PURPOSE OF REVIEWAlmost half of all childhood deaths worldwide occur in children with malnutrition, predominantly in sub-Saharan Africa and South Asia. This review summarizes the mechanisms by which ...malnutrition and serious infections interact with each other and with childrenʼs environments.
RECENT FINDINGSIt has become clear that whilst malnutrition results in increased incidence, severity and case fatality of common infections, risks continue beyond acute episodes resulting in significant postdischarge mortality. A well established concept of a ‘vicious-cycle’ between nutrition and infection has now evolving to encompass dysbiosis and pathogen colonization as precursors to infection; enteric dysfunction constituting malabsorption, dysregulation of nutrients and metabolism, inflammation and bacterial translocation. All of these interact with a childʼs diet and environment. Published trials aiming to break this cycle using antimicrobial prophylaxis or water, sanitation and hygiene interventions have not demonstrated public health benefit so far.
SUMMARYAs further trials are planned, key gaps in knowledge can be filled by applying new tools to re-examine old questions relating to immune competence during and after infection events and changes in nutritional status; and how to characterize overt and subclinical infection, intestinal permeability to bacteria and the role of antimicrobial resistance using specific biomarkers.
IMPORTANCE: Rotavirus infection is the global leading cause of diarrhea-associated morbidity and mortality among children younger than 5 years. OBJECTIVES: To examine the extent of rotavirus ...infection among children younger than 5 years by country and the number of deaths averted because of the rotavirus vaccine. DESIGN, SETTING, AND PARTICIPANTS: This report builds on findings from the Global Burden of Disease Study 2016, a cross-sectional study that measured diarrheal diseases and their etiologic agents. Models were used to estimate burden in data-sparse locations. EXPOSURE: Diarrhea due to rotavirus infection. MAIN OUTCOMES AND MEASURES: Rotavirus-associated mortality and morbidity by country and year and averted deaths attributable to the rotavirus vaccine by country. RESULTS: Rotavirus infection was responsible for an estimated 128 500 deaths (95% uncertainty interval UI, 104 500-155 600) among children younger than 5 years throughout the world in 2016, with 104 733 deaths occurring in sub-Saharan Africa (95% UI, 83 406-128 842). Rotavirus infection was responsible for more than 258 million episodes of diarrhea among children younger than 5 years in 2016 (95% UI, 193 million to 341 million), an incidence of 0.42 cases per child-year (95% UI, 0.30-0.53). Vaccine use is estimated to have averted more than 28 000 deaths (95% UI, 14 600-46 700) among children younger than 5 years, and expanded use of the rotavirus vaccine, particularly in sub-Saharan Africa, could have prevented approximately 20% of all deaths attributable to diarrhea among children younger than 5 years. CONCLUSIONS AND RELEVANCE: Rotavirus-associated mortality has decreased markedly over time in part because of the introduction of the rotavirus vaccine. This study suggests that prioritizing vaccine introduction and interventions to reduce diarrhea-associated morbidity and mortality is necessary in the continued global reduction of rotavirus infection.
Environmental enteric dysfunction (EED) is an acquired enteropathy of the small intestine, characterized by enteric inflammation, villus blunting and decreased crypt-to-villus ratio. EED has been ...associated with poor outcomes, including chronic malnutrition (stunting), wasting and reduced vaccine efficacy among children living in low-resource settings. As a result, EED may be a valuable interventional target for programs aiming to reduce childhood morbidity in low and middle-income countries.
Several highly plausible mechanisms link the proposed pathophysiology underlying EED to adverse outcomes, but causal attribution of these pathways has proved challenging. We provide an overview of recent studies evaluating the causes and consequences of EED. These include studies of the role of subclinical enteric infection as a primary cause of EED, and efforts to understand how EED-associated systemic inflammation and malabsorption may result in long-term morbidity. Finally, we outline recently completed and upcoming clinical trials that test novel interventions to prevent or treat this highly prevalent condition.
