Oral application of Escherichia coli bacteriophage: safety tests in healthy and diarrheal children from Bangladesh.

A T4-like coliphage cocktail was given with different oral doses to healthy Bangladeshi children in a placebo-controlled randomized phase I safety trial. Fecal phage detection was oral dose dependent suggesting passive gut transit of coliphages through the gut. No adverse effects of phage application were seen clinically and by clinical chemistry. Similar results were obtained for a commercial phage preparation (Coliproteus from Microgen/Russia). By 16S rRNA gene sequencing, only a low degree of fecal microbiota conservation was seen in healthy children from Bangladesh who were sampled over a time interval of 7 days suggesting a substantial temporal fluctuation of the fecal microbiota composition. Microbiota variability was not associated with the age of the children or the presence of phage in the stool. Stool microbiota composition of Bangladeshi children resembled that found in children of other regions of the world. Marked variability in fecal microbiota composition was also seen in 71 pediatric diarrhea patients receiving only oral rehydration therapy and in 38 patients receiving coliphage preparations or placebo when sampled 1.2 or 4 days apart respectively. Temporal stability of the gut microbiota should be assessed in case-control studies involving children before associating fecal microbiota composition with health or disease phenotypes.

The Prevalence of Mixed Helicobacter pylori Infections in Symptomatic and Asymptomatic Subjects in Dhaka, Bangladesh.

BACKGROUND: Helicobacter pylori is a highly genetically diverse bacterial species, which can persist in the gastric environment for decades. Recent studies have shown that single infections predominate in developed countries, whereas mixed infections are more prevalent in developing countries. Mixed infections of this bacterium may be important for adaptation to the hostile gastric environment and may facilitate dyspeptic symptoms. MATERIALS AND METHODS: To calculate the prevalence of mixed infections in symptomatic and asymptomatic subjects, 2010 H. pylori isolates collected from 83 symptomatic and 91 asymptomatic subjects from Dhaka, Bangladesh, were analyzed by (i) random amplified polymorphic DNA fingerprinting (RAPD) and (ii) multiplex PCR amplification for cagA and vacA virulence gene alleles. RESULTS: The overall prevalence of mixed H. pylori infection was 60.15% (77/128), indicating substantial co-colonization in this population. We additionally found that symptomatic subjects (53%) had a significantly higher rate of mixed infection than asymptomatic individuals (36.3%) (p = .016) and that the prevalence of the cagA and vacA and vacA m1/s1 and vacA m2/s1 alleles were higher in subjects with mixed infection. CONCLUSION: Our findings suggest that an increased diversity of the H. pylori strains in the gastric environment may contribute to the development of disease symptoms.

Urban-rural differentials in overweight and obese individuals with diarrhea in bangladesh.

OBJECTIVE: The study aimed to determine urban and rural differences in overweight and obesity (OO) with diarrhea regarding subjects' sociodemographic, clinical characteristics, etiology, and antimicrobial susceptibility. METHODS: Relevant information from 2000 to 2011 were extracted from the data archive of the Diarrheal Disease Surveillance System of urban Dhaka (1248, 4.5%) and rural Matlab (615, 3.4%) hospitals of the International Centre for Diarrheal Disease Research, Bangladesh (icddr,b). RESULTS: The proportion of OO significantly increased in both urban (3-7%; chi-square for trend p < 0.001) and rural (1-6%; p < 0.001) areas over the study period. In multivariate modeling, monthly income more than US$100 (odds ratio [OR] = 54.44, 95% confidence interval [CI], 25.37-116.82, p < 0.001), high wealth quintile (OR = 18.23, 95% CI, 8.63-38.49, p < 0.001), access to sanitary toilet (OR = 3.07. 95% CI. 1.76-5.26. p < 0.001), boiled drinking water (OR = 2.77, 95% CI, 1.09-7.05, p = 0.032), antimicrobial use before hospitalization (OR = 4.99, 95% CI, 2.85-8.74, p < 0.001), fever (OR = 0.14, 95% CI, 0.37, 0.50, p < 0.001), watery stools (OR = 5.59, 95% CI, 2.11-14.80, p < 0.001), dehydrating diarrhea (OR = 5.17, 95% CI, 2.54-10.52, p < 0.001), intravenous saline infusion after hospitalization (OR = 2.65, 95% CI, 1.28-5.49, p = 0.009), and Salmonella infection (OR = 0.20, 95% CI, 0.50-0.83, p = 0.027) remained significantly associated with urban OO individuals. At least 88% of Shigella isolates were susceptible to ciprofloxacin in both urban and rural areas; for mecillinum it was 90%. Ciprofloxacin had the least detected resistance for Vibrio cholerae (0%) and trimethoprim-sulfamethoxazole (TMP-SMX) showed the greatest resistance (Dhaka 86%; Matlab 98%). Susceptibility for Salmonella showed ampicillin (95%), chloramphenecol (100%), ciprofloxacin (95%), ceftraxone (93%), TMP-SMX (95%) at both sites. CONCLUSION: Urban OO with diarrheal illnesses was significantly different from that in rural areas, including antimicrobial susceptibility.

