Inferring the proportion of undetected cholera infections from serological and clinical surveillance in an immunologically naive population.

Most infections with pandemic Vibrio cholerae are thought to result in subclinical disease and are not captured by surveillance. Previous estimates of the ratio of infections to clinical cases have varied widely (2 to 100). Understanding cholera epidemiology and immunity relies on the ability to translate between numbers of clinical cases and the underlying number of infections in the population. We estimated the infection incidence during the first months of an outbreak in a cholera-naive population using a Bayesian vibriocidal antibody titer decay model combining measurements from a representative serosurvey and clinical surveillance data. 3,880 suspected cases were reported in Grande Saline, Haiti, between 20 October 2010 and 6 April 2011 (clinical attack rate 18.4%). We found that more than 52.6% (95% Credible Interval (CrI) 49.4-55.7) of the population ≥2 years showed serologic evidence of infection, with a lower infection rate among children aged 2-4 years (35.5%; 95%CrI 24.2-51.6) compared with people ≥5 years (53.1%; 95%CrI 49.4-56.4). This estimated infection rate, nearly three times the clinical attack rate, with underdetection mainly seen in those ≥5 years, has likely impacted subsequent outbreak dynamics. Our findings show how seroincidence estimates improve understanding of links between cholera burden, transmission dynamics and immunity.

A Cannabinoid Receptor 1 Agonist Reduces Light-induced Phase Delays in Male But Not Female Mice.

Animals adapt to a changing environment by synchronizing their circadian rhythms to different stimuli, the strongest and most reliable being the daily light-dark cycle. Photic information reaches the central circadian pacemaker, the suprachiasmatic nucleus (SCN), which drives rhythms in physiology and behavior throughout the brain and body. The endocannabinoid system (ECS) is a neuromodulatory system that is present within the SCN, including the primary receptor, cannabinoid receptor 1 (CB1). Exogenous cannabinoids that target CB1 inhibit the phase-shifting effects of light in hamsters, mice, and rats. Furthermore, there is evidence in cultured microglial cells that cannabidiol (CBD), a constituent of Cannabis sativa, alters core circadian clock genes, while the CB1 agonist delta-9-tetrahydrocannabinol (THC) does not. The CB1 agonist studies were conducted using male animals only, but cannabinoids exhibit sex-dependent effects in various aspects of physiology and behavior. In addition, the effects of CBD on circadian behavioral rhythms have yet to be investigated. Therefore, we decided to test the effects of acute injections of CBD or the CB1 agonist CP 55,940 on light-induced phase delays in male and female C57BL/6J mice. Animals received a single injection at circadian time (CT) 15.5, followed by a 10-min light or dark (sham) pulse at CT 16. Running-wheel activity was monitored to determine activity levels and the behavioral phase shifts from different treatments. We observed a sex difference in the magnitude of phase delay size in response to CP 55,940 administration. Males had attenuated phase delays with increasing doses of CP 55,940, while females did not differ from control. Various doses of CBD had no effect on the phase-delaying effects of light in either sex. Our results show a sex difference in the gating of photic phase shifts by CB1 activation.

Dynamic Incidence of Typhoid Fever over a 10-Year Period (2010-2019) in Kibera, an Urban Informal Settlement in Nairobi, Kenya.

Typhoid fever burden can vary over time. Long-term data can inform prevention strategies; however, such data are lacking in many African settings. We reexamined typhoid fever incidence and antimicrobial resistance (AMR) over a 10-year period in Kibera, a densely populated urban informal settlement where a high burden has been previously described. We used data from the Population Based Infectious Diseases Surveillance platform to estimate crude and adjusted incidence rates and prevalence of AMR in nearly 26,000 individuals of all ages. Demographic and healthcare-seeking information was collected through household visits. Blood cultures were processed for patients with acute fever or lower respiratory infection. Between 2010 and 2019, 16,437 participants were eligible for blood culture and 11,848 (72.1%) had a culture performed. Among 11,417 noncontaminated cultures (96.4%), 237 grew Salmonella enterica serovar Typhi (2.1%). Overall crude and adjusted incidences were 95 and 188 cases per 100,000 person-years of observation (pyo), respectively. Annual crude incidence varied from 144 to 233 between 2010 and 2012 and from 9 to 55 between 2013 and 2018 and reached 130 per 100,000 pyo in 2019. Children 5-9 years old had the highest overall incidence (crude, 208; adjusted, 359 per 100,000 pyo). Among isolates tested, 156 of 217 were multidrug resistant (resistant to chloramphenicol, ampicillin, and trimethoprim/sulfamethoxazole [71.9%]) and 6 of 223 were resistant to ciprofloxacin (2.7%). Typhoid fever incidence resurged in 2019 after a prolonged period of low rates, with the highest incidence among children. Typhoid fever control measures, including vaccines, could reduce morbidity in this setting.