Significant strides have been made in linking environmental exposure to enteric pathogens and toxins with EED, and in understanding the multifactorial mechanisms underlying this complex condition. Further insights may come from several ongoing and upcoming interventional studies trialing a variety of novel management strategies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There has been substantial progress over the past decade in efforts to reduce morbidity from soil-transmitted helminth infections (STH). Morbidity control through preventative chemotherapy (PC) has ...been embraced by endemic countries, the World Health Organization (WHO) and by partners as a clear and achievable goal. Few global health programs have achieved delivery of an intervention at a scale comparable to STH morbidity programs; over 4 billion tablets have been distributed to over 1 billion of the world’s most vulnerable populations 1. Prior to the establishment of the albendazole and mebendazole donation program in 2012, global PC coverage had stagnated at approximately 30%. However, since 2015, treatment coverage has almost doubled (59%) and drug requests and donations continue to increase 2. This progress has been particularly remarkable in the WHO South East Asia Region, home to the largest number of children in need of PC. In 2015 more than 75% of at-risk children in this region received STH PC. This remarkable global success is the result of significant collaborative efforts championed by endemic country governments, non-governmental organisations, philanthropic foundations and pharmaceutical companies 3.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Current control strategies for soil-transmitted helminths (STH) emphasize morbidity control through mass drug administration (MDA) targeting preschool- and school-age children, women of childbearing ...age and adults in certain high-risk occupations such as agricultural laborers or miners. This strategy is effective at reducing morbidity in those treated but, without massive economic development, it is unlikely it will interrupt transmission. MDA will therefore need to continue indefinitely to maintain benefit. Mathematical models suggest that transmission interruption may be achievable through MDA alone, provided that all age groups are targeted with high coverage. The DeWorm3 Project will test the feasibility of interrupting STH transmission using biannual MDA targeting all age groups. Study sites (population ≥80,000) have been identified in Benin, Malawi and India. Each site will be divided into 40 clusters, to be randomized 1:1 to three years of twice-annual community-wide MDA or standard-of-care MDA, typically annual school-based deworming. Community-wide MDA will be delivered door-to-door, while standard-of-care MDA will be delivered according to national guidelines. The primary outcome is transmission interruption of the STH species present at each site, defined as weighted cluster-level prevalence ≤2% by quantitative polymerase chain reaction (qPCR), 24 months after the final round of MDA. Secondary outcomes include the endline prevalence of STH, overall and by species, and the endline prevalence of STH among children under five as an indicator of incident infections. Secondary analyses will identify cluster-level factors associated with transmission interruption. Prevalence will be assessed using qPCR of stool samples collected from a random sample of cluster residents at baseline, six months after the final round of MDA and 24 months post-MDA. A smaller number of individuals in each cluster will be followed with annual sampling to monitor trends in prevalence and reinfection throughout the trial.
ClinicalTrials.gov NCT03014167.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The gut microbiome community structure and development are associated with several health outcomes in young children. To determine the household influences of gut microbiome structure, we assessed ...microbial sharing within households in western Kenya by sequencing 16S rRNA libraries of fecal samples from children and cattle, cloacal swabs from chickens, and swabs of household surfaces. Among the 156 households studied, children within the same household significantly shared their gut microbiome with each other, although we did not find significant sharing of gut microbiome across host species or household surfaces. Higher gut microbiome diversity among children was associated with lower wealth status and involvement in livestock feeding chores. Although more research is necessary to identify further drivers of microbiota development, these results suggest that the household should be considered as a unit. Livestock activities, health and microbiome perturbations among an individual child may have implications for other children in the household.