Clinical severity of enteric viruses detected using a quantitative molecular assay compared to conventional assays in the Global Enteric Multicenter Study.

BACKGROUND: Quantitative molecular assays are increasingly used for detection of enteric viruses. METHODS: We compared the clinical severity using modified Vesikari score (mVS) of enteric viruses detected by conventional assays (enzyme immunoassays [EIA] for rotavirus and adenovirus 40/41 and conventional polymerase chain reaction for astrovirus, sapovirus, and norovirus) and a quantitative molecular assay (TaqMan Array Card [TAC]) among children aged 0-59 months in the Global Enteric Multicenter Study. For rotavirus and adenovirus 40/41, we compared severity between EIA-positive and TAC-positive cases assigned etiologies using different cycle threshold (CT) cutoffs. RESULTS: Using conventional assays, the median (interquartile range) mVS was 10 (8, 11) for rotavirus, 9 (7, 11) for adenovirus 40/41, 8 (6, 10) for astrovirus, sapovirus, and norovirus GII, and 7 (6, 9) for norovirus GI. Compared to rotavirus EIA-positive cases, the median mVS was 2 and 3 points lower for EIA-negative/TAC-positive cases with CT<32.6 and 32.6≤CT<35, respectively (p-value<.0001). Adenovirus 40/41 EIA-positive and EIA-negative/TAC-positive cases were similar, regardless of CT cutoff. CONCLUSIONS: Quantitative molecular assays compared to conventional assays, such as EIA, may influence severity of identified cases, especially for rotavirus. Cutoffs to assign etiology for quantitative assays should be considered in the design and interpretation of enteric virus studies.

Co-carriage of Staphylococcus aureus and Streptococcus pneumoniae among children younger than 2 years of age in a rural population in Pakistan.

Objectives: Staphylococcus aureus and Streptococcus pneumoniae are common colonizers of the human nasopharynx. In this study, we describe S. aureus nasopharyngeal carriage and evaluate its association with S. pneumoniae carriage post-10-valent pneumococcal conjugate vaccine (PCV10) introduction in Pakistan. Methods: A serial cross-sectional study was undertaken from 2014 to 2018, children <2 years were randomly selected, and nasopharyngeal swabs were collected using standard WHO guidelines. S. aureus and S. pneumoniae isolates were identified using standard methods and tested for antimicrobial susceptibility by the standard Kirby-Bauer disk-diffusion method as per Clinical & Laboratory Standards Institute (CLSI) recommendations. Regression analysis was used to determine predictors associated with S. aureus carriage. Results: We enrolled 3140 children. S. aureus carriage prevalence was 5.6% (176/3140), and 50.1% (81/176) of the isolates were methicillin-resistant S. aureus (MRSA). S. aureus carriage was higher in the absence of pneumococcus compared to isolates in which pneumococcus was present (7.5% vs 5.0%). S. aureus carriage was negatively associated with pneumococcal carriage, being in 3rd and 4th year of enrollment, and vaccination with two and three PCV10 doses, in addition, fast breathing, ≥2 outpatients visits, and rainy season were positively associated. The following resistance rates were observed: 98.9% for penicillin, 74.4% for fusidic acid, and 23.3% for gentamicin, 10.2% for erythromycin, and 8.5% for cotrimoxazole. All isolates were susceptible to amikacin. Conclusions: Overall S. aureus carriage prevalence was low, PCV10 vaccine was protective against the carriage. The proportion of MRSA carriage and antimicrobial resistance was high in this community warranting continuous monitoring for invasive infections.

Taking on Typhoid: Eliminating Typhoid Fever as a Global Health Problem.

Typhoid fever is a significant global health problem that impacts people living in areas without access to clean water and sanitation. However, collaborative international partnerships and new research have improved both knowledge of the burden in countries with endemic disease and the tools for improved surveillance, including environmental surveillance. Two typhoid conjugate vaccines (TCVs) have achieved World Health Organization prequalification, with several more in the development pipeline. Despite hurdles posed by the coronavirus disease 2019 pandemic, multiple TCV efficacy trials have been conducted in high-burden countries, and data indicate that TCVs provide a high degree of protection from typhoid fever, are safe to use in young children, provide lasting protection, and have the potential to combat typhoid antimicrobial resistance. Now is the time to double down on typhoid control and elimination by sustaining progress made through water, sanitation, and hygiene improvements and accelerating TCV introduction in high-burden locations.