Food as a Driver of a Cholera Epidemic in Jijiga, Ethiopia-June 2017.

We conducted a case-control study to identify risk and protective factors during a cholera outbreak in Jijiga, Ethiopia, in June 2017. A case-patient was defined as anyone > 5 years old with at least three loose stools in 24 hours who was admitted to a cholera treatment center in Jijiga on or after June 16, 2017. Two controls were matched to each case by type of residency (rural or urban) and age group. We enrolled 55 case-patients and 102 controls from June 16 to June 23, 2017. Identified risk factors for cholera were male sex, eating cold food, and eating food outside the home. Eating hot food was protective, as was reported handwashing after defecation; no other reported water, sanitation, and hygiene factors were associated with cholera risk. Recommendations included continuing messaging about safe food handling practices at home, the dangers of consuming meals prepared away from home, and the importance of hand hygiene practices.

Antibiotic-Prescribing Practices for Management of Childhood Diarrhea in 3 Sub-Saharan African Countries: Findings From the Vaccine Impact on Diarrhea in Africa (VIDA) Study, 2015-2018.

BACKGROUND: Despite antibiotic prescription being recommended for dysentery and suspected cholera only, diarrhea still triggers unwarranted antibiotic prescription. We evaluated antibiotic-prescribing practices and their predictors among children aged 2-59 months in the Vaccine Impact on Diarrhea in Africa (VIDA) Study performed in The Gambia, Mali, and Kenya. METHODS: VIDA was a prospective case-control study (May 2015-July 2018) among children presenting for care with moderate-to-severe diarrhea (MSD). We defined inappropriate antibiotic use as prescription or use of antibiotics when not indicated by World Health Organization (WHO) guidelines. We used logistic regression to assess factors associated with antibiotic prescription for MSD cases who had no indication for an antibiotic, at each site. RESULTS: VIDA enrolled 4840 cases. Among 1757 (36.3%) who had no apparent indication for antibiotic treatment, 1358 (77.3%) were prescribed antibiotics. In The Gambia, children who presented with a cough (adjusted odds ratio [aOR]: 2.05; 95% confidence interval [95% CI]: 1.21-3.48) were more likely to be prescribed an antibiotic. In Mali, those who presented with dry mouth (aOR: 3.16; 95% CI: 1.02-9.73) were more likely to be prescribed antibiotics. In Kenya, those who presented with a cough (aOR: 2.18; 95% CI: 1.01-4.70), decreased skin turgor (aOR: 2.06; 95% CI: 1.02-4.16), and were very thirsty (aOR: 4.15; 95% CI: 1.78-9.68) were more likely to be prescribed antibiotics. CONCLUSIONS: Antibiotic prescription was associated with signs and symptoms inconsistent with WHO guidelines, suggesting the need for antibiotic stewardship and clinician awareness of diarrhea case-management recommendations in these settings.

Giardia Detection and Codetection With Other Enteric Pathogens in Young Children in the Vaccine Impact on Diarrhea in Africa (VIDA) Case-Control Study: 2015-2018.

