Determinants of linear growth faltering among children with moderate-to-severe diarrhea in the global enteric multicenter study

Background: Moderate-to-severe diarrhea (MSD) in the first 2 years of life can impair linear growth. We sought to determine risk factors for linear growth faltering and to build a clinical prediction tool to identify children most likely to experience growth faltering following an episode of MSD.Methods: Using data from the Global Enteric Multicenter Study of children 0-23 months old presenting with MSD in Africa and Asia, we performed log-binomial regression to determine clinical and sociodemographic factors associated with severe linear growth faltering (loss of ≥ 0.5 length-for-age z-score [LAZ]). Linear regression was used to estimate associations with ΔLAZ. A clinical prediction tool was developed using backward elimination of potential variables, and Akaike Information Criterion to select the best fit model.Results: Of the 5902 included children, mean age was 10 months and 43.2% were female. Over the 50-90-day follow-up period, 24.2% of children had severe linear growth faltering and the mean ΔLAZ over follow-up was - 0.17 (standard deviation [SD] 0.54). After adjustment for age, baseline LAZ, and site, several factors were associated with decline in LAZ: young age, acute malnutrition, hospitalization at presentation, non-dysenteric diarrhea, unimproved sanitation, lower wealth, fever, co-morbidity, or an IMCI danger sign. Compared to children 12-23 months old, those 0-6 months were more likely to experience severe linear growth faltering (adjusted prevalence ratio [aPR] 1.97 [95% CI 1.70, 2.28]), as were children 6-12 months of age (aPR 1.72 [95% CI 1.51, 1.95]). A prediction model that included age, wasting, stunting, presentation with fever, and presentation with an IMCI danger sign had an area under the ROC (AUC) of 0.67 (95% CI 0.64, 0.69). Risk scores ranged from 0 to 37, and a cut-off of 21 maximized sensitivity (60.7%) and specificity (63.5%).Conclusion: Younger age, acute malnutrition, MSD severity, and sociodemographic factors were associated with short-term linear growth deterioration following MSD. Data routinely obtained at MSD may be useful to predict children at risk for growth deterioration who would benefit from interventions

High-Throughput High-Resolution Class I HLA Genotyping in East Africa

HLA, the most genetically diverse loci in the human genome, play a crucial role in host-pathogen interaction by mediating innate and adaptive cellular immune responses. A vast number of infectious diseases affect East Africa, including HIV/AIDS, malaria, and tuberculosis, but the HLA genetic diversity in this region remains incompletely described. This is a major obstacle for the design and evaluation of preventive vaccines. Available HLA typing techniques, that provide the 4-digit level resolution needed to interpret immune responses, lack sufficient throughput for large immunoepidemiological studies. Here we present a novel HLA typing assay bridging the gap between high resolution and high throughput. The assay is based on real-time PCR using sequence-specific primers (SSP) and can genotype carriers of the 49 most common East African class I HLA-A, -B, and -C alleles, at the 4-digit level. Using a validation panel of 175 samples from Kampala, Uganda, previously defined by sequence-based typing, the new assay performed with 100% sensitivity and specificity. The assay was also implemented to define the HLA genetic complexity of a previously uncharacterized Tanzanian population, demonstrating its inclusion in the major East African genetic cluster. The availability of genotyping tools with this capacity will be extremely useful in the identification of correlates of immune protection and the evaluation of candidate vaccine efficacy

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Host and Environmental Correlates of Multi-Drug Resistance in Kenyan Children with Acute Bacterial Diarrhea

