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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Recognizing that enteric fever disproportionately affects the poorest and the most vulnerable communities that have limited access to improved sanitation, safe water sources, and optimal medical care, the Bill & Melinda Gates Foundation has funded efforts to augment global understanding of the disease since the foundation's inception. At the turn of the century, early efforts focused on characterizing the burden of disease in Asia and evaluating use of the available Vi-polysaccharide vaccines through the Diseases of the Most Impoverished projects at the International Vaccine Institute (IVI). More recent efforts have centered on supporting development of typhoid conjugate vaccines and expanding disease surveillance efforts into Africa, as well as generating a greater understanding of the clinical severity and sequelae of enteric fever in Africa, Asia, and India. The Typhoid Vaccine Accelerator Consortium is playing a critical role in coordinating these and other global efforts for the control of typhoid fever. Here, we outline the scope of support and strategic view of the foundation and describe how, by working through strong partnerships, we can realize a radical reduction of the significance of enteric fever as a global public health problem in the next 10 to 15 years. [ABSTRACT FROM AUTHOR]

Background: We assessed immunity against polioviruses induced with a new Pakistani poliovirus immunization schedule and compared it to alternative poliovirus immunization schedules.Methods: Newborns were randomized to undergo vaccination based on 1 of 5 vaccination schedules, with doses administered at birth and at 6, 10, and 14 weeks of age. Arm A received inactivated poliovirus vaccine (IPV) at all time points. Arm B received bivalent oral poliovirus vaccine (bOPV) at all time points. Arms C and D received bOPV at the first 3 time points and bOPV plus IPV at the final time point (the current schedule). Arm E received trivalent OPV (tOPV) at all time points. At 22 weeks of age, all children received 1 challenge dose of tOPV, and children in arm D received 1 additional IPV dose. Sera were analyzed for the presence of poliovirus neutralizing antibodies at birth and 14 and 22 weeks of age.Results: Seroconversion for poliovirus type 1 (PV1) at 22 weeks of age was observed in 80% of individuals in arm A, 97% in arm B, 94% in arm C, 96% in arm D, and 94% in arm E; for PV2, seroconversion frequencies were 84%, 19%, 53%, 49%, and 93%, respectively; and for PV3, seroconversion frequencies were 93%, 94%, 98%, 94%, and 85%, respectively.Conclusions: The current immunization schedule in Pakistan induced high seroconversion rates for PV1 and PV3; however, it induced PV2 seroconversion in only half of study subjects. There is a growing cohort of young children in Pakistan who are unprotected against PV2; and this creates an increasing risk of a large-scale outbreak of poliomyelitis caused by circulating vaccine-derived PV2. [ABSTRACT FROM AUTHOR]

Background: In a multicountry birth cohort study, we describe rotavirus infection in the first 2 years of life in sites with and without rotavirus vaccination programs.Methods: Children were recruited by 17 days of age and followed to 24 months with collection of monthly surveillance and diarrheal stools. Data on sociodemographics, feeding, and illness were collected at defined intervals. Stools were tested for rotavirus and sera for antirotavirus immunoglobulins by enzyme immunoassays.Results: A total of 1737 children contributed 22646 surveillance and 7440 diarrheal specimens. Overall, rotavirus was detected in 5.5% (408/7440) of diarrheal stools, and 344 (19.8%) children ever had rotavirus gastroenteritis. Household overcrowding and a high pathogen load were consistent risk factors for infection and disease. Three prior infections conferred 74% (P < .001) protection against subsequent infection in sites not using vaccine. In Peru, incidence of rotavirus disease was relatively higher during the second year of life despite high vaccination coverage.Conclusions: Rotavirus infection and disease were common, but with significant heterogeneity by site. Protection by vaccination may not be sustained in the second year of life in settings with high burdens of transmission and poor response to oral vaccines. [ABSTRACT FROM AUTHOR]