Differential coverage for vaccines in the expanded program on immunization (EPI) among children in rural Pakistan.

BACKGROUND: Pakistan has a well-established Expanded Program on Immunization (EPI) however vaccine-preventable diseases still account for high infant and child mortality rates. This study describes the differential vaccine coverage and determinants of vaccine uptake in rural Pakistan. METHODS: From October 2014 to September 2018, we enrolled children younger than 2 years of age from the Matiari Demographic Surveillance System in Sindh, Pakistan. Socio-demographic and vaccination history were collected from all participants. Vaccine coverage rates and timeliness were reported. Socio-demographic variables for missed and untimely vaccination were studied in multivariable logistic regression. RESULTS: Of the 3140 enrolled children, 48.4 % received all EPI recommended vaccines. Only 21.2 % of these were age appropriate. Around 45.4 % of the children were partially vaccinated, and 6.2 % were unvaccinated. Highest coverage was seen for the first dose of pentavalent (72.8 %), 10-valent Pneumococcal Conjugate Vaccine (PCV10) (70.4 %) and Oral Polio Vaccine (OPV) (69.2 %) and the lowest coverage was for measles (29.3 %) and rotavirus (1.8 %) vaccines. Primary caretakers and wage earners with a higher level of education were protective against missed and untimely vaccination. Enrollment in the 2nd, 3rd and 4th study year was negatively associated with being unvaccinated whereas distance from a major road was positively associated with non-adherence to schedule. CONCLUSION: Vaccine coverage was low among children in Matiari, Pakistan, and majority received delayed doses. Parents' education status and year of study enrollment was protective against vaccine dropout and delayed vaccination whereas geographical distance from a major road was a predictor. Vaccine promotion and outreach efforts may have had a beneficial impact on vaccine coverage and timeliness.

Spatiotemporal variation in risk of Shigella infection in childhood: a global risk mapping and prediction model using individual participant data.

BACKGROUND: Diarrhoeal disease is a leading cause of childhood illness and death globally, and Shigella is a major aetiological contributor for which a vaccine might soon be available. The primary objective of this study was to model the spatiotemporal variation in paediatric Shigella infection and map its predicted prevalence across low-income and middle-income countries (LMICs). METHODS: Individual participant data for Shigella positivity in stool samples were sourced from multiple LMIC-based studies of children aged 59 months or younger. Covariates included household-level and participant-level factors ascertained by study investigators and environmental and hydrometeorological variables extracted from various data products at georeferenced child locations. Multivariate models were fitted and prevalence predictions obtained by syndrome and age stratum. FINDINGS: 20 studies from 23 countries (including locations in Central America and South America, sub-Saharan Africa, and south and southeast Asia) contributed 66 563 sample results. Age, symptom status, and study design contributed most to model performance followed by temperature, wind speed, relative humidity, and soil moisture. Probability of Shigella infection exceeded 20% when both precipitation and soil moisture were above average and had a 43% peak in uncomplicated diarrhoea cases at 33°C temperatures, above which it decreased. Compared with unimproved sanitation, improved sanitation decreased the odds of Shigella infection by 19% (odds ratio [OR]=0·81 [95% CI 0·76-0·86]) and open defecation decreased them by 18% (OR=0·82 [0·76-0·88]). INTERPRETATION: The distribution of Shigella is more sensitive to climatological factors, such as temperature, than previously recognised. Conditions in much of sub-Saharan Africa are particularly propitious for Shigella transmission, although hotspots also occur in South America and Central America, the Ganges-Brahmaputra Delta, and the island of New Guinea. These findings can inform prioritisation of populations for future vaccine trials and campaigns. FUNDING: NASA, National Institutes of Health-The National Institute of Allergy and Infectious Diseases, and Bill & Melinda Gates Foundation.

Risk factors for community-acquired bacterial infection among young infants in South Asia: a longitudinal cohort study with nested case-control analysis.

