Rotavirus Diarrhea Among Young Children Before Introduction of the Rotavirus Vaccine Program in Kenya : Baseline Data and Implications for Vaccine Safety Monitoring and Impact Evaluation

Ripulitaudit ovat toiseksi yleisin alle viisivuotiaiden lasten kuolinsyy maailmanlaajuisesti. Rotavirus on tärkein lasten vakavien, kuivumista aiheuttavien ripulitautien aiheuttajista ja merkittävä kansanterveysongelma etenkin matalan ja keskitulotason maissa. Rotavirusrokotukset aloitettiin Kenian kansallisessa rokotusohjelmassa heinäkuussa 2014 (kaksi annosta, kuuden ja kymmenen viikon ikäisenä). Rotaviruksen aiheuttaman tautitaakan perustason määrittäminen paikallisesti ennen rokotusten aloittamista on välttämätöntä, jotta rokotusohjelman vaikuttavuutta väestötasolla voidaan jatkotutkimuksissa arvioida. Tämän väitöskirjatyön tavoitteena oli arvioida kattavasti alle viisivuotiaiden lasten ripulitaudin ja rotaviruksen aiheuttamaa tautitaakkaa, hoitoon hakeutumista ja komplikaatioita ennen rotavirusrokotusten aloitusta Keniassa. Väitöskirjan tutkimuksissa käytettiin Kenian lääketieteellisen tutkimuslaitoksen (Kenya Medical Research Institute, KEMRI) ja USA:n tautikeskuksen (Centers for Disease Control and Prevention, CDC) länsi-Keniassa sijaitsevan väestöpohjaisen, aktiivisen seurantajärjestelmän tietoja. Näiden tietojen perusteella määritettiin hoitoon hakeutumisen syyt ja yleisyys, taudin ilmaantuvuus ja riskitekijät, sekä sairaalahoidot ja kuolleisuus. Lisäksi vakavan ripulitaudin aiheuttamien komplikaatioiden (suolentukkeuma - intussusception) esiintyvyyttä ja ennusteeseen vaikuttavia tekijöitä arvioitiin takautuvasti sairaalojen potilaskertomustietojen avulla. Tutkimusten tavoitteena oli muodostaa kattava kuva rotavirustaudin epidemiologiasta, jota voidaan jatkotutkimuksissa käyttää vertailukohtana arvioitaessa rotavirusrokotusohjelman kansanterveydellistä vaikuttavuutta Keniassa. Väitöskirja koostuu neljästä alkuperäistutkimuksesta (I-IV). Väestöpohjaisessa kenttätutkimuksessa (I) haastateltiin ensin 1 043 alle viiden vuoden ikäisen lapsen huoltajaa (yleensä äitiä) poikkileikkaustutkimuksessa (huhti–toukokuu 2007) lasten ripulitauteihin liittyvän hoitoon hakeutumisen käytäntöjen määrittämiseksi (ripulin määritelma ≥ 3 loysaa ulostetta 24 tunnin aikana). Taman jalkeen yli 20 000:n lapsen huoltajia haastateltiin viidessä peräkkäisessä poikkileikkaustutkimuksessa toukokuun 2009 ja joulukuun 2010 välisenä aikana. Tutkimuksessa (II) tunnistettiin sairaalahoitoon tulleet potilaat, joilla oli äkillinen ripulitauti (akuutti gastroenteriitti, AGE) - potilaalla ripuli ja/tai yksi/useampi selittämätön oksenteluepisodi seitsemän päivän sisällä sairaalaan tulosta. Tutkimuksessa määritettiin sairaalahoitoa vaativan akuutin gastroenteriitin sekä rotaviruksen aiheuttaman gastroenteriitin (RVAGE) ilmaantuvuudet ja niihin liittyvä kuolleisuus. Nimittäjätiedot saatiin länsi-Kenian terveys- ja demografiatietojen seurantajärjestelmästä (HDSS). Sairaalapohjaisessa tutkimuksessa (III) selvitettiin rotaviruksen aiheuttaman ripulitaudin riskitekijöitä ja taudinkuvan vakavuutta. Seurannassa tunnistettiin sairaalahoitoon tulleet lapset, joilla oli akuutti, ei-verinen kohtalaisen vakava tai vakava ripulitauti (MSD). Rotavirus taudinaiheuttajana tunnistettiin tutkimuksiin II ja III osallistuneiden lasten ulosteenäytteistä EIA-määrityksellä. Takautuvassa tutkimuksessa (IV) selvitettiin potilaskertomustietojen avulla suolentukkeumaan liittyviä tekijöitä ja tapauskuolleisuutta alle viiden vuoden ikäisillä potilailla, joilla oli diagnosoitu suolentukkeuma 12 Kenialaisessa keskussairaalassa vuosina 2002-2013. Väestöpohjainen ripulin ilmaantuvuusosuus kahden viikon aikana vaihteli ensimmäisen seurantavuoden (2007) 26%:sta 4–11%:iin vuosina 2009–2010. Alle puolet ripulitautia sairastavista lapsista hoidettiin terveydenhuollon yksiköissä. Huoltajat veivät imeväisikäisiä lapsiaan hoitoon kodin ulkopuolelle merkitsevästi harvemmin kuin vanhempia lapsia. Hoitoon vieminen kodin ulkopuolelle oli kuitenkin yleisempää niillä lapsilla, joiden silmät olivat painuneet sisään kuivumisen takia ripulijakson aikana. Merkittävälle osalle sairaista lapsista annettiin myös vähemmän nestettä ja ruokaa kuin normaalisti, eikä heille tarjottu nestelisää suun kautta (oral rehydration solution - ORS) kotona. Koulutetut äidit antoivat kuitenkin useammin lapsilleen kotona ORS nestettä ja veivät heidät hoitoon terveydenhuollon yksikköön kuin