Histo-blood group antigens (HBGAs) expressed on enterocytes are proposed receptors for rotaviruses and can be measured in saliva. Among 181 Pakistani infants in a G1P[8] rotavirus vaccine trial who were seronegative at baseline, anti-rotavirus immunoglobulin A seroconversion rates after 3 vaccine doses differed significantly by salivary HBGA phenotype, with the lowest rate (19%) among infants who were nonsecretors (ie, who did not express the carbohydrate synthesized by FUT2), an intermediate rate (30%) among secretors with non-blood group O, and the highest rate (51%) among secretors with O blood group. Differences in HBGA expression may be responsible for some of the discrepancy in the level of protection detected for the current rotavirus vaccines in low-income versus high-income settings. [ABSTRACT FROM AUTHOR]

Background. Integrated Management of Childhood Illness recommends that young infants with isolated fast breathing be referred to a hospital for antibiotic treatment, which is often impractical in resource-limited settings. Additionally, antibiotics may be unnecessary for physiologic tachypnea in otherwise well newborns. We tested the hypothesis that ambulatory treatment with oral amoxicillin for 7 days was equivalent (similarity margin of 3%) to placebo in young infants with isolated fast breathing in primary care settings where hospital referral is often unfeasible. Methods. This randomized equivalence trial was conducted in 4 primary health centers of Karachi, Pakistan. Infants presenting with isolated fast breathing and oxygen saturation ≥90% were randomly assigned to receive either oral amoxicillin or placebo twice daily for 7 days. Enrolled infants were followed on days 1–8, 11, and 14. The primary outcome was treatment failure by day 8, analyzed per protocol. The trial was stopped by the data safety monitoring board due to higher treatment failure rate and the occurrence of 2 deaths in the placebo arm in an interim analysis. Results. Four hundred twenty-three infants fulfilled per protocol criteria in the amoxicillin arm and 426 in the placebo arm. Twelve infants (2.8%) had treatment failure in the amoxicillin arm and 25 (5.9%) in the placebo arm (risk difference, 3.1; P value .04). Two infants in the placebo arm died, whereas no deaths occurred in the amoxicillin arm. Other adverse outcomes, as well as the proportions of relapse, were evenly distributed across both study arms. Conclusions. This trial failed to show equivalence of placebo to amoxicillin in the management of isolated fast breathing without hypoxemia or other clinical signs of illness in term young infants. Clinical Trials Registration. NCT01533818. [ABSTRACT FROM AUTHOR]

The burden of enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi is substantial and has high impact in toddlers and young children. This burden is relatively well documented in Asia, and this supplement provides new data on the substantial burden in several sub-Saharan African countries. Challenges in standardized surveillance and imperfect diagnostic tools have resulted in patchy local disease data, which are not well acknowledged or integrated into local country evidence and health awareness for decision making. There is a need to strengthen diagnostics for the generation of burden data in country. Furthermore, the guidelines and training for treatment of enteric fever cases in Africa are sorely needed to help mitigate the inappropriate use of antimicrobial treatment. Classic water safety and access to sanitation development remain powerful tools for the control of typhoid fever, yet the huge economic costs and long timelines are unlikely to provide a short- to middle-term solution. Emerging threats, including multidrug resistance and increasing urbanization in regions such as sub-Saharan Africa, warrant focused attention to shorterterm interventions including immunization, and must include vaccine strategies with the new typhoid conjugate vaccines. [ABSTRACT FROM AUTHOR]

Background. Information about the burden of invasive pneumococcal disease among children in Pakistan is limited. Methods. Surveillance of bacterial meningitis among children aged <5 years was set up at 18 hospitals in southern Pakistan that fulfilled the following criteria: (1) >30 pediatric admissions weekly, (2) skilled personnel to perform lumbar punctures, and (3) close proximity to an Aga Khan University Hospital laboratory collection point. Results. A total of 2690 children were admitted to the hospital with suspected acute bacterial meningitis, and 2646 (98%) underwent lumbar puncture. Of the 2646 cerebrospinal fluid specimens obtained, 412 (16%) were purulent, and pathogens were detected by culture or latex agglutination testing in 83 (20.1%) of the purulent specimens. Of the 83 isolates detected, 48 (57.8%) were Haemophilus influenzae type b, 32(38.5%) were Streptococcus pneumoniae, and 3 (3.6%) were Neisseria meningiditis. Overall, 81% of the pathogens detected were from children aged <1 year. More than 50% of families reported definite prior antimicrobial use. The minimum detected incidence rates of purulent meningitis in Hyderabad were 112 cases per 100,000 children aged <1 year and 45.3 cases per 100,000 children aged <5 years. After adjustment for limitations in access to care and the low sensitivity of cerebrospinal fluid culture, the adjusted incidence rates of pneumococcal meningitis were 81 cases per 100,000 children aged <1 year (95% confidence interval, 26.2-190.5 cases per 100,000) and 20 cases per 100,000 children aged <5 years (95% confidence interval, 7.3-43.7 cases per 100,000). Of the 32 children with pneumococcal meningitis, 8 (25%) died during hospitalization. Conclusions. Our surveillance system detected a substantial burden of purulent meningitis among infants and children in southern Pakistan. H. influenzae type b and S. pneumoniae accounted for >90% of detected pathogens. The use of vaccines against these 2 pathogens could prevent a substantial portion of disease and deaths in Pakistan. [ABSTRACT FROM AUTHOR]