OBJECTIVE: Risk factors predisposing infants to community-acquired bacterial infections during the first 2 months of life are poorly understood in South Asia. Identifying risk factors for infection could lead to improved preventive measures and antibiotic stewardship. METHODS: Five sites in Bangladesh, India and Pakistan enrolled mother-child pairs via population-based pregnancy surveillance by community health workers. Medical, sociodemographic and epidemiological risk factor data were collected. Young infants aged 0-59 days with signs of possible serious bacterial infection (pSBI) and age-matched controls provided blood and respiratory specimens that were analysed by blood culture and real-time PCR. These tests were used to build a Bayesian partial latent class model (PLCM) capable of attributing the probable cause of each infant's infection in the ANISA study. The collected risk factors from all mother-child pairs were classified and analysed against the PLCM using bivariate and stepwise logistic multivariable regression modelling to determine risk factors of probable bacterial infection. RESULTS: Among 63 114 infants born, 14 655 were assessed and 6022 had signs of pSBI; of these, 81% (4859) provided blood samples for culture, 71% (4216) provided blood samples for quantitative PCR (qPCR) and 86% (5209) provided respiratory qPCR samples. Risk factors associated with bacterial-attributed infections included: low (relative risk (RR) 1.73, 95% credible interval (CrI) 1.42 to 2.11) and very low birth weight (RR 5.77, 95% CrI 3.73 to 8.94), male sex (RR 1.27, 95% CrI 1.07 to 1.52), breathing problems at birth (RR 2.50, 95% CrI 1.96 to 3.18), premature rupture of membranes (PROMs) (RR 1.27, 95% CrI 1.03 to 1.58) and being in the lowest three socioeconomic status quintiles (first RR 1.52, 95% CrI 1.07 to 2.16; second RR 1.41, 95% CrI 1.00 to 1.97; third RR 1.42, 95% CrI 1.01 to 1.99). CONCLUSION: Distinct risk factors: birth weight, male sex, breathing problems at birth and PROM were significantly associated with the development of bacterial sepsis across South Asian community settings, supporting refined clinical discernment and targeted use of antimicrobials.

Exploring terminology for puerperal sepsis and its symptoms in urban Karachi, Pakistan to improve communication, care-seeking, and illness recognition.

Puerperal sepsis is an important cause of maternal morbidity and mortality in developing countries. Awareness of local terminology for its signs and symptoms may improve communication about this illness, what actions to take when symptoms appear, timely care seeking, and clinical outcomes. This formative research aimed to improve recognition and management of postpartum sepsis in Pakistan by eliciting local terms used for postpartum illnesses and symptoms. We conducted 32 in-depth interviews with recently delivered women, their relatives, traditional birth attendants, and health care providers to explore postpartum experiences. Terms for symptoms and illness are used interchangeably (i.e. bukhar, the Urdu word for fever), many variations exist for the same term, and gradations of severity for each term as not associated with different types of illnesses. The lack of a designated term for postpartum sepsis in Urdu delays care-seeking and proper diagnosis, particularly at the community level. Ideally, a common lexicon for symptoms and postpartum sepsis would be developed but this may not be feasible or appropriate given the nature of the Urdu language and local understandings of postpartum illness. These insights can inform how we approach educational campaigns, the development of clinical algorithms that focus on symptoms, and counselling protocols.

Infectious aetiologies of neonatal illness in south Asia classified using WHO definitions: a primary analysis of the ANISA study.