Assessing safety and efficacy of a novel glucose-free amino acid oral rehydration solution for watery diarrhea management in children: a randomized, controlled, phase III trial.

Background: Diarrhoeal disease poses a significant global health challenge, especially in children under three years old. Despite the effectiveness of oral rehydration therapy (ORT), its adoption remains low. Glucose-based ORS (GORS) is the standard, but novel formulations like glucose-free amino acid-based VS002A have emerged as potential alternatives. This study aimed to compare the safety and efficacy of VS002A against the standard WHO-ORS in treating non-cholera acute watery diarrhoea in children. Methods: A triple-blind, randomized trial enrolled 310 male infants and children aged 6-36 months, who were assigned to receive WHO-ORS or VS002A over a 16-month period, from June 2021 to September 2022. Both groups received standard of care, including zinc supplementation. The Primary study outcome measured was the duration of diarrhoea. Secondary outcomes included stool output, treatment failure and adverse events. Exploratory endpoints included urinary output, body weight changes, blood biochemistry, stool microbiology and gut health biomarkers. Findings: Both VS002A and WHO-ORS were well-tolerated with a low adverse event rate. While not different statistically (p = 0.10), duration of diarrhoea was shorter in children treated with VS002A vs. WHO-ORS (65.4 h vs. 72.6 h). Similarly, stool output was also lower vs. WHO-ORS in children treated with VS002A, though not statistically different (p = 0.40). Serum citrulline levels, an indicator of gut health, were higher in the VS002A group at 24 h suggesting a potential protective effect (p = 0.06). Interpretation: The findings of this study support the non-inferiority of VS002A, a glucose-free amino acid-based ORS compared to the WHO-ORS standard of care. VS002A was shown to be safe and effective in treating non-cholera acute watery diarrhoea in young children. VS002A may offer advantages in pathogen-driven diarrhoea, supported by trends toward a lower duration of diarrhoea and stool output within the per protocol group. Furthermore, individuals with prolonged diarrhoea, severe malnutrition, environmental enteric dysfunction or have issues with obesity or insulin resistance, could benefit from a glucose-free ORS. This research contributes to addressing the persistent challenge of childhood diarrhoea by presenting an alternative glucose-free ORS formulation with potential advantages in select scenarios, offering a promising avenue for improving paediatric diarrhoea management worldwide. Funding: The study was funded by Entrinsic Bioscience, LLC., Norwood, MA, USA.

Citrulline and kynurenine to tryptophan ratio: potential EED (environmental enteric dysfunction) biomarkers in acute watery diarrhea among children in Bangladesh.