Thesis (Master's)--University of Washington, 2016-06Bacterial diarrhea results in significant morbidity and mortality in children in sub-Saharan Africa. Antibiotic treatment can be a life-saving intervention, but the emergence of antibiotic resistance limits its clinical efficacy. Data on the burden and risk factors for antibiotic resistance in enteric pathogens are needed to inform diarrhea management recommendations and resistance control interventions. Stool/rectal swab samples of children aged 6 mos - 15 yrs presenting with acute diarrhea in western Kenya were cultured for bacterial pathogens. HIV-uninfected children with identified Shigella or Salmonella species, or enteropathogenic [EPEC], enterotoxigenic [ETEC], enteroaggregative [EAEC], or enteroinvasive Escherichia coli [EIEC] were included in this substudy. Resistance to ampicillin, ceftriaxone, ciprofloxacin, cotrimoxazole, and tetracycline was determined using MicroScan Walkaway40 Plus. To evaluate correlates of multi- !3 drug resistance (MDR [resistance to ≥ 3 classes of antibiotics]), we used multivariable log- binomial regression to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs). Of 292 children in the analysis, median age was 22.5 mos (interquartile range: 10.5-41.5 mos), 60.6% used pit latrines and 8.6% were HIV-exposed. Resistance to cotrimoxazole (96.2%) was most common among all pathogens, followed by ampicillin (79.1%) and tetracycline (73.0%). Phenotypic MDR was identified in 60.3% of children; and in 38.2% of Shigella, 40.0% of Salmonella, 73.0% of EPEC, 54.1% of ETEC, 76.0% of EAEC, and 72.2% of EIEC isolates. Children 6-24 mos were more likely to have MDR infections identified than those 24-59 mos (PR = 1.51 [95% CI: 1.19, 1.90]) whereas there was no difference in MDR prevalence between children in the two older age categories, >59m vs. 24-59m (PR = 1.30 [95% CI: 0.91, 1.87]). Children in households with a shared pit latrine were more likely to have MDR (aPR = 1.92 [95% CI: 1.08, 3.38]), than those with flush toilets, as were children in households that practiced open defecation (aPR = 1.91 [95% CI: 1.11, 3.30]). Children living in a household with 2 or more persons per room were 22% more likely to have an MDR pathogen than children living with fewer than 2 persons per room (PR = 1.22 [95% CI: 1.04, 1.43]). Duration of exclusive breastfeeding, malnutrition, maternal HIV, and water source were not associated with MDR infections in this study. Young children and those living in contaminated environments may be at higher risk for infection by antibiotic resistant enteric pathogens

Interventions to reduce post-acute consequences of diarrheal disease in children: a systematic review

Abstract Background Although acute diarrhea often leads to acute dehydration and electrolyte imbalance, children with diarrhea also suffer long term morbidity, including recurrent or prolonged diarrhea, loss of weight, and linear growth faltering. They are also at increased risk of post-acute mortality. The objective of this systematic review was to identify interventions that address these longer term consequences of diarrhea. Methods We searched Medline for randomized controlled trials (RCTs) of interventions conducted in low- and middle-income countries, published between 1980 and 2016 that included children under 15 years of age with diarrhea and follow-up of at least 7 days. Effect measures were summarized by intervention. PRISMA guidelines were followed. Results Among 314 otherwise eligible RCTs, 65% were excluded because follow-up did not extend beyond 7 days. Forty-six trials were included, the majority of which (59%) were conducted in Southeast Asia (41% in Bangladesh alone). Most studies were small, 76% included less than 200 participants. Interventions included: therapeutic zinc alone (28.3%) or in combination with vitamin A (4.3%), high protein diets (19.6%), probiotics (10.9%), lactose free diets (10.9%), oral rehydration solution (ORS) formulations (8.7%), dietary supplements (6.5%), other dietary interventions (6.5%), and antimicrobials (4.3%). Prolonged or recurrent diarrhea was the most commonly reported outcome, and was assessed in ORS, probiotic, vitamin A, and zinc trials with no consistent benefit observed. Seven trials evaluated mortality, with follow-up times ranging from 8 days to 2 years. Only a single trial found a mortality benefit (therapeutic zinc). There were mixed results for dietary interventions affecting growth and diarrhea outcomes in the post-acute period. Conclusion Despite the significant post-acute mortality and morbidity associated with diarrheal episodes, there is sparse evidence evaluating the effects of interventions to decrease these sequelae. Adequately powered trials with extended follow-up are needed to identify effective interventions to prevent post-acute diarrhea outcomes

Identification and management of Shigella infection in children with diarrhoea: a systematic review and meta-analysis