Background. Accurate etiological diagnosis of meningitis in developing countries is needed, to improve clinical care and to optimize disease-prevention strategies. Cerebrospinal fluid (CSF) culture and latex agglutination testing are currently the standard diagnostic methods but lack sensitivity. Methods. We prospectively assessed the utility of an immunochromatographic test (ICT) of pneumococcal antigen (NOW Streptococcus pneumouiae Antigen Test; Binax), compared with culture, in 5 countries that are conducting bacterial meningitis surveillance in Africa and Asia. Most CSF samples were collected from patients aged 1-59 months. Results. A total of 1173 CSF samples from suspected meningitis cases were included. The ICT results were positive for 68 (99%) of the 69 culture-confirmed pneumococcal meningitis cases and negative for 124 (99%) of 125 culture-confirmed bacterial meningitis cases caused by other pathogens. By use of culture and latex agglutination testing alone, pneumococci were detected in samples from 7.4% of patients in Asia and 15.6% in Africa. The ICT increased pneumococcal detection, resulting in similar identification rates across sites, ranging from 16.2% in Nigeria to 20% in Bangladesh. ICT detection in specimens from culture-negative cases varied according to region (8.5% in Africa vs.18.8% in Asia; P< .001), prior antibiotic use (24.2% with prior antibiotic use vs. 12.2% without; P< .001), and WBC count (9.0% for WBC count of 10-99 cells/mL, 22.1% for 100-999 cells/mL, and 25.4% for ⩾1000 cells/mL; P< .001 by test for trend). Conclusions. The ICT provided substantial benefit over the latex agglutination test and culture at Asian sites but not at African sites. With the addition of the ICT, the proportion of meningitis cases attributable to pneumococci was determined to be similar in Asia and Africa. These results suggest that previous studies have underestimated the proportion of pediatric bacterial meningitis cases caused by pneumococci. [ABSTRACT FROM AUTHOR]

A central hypothesis of The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study is that enteropathogens contribute to growth faltering. To examine this question, the MAL-ED network of investigators set out to achieve 3 goals: (1) develop harmonized protocols to test for a diverse range of enteropathogens, (2) provide quality-assured and comparable results from 8 global sites, and (3) achieve maximum laboratory throughput and minimum cost. This paper describes the rationale for the microbiologic assays chosen and methodologies used to accomplish the 3 goals. [ABSTRACT FROM AUTHOR]

Stunting is common in young children in developing countries, and is associated with increased morbidity, developmental delays, and mortality. Its complex pathogenesis likely involves poor intrauterine and postnatal nutrition, exposure to microbes, and the metabolic consequences of repeated infections. Acquired enteropathy affecting both gut structure and function likely plays a significant role in this outcome, especially in the first few months of life, and serve as a precursor to later interactions of infection and malnutrition. However, the lack of validated clinical diagnostic criteria has limited the ability to study its role, identify causative factors, and determine cost-effective interventions. This review addresses these issues through a historical approach, and provides recommendations to define and validate a working clinical diagnosis and to guide critical research in this area to effectively proceed. Prevention of early gut functional changes and inflammation may preclude or mitigate the later adverse vicious cycle of malnutrition and infection. [ABSTRACT FROM AUTHOR]