BACKGROUND: Globally, neonatal mortality accounts for almost half of all deaths in children younger than 5 years. Aetiological agents of neonatal infection are difficult to identify because the clinical signs are non-specific. Using data from the Aetiology of Neonatal Infections in south Asia (ANISA) cohort, we aimed to describe the spectrum of infectious aetiologies of acute neonatal illness categorised post-hoc using the 2015 WHO case definitions of critical illness, clinical severe infection, and fast breathing only. METHODS: Eligible infants were aged 0-59 days with possible serious bacterial infection and healthy infants enrolled in the ANISA study in Bangladesh, India, and Pakistan. We applied a partial latent class Bayesian model to estimate the prevalence of 27 pathogens detectable on PCR, pathogens detected by blood culture only, and illness not attributed to any infectious aetiology. Infants with at least one clinical specimen available were included in the analysis. We assessed the prevalence of these aetiologies according to WHO's case definitions of critically ill, clinical severe infection, and infants with late onset, isolated fast breathing. For the clinical severe definition, we compared the prevalence of signs by bacterial versus viral aetiology. FINDINGS: There were 934 infants (992 episodes) in the critically ill category, 3769 (4000 episodes) in the clinical severe infection category, and 738 (771 episodes) in the late-onset isolated fast breathing category. We estimated the proportion of illness attributable to bacterial infection was 32·7% in infants in the critically ill group, 15·6% in the clinical severe infection group, and 8·8% among infants with late-onset isolated fast breathing group. An infectious aetiology was not identified in 58-82% of infants in these categories. Among 4000 episodes of clinical severe infection, those with bacterial versus viral attribution had higher proportions of hypothermia, movement only when stimulated, convulsions, and poor feeding. INTERPRETATION: Our modelled results generally support the revised WHO case definitions, although a revision of the most severe case definition could be considered. Clinical criteria do not clearly differentiate between young infants with and without infectious aetiologies. Our results highlight the need for improved point-of-care diagnostics, and further study into neonatal deaths and episodes with no identified aetiology, to ensure antibiotic stewardship and targeted interventions. FUNDING: The Bill and Melinda Gates Foundation.

Pneumococcal Carriage in Infants Post-PCV10 Introduction in Pakistan: Results from Serial Cross-Sectional Surveys.

The 10-valent pneumococcal vaccine was introduced in Pakistan's Expanded Program on Immunization (EPI) in 2013 as a 3 + 0 schedule without catchup. We conducted three annual cross-sectional surveys from 2014−2016 to measure vaccine-type (VT) carriage in infants from a rural part of Pakistan. Nasopharyngeal specimens were collected by random sampling of infants from two union councils of Matiari. Samples were then transported to the Infectious Disease Research Laboratory (IDRL) at the Aga Khan University within 6−8 h of collection. Serotypes were established using sequential multiplex PCR. Of the 665 children enrolled across three surveys, 547 were culture-positive for pneumococcus. VT carriage decreased from 21.8% in 2014 to 12.7% in 2016 (p-value for trend <0.001). Those who were not vaccinated or partially vaccinated were found to be at higher risk of carrying a VT serotype ((aOR 2.53, 95% CI 1.39, 4.63 for non-vaccinated) and (aOR 3.35, 95% CI 1.82, 6.16 for partially vaccinated)). On the other hand, being enrolled in the most recent survey was negatively associated with VT carriage (aOR 0.51, 95% CI 0.28, 0.93). We found that PCV10 was effective in decreasing the carriage of vaccine-type serotypes in Pakistani infants.

Serotype-specific effectiveness against pneumococcal carriage and serotype replacement after ten-valent Pneumococcal Conjugate Vaccine (PCV10) introduction in Pakistan.

OBJECTIVE: Pakistan was one of the first South-Asian countries to introduce the ten-valent pneumococcal conjugate vaccine (PCV10) at the national level, using a 3+0 schedule without catchup, in 2013. METHODS: From 2014-18, fifteen children <2 years old were recruited every week in Matiari, Sindh, and nasopharyngeal swabs were collected. The samples were cultured, and pneumococcus was further serotyped through multiplex PCR at the Aga Khan University Hospital as per the method described by the Centers for Disease Control and Prevention, USA. RESULTS: Pneumococcus was detected in 2370/3140 (75%) children. Vaccine type (VT) and non-vaccine type (NVT) serotypes were carried by 379 and 1990 children. There was a significant decline in VT carriage (by 40.3%, p-value <0.001), whereas overall NVT carriage remained the same. The prevalence of VT serotypes 6B, 9V/9A, and 19F showed a significant decline by 58.8%, 79.3%, and 56%, respectively. The prevalence of NVT serotypes 19A, 21, and 10A increased by 70%, 33.3%, and 65.6%, respectively, whereas serotypes 13 and 9N/9L decreased by 53.4% and 51.8%, respectively. Serotype-specific vaccine effectiveness estimates that reached statistical significance were for 9V/9A (VE = 65.0, 95% CI 26.0-83.5%), 19F (VE = 55.3, 95% CI 15.5-76.4%) and for the vaccine related serotype 6A (VE = 28.4, 95% CI 0.9-48.2%). CONCLUSION: The emergence of NVT serotypes, primarily 19A replacing VT serotypes in this rural community, necessitates continuous monitoring of serotypes in the carriage and invasive disease to evaluate the utility of existing vaccine formulations.