BACKGROUND: Giardia has been associated with reduced risk of diarrhea in children in low-resource settings, but the mechanism underlying this association is unknown. To assess whether Giardia may shape colonization or infection with other enteric pathogens and impact associations with diarrhea, we examined Giardia and enteric pathogen codetection among children <5 years old in Kenya, The Gambia, and Mali as part of the Vaccine Impact on Diarrhea in Africa study. METHODS: We tested for Giardia and other enteric pathogens using enzyme-linked immunosorbent assays and real-time polymerase chain reaction (PCR) on stool, respectively. We evaluated associations between Giardia and enteric pathogen detection using multivariable logistic regression models separately for children with moderate-to-severe diarrhea (MSD, cases) and free of diarrhea (controls). RESULTS: Among 11 039 enrolled children, Giardia detection was more common among controls (35%) than cases (28%, P < .001). Campylobacter coli/jejuni detection was associated with Giardia in controls in The Gambia (adjusted odds ratio [aOR] [95% confidence interval {CI}]: 1.51 [1.22‒1.86]) and cases across all sites (1.16 [1.00‒1.33]). Among controls, the odds of astrovirus (1.43 [1.05‒1.93]) and Cryptosporidium spp. (1.24 [1.06‒1.46]) detection were higher among children with Giardia. Among cases, the odds of rotavirus detection were lower in children with Giardia in Mali (.45 [.30‒.66]) and Kenya (.31 [.17‒.56]). CONCLUSIONS: Giardia was prevalent in children <5 years old and was associated with detection of other enteric pathogens, with differing associations in cases versus controls and by site. Giardia may affect colonization or infection by certain enteric pathogens associated with MSD, suggesting an indirect mechanism of clinical impact.

Epidemiology of Enteroaggregative, Enteropathogenic, and Shiga Toxin-Producing Escherichia coli Among Children Aged <5 Years in 3 Countries in Africa, 2015-2018: Vaccine Impact on Diarrhea in Africa (VIDA) Study.

BACKGROUND: To address knowledge gaps regarding diarrheagenic Escherichia coli (DEC) in Africa, we assessed the clinical and epidemiological features of enteroaggregative E. coli (EAEC), enteropathogenic E. coli (EPEC), and Shiga toxin-producing E. coli (STEC) positive children with moderate-to-severe diarrhea (MSD) in Mali, The Gambia, and Kenya. METHODS: Between May 2015 and July 2018, children aged 0-59 months with medically attended MSD and matched controls without diarrhea were enrolled. Stools were tested conventionally using culture and multiplex polymerase chain reaction (PCR), and by quantitative PCR (qPCR). We assessed DEC detection by site, age, clinical characteristics, and enteric coinfection. RESULTS: Among 4840 children with MSD and 6213 matched controls enrolled, 4836 cases and 1 control per case were tested using qPCR. Of the DEC detected with TAC, 61.1% were EAEC, 25.3% atypical EPEC (aEPEC), 22.4% typical EPEC (tEPEC), and 7.2% STEC. Detection was higher in controls than in MSD cases for EAEC (63.9% vs 58.3%, P < .01), aEPEC (27.3% vs 23.3%, P < .01), and STEC (9.3% vs 5.1%, P < .01). EAEC and tEPEC were more frequent in children aged <23 months, aEPEC was similar across age strata, and STEC increased with age. No association between nutritional status at follow-up and DEC pathotypes was found. DEC coinfection with Shigella/enteroinvasive E. coli was more common among cases (P < .01). CONCLUSIONS: No significant association was detected between EAEC, tEPEC, aEPEC, or STEC and MSD using either conventional assay or TAC. Genomic analysis may provide a better definition of the virulence factors associated with diarrheal disease.

Survey-Based Assessment of Water, Sanitation, and Animal-Associated Risk Factors for Moderate-to-Severe Diarrhea in the Vaccine Impact on Diarrhea in Africa (VIDA) Study: The Gambia, Mali, and Kenya, 2015-2018.

BACKGROUND: Pediatric exposures to unsafe sources of water, unsafely managed sanitation, and animals are prevalent in low- and middle-income countries. In the Vaccine Impact on Diarrhea in Africa case-control study, we examined associations between these risk factors and moderate-to-severe diarrhea (MSD) in children <5 years old in The Gambia, Kenya, and Mali. METHODS: We enrolled children <5 years old seeking care for MSD at health centers; age-, sex-, and community-matched controls were enrolled at home. Conditional logistic regression models, adjusted for a priori confounders, were used to evaluate associations between MSD and survey-based assessments of water, sanitation, and animals living in the compound. RESULTS: From 2015 to 2018, 4840 cases and 6213 controls were enrolled. In pan-site analyses, children with drinking water sources below "safely managed" (onsite, continuously accessible sources of good water quality) had 1.5-2.0-fold higher odds of MSD (95% confidence intervals [CIs] ranging from 1.0 to 2.5), driven by rural site results (The Gambia and Kenya). In the urban site (Mali), children whose drinking water source was less available (several hours/day vs all the time) had higher odds of MSD (matched odds ratio [mOR]: 1.4, 95% CI: 1.1, 1.7). Associations between MSD and sanitation were site-specific. Goats were associated with slightly increased odds of MSD in pan-site analyses, whereas associations with cows and fowl varied by site. CONCLUSIONS: Poorer types and availability of drinking water sources were consistently associated with MSD, whereas the impacts of sanitation and household animals were context-specific. The association between MSD and access to safely managed drinking water sources post-rotavirus introduction calls for transformational changes in drinking water services to prevent acute child morbidity from MSD.