The Pakistan study site of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study is located in Molhan union council of Naushahro Feroze district in the Sindh province. The study site is located in a rural district, where the majority of the population has an agrarian livelihood. Most families are nuclear families and the average household has 7 persons. More than half the women in the region have no formal education, and the median parity is 6. Only 48%–61% of the households across the district, province, and country have access to an improved toilet facility. Similar to the provincial and national estimates, the district has a low rate of exclusive breastfeeding at 6 months, and the prevalence of prelacteal feeding is high. There is also a high proportion of malnourished children. In addition, the acute respiratory infection and diarrheal illness burden and the mortality rates in children <5 years old in the district are high but comparable with the provincial and national estimates. Overall, the district is representative of rural populations at the regional and national level in terms of demographics, socioeconomic status, and general health and mortality indicators. [ABSTRACT FROM AUTHOR]

To understand the etiology of moderate-to-severe diarrhea among children in high mortality areas of sub-Saharan Africa and South Asia, we performed a comprehensive case/control study of children aged <5 years at 7 sites. Each site employed an identical case/control study design and each utilized a uniform comprehensive set of microbiological assays to identify the likely bacterial, viral and protozoal etiologies. The selected assays effected a balanced consideration of cost, robustness and performance, and all assays were performed at the study sites. Identification of bacterial pathogens employed streamlined conventional bacteriologic biochemical and serological algorithms. Diarrheagenic Escherichia coli were identified by application of a multiplex polymerase chain reaction assay for enterotoxigenic, enteroaggregative, and enteropathogenic E. coli. Rotavirus, adenovirus, Entamoeba histolytica, Giardia enterica, and Cryptosporidium species were detected by commercially available enzyme immunoassays on stool samples. Samples positive for adenovirus were further evaluated for adenovirus serotypes 40 and 41. We developed a novel multiplex assay to detect norovirus (types 1 and 2), astrovirus, and sapovirus. The portfolio of diagnostic assays used in the GEMS study can be broadly applied in developing countries seeking robust cost-effective methods for enteric pathogen detection. [ABSTRACT FROM AUTHOR]

In addition to being a major cause of mortality in South Asia, childhood diarrhea creates economic burden for affected households. We used survey data from sites in Bangladesh, India, and Pakistan to estimate the costs borne by households due to childhood diarrhea, including direct medical costs, direct nonmedical costs, and productivity losses. Mean cost per episode was $1.82 in Bangladesh, $3.33 in India, and $6.47 in Pakistan. The majority of costs for households were associated with direct medical costs from treatment. Mean costs understate the distribution of costs, with 10% of cases exceeding $6.61, $8.07, and $10.11 in Bangladesh, India, and Pakistan, respectively. In all countries there was a trend toward lower costs among poorer households and in India and Pakistan there were lower costs for episodes among girls. For both poor children and girls this may reflect rationing of care, which may result in increased risks of mortality. [ABSTRACT FROM AUTHOR]

Background. Diarrhea is a leading cause of illness and death among children aged <5 years in developing countries. This paper describes the clinical and epidemiological methods used to conduct the Global Enteric Multicenter Study (GEMS), a 3-year, prospective, age-stratified, case/control study to estimate the population-based burden, microbiologic etiology, and adverse clinical consequences of acute moderate-to-severe diarrhea (MSD) among a censused population of children aged 0–59 months seeking care at health centers in sub-Saharan Africa and South Asia.Methods. GEMS was conducted at 7 field sites, each serving a population whose demography and healthcare utilization practices for childhood diarrhea were documented. We aimed to enroll 220 MSD cases per year from selected health centers serving each site in each of 3 age strata (0–11, 12–23, and 24–59 months), along with 1–3 matched community controls. Cases and controls supplied clinical, epidemiologic, and anthropometric data at enrollment and again approximately 60 days later, and provided enrollment stool specimens for identification and characterization of potential diarrheal pathogens. Verbal autopsy was performed if a child died. Analytic strategies will calculate the fraction of MSD attributable to each pathogen and the incidence, financial costs, nutritional consequences, and case fatality overall and by pathogen.Conclusions. When completed, GEMS will provide estimates of the incidence, etiology, and outcomes of MSD among infants and young children in sub-Saharan Africa and South Asia. This information can guide development and implementation of public health interventions to diminish morbidity and mortality from diarrheal diseases. [ABSTRACT FROM AUTHOR]