Associations Between Eight Earth Observation-Derived Climate Variables and Enteropathogen Infection: An Independent Participant Data Meta-Analysis of Surveillance Studies With Broad Spectrum Nucleic Acid Diagnostics.

Diarrheal disease, still a major cause of childhood illness, is caused by numerous, diverse infectious microorganisms, which are differentially sensitive to environmental conditions. Enteropathogen-specific impacts of climate remain underexplored. Results from 15 studies that diagnosed enteropathogens in 64,788 stool samples from 20,760 children in 19 countries were combined. Infection status for 10 common enteropathogens-adenovirus, astrovirus, norovirus, rotavirus, sapovirus, Campylobacter, ETEC, Shigella, Cryptosporidium and Giardia-was matched by date with hydrometeorological variables from a global Earth observation dataset-precipitation and runoff volume, humidity, soil moisture, solar radiation, air pressure, temperature, and wind speed. Models were fitted for each pathogen, accounting for lags, nonlinearity, confounders, and threshold effects. Different variables showed complex, non-linear associations with infection risk varying in magnitude and direction depending on pathogen species. Rotavirus infection decreased markedly following increasing 7-day average temperatures-a relative risk of 0.76 (95% confidence interval: 0.69-0.85) above 28°C-while ETEC risk increased by almost half, 1.43 (1.36-1.50), in the 20-35°C range. Risk for all pathogens was highest following soil moistures in the upper range. Humidity was associated with increases in bacterial infections and decreases in most viral infections. Several virus species' risk increased following lower-than-average rainfall, while rotavirus and ETEC increased with heavier runoff. Temperature, soil moisture, and humidity are particularly influential parameters across all enteropathogens, likely impacting pathogen survival outside the host. Precipitation and runoff have divergent associations with different enteric viruses. These effects may engender shifts in the relative burden of diarrhea-causing agents as the global climate changes.

Antimicrobial Resistance in Pneumococcal Carriage Isolates from Children under 2 Years of Age in Rural Pakistan.

Antimicrobial resistance is an emerging public health concern. Ten-valent pneumococcal vaccine (PCV10) was introduced in Pakistan's Expanded Program on Immunization (EPI) in 2012 as a 3 + 0 schedule without catchup. From 2014 to 2018, children <2 years were randomly selected in two rural union councils of Matiari, Pakistan. Nasopharyngeal swabs were collected using standard WHO guidelines by trained staff and processed at Infectious Disease Research Laboratory at The Aga Khan University, Karachi using culture on sheep blood agar and Multiplex PCR methods described by CDC, USA. Pneumococcal isolates were identified by optochin sensitivity and bile solubility tests. Isolates were then tested for antimicrobial susceptibility by standard Kirby-Bauer disk-diffusion method on Mueller-Hinton Agar (MHA) with 5% sheep blood agar as per Clinical & Laboratory Standards Institute (CLSI) recommendations. Of 3140 children enrolled, pneumococcal isolates were detected in 2370 (75%). Vaccine coverage improved from 41% to 68.4%. Out of the 2370 isolates, 88.4%, 37.6% and 25% were resistant to cotrimoxazole, tetracycline and erythromycin, respectively. There was no resistance to penicillin, ceftriaxone, and vancomycin. For erythromycin, resistance increased from 20% in 2014/15 to 30.8% in 2017/18 and for tetracycline it increased from 34.9% to 41.8% both of which were explained by an increase in prevalence of serotype 19A. Pneumococcal isolates were susceptible to penicillin, ceftriaxone, and vancomycin. They were largely resistant to cotrimoxazole and tetracycline. There was an increase in erythromycin and tetracycline resistance attributed to increasing prevalence of serotype 19A. Pneumococcal isolates from carriage and invasive disease should be closely monitored for antimicrobial susceptibility. IMPORTANCE Antimicrobial resistance is an emerging public health concern particularly in low- and middle-income countries where there is poor regulation and easy availability of antibiotics. This is the first study from Pakistan to report antimicrobial resistance patterns of pneumococcus after vaccine introduction in the community. Pakistan was the first South-Asian country to introduce PCV10 in its Expanded Program on Immunization (EPI) in 2012 as a 3 + 0 schedule without catchup. In this study, we describe the PCV10 impact on antimicrobial resistance patterns of pneumococcal nasopharyngeal carriage in children younger than 2 years of age in a rural district in Pakistan after the introduction of the vaccine.