Norovirus Disease Among Children <5 Years in 3 Sub-Saharan African Countries: Findings From the Vaccine Impact on Diarrhea in Africa (VIDA) Study, 2015-2018.

BACKGROUND: To address a paucity of data from sub-Saharan Africa, we examined the prevalence, severity, and seasonality of norovirus genogroup II (NVII) among children <5 years old in The Gambia, Kenya, and Mali following rotavirus vaccine introduction. METHODS: Population-based surveillance was conducted to capture medically-attended moderate-to-severe diarrhea (MSD) cases, defined as a child 0-59 months old passing ≥3 loose stools in a 24-hour period with ≥1 of the following: sunken eyes, poor skin turgor, dysentery, intravenous rehydration, or hospitalization within 7 days of diarrhea onset. Diarrhea-free matched controls randomly selected from a censused population were enrolled at home. Stools from cases and controls were tested for enteropathogens, including norovirus and rotavirus, by TaqMan quantitative polymerase chain reaction (PCR) and conventional reverse transcription PCR. We used multiple logistic regression to derive adjusted attributable fractions (AFe) for each pathogen causing MSD, which takes into consideration the prevalence in both cases and controls, for each site and age. A pathogen was considered etiologic if AFe was ≥0.5. In further analyses focusing on the predominant NVII strains, we compared rotavirus and NVII severity using a 20-point modified Vesikari score and examined seasonal fluctuations. RESULTS: From May 2015 to July 2018, we enrolled 4840 MSD cases and 6213 controls. NVI was attributed to only 1 MSD episode. NVII was attributed to 185 (3.8%) of all MSD episodes and was the sole attributable pathogen in 139 (2.9%); peaking (36.0%) at age 6-8 months with majority (61.2%) aged 6-11 months. MSD cases whose episodes were attributed to NVII alone compared with rotavirus alone were younger (median age, 8 vs 12 months, P < .0001) and had less severe illness (median Vesikari severity score, 9 vs 11, P = .0003) but equally likely to be dehydrated. NVII occurred year-round at all study sites. CONCLUSIONS: Infants aged 6-11 months bear the greatest burden of norovirus disease, with NVII predominating. An early infant vaccine schedule and rigorous adherence to guidelines recommended for management of dehydrating diarrhea may offer substantial benefit in these African settings.

Exploring Survey-Based Water, Sanitation, and Animal Associations With Enteric Pathogen Carriage: Comparing Results in a Cohort of Cases With Moderate-to-Severe Diarrhea to Those in Controls in the Vaccine Impact on Diarrhea in Africa (VIDA) Study, 2015-2018.

BACKGROUND: The magnitude of pediatric enteric pathogen exposures in low-income settings necessitates substantive water and sanitation interventions, including animal feces management. We assessed associations between pediatric enteric pathogen detection and survey-based water, sanitation, and animal characteristics within the Vaccine Impact on Diarrhea in Africa case-control study. METHODS: In The Gambia, Kenya, and Mali, we assessed enteric pathogens in stool of children aged <5 years with moderate-to-severe diarrhea and their matched controls (diarrhea-free in prior 7 days) via the TaqMan Array Card and surveyed caregivers about household drinking water and sanitation conditions and animals living in the compound. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using modified Poisson regression models, stratified for cases and controls and adjusted for age, sex, site, and demographics. RESULTS: Bacterial (cases, 93%; controls, 72%), viral (63%, 56%), and protozoal (50%, 38%) pathogens were commonly detected (cycle threshold <35) in the 4840 cases and 6213 controls. In cases, unimproved sanitation (RR, 1.56; 95% CI, 1.12-2.17), as well as cows (RR, 1.61; 95% CI, 1.16-2.24) and sheep (RR, 1.48; 95% CI, 1.11-1.96) living in the compound, were associated with Shiga toxin-producing Escherichia coli. In controls, fowl (RR, 1.30; 95% CI, 1.15-1.47) were associated with Campylobacter spp. In controls, surface water sources were associated with Cryptosporidium spp., Shigella spp., heat-stable toxin-producing enterotoxigenic E. coli, and Giardia spp. CONCLUSIONS: Findings underscore the importance of enteric pathogen exposure risks from animals alongside more broadly recognized water and sanitation risk factors in children.