Two emerging biomarkers of environmental enteric dysfunction (EED) include plasma citrulline (CIT), and the kynurenine (KYN): tryptophan (TRP)/ (KT) ratio. We sought to investigate the plasma concentration of CIT and KT ratio among the children having dehydrating diarrhea and examine associations between concentrations of CIT and KT ratio with concurrent factors. For this analysis, we used cross-sectional data from a total of 102, 6-36 months old male children who suffered from non-cholera acute watery diarrhea and had some dehydration admitted to an urban diarrheal hospital, in Bangladesh. CIT, TRP, and KYN concentrations were determined at enrollment from plasma samples using ELIZA. At enrollment, the mean plasma CIT concentration was 864.48 ± 388.55 µmol/L. The mean plasma kynurenine, tryptophan concentrations, and the KT ratio (× 1000) were 6.93 ± 3.08 µmol/L, 33.44 ± 16.39 µmol/L, and 12.12 ± 18.10, respectively. With increasing child age, KYN concentration decreased (coefficient: - 0.26; 95%CI: - 0.49, - 0.04; p = 0.021); with increasing lymphocyte count, CIT concentration decreased (coef.: - 0.01; 95% CI: - 0.02,0.001, p = 0.004); the wasted child had decreased KT ratio (coef.: - 0.6; 95% CI: - 1.18, - 0.02; p = 0.042) after adjusting for potential covariates. The CIT concentration was associated with blood neutrophils (coef.: 0.02; 95% CI: 0.01, 0.03; p < 0.001), lymphocytes (coef.: - 0.02; 95% CI: - 0.03, - 0.02; p < 0.001) and monocyte (coef.: 0.06; 95% CI: 0.01, 0.11; p = 0.021); KYN concentration was negatively associated with basophil (coef.: - 0.62; 95% CI: - 1.23, - 0.01; p = 0.048) after adjusting for age. In addition, total stool output (gm) increased (coef.: 793.84; 95% CI: 187.16, 1400.52; p = 0.011) and also increased duration of hospital stay (hour) (coef.: 22.89; 95% CI: 10.24, 35.54; p = 0.001) with increasing CIT concentration. The morphological changes associated with EED may increase the risk of enteric infection and diarrheal disease among children. Further research is critically needed to better understand the complex mechanisms by which EED biomarkers may impact susceptibility to dehydrating diarrhea in children.

A double-blind clinical trial to compare the efficacy and safety of a multiple amino acid-based ORS with the standard WHO-ORS in the management of non-cholera acute watery diarrhea in infants and young children: "VS002A" trial protocol.

BACKGROUND: Diarrhea is the second deadliest disease for under-five children globally and the situation is more serious in developing countries. Oral rehydration solution (ORS) is being used as a standard treatment for acute watery diarrhea for a long time. Our objective is to compare the efficacy of amino acid-based ORS "VS002A" compared to standard glucose-based WHO-ORS in infants and young children suffering from acute non-cholera watery diarrhea. METHODS: It is a randomized, double-blind, two-cell clinical trial at Dhaka Hospital of icddr,b. A total of 312 male children aged 6-36 months old with acute non-bloody watery diarrhea are included in this study. Intervention arm participants get amino acid-based ORS (VS002A) and the control arm gets standard glucose-based WHO-ORS. The primary efficacy endpoint is the duration of diarrhea in the hospital. DISCUSSION: Oral rehydration therapy (ORT) with the present ORS formulation has certain limitations - it does not reduce the volume, frequency, or duration of diarrhea. Additionally, the failure of present standard ORS to significantly reduce stool output likely contributes to the relatively limited use of ORS by mothers as they do not feel that ORS is helping their child recover from the episode of diarrhea. Certain neutral amino acids (e.g., glycine, L-alanine, L-glutamine) can enhance the absorption of sodium ions and water from the gut. By using this concept, a shelf-stable, sugar-free amino acid-based hydration medicinal food named 'VS002A' that effectively rehydrates, and improves the barrier function of the bowel following infections targeting the gastrointestinal tract has been developed. If the trial shows significant benefits of VS002A use, this may provide evidence to support consideration of the use of VS002A in the present WHO diarrhea management guidelines. Conversely, if there is no evidence of benefit, these results will reaffirm the current guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT04677296 . Registered on December 21, 2020.

Different Features of Cholera in Malnourished and Non-Malnourished Children: Analysis of 20 Years of Surveillance Data from a Large Diarrheal Disease Hospital in Urban Bangladesh.

Malnourished children are more prone to infectious diseases including severe diarrhea compared to non-malnourished children. However, data are scarce on differences in the presentation in such children. We aimed to identify clinical differentials among children with cholera with or without malnutrition. Data were extracted from the diarrheal disease surveillance system (DDSS) of Dhaka Hospital of International Centre for Diarrheal Disease Research, Bangladesh (icddr,b) from January 2001 to December 2020. Among children under five in DDSS, cholera positive (culture confirmed) malnourished children (WAZ, WL/HZ or L/HAZ ˂ -2) were considered as cases (n = 920) and children with cholera but non-malnourished (WAZ, WL/HZ or L/HAZ ≥-2.00 to ≤+2.00) were controls (n = 586). After adjusting for potential confounders such as maternal illiteracy, day labor fathers, maternal employment, slum dwelling, non-sanitary latrine use, use of untreated water, and history of cough, it was revealed that malnourished cholera children significantly more often presented in hospital during evening hours (6 p.m. to 12 mid-night) (p < 0.05), had illiterate fathers (p < 0.05), >24 h history of diarrheal duration (p < 0.05), dehydrating diarrhea (p < 0.05), and had longer hospitalization (p < 0.05). The study results underscore the importance of understanding of basic differences in the presentation of severity of cholera in malnourished children for prompt identification and subsequent management of these vulnerable children.