Pathogens Associated With Linear Growth Faltering in Children With Diarrhea and Impact of Antibiotic Treatment: The Global Enteric Multicenter Study.

BACKGROUND: The association between childhood diarrheal disease and linear growth faltering in developing countries is well described. However, the impact attributed to specific pathogens has not been elucidated, nor has the impact of recommended antibiotic treatment. METHODS: The Global Enteric Multicenter Study enrolled children with moderate to severe diarrhea (MSD) seeking healthcare at 7 sites in sub-Saharan Africa and South Asia. At enrollment, we collected stool samples to identify enteropathogens. Length/height was measured at enrollment and follow-up, approximately 60 days later, to calculate change in height-for-age z scores (ΔHAZ). The association of pathogens with ΔHAZ was tested using linear mixed effects regression models. RESULTS: Among 8077 MSD cases analyzed, the proportion with stunting (HAZ below -1) increased from 59% at enrollment to 65% at follow-up (P < .0001). Pathogens significantly associated with linear growth decline included Cryptosporidium (P < .001), typical enteropathogenic Escherichia coli (P = .01), and untreated Shigella (P = .009) among infants (aged 0-11 months) and enterotoxigenic E. coli encoding heat-stable toxin (P < .001) and Cryptosporidium (P = .03) among toddlers (aged 12-23 months). Shigella-infected toddlers given antibiotics had improved linear growth (P = .02). CONCLUSIONS: Linear growth faltering among children aged 0-23 months with MSD is associated with specific pathogens and can be mitigated with targeted treatment strategies, as demonstrated for Shigella.

Clinical signs predictive of severe illness in young Pakistani infants.

OBJECTIVE: Early detection of specific signs and symptoms to predict severe illness is essential to prevent infant mortality. As a continuation of the results from the multicenter Young Infants Clinical Signs and Symptoms (YICSS) study, we present here the performance of the seven-sign algorithm in 3 age categories (0-6 days, 7-27 days and 28-59 days) in Pakistani infants aged 0-59 days. RESULTS: From September 2003 to November 2004, 2950 infants were enrolled (age group 0-6 days = 1633, 7-27 days = 817, 28-59 days = 500). The common reason for seeking care was umbilical redness or discharge (29.2%) in the 0-6 days group. Older age groups presented with cough (16.9%) in the 7-27 age group and (26.9%) infants in the 28-59 days group. Severe infection/sepsis was the most common primary diagnoses in infants requiring hospitalization across all age groups. The algorithm performed well in every age group, with a sensitivity of 85.9% and specificity of 71.6% in the 0-6 days age group and a sensitivity of 80.5% and specificity of 80.2% in the 28-59 days group; the sensitivity was slightly lower in the 7-27 age group (72.4%) but the specificity remained high (83.1%).

Direct and indirect effect of 10 valent pneumococcal vaccine on nasopharyngeal carriage in children under 2 years of age in Matiari, Pakistan.