kouluttamattomat äidit. Akuuttia gastroenteriittiä ja rotavirusripulitautia sairastavien lasten joutuminen sairaalahoitoon oli yleisintä 6– 11 kuukauden iässä. Myös kuolleisuus oli suurin tässä ikäryhmässä. Rotaviruspositiiviset potilaat olivat nuorempia (mediaani-ikä, 8 vs. 13 kuukautta), heillä oli vakavampi tauti ja he joutuivat sairaalahoitoon merkitsevästi useammin kuin ne potilaat, joiden ulosteviljely oli negatiivinen rotaviruksen suhteen. Rotavirusripulin itsenäisiä riskitekijöitä olivat imeväisikä ja runsas oksentelu. Kahdessatoista Kenialaisessa sairaalassa vuosina 2002-2013 hoidetuista suolentukkeumapotilaista kaksi kolmasosaa oli vauvoja, joilla oli ainakin yksi seuraavista oireista: oksentelu, ripuli tai verta ulosteessa. Suolentukkeuman tapauskuolleisuus oli 6,4%. Verrattuna potilaisiin, jotka toipuivat, menehtyneet potilaat olivat nuorempia, heillä oli kuumetta ja he tulivat hoitoon myöhemmin oireiden puhkeamisen jälkeen. Heitä oli myös hoidettu kirurgisesti useammin kuin taudista selviytyneitä. Yhteenvetona tämän tutkielman tutkimukset osoittavat, että lasten akuutti ripulitauti ja etenkin rotaviruksen aiheuttama vaikeaoireinen ripuli ovat merkittävä kansanterveysongelma Kenialaisten pikkulasten keskuudessa. Terveydenhuollon piiriin tulevat tautitapaukset ovat kuitenkin vain jäävuoren huippu. Siksi on huolestuttavaa, että monien lasten huoltajat viivyttivät hoitoon hakeutumista ripuliepisodin alettua ja jopa vähensivät nesteen ja ruoan antamista. Myös suolentukkeumaan kuolleiden potilaiden hoitoon hakeutuminen oireiden alkamisen jälkeen oli viivästynyt. Tutkimukset vahvistivat gastroenteriitin, rotavirusripuliin ja suolentukkeumaan liittyvän sairastuvuuden ja kuolleisuuden olevan yleisintä imeväisiässä. Tulokset tukivat Kenian terveysministeriön päätöstä aloittaa rotavirusrokotusohjelma heinäkuussa 2014. Ne ovat myös linjassa Maailman Terveysjärjestön (WHO) suosituksen kanssa, jonka mukaan rotavirusrokotteet tulee antaa kuuden ja kymmenen viikon ikäisenä. Näin lapset saavat rokotteet ennen kuin taudin ilmaantuvuus on Keniassa huipussaan. Kokonaisuutena väitöskirjan tutkimusten tulokset muodostavat kattavan perustason, johon vertaamalla Kenian rotavirusrokotusohjelman väestötason vaikuttavuutta rotavirustaudin esiintyvyyteen, riskitekijöihin ja komplikaatioiden yleisyyteen voidaan jatkotutkimuksissa täsmällisesti arvioida. Tutkimusten perusteella arvioinneissa ja ehkäisyohjelmissa on erityisesti otettava huomioon havainnot vakavasti sairastuneiden lasten huoltajien terveydenhuoltoon hakeutumisen käytännöistä ja hoidon viivästymisestä. Jatkuva väestöpohjainen seuranta on avainasemassa rotavirusrokotusohjelman kansanterveydellisen vaikuttavuuden osoittamiseksi Keniassa.Diarrheal diseases are the second leading cause of childhood deaths globally. Rotavirus is a leading cause of severe dehydrating diarrhea which is particularly associated with morbidity and mortality among children under five years of age in low- and middle-income countries. The rotavirus vaccine was introduced into Kenya’s public immunization program in July 2014, with a two-dose schedule at six and ten weeks of age. Estimating the burden of rotavirus-associated disease before vaccine introduction is essential for assessing the population-level impact of vaccination programs. The aim of this dissertation is to estimate the burden of diarrheal illness among children under five years of age before the introduction of rotavirus vaccine in Kenya and to provide baseline information on health care seeking, prevalence, hospitalizations, and potential complications of childhood diarrhea to help evaluate the impact of rotavirus vaccine program implementation in Kenya. This dissertation consists of four original studies. In Study I, we conducted household interviews with caretakers of 1,043 children under five in a baseline cross-sectional survey (April–May 2007) and of more than 20,000 children on five subsequent surveys between May 2009 and December 2010 to assess healthcare- seeking patterns for childhood diarrhea (defined as 2 ≥ 3 loose stools in 24 hours). In Study II, we conducted inpatient surveillance of children with acute gastroenteritis (AGE) (diarrhea and/or one or more episodes of unexplained vomiting occurring within seven days of admission) to estimate hospitalization and mortality rates due to all-cause and rotavirus acute gastroenteritis (RVAGE). Person-years of observation from an active Health