Typhoid Fever in the Eastern Mediterranean Region: A Systematic Review, 1990-2021.

The occurrence and antimicrobial resistance (AMR) of typhoid fever in the WHO Eastern Mediterranean Region (EMR) are poorly characterized. Robust surveillance data are needed to inform strategies for typhoid control and prevention in the region. We conducted a systematic review of typhoid fever occurrence, complications, and AMR patterns in EMR countries. We identified 70 studies published from 1990 to 2021, including a total of 44,541 cases with blood culture confirmed typhoid fever in 12 EMR countries, with 48 (69%) studies and 42,008 cases from Pakistan. Among 56 studies with AMR data, fluroquinolone (68% of 13,013 tested isolates), and multidrug resistance (40% of 15,765 tested isolates) were common. Forty (57%) of the 56 studies were from Pakistan, and all reports of extensively drug resistant Salmonella Typhi (48% of 9,578 tested isolates) were from studies in Pakistan. Our findings support the need for continued efforts to strengthen surveillance and laboratory capacity for blood-culture detection of typhoid fever in the region, including data from an ongoing collaboration among CDC, the American University of Beirut, and the WHO EMR office.

Molecular characterization of circulating Salmonella Typhi strains in an urban informal settlement in Kenya.

A high burden of Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) bacteremia has been reported from urban informal settlements in sub-Saharan Africa, yet little is known about the introduction of these strains to the region. Understanding regional differences in the predominant strains of S. Typhi can provide insight into the genomic epidemiology. We genetically characterized 310 S. Typhi isolates from typhoid fever surveillance conducted over a 12-year period (2007-2019) in Kibera, an urban informal settlement in Nairobi, Kenya, to assess the circulating strains, their antimicrobial resistance attributes, and how they relate to global S. Typhi isolates. Whole genome multi-locus sequence typing (wgMLST) identified 4 clades, with up to 303 pairwise allelic differences. The identified genotypes correlated with wgMLST clades. The predominant clade contained 290 (93.5%) isolates with a median of 14 allele differences (range 0-52) and consisted entirely of genotypes 4.3.1.1 and 4.3.1.2. Resistance determinants were identified exclusively in the predominant clade. Determinants associated with resistance to aminoglycosides were observed in 245 isolates (79.0%), sulphonamide in 243 isolates (78.4%), trimethoprim in 247 isolates (79.7%), tetracycline in 224 isolates (72.3%), chloramphenicol in 247 isolates (79.6%), ß-lactams in 239 isolates (77.1%) and quinolones in 62 isolates (20.0%). Multidrug resistance (MDR) determinants (defined as determinants conferring resistance to ampicillin, chloramphenicol and cotrimoxazole) were found in 235 (75.8%) isolates. The prevalence of MDR associated genes was similar throughout the study period (2007-2012: 203, 76.3% vs 2013-2019: 32, 72.7%; Fisher's Exact Test: P = 0.5478, while the proportion of isolates harboring quinolone resistance determinants increased (2007-2012: 42, 15.8% and 2013-2019: 20, 45.5%; Fisher's Exact Test: P<0.0001) following a decline in S. Typhi in Kibera. Some isolates (49, 15.8%) harbored both MDR and quinolone resistance determinants. There were no determinants associated with resistance to cephalosporins or azithromycin detected among the isolates sequenced in this study. Plasmid markers were only identified in the main clade including IncHI1A and IncHI1B(R27) in 226 (72.9%) isolates, and IncQ1 in 238 (76.8%) isolates. Molecular clock analysis of global typhoid isolates and isolates from Kibera suggests that genotype 4.3.1 has been introduced multiple times in Kibera. Several genomes from Kibera formed a clade with genomes from Kenya, Malawi, South Africa, and Tanzania. The most recent common ancestor (MRCA) for these isolates was from around 1997. Another isolate from Kibera grouped with several isolates from Uganda, sharing a common ancestor from around 2009. In summary, S. Typhi in Kibera belong to four wgMLST clades one of which is frequently associated with MDR genes and this poses a challenge in treatment and control.