The 2008 cholera epidemic in Zimbabwe: experience of the icddr,b team in the field.

During August 2008-June 2009, an estimated 95,531 suspected cases of cholera and 4,282 deaths due to cholera were reported during the 2008 cholera outbreak in Zimbabwe. Despite the efforts by local and international organizations supported by the Zimbabwean Ministry of Health and Child Welfare in the establishment of cholera treatment centres throughout the country, the case-fatality rate (CFR) was much higher than expected. Over two-thirds of the deaths occurred in areas without access to treatment facilities, with the highest CFRs (>5%) reported from Masvingo, Manicaland, Mashonaland West, Mashonaland East, Midland, and Matabeleland North provinces. Some factors attributing to this high CFR included inappropriate cholera case management with inadequate use of oral rehydration therapy, inappropriate use of antibiotics, and a shortage of experienced healthcare professionals. The breakdown of both potable water and sanitation systems and the widespread contamination of available drinking-water sources were also considered responsible for the rapid and widespread distribution of the epidemic throughout the country. Training of healthcare professionals on appropriate cholera case management and implementation of recommended strategies to reduce the environmental contamination of drinking-water sources could have contributed to the progressive reduction in number of cases and deaths as observed at the end of February 2009.

High-dose intravenous dexamethasone in the management of diarrheal patients with enteric fever and encephalopathy.

We conducted a retrospective chart analysis of diarrheal patients with enteric fever and encephalopathy (among survivors and non-survivors) to examine the role of high-dose, intravenous dexamethasone as an adjunct to appropriate antimicrobial therapy in their management. We studied all patients admitted to the Special Care Ward (SCW) of Dhaka Hospital between October 2006 and October 2007 with a diagnosis of encephalopathy in association with enteric fever. Twenty-three cases were identified with three mortalities. All bacterial isolates (Salmonella Typhi and Salmonella Paratyphi) were multi-drug resistant. Survivors were significantly more likely to have received high dose dexamethasone (100% vs 00%; p < 0.001) and had hypoglycemia less often (6% vs 67%; p = 0.045) compared to those who died. The results suggest high dose intravenous dexamethasone, as an adjunct to appropriate antimicrobial therapy, substantially reduces mortality among diarrheal patients presenting with enteric encephalopathy.

Evaluation of faecal occult blood test and lactoferrin latex agglutination test in screening hospitalized patients for diagnosing inflammatory and non-inflammatory diarrhoea in Dhaka, Bangladesh.

BACKGROUND: Inflammatory diarrhoea (ID) resulting from Shigella, Salmonella, Campylobacter and Entamoeba histolytica requires specific diagnosis for therapy. Differentiation between ID and non-inflammatory diarrhoea (NID) is often not clinically possible. A faecal occult blood test (FOBT) correlates with faecal leucocytes. Lactoferrin indicates an inflammatory process as a marker for faecal leucocytes. We evaluated diagnostic values of lactoferrin latex agglutination test (LT) either alone or in combination with FOBT, correlating with stool microscopy and microbiology in differentiating ID from NID. METHODS: The study population constituted patients enrolled in 2% systematic sampling of patients under Diarrhoeal Disease Surveillance System of Dhaka Hospital, ICDDR,B. RESULTS: Between July and November 2002, 594 patients were enrolled; evaluation of FOBT and LT were done in 448/594 (75%) patients from whom either a single enteropathogen (315/594, 53%) or no pathogen (133/594, 22%) were identified and 146 were excluded for multiple pathogens. Invasive and non-invasive pathogens were isolated from 24% and 76% of the patients. FOBT and LT were positive in 40% and 39% of the samples. The sensitivities, specificities, PPVs, NPVs, and accuracies of FOBT were 55, 63, 24, 87 and 62%, and LT were 52, 64, 23, 86 and 62%, respectively. CONCLUSION: FOBT and LT are not useful in differentiating ID from NID in diarrhoeal patients in Dhaka, Bangladesh.

Diagnosis of Tuberculosis Following World Health Organization-Recommended Criteria in Severely Malnourished Children Presenting With Pneumonia.