and Demographic Surveillance System (HDSS) in western Kenya were used as denominators. In Study III, we conducted hospital-based surveillance of children under five years with acute, nondysenteric moderate-to-severe diarrhea (MSD) to assess factors associated with rotavirus gastroenteritis and to describe illness severity. We defined non-dysenteric MSD as diarrhea with one or more of the following: sunken eyes, skin tenting, intravenous rehydration, or hospitalization, and acute to mean seeking care for the diarrhea episode within seven days of illness onset at a study sentinel health center located within the HDSS. Stool specimens from participants enrolled in Studies II and III were tested for rotavirus using an enzyme immunoassay. To describe the epidemiology and risk factors for intussusception-related mortality, we retrospectively reviewed medical chart data of patients under five years old diagnosed with intussusception in 12 Kenyan leading referral hospitals (Study IV). Our results showed that the two-week population-based incidence proportion of any diarrhea during the study period ranged from 26% at baseline (2007) to 4– 11% during 2009–2010. A key finding of the surveys was that less than half of the children with diarrheal illness received care at a healthcare facility. Caretakers were actually less likely to seek health care outside the home for infants with diarrhea than for older children. Seeking care outside the home for childhood diarrhea was significantly more common for children who had sunken eyes during their diarrheal episode. Substantial proportion of children with diarrhea were given less food and drink than normally, even when vomiting accompanied their diarrheal episode. They were also not offered oral rehydration solution (ORS) at home. Mothers with formal education, however, were more likely than those without formal education to provide their children with ORS at home and to take them to a health care facility. Furthermore, caretakers sought care from a healthcare facility when their child`s diarrheal illness became more severe— possibly as a consequence of giving no remedy at home. Infants 6–11 months had the highest population-based incidence rates for hospitalization and mortality due to AGE and RVAGE. Rotavirus-positive cases were younger (median age, 8 vs. 13 months), had more severe illness, and had to be hospitalized more frequently than those who were negative for rotavirus. Independent factors that were associated with rotavirus disease included being an infant and presenting with vomiting 3 or more times within 24 hours during the diarrhea episode. Two-thirds of intussusception cases treated from 2002 through 2013 were infants who presented with at least one of the following symptoms: vomiting, diarrhea, or blood in stool. The case-fatality proportion was 6.4%. Compared with patients who survived, patients who died were younger, more likely to seek care late after illness symptom onset, to report history of fever on admission or, to have undergone surgery. In summary, the studies in this thesis demonstrate that diarrhea among young children presenting to health care facilities is a significant public health problem in Kenya. However, the cases attending health care facility are only the tip of an iceberg. Our findings that suggest delay in seeking care for the child`s severe diarrheal illness are disconcerting. In addition, among children with severe disease symptoms and intussusception patients who died had sought care later after symptom onset than those who survived. Our data also confirmed that morbidity and mortality associated with AGE, RVAGE, and intussusception was most common among infants. These findings supported the Kenyan Ministry of Health’s decision to introduce a rotavirus vaccination program in July 2014. They are also consistent with the WHO recommendation to administer rotavirus vaccines to children at six and ten weeks of age, before the peak of disease incidence in Kenya. As a whole, the results of this thesis provide a comprehensive baseline data on occurrence, risk factors and complications of rotavirus diarrhea among young children in Kenya against which the population-level vaccine program impact can be evaluated in the future. Continuing surveillance efforts aimed at demonstrating the real-world impact and value of rotavirus vaccines need to take into consideration the observed trends in health care utilization