Extensively Drug-Resistant Typhoid Fever in the United States.

Cases of extensively drug-resistant (XDR) typhoid fever have been reported in the United States among patients who did not travel internationally. Clinicians should consider if and where the patient traveled when selecting empiric treatment for typhoid fever. XDR typhoid fever should be treated with a carbapenem, azithromycin, or both.

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.

Salmonella Bloodstream Infections in Hospitalized Children with Acute Febrile Illness-Uganda, 2016-2019.

Invasive Salmonella infection is a common cause of acute febrile illness (AFI) among children in sub-Saharan Africa; however, diagnosing Salmonella bacteremia is challenging in settings without blood culture. The Uganda AFI surveillance system includes blood culture-based surveillance for etiologies of bloodstream infection (BSIs) in hospitalized febrile children in Uganda. We analyzed demographic, clinical, blood culture, and antimicrobial resistance data from hospitalized children at six sentinel AFI sites from July 2016 to January 2019. A total of 47,261 children were hospitalized. Median age was 2 years (interquartile range, 1-4) and 26,695 (57%) were male. Of 7,203 blood cultures, 242 (3%) yielded bacterial pathogens including Salmonella (N = 67, 28%), Staphylococcus aureus (N = 40, 17%), Escherichia spp. (N = 25, 10%), Enterococcus spp. (N = 18, 7%), and Klebsiella pneumoniae (N = 17, 7%). Children with BSIs had longer median length of hospitalization (5 days versus 4 days), and a higher case-fatality ratio (13% versus 2%) than children without BSI (all P < 0.001). Children with Salmonella BSIs did not differ significantly in length of hospitalization or mortality from children with BSI resulting from other organisms. Serotype and antimicrobial susceptibility results were available for 49 Salmonella isolates, including 35 (71%) non-typhoidal serotypes and 14 Salmonella serotype Typhi (Typhi). Among Typhi isolates, 10 (71%) were multi-drug resistant and 13 (93%) had decreased ciprofloxacin susceptibility. Salmonella strains, particularly non-typhoidal serotypes and drug-resistant Typhi, were the most common cause of BSI. These data can inform regional Salmonella surveillance in East Africa and guide empiric therapy and prevention in Uganda.

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.

Typhoid Fever in the US Pediatric Population, 1999-2015: Opportunities for Improvement.

BACKGROUND: Typhoid fever in the United States is acquired primarily through international travel by unvaccinated travelers. There is currently no typhoid vaccine licensed in the United States for use in children <2 years. METHODS: We reviewed Salmonella enterica serotype Typhi infections reported to the Centers for Disease Control and Prevention (CDC) and antimicrobial-resistance data on Typhi isolates in CDC's National Antimicrobial Resistance Monitoring System from 1999 through 2015. RESULTS: 5131 cases of typhoid fever were diagnosed and 5004 Typhi isolates tested for antimicrobial susceptibility. Among 1992 pediatric typhoid fever patients, 1616 (81%) had traveled internationally within 30 days of illness onset, 1544 (81%) of 1906 were hospitalized (median duration, 6 days; range, 0-50), and none died. Forty percent (799) were <6 years old; 12% were <2 years old. Based on age and travel destination, 1435 (83%) of 1722 pediatric patients were vaccine-eligible; only 68 (5%) of 1361 were known to be vaccinated. Of 2003 isolates tested for antimicrobial susceptibility, 1216 (61%) were fluoroquinolone-nonsusceptible, of which 272 (22%) were also resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole (multidrug-resistant [MDR]). All were susceptible to ceftriaxone and azithromycin. MDR and fluoroquinolone-nonsusceptible isolates were more common in children than adults (16% vs 9%, P < .001, and 61% vs 54%, P < .001, respectively). Fluoroquinolone nonsusceptibility was more common among travel-associated than domestically acquired cases (70% vs 17%, P < .001). CONCLUSIONS: Approximately 95% of currently vaccine-eligible pediatric travelers were unvaccinated, and antimicrobial-resistant infections were common. New public health strategies are needed to improve coverage with currently licensed vaccines. Introduction of an effective pretravel typhoid vaccine for children <2 years could reduce disease burden and prevent drug-resistant infections.