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Current soil-transmitted helminth (STH) programs target morbidity control with school-based deworming. Increasing interest in steering neglected tropical disease (NTD) programmes from morbidity ...control towards disease elimination has prompted evaluation of strategies that may interrupt transmission. The feasibility of interrupting transmission of STH with community-wide deworming is being tested in the ongoing DeWorm3 cluster randomized trial. Gender-based perspectives about susceptibility to infection and need for treatment have been shown to influence both health-seeking behaviour and health outcomes. We carried out a qualitative study among men and women in the community to understand their knowledge, beliefs, and attitudes about STH infections and community-wide mass drug administration (cMDA). Eight semi-structured focus group discussions were conducted among men and women residing in the DeWorm3 study site in India-Vellore and Tiruvannamalai districts of Tamil Nadu. Thematic coding was used to analyse the transcripts in ATLAS.ti 8.0. Both men and women in this study demonstrated a high level of STH knowledge but some men had misconceptions that intestinal worms were beneficial. Men and women shared several similar beliefs and attitudes regarding STH treatment. Both believed that adults were likely to have STH infections and both reported that stigma prevented them from seeking treatment. Influenced by gender norms, women were more likely to associate STH infections with inadequate sanitation and hygiene, while men were more likely to believe that those engaged in agricultural work were at risk. Both genders reported a positive attitude towards cMDA for STH. Barriers to cMDA implementation differed by gender; women expressed concern regarding side-effects and drug quality while men were concerned that treatment coverage may be affected due to the absence of people during the day when the drug is distributed. Both men and women perceived the treatment of adults for STH infections to be important, however, the perceived barriers to participating in cMDA differed by gender in this community. The study identified key messages to be incorporated in communication and outreach strategies for cMDA programmes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Worm expulsion studies required to quantify worm burden have suboptimal accuracy, are laborious, and are rarely done. ...STH programs employ indirect methods to infer worm burden, such as ...microscopy-based technologies for visual identification and quantification of STH-specific eggs from a stool sample. Other considerations include external quality assurance requirements and regulatory pathway as well as program recommendations, policies, and guidelines. Because diagnostics only approximate a true state of infection, mathematical models can be used to further inform performance requirements by estimating the impact of different levels of uncertainty on the accuracy of program decision-making and ultimately on health outcomes 37. Only the lower LOD needs to be defined for a qualitative test and set below the confidence intervals for a diagnostic cutoff. Since this cutoff cannot yet be defined, key opinion leaders agreed that a test must have superior analytical sensitivity compared to current FEC methods. Because targeted population-level data are required for the program decision, minimum data requirements also include geospatial information.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Shigella and enterotoxigenic Escherichia coli (ETEC) are bacterial pathogens that are frequently associated with diarrhoeal disease, and are a significant cause of mortality and morbidity worldwide. ...The Global Burden of Diseases, Injuries, and Risk Factors study 2016 (GBD 2016) is a systematic, scientific effort to quantify the morbidity and mortality due to over 300 causes of death and disability. We aimed to analyse the global burden of shigella and ETEC diarrhoea according to age, sex, geography, and year from 1990 to 2016.
We modelled shigella and ETEC-related mortality using a Bayesian hierarchical modelling platform that evaluates a wide range of covariates and model types on the basis of vital registration and verbal autopsy data. We used a compartmental meta-regression tool to model the incidence of shigella and ETEC, which enforces an association between incidence, prevalence, and remission on the basis of scientific literature, population representative surveys, and health-care data. We calculated 95% uncertainty intervals (UIs) for the point estimates.
Shigella was the second leading cause of diarrhoeal mortality in 2016 among all ages, accounting for 212 438 deaths (95% UI 136 979–326 913) and about 13·2% (9·2–17·4) of all diarrhoea deaths. Shigella was responsible for 63 713 deaths (41 191–93 611) among children younger than 5 years and was frequently associated with diarrhoea across all adult age groups, increasing in elderly people, with broad geographical distribution. ETEC was the eighth leading cause of diarrhoea mortality in 2016 among all age groups, accounting for 51 186 deaths (26 757–83 064) and about 3·2% (1·8–4·7) of diarrhoea deaths. ETEC was responsible for about 4·2% (2·2–6·8) of diarrhoea deaths in children younger than 5 years.
The health burden of bacterial diarrhoeal pathogens is difficult to estimate. Despite existing prevention and treatment options, they remain a major cause of morbidity and mortality globally. Additional emphasis by public health officials is needed on a reduction in disease due to shigella and ETEC to reduce disease burden.
Bill & Melinda Gates Foundation.
Licensed mRNA COVID-19 vaccines require booster doses to sustain SARS-CoV-2-specific responses, creating the need for novel, broadly immunogenic vaccines. We aimed to compare the immunogenicity, ...safety, and tolerability of ARCT-154—a self-amplifying mRNA vaccine against SARS-CoV-2 D614G variant—with the BNT162b2 (Comirnaty; Pfizer–BioNTech) mRNA vaccine when administered as a fourth-dose booster.