BACKGROUND: Pakistan introduced Ten-valent pneumococcal-conjugate-vaccine PCV10 in 2012 as a 3 + 0 schedule without catch-up. METHODS: Children <2 years old in Matiari, Sindh provided nasopharyngeal swabs between 2014 and 2018, which were cultured for pneumococcus and serotyped through multiplex PCR at the Aga Khan University Hospital. Carriage rates over time for Vaccine-Type (VT) and Non-VT (NVT) serotypes were used to estimate direct, indirect, total and overall effects of vaccination. Regression analysis was used to determine factors associated with VT carriage. RESULTS: Pneumococcus was detected in 2370/3140 (75%). VT carriage decreased overall, 16.1-9.6% (p-trend <0.001); vaccinated (all 3 doses of PCV10 received) 11.3-8.1% (p-trend 0.031) and unvaccinated (no PCV10 dose received) 17.4-10.3% (p-trend 0.003) with a decline in serotypes 6B, 9V/9A and 19F. Immunization increased from 41.0% to 68.4% (p-trend 0.001). Direct effect of vaccine was 32.8% (95% CI 14.7-47.0%) and indirect effect 44.6%(95% CI 40.6-48.6%). Factors associated with decreased VT colonization were education 1-5 years (aOR 0.7, 95%CI 0.6-1.0), history of difficulty breathing (aOR 0.7, 95%CI 0.5-1.0), exposure to smoke (aOR 0.8, 95% CI 0.6-1.0), child fully immunized (aOR 0.7, 95%CI 0.5-1.0) and enrolled in 3rd (aOR 0.6, 95%CI 0.4-0.8) and 4th (aOR 0.6, 95%CI 0.5-0.9) year of the study whereas history of runny nose (aOR 1.5, 95% CI 1.2-1.9) was positively associated. CONCLUSIONS: Decrease in VT pneumococcal carriage in vaccinated and unvaccinated children indicates herd immunity. Sustained increase in vaccine coverage and close long-term surveillance is warranted.

Characteristics of Salmonella Recovered From Stools of Children Enrolled in the Global Enteric Multicenter Study.

BACKGROUND: The Global Enteric Multicenter Study (GEMS) determined the etiologic agents of moderate-to-severe diarrhea (MSD) in children under 5 years old in Africa and Asia. Here, we describe the prevalence and antimicrobial susceptibility of nontyphoidal Salmonella (NTS) serovars in GEMS and examine the phylogenetics of Salmonella Typhimurium ST313 isolates. METHODS: Salmonella isolated from children with MSD or diarrhea-free controls were identified by classical clinical microbiology and serotyped using antisera and/or whole-genome sequence data. We evaluated antimicrobial susceptibility using the Kirby-Bauer disk-diffusion method. Salmonella Typhimurium sequence types were determined using multi-locus sequence typing, and whole-genome sequencing was performed to assess the phylogeny of ST313. RESULTS: Of 370 Salmonella-positive individuals, 190 (51.4%) were MSD cases and 180 (48.6%) were diarrhea-free controls. The most frequent Salmonella serovars identified were Salmonella Typhimurium, serogroup O:8 (C2-C3), serogroup O:6,7 (C1), Salmonella Paratyphi B Java, and serogroup O:4 (B). The prevalence of NTS was low but similar across sites, regardless of age, and was similar among both cases and controls except in Kenya, where Salmonella Typhimurium was more commonly associated with cases than controls. Phylogenetic analysis showed that these Salmonella Typhimurium isolates, all ST313, were highly genetically related to isolates from controls. Generally, Salmonella isolates from Asia were resistant to ciprofloxacin and ceftriaxone, but African isolates were susceptible to these antibiotics. CONCLUSIONS: Our data confirm that NTS is prevalent, albeit at low levels, in Africa and South Asia. Our findings provide further evidence that multidrug-resistant Salmonella Typhimurium ST313 can be carried asymptomatically by humans in sub-Saharan Africa.

One-Year Decline of Poliovirus Antibodies Following Fractional-Dose Inactivated Poliovirus Vaccine.

BACKGROUND: Fractional dose (one-fifth of full intramuscular dose) of inactivated poliovirus vaccine (fIPV) administered intradermally is used as IPV dose-sparing strategy. We compared the rate of decline of poliovirus antibodies (PVA) in recipients of 2 doses of fIPV or IPV. METHODS: A community-based randomized controlled trial was conducted in Karachi, Pakistan. Children aged 14 weeks were randomized into fIPV or full IPV (study arms A, B) and received 1 vaccine dose at age 14 weeks and 1 at age 9 months. PVAs were measured at age 14, 18 weeks and 10, 21 months. RESULTS: Seroprevalence of poliovirus type 2 antibodies in 170/250 (68%) children after 2 IPV or fIPV doses at age 10 months in A and B reached 100% vs 99% (P = .339), and at 21 months, 86% vs 67% (P = .004). Between age 10 and 21 months antibody log2 titers dropped from ≥ 10.5 to 6.8 in A and from 9.2 to 3.7 in B. CONCLUSIONS: There was a significant decline in antibody titers 12 months following the second IPV dose. The slope of decline was similar for full IPV and fIPV recipients. The results provide further evidence that fIPV is a viable option for IPV dose-sparing. CLINICAL TRIALS REGISTRATION: NCT03286803.