Associations among Water, Sanitation, and Hygiene, and Food Exposures and Typhoid Fever in Case-Control Studies: A Systematic Review and Meta-Analysis.

Typhoid fever transmission occurs through ingestion of food or water contaminated with Salmonella Typhi, and case-control studies are often conducted to identify outbreak sources and transmission vehicles. However, there is no current summary of the associations among water, sanitation, and hygiene (WASH); and food exposures and typhoid from case-control studies. We conducted a systematic review and meta-analysis of case-control studies to evaluate the associations among typhoid fever and predicted WASH or food exposure risk factors (13), and protective factors (7). Overall, 19 manuscripts describing 22 case-control studies were included. Two studies were characterized as having low risk of bias, one as medium risk, and 19 as high risk. In total, nine of 13 predicted risk factors were associated with increased odds of typhoid (odds ratio [OR] = 1.4-2.4, I 2 = 30.5-74.8%.), whereas five of seven predicted protective factors were associated with lower odds of typhoid (OR = 0.52-0.73, I 2 = 38.7-84.3%). In five types of sensitivity analyses, two (8%) of 26 summary associations changed significance from the original analysis. Results highlight the following: the importance of household hygiene transmission pathways, the need for further research around appropriate food interventions and the risk of consuming specific foods and beverages outside the home, and the absence of any observed association between sanitation exposures and typhoid fever. We recommend that typhoid interventions focus on interrupting household transmission routes and that future studies provide more detailed information about WASH and food exposures to inform better targeted interventions.

Increased immediate early gene activation in the basolateral amygdala following persistent peripheral inflammation.

Chronic pain results in a variety of neural adaptations, many of which are maladaptive and result in hypersensitivity to pain. In humans, this hypersensitivity can be debilitating and treatment options are limited. Fortunately, there are numerous animal models that mimic clinical populations and have the potential to aid in the evaluation of underlying mechanisms and ultimately the development of better treatments. One of these is the complete Freund's adjuvant (CFA)-model of chronic inflammatory pain. In rodents, this model requires the injection of CFA into the hindpaw, muscle, or joint, which induces inflammation similar to what might be found in individuals with rheumatoid arthritis or tendonitis. While the mechanistic effects CFA on the spinal cord are well established, less is known about the effects of CFA on the brain. Thus, in this study, neuronal activation, as measured by c-Fos immunocytochemistry, in brain regions important to control of pain was evaluated. Animals that received CFA treatment, and tested 3 days later for mechanical allodynia and edema, had an increase in the number of c-Fos immunopositive cells in the basolateral amygdala, but not in any of the other brain regions that were evaluated. Given that the basolateral amygdala is known to be important for pain-related emotional responses, these data suggest that the CFA-model may provide an opportunity to further explore how pain affects this brain region at a mechanistic level, which in turn may shed light on what may be occurring in clinical populations.

Update on Extensively Drug-Resistant Salmonella Serotype Typhi Infections Among Travelers to or from Pakistan and Report of Ceftriaxone-Resistant Salmonella Serotype Typhi Infections Among Travelers to Iraq - United States, 2018-2019.

Ceftriaxone-resistant Salmonella enterica serotype Typhi (Typhi), the bacterium that causes typhoid fever, is a growing public health threat. Extensively drug-resistant (XDR) Typhi is resistant to ceftriaxone and other antibiotics used for treatment, including ampicillin, chloramphenicol, ciprofloxacin, and trimethoprim-sulfamethoxazole (1). In March 2018, CDC began enhanced surveillance for ceftriaxone-resistant Typhi in response to an ongoing outbreak of XDR typhoid fever in Pakistan. CDC had previously reported the first five cases of XDR Typhi in the United States among patients who had spent time in Pakistan (2). These illnesses represented the first cases of ceftriaxone-resistant Typhi documented in the United States (3). This report provides an update on U.S. cases of XDR typhoid fever linked to Pakistan and describes a new, unrelated cluster of ceftriaxone-resistant Typhi infections linked to Iraq. Travelers to areas with endemic Typhi should receive typhoid vaccination before traveling and adhere to safe food and water precautions (4). Treatment of patients with typhoid fever should be guided by antimicrobial susceptibility testing whenever possible (5), and clinicians should consider travel history when selecting empiric therapy.