Enteropathogen antibody dynamics and force of infection among children in low-resource settings.

Little is known about enteropathogen seroepidemiology among children in low-resource settings. We measured serological IgG responses to eight enteropathogens (Giardia intestinalis, Cryptosporidium parvum, Entamoeba histolytica, Salmonella enterica, enterotoxigenic Escherichia coli, Vibrio cholerae, Campylobacter jejuni, norovirus) in cohorts from Haiti, Kenya, and Tanzania. We studied antibody dynamics and force of infection across pathogens and cohorts. Enteropathogens shared common seroepidemiologic features that enabled between-pathogen comparisons of transmission. Overall, exposure was intense: for most pathogens the window of primary infection was <3 years old; for highest transmission pathogens primary infection occurred within the first year. Longitudinal profiles demonstrated significant IgG boosting and waning above seropositivity cutoffs, underscoring the value of longitudinal designs to estimate force of infection. Seroprevalence and force of infection were rank-preserving across pathogens, illustrating the measures provide similar information about transmission heterogeneity. Our findings suggest antibody response can be used to measure population-level transmission of diverse enteropathogens in serologic surveillance

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

Diarrhea in young children from low-income countries leads to large-scale alterations in intestinal microbiota composition

Acknowledgments This work was funded in part by the William and Melinda Gates Foundation, award 42917 to JPN and OCS; US National Institutes of Health grants 5R01HG005220 to HCB, 5R01HG004885 to MP; US National Science Foundation Graduate Research Fellowship award DGE0750616 to JNP; AWW and JP are funded by The Wellcome Trust (Grant No. WT098051).Peer reviewedPublisher PD

Has Authorship in the Decolonizing Global Health Movement Been Colonized?

Background: Decolonization in global health is a recent movement aimed at relinquishing remnants of supremacist mindsets, inequitable structures, and power differentials in global health. Objective: To determine the author demographics of publications on decolonizing global health and global health partnerships between low- and middle-income countries (LMICs) and high-income countries (HICs). Methods: We conducted a cross-sectional analysis of publications related to decolonizing global health and global health partnerships from the inception of the selected journal databases (i.e., Medline, CAB Global Health, EMBASE, CINAHL, and Web of Science) to November 14, 2022. Author country affiliations were assigned as listed in each publication. Author gender was assigned using author first name and the software genderize.io. Descriptive statistics were used for author country income bracket, gender, and distribution. Findings: Among 197 publications on decolonizing global health and global health partnerships, there were 691 total authors (median 2 authors per publication, interquartile range 1, 4). Publications with author bylines comprised exclusively of authors affiliated with HICs were most common (70.0%, n = 138) followed by those with authors affiliated both with HICs and LMICs (22.3%, n = 44). Only 7.6% (n = 15) of publications had author bylines comprised exclusively of authors affiliated with LMICs. Over half (54.0%, n = 373) of the included authors had names that were female and female authors affiliated with HICs most commonly occupied first author positions (51.8%, n = 102). Conclusions: Authors in publications on decolonizing global health and global health partnerships have largely been comprised of individuals affiliated with HICs. There was a marked paucity of publications with authors affiliated with LMICs, whose voices provide context and crucial insight into the needs of the decolonizing global health movement

Prevalence of classic, MLB-clade and VA-clade Astroviruses in Kenya and The Gambia.