Young infant clinical signs study--, Pakistan: a data note.

Neonatal sepsis is the leading cause of child death globally with most of these deaths occurring in the first week of life. It is of utmost public health importance that clinical signs predictive of severe illness and need for referral are identified early in the course of illness. From 2002-2005, a multi country trial called the Young Infant Clinical Signs Study (YICSS) was conducted in seven sites across three South-Asian (Bangladesh, India, and Pakistan), two African (Ghana, and South Africa), and one South American (Bolivia) country. The study aimed to develop a simplified algorithm to be used by primary healthcare workers for the identification of sick young infants needing prompt referral and treatment. The main study enrolled 8,889 young infants between the ages of 0-59 days old. This dataset contains observations on 2950 young infants aged 0-59 days from the Pakistan site. The data was collected between 2003-2004 with information on the most prevalent signs and symptoms. The data from this study was used to update the Integrated Management of Childhood Illness guidelines. The World Health Organisation (WHO) seven-sign algorithm has been used in other major community-based trials to study possible serious bacterial infection and its treatment regimens.

Associations between Household-Level Exposures and All-Cause Diarrhea and Pathogen-Specific Enteric Infections in Children Enrolled in Five Sentinel Surveillance Studies.

Diarrheal disease remains a major cause of childhood mortality and morbidity causing poor health and economic outcomes. In low-resource settings, young children are exposed to numerous risk factors for enteric pathogen transmission within their dwellings, though the relative importance of different transmission pathways varies by pathogen species. The objective of this analysis was to model associations between five household-level risk factors-water, sanitation, flooring, caregiver education, and crowding-and infection status for endemic enteric pathogens in children in five surveillance studies. Data were combined from 22 sites in which a total of 58,000 stool samples were tested for 16 specific enteropathogens using qPCR. Risk ratios for pathogen- and taxon-specific infection status were modeled using generalized linear models along with hazard ratios for all-cause diarrhea in proportional hazard models, with the five household-level variables as primary exposures adjusting for covariates. Improved drinking water sources conferred a 17% reduction in diarrhea risk; however, the direction of its association with particular pathogens was inconsistent. Improved sanitation was associated with a 9% reduction in diarrhea risk with protective effects across pathogen species and taxa of around 10-20% risk reduction. A 9% reduction in diarrhea risk was observed in subjects with covered floors, which were also associated with decreases in risk for zoonotic enteropathogens. Caregiver education and household crowding showed more modest, inconclusive results. Combining data from diverse sites, this analysis quantified associations between five household-level exposures on risk of specific enteric infections, effects which differed by pathogen species but were broadly consistent with hypothesized transmission mechanisms. Such estimates may be used within expanded water, sanitation, and hygiene (WASH) programs to target interventions to the particular pathogen profiles of individual communities and prioritize resources.

Typhoid Conjugate Vaccines and Enteric Fever Control: Where to Next?

After the unprecedented success and acceleration of the global agenda towards typhoid fever control with a strong World Health Organization recommendation and the approval of funding from Gavi, the Vaccine Alliance (Gavi), for the use of a new typhoid conjugate vaccine (TCV), we should turn our minds to the challenges that remain ahead. Despite the evidence showing the safety and clinical efficacy of TCV in endemic populations in developing countries, we should remain vigilant and explore hurdles for the full public health impact of TCV, including vaccine supply for the potential global demand, immunization strategies to optimize the effectiveness and long-term protection provided by the vaccines, potential use of TCV in outbreak settings, and scenarios for addressing chronic carriers. Finally, challenges face endemic countries with poor surveillance systems concerning awareness of the need for TCV and the extent of the issue across their populations, and how to target immunization strategies appropriately.