Evidences on diagnosis of tuberculosis (TB) following the World Health Organization (WHO) criteria in children with severe acute malnutrition (SAM) are lacking. We sought to evaluate the WHO criteria for the diagnosis of TB in such children. In this prospective study, we enrolled SAM children aged <5 with radiological pneumonia. We collected induced sputum and gastric lavage for smear microscopy, mycobacterial culture, and Xpert MTB/RIF. Using the last 2 methods as the gold standard, we determined sensitivity, specificity, and positive and negative predictive values of WHO criteria (n = 388). However, Xpert MTB/RIF was performed on the last 214 children. Compared to mycobacterial culture-confirmed TB, sensitivity and specificity (95% confidence interval) of WHO criteria were 40 (14% to 73%) and 84 (80% to 87%), respectively. Compared to culture- and/or Xpert MTB/RIF-confirmed TB, the values were 22% (9% to 43%) and 83 (79% to 87%), respectively. Thus, the good specificity of the WHO criteria may help minimize overtreatment with anti-TB therapy in SAM children, especially in resource-limited settings.

Risk Factors for Death in Bangladeshi Children Under 5 Years of Age Hospitalized for Diarrhea and Severe Respiratory Distress in an Urban Critical Care Ward.

Children with diarrhea hospitalized for respiratory distress often have fatal outcome in resource-limited settings, although data are lacking on risk factors for death in such children. We sought to evaluate clinical predictors for death in such children. In this prospective cohort study, we enrolled under-5 children with diarrhea admitted with severe respiratory distress to the intensive care unit of Dhaka Hospital of International Centre for Diarhoeal Disease Research, Bangladesh, from September 2014 through September 2015. We compared clinical and laboratory characteristics between study children those who died (n = 29) and those who survived (n = 62). In logistic regression analysis, after adjusting for potential confounders, the independent predictors for death in children hospitalized for diarrhea and severe respiratory distress were severe sepsis and hypoglycemia (P < .05 for all). Thus, recognition of these simple parameters may help clinicians identify children with diarrhea at risk of deaths in order to initiate prompt management for the better outcome, especially in resource-poor settings.

Ileus in children presenting with diarrhea and severe acute malnutrition: A chart review.

BACKGROUND: Severely malnourished children aged under five years requiring hospital admission for diarrheal illness frequently develop ileus during hospitalization with often fatal outcomes. However, there is no data on risk factors and outcome of ileus in such children. We intended to evaluate predictive factors for ileus during hospitalization and their outcomes. METHODOLOGY/PRINCIPAL FINDINGS: This was a retrospective chart review that enrolled severely malnourished children under five years old with diarrhea, admitted to the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh between April 2011 and August 2012. We used electronic database to have our chart abstraction from previously admitted children in the hospital. The clinical and laboratory characteristics of children with (cases = 45), and without ileus (controls = 261) were compared. Cases were first identified by observation of abnormal bowel sounds on physical examination and confirmed with abdominal radiographs. For this comparison, Chi-square test was used to measure the difference in proportion, Student's t-test to calculate the difference in mean for normally distributed data and Mann-Whitney test for data that were not normally distributed. Finally, in identifying independent risk factors for ileus, logistical regression analysis was performed. Ileus was defined if a child developed abdominal distension and had hyperactive or sluggish or absent bowel sound and a radiologic evidence of abdominal gas-fluid level during hospitalization. Logistic regression analysis adjusting for potential confounders revealed that the independent risk factors for admission for ileus were reluctance to feed (odds ratio [OR] = 3.22, 95% confidence interval [CI] = 1.24-8.39, p = 0.02), septic shock (OR = 3.62, 95% CI = 1.247-8.95, p<0.01), and hypokalemia (OR = 1.99, 95% CI = 1.03-3.86, p = 0.04). Mortality was significantly higher in cases compared to controls (22% vs. 8%, p<0.01) in univariate analysis; however, in multivariable regression analysis, after adjusting for potential confounders such as septic shock, no association was found between ileus and death (OR = 2.05, 95% CI = 0.68-6.14, p = 0.20). In a separate regression analysis model, after adjusting for potential confounders such as ileus, reluctance to feed, hypokalemia, hypocalcemia, and blood transfusion, septic shock (OR = 168.84, 95% CI = 19.27-1479.17, p<0.01) emerged as the only independent predictor of death in severely malnourished diarrheal children. CONCLUSIONS/SIGNIFICANCE: This study suggests that the identification of simple independent admission risk factors for ileus and risk factors for death in hospitalized severely malnourished diarrheal children may prompt clinicians to be more vigilant in managing these conditions, especially in resource-limited settings in order to decrease ileus and ileus-related fatal outcomes in such children.