This double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial, conducted at 11 outpatient clinical sites in Japan, enrolled healthy adults aged at least 18 years who had previously been immunised with two doses of an mRNA COVID-19 vaccine (BNT162b2 or mRNA-1273 Spikevax; Moderna) followed by a third dose of BNT162b2 at least 3 months before enrolment. Participants were randomly assigned, in a 1:1 ratio using an Interactive Response Technology system with a block size of four, and with stratification by age (18–64 years or ≥65 years) and by interval since last COVID-19 vaccination (<5 months or ≥5 months), to receive either ARCT-154 or BNT162b2 as a fourth-dose booster via deltoid intramuscular injection. Participants and investigators assessing outcomes were masked to group assignment. The primary objective, measured in per-protocol set 1 (consisting of participants with no evidence of previous SARS-CoV-2 infection who received their intended injection according to protocol), was to show that the immune response 28 days after the ARCT-154 vaccine was non-inferior to that of the BNT162b2 vaccine, measured in terms of both pseudovirus neutralising antibody geometric mean titre (GMT) ratios and seroresponse rates against the wild-type Wuhan-Hu-1 strain of SARS-CoV-2. Non-inferiority was declared when the lower limit of the 95% CI of the ARCT-154 to BNT162b2 GMT ratio exceeded 0·67, and when the lower limit for the difference in seroresponse rates exceeded −10%. Key secondary endpoints included the immune response against the omicron BA.4/5 subvariant, which was assessed for non-inferiority and superiority in per-protocol set 1. Safety was assessed in the full analysis set. This study was registered on the Japan Registry for Clinical Trials, jRCT 2071220080, and is ongoing.
Between Dec 13, 2022, and Feb 25, 2023, we enrolled and randomly assigned 828 participants to receive ARCT-154 (n=420) or BNT162b2 (n=408) vaccines as a fourth-dose booster. In per-protocol set 1, the GMTs of surrogate neutralising antibodies induced against the Wuhan-Hu-1 SARS-CoV-2 strain in the ARCT-154 group (5641 95% CI 4321–7363) were non-inferior to those in the BNT162b2 group (3934 2993–5169) when measured at 28 days after boosting, with a GMT ratio of 1·43 (95% CI 1·26–1·63). Seroresponse rates were 65·2% (95% CI 60·2–69·9) in the ARCT-154 group versus 51·6% (46·4–56·8) in the BNT162b2 group, a difference of 13·6% (95% CI 6·8–20·5). GMTs against the omicron BA.4/5 variant on day 29 were 2551 (1687–3859) in the ARCT-154 group and 1958 (1281–2993) in the BNT162b2 group—a GMT ratio of 1·30 (1·07–1·58)—with seroresponse rates of 69·9% (65·0–74·4) and 58·0% (52·8–63·1). Both boosters were equally well tolerated. No treatment-related deaths were reported, nor were there severe or serious adverse events considered to be causally associated related to study vaccination. One serious adverse event, a foot deformity reported in a participant in the BNT162b2 group, was observed but determined not to have a causal relationship to the study vaccination. One severe adverse event, a case of abnormal hepatic function in the ARCT-154 group, was considered to be related to study vaccine. Adverse events of special interest for detection of myocarditis and pericarditis included chest pain (one case in the ARCT-154 group and three cases in the BNT162b2 group) and shortness of breath (two cases in the BNT162b2 group), all of which were considered to have a reasonable possibility of being related to vaccination. Local reactions were reported by 398 (95%) of 420 participants receiving the ARCT-154 vaccine and 395 (97%) of 408 participants receiving the BNT162b2 vaccine, and solicited systemic adverse events by 276 (66%) of those receiving the ARCT-154 vaccine and 255 (63%) of those receiving the BNT162b2 vaccine. Adverse events were mainly mild in severity, occurring and resolving within 3–4 days after vaccination.
In adults who had previously received three doses of an mRNA COVID-19 vaccine, immune responses 28 days after an ARCT-154 booster dose were non-inferior to those observed after a BNT162b2 booster dose for the Wuhan-Hu-1 strain of SARS-CoV-2 and superior for the Omicron BA.4/5 variant. Increased immune responses at 28 days might provide increased likelihood of protection against these strains during this period and could also result in longer duration of protection. Further studies will assess the immunogenicity induced against more recent SARS-CoV-2 variants.
Japanese Ministry of Health, Labour, and Welfare.
For the Japanese translation of the abstract see Supplementary Materials section.
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