Summary: Background: Shigella infections are a leading cause of diarrhoeal death among children in low-income and middle-income countries. WHO guidelines reserve antibiotics for treating children with dysentery. Reliance on dysentery for identification and management of Shigella infection might miss an opportunity to reduce Shigella-associated morbidity and mortality. We aimed to systematically review and evaluate Shigella-associated and dysentery-associated mortality, the diagnostic value of dysentery for the identification of Shigella infection, and the efficacy of antibiotics for children with Shigella or dysentery, or both. Methods: We did three systematic reviews (for mortality, diagnostic value, and antibiotic treatment of Shigella and dysentery), and meta-analyses where appropriate, of studies in resource-limited settings. We searched MEDLINE, Embase, and LILACS database for studies published before Jan 1, 2017, in English, French, and Spanish. We included studies of human beings with diarrhoea and accepted all study-specific definitions of dysentery. For the mortality and diagnostic value searches, we excluded studies that did not include an effect estimate or data necessary to calculate this estimate. The search for treatment included only randomised controlled trials that were done after Jan 1, 1980, and assessed antibiotics in children (aged <18 years) with dysentery or laboratory-confirmed Shigella. We extracted or calculated odds ratios (ORs) and 95% CIs for relative mortality and did random-effects meta-analysis to arrive at pooled ORs. We calculated 95% CIs assuming a binomial distribution and did random-effects meta-regression of log-transformed sensitivity and specificity estimates for diagnostic value. We assessed the heterogeneity of papers included in these meta-analyses using the I2 statistic and evaluated publication bias using funnel plots. This review is registered with PROSPERO (CRD42017063896). Findings: 3649 papers were identified and 60 studies were included for analyses: 13 for mortality, 27 for diagnostic value, and 20 for treatment. Shigella infection was associated with mortality (pooled OR 2·8, 95% CI 1·6–4·8; p=0·000) whereas dysentery was not associated with mortality (1·3, 0·7–2·3; p=0·37). Between 1977 and 2016, dysentery identified 1·9–85·9% of confirmed Shigella infections, with sensitivity decreasing over time (p=0·04). Ten (50%) of 20 included antibiotic trials were among children with dysentery, none were placebo-controlled, and two (10%) evaluated antibiotics no longer recommended for acute infectious diarrhoea. Ciprofloxacin showed superior microbiological, but not clinical, effectiveness compared with pivmecillinam, and no superior microbiological and clinical effectiveness compared with gatifloxacin. Substantial heterogeneity was reported for meta-analyses of the Shigella-associated mortality studies (I2=78·3%) and dysentery-associated mortality studies (I2=73·2%). Too few mortality studies were identified to meaningfully test for publication bias. No evidence of publication bias was found in this analysis of studies of diagnostic value. Interpretation: Current WHO guidelines appear to manage dysentery effectively, but might miss opportunities to reduce mortality among children infected with Shigella who present without bloody stool. Further studies should quantify potential decreases in mortality and morbidity associated with antibiotic therapy for children with non-dysenteric Shigella infection. Funding: Bill & Melinda Gates Foundation and the Center for AIDS Research International Core

Correlates of multi-drug non-susceptibility in enteric bacteria isolated from Kenyan children with acute diarrhea.

Reduced antimicrobial susceptibility threatens treatment efficacy in sub-Saharan Africa, where data on the burden and correlates of antibiotic resistance among enteric pathogens are limited.Fecal samples from children aged 6 mos-15 yrs presenting with acute diarrhea in western Kenya were cultured for bacterial pathogens. HIV-uninfected children with identified Shigella or Salmonella species or pathogenic Escherichia coli (EPEC, ETEC, EAEC or EIEC) were included in this cross-sectional sub-study. Non-susceptibility to ampicillin, ceftriaxone, ciprofloxacin, cotrimoxazole, and tetracycline was determined using MicroScan Walkaway40 Plus. Multivariable log-binomial regression was used to identify correlates of multi-drug non-susceptibility (MDNS, non-susceptibility to ≥ 3 of these antibiotics).Of 292 included children, median age was 22.5 mos. MDNS was identified in 62.5% of 318 isolates. Non-susceptibility to cotrimoxazole (92.8%), ampicillin (81.3%), and tetracycline (75.0%) was common. Young age (6-24 mos vs. 24-59 mos adjusted prevalence ratio [aPR] = 1.519 [95% confidence interval: 1.19, 1.91]), maternal HIV (aPR = 1.29 [1.01, 1.66]); and acute malnutrition (aPR = 1.28 [1.06, 1.55]) were associated with higher prevalence of MDNS, as were open defecation (aPR = 2.25 [1.13, 4.50]), household crowding (aPR = 1.29 [1.08, 1.53]) and infrequent caregiver hand-washing (aPR = 1.50 [1.15, 1.95]).Young age, HIV exposure, acute malnutrition and poor sanitation may increase risk of antibiotic non-susceptible enteric pathogen infections among children in Kenya

Non-susceptibility patterns of <i>Shigella</i> spp., <i>Salmonella</i> spp., and select <i>E</i>. <i>Coli</i> strains isolated from study participants all Salmonella spp., Shigella spp., EPEC, ETEC, and EIEC isolates were susceptible to ceftriaxone.

<p>All Salmonella spp., Shigella spp., and ETEC isolates were susceptible to ciprofloxacin.</p

Correlates of multi-drug non-susceptibility (MDNS) in enteropathogens in Kenyan children 6 mos–15 yrs with acute diarrhea.

<p>Correlates of multi-drug non-susceptibility (MDNS) in enteropathogens in Kenyan children 6 mos–15 yrs with acute diarrhea.</p