, including availability of rehydration supplies.

Quantitative PCR for detection of Shigella improves ascertainment of Shigella burden in children with moderate-to-severe diarrhea in low-income countries.

Estimates of the prevalence of Shigella spp. are limited by the suboptimal sensitivity of current diagnostic and surveillance methods. We used a quantitative PCR (qPCR) assay to detect Shigella in the stool samples of 3,533 children aged <59 months from the Gambia, Mali, Kenya, and Bangladesh, with or without moderate-to-severe diarrhea (MSD). We compared the results from conventional culture to those from qPCR for the Shigella ipaH gene. Using MSD as the reference standard, we determined the optimal cutpoint to be 2.9 × 10(4) ipaH copies per 100 ng of stool DNA for set 1 (n = 877). One hundred fifty-eight (18%) specimens yielded >2.9 × 10(4) ipaH copies. Ninety (10%) specimens were positive by traditional culture for Shigella. Individuals with ≥ 2.9 × 10(4) ipaH copies have 5.6-times-higher odds of having diarrhea than those with <2.9 × 10(4) ipaH copies (95% confidence interval, 3.7 to 8.5; P < 0.0001). Nearly identical results were found using an independent set of samples. qPCR detected 155 additional MSD cases with high copy numbers of ipaH, a 90% increase from the 172 cases detected by culture in both samples. Among a subset (n = 2,874) comprising MSD cases and their age-, gender-, and location-matched controls, the fraction of MSD cases that were attributable to Shigella infection increased from 9.6% (n = 129) for culture to 17.6% (n = 262) for qPCR when employing our cutpoint. We suggest that qPCR with a cutpoint of approximately 1.4 × 10(4) ipaH copies be the new reference standard for the detection and diagnosis of shigellosis in children in low-income countries. The acceptance of this new standard would substantially increase the fraction of MSD cases that are attributable to Shigella.

Differing burden and epidemiology of non-Typhi Salmonella bacteremia in rural and urban Kenya, 2006-2009.

BACKGROUND: The epidemiology of non-Typhi Salmonella (NTS) bacteremia in Africa will likely evolve as potential co-factors, such as HIV, malaria, and urbanization, also change. METHODS: As part of population-based surveillance among 55,000 persons in malaria-endemic, rural and malaria-nonendemic, urban Kenya from 2006-2009, blood cultures were obtained from patients presenting to referral clinics with fever ≥38.0°C or severe acute respiratory infection. Incidence rates were adjusted based on persons with compatible illnesses, but whose blood was not cultured. RESULTS: NTS accounted for 60/155 (39%) of blood culture isolates in the rural and 7/230 (3%) in the urban sites. The adjusted incidence in the rural site was 568/100,000 person-years, and the urban site was 51/100,000 person-years. In both sites, the incidence was highest in children <5 years old. The NTS-to-typhoid bacteremia ratio in the rural site was 4.6 and in the urban site was 0.05. S. Typhimurium represented >85% of blood NTS isolates in both sites, but only 21% (urban) and 64% (rural) of stool NTS isolates. Overall, 76% of S. Typhimurium blood isolates were multi-drug resistant, most of which had an identical profile in Pulse Field Gel Electrophoresis. In the rural site, the incidence of NTS bacteremia increased during the study period, concomitant with rising malaria prevalence (monthly correlation of malaria positive blood smears and NTS bacteremia cases, Spearman's correlation, p = 0.018 for children, p = 0.16 adults). In the rural site, 80% of adults with NTS bacteremia were HIV-infected. Six of 7 deaths within 90 days of NTS bacteremia had HIV/AIDS as the primary cause of death assigned on verbal autopsy. CONCLUSIONS: NTS caused the majority of bacteremias in rural Kenya, but typhoid predominated in urban Kenya, which most likely reflects differences in malaria endemicity. Control measures for malaria, as well as HIV, will likely decrease the burden of NTS bacteremia in Africa.

Salmonella bacteremia in Kenyan children.

BACKGROUND: Nontyphoidal Salmonella spp. are among the leading causes of childhood bacteremia in sub-Saharan Africa, yet there are few published clinical series, and the risk factors for acquiring infection are not fully understood. METHODS: We examined data from 166 cases of nontyphoidal Salmonella bacteremia identified during a large prospective study of bacteremia among all children admitted to a district hospital in Kenya. We also investigated the importance of comorbidities, including current malaria parasitemia, recent malaria (detectable Plasmodium falciparum histidine rich protein 2 in the absence of parasitemia), sickle cell disease, malnutrition and human immunodeficiency virus (HIV) infection. RESULTS: Nontyphoidal Salmonella bacteremia was associated with severe malnutrition (33% cases), HIV infection (18% cases), a history of illness >7 days, recent hospital admission, splenomegaly, anemia and recent (but not current) malaria but was not associated with diarrhea. Seventy-seven (46%) children with nontyphoidal Salmonella bacteremia fulfilled World Health Organization clinical criteria for a diagnosis of pneumonia. Independent risk factors for death were diarrhea, tachypnea, HIV infection, severe malnutrition, meningitis and young age. CONCLUSIONS: Clinical diagnosis of invasive nontyphoidal Salmonella infection in African children is difficult without microbiology facilities because clinical features overlap with other conditions. The common risk factors for nontyphoidal Salmonella infection differ from developed countries, with high a prevalence of malnutrition, HIV, malaria and anemia. Children with nontyphoidal Salmonella infection who fulfill World Health Organization clinical criteria for severe pneumonia may receive ineffective therapy in the form of penicillin.