BACKGROUND: Infectious diarrhea leads to significant mortality in children, with 40 % of these deaths occurring in Africa. Classic human astroviruses are a well-established etiology of diarrhea. In recent years, seven novel astroviruses have been discovered (MLB1, MLB2, MLB3, VA1/HMO-C, VA2/HMO-B, VA3/HMO-A, VA4); however, there have been few studies on their prevalence or potential association with diarrhea. METHODS: To investigate the prevalence and diversity of these classic and recently described astroviruses in a pediatric population, a case-control study was performed. Nine hundred and forty nine stools were previously collected from cases of moderate-to-severe diarrhea and matched controls of patients less than 5 years of age in Kenya and The Gambia. RT-PCR screening was performed using pan-astrovirus primers. RESULTS: Astroviruses were present in 9.9 % of all stool samples. MLB3 was the most common astrovirus with a prevalence of 2.6 %. Two subtypes of MLB3 were detected that varied based on location in Africa. In this case-control study, Astrovirus MLB1 was associated with diarrhea in Kenya, whereas Astrovirus MLB3 was associated with the control state in The Gambia. Classic human astrovirus was not associated with diarrhea in this study. Unexpectedly, astroviruses with high similarity to Canine Astrovirus and Avian Nephritis Virus 1 and 2 were also found in one case of diarrhea and two control stools respectively. CONCLUSIONS: Astroviruses including novel MLB- and VA-clade members are commonly found in pediatric stools in Kenya and The Gambia. The most recently discovered astrovirus, MLB3, was the most prevalent and was found more commonly in control stools in The Gambia, while astrovirus MLB1 was associated with diarrhea in Kenya. Furthermore, a distinct subtype of MLB3 was noted, as well as 3 unanticipated avian or canine astroviruses in the human stool samples. As a result of a broadly reactive PCR screen for astroviruses, new insight was gained regarding the epidemiology of astroviruses in Africa, where a large proportion of diarrheal morbidity and mortality occur

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

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

Microbiome sharing between children, livestock and household surfaces in western Kenya

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

Effectiveness of monovalent rotavirus vaccine against hospitalization with acute rotavirus gastroenteritis in Kenyan children

Rotavirus remains a leading cause of diarrheal illness and death among children worldwide. Data on rotavirus vaccine effectiveness in sub-Saharan Africa are limited. Kenya introduced monovalent rotavirus vaccine (RV1) in July 2014. We assessed RV1 effectiveness against rotavirus-associated hospitalization in Kenyan children. Between July-2014 and December-2017, we conducted surveillance for acute gastroenteritis (AGE) in three hospitals across Kenya. We analysed data from children age-eligible for ≥1 RV1 dose, with stool tested for rotavirus and confirmed vaccination history. We compared RV1 coverage among those who tested rotavirus-positive (cases) versus rotavirus-negative (controls) using multivariable logistic regression; effectiveness was 1-adjusted odds ratio for vaccination x100%. Among 677 eligible children, 110 (16%) were rotavirus-positive. Vaccination data were available for 91 (83%) cases; 51 (56%) had received 2 RV1 doses and 33 (36%) 0 doses. Among 567 controls, 418 (74%) had vaccination data; 308 (74%) had 2 doses and 69 (16%) 0 doses. Overall 2-dose effectiveness was 64% (95% confidence interval [CI]: 35-80%); for children aged <12 months 67% (95%CI: 30-84%) and children aged ≥12 months 72% (95%CI: 10-91%). Significant effectiveness was seen in children with normal weight-for-age (84% [95%CI: 62-93%]), length/height-for-age (75% [95%CI: 48-88%]) and weight-for-length/height (84% [95%CI: 64-93%]); however, no protection was found among underweight, stunted nor wasted children. RV1 in the routine Kenyan immunization program provides significant protection against rotavirus AGE hospitalization. Protection was sustained beyond infancy. Malnutrition appears to diminish vaccine effectiveness. Efforts to improve rotavirus vaccine uptake and nutritional status are important to maximize vaccine benefit. [Abstract copyright: © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.