Impact of Diarrhea on the Clinical Presentation and Outcome of Severe Pneumonia in Bangladeshi Children.

We compared clinical presentation and outcome of 225 children with severe pneumonia between those with and those without diarrhea. Having diarrhea was associated with metabolic acidosis (P < 0.001) and hypocalcemia (P = 0.002) on presentation, and with a fatal outcome: 20/113 (20%) died with diarrhea versus 3/112 (3%) without diarrhea. Diarrhea is an important comorbidity in Bangladeshi children with severe pneumonia requiring attention for improved case management.

Hypernatremia in Children With Diarrhea: Presenting Features, Management, Outcome, and Risk Factors for Death.

We sought to investigate the magnitude, clinical features, treatment, and outcome of children suffering from hypernatremic diarrhea and to identify risk factors for fatal outcome among them. We reviewed 2 data sets of children <15 years admitted to the in-patient ward of the Dhaka Hospital of International Centre for Diarrhoeal Disease Research, Bangladesh (icddr, b) with diarrhea and hypernatremia (serum sodium ≥150 mmol/L): (a) March 2001 to March 2002 (n = 371) and (b) March 2009 to August 2011 (n = 360). We reviewed their records and collected relevant information for analyses. The prevalence of hypernatremia was 5.1% (371/7212) and 2.4% (360/15 219), case fatality rate was 15% and 19%, respectively. In logistic regression analysis, the risk for death significantly increased in association with serum sodium ≥170 mmol/L, nutritional edema, hypoglycemia, respiratory distress, and absent peripheral pulses and reduced with the sole use of oral rehydration salts (ORS) or ORS following intravenous fluid, if indicated (for all, P < .05). Thus, managing children with hypernatremia using only ORS or ORS following intravenous fluid may help reduce the number of deaths.

Factors Associated with Streptococcal Bacteremia in Diarrheal Children under Five Years of Age and Their Outcome in an Urban Hospital in Bangladesh.

BACKGROUND: Although Streptococcal bacteremia is common in diarrheal children with high morbidity and mortality, no systematic data are available on Streptococcal bacteremia in diarrheal children. We sought to evaluate the factors associated with Streptococcal bacteremia in diarrheal children under five years of age and their outcome. METHODS: We used an unmatched case-control design to investigate the associated factors with Streptococcal bacteremia in all the diarrheal children under five years of age through electronic medical record system of Dhaka hospital of International Centre for Diarrhoeal Disease Research, Bangladesh. We had simultaneously used a retrospective cohort design to further evaluate the outcome of our study children. All the enrolled children had their blood culture done between January 2010 and December 2012. Comparison was made among the children with (cases = 26) and without Streptococcal bacteremia (controls = 78). Controls were selected randomly from hospitalized diarrheal children under five years of age. RESULTS: Cases had proportionately higher deaths compared to controls, but it was statistically insignificant (15% vs. 10%, p = 0.49). The cases more often presented with severe dehydration, fever, respiratory distress, severe sepsis, and abnormal mental status compared to the controls (for all p<0.05). In the logistic regression analysis, after adjusting for potential confounders, it has been found that Streptococcal bacteremia in diarrheal children under five years of age was independently associated with nutritional edema (OR: 5.86, 95% CI = 1.28-26.80), hypoxemia (OR: 19.39, 95% CI = 2.14-175.91), fever (OR: 4.44, 95% CI = 1.13-17.42), delayed capillary refill time (OR: 7.00, 95% CI = 1.36-35.93), and respiratory distress (OR: 2.69, 95% CI = 1.02-7.12). CONCLUSIONS AND SIGNIFICANCE: The results of our analyses suggest that diarrheal children under five years of age presenting with nutritional edema, hypoxemia, fever, delayed capillary refill time, and respiratory distress may be at risk of Streptococcal bacteremia. It underscores the importance of identification of these simple clinical parameters for the prompt recognition and management in order to reduce the morbidity and death of such children especially in resource limited settings.

Factors Associated with Non-typhoidal Salmonella Bacteremia versus Typhoidal Salmonella Bacteremia in Patients Presenting for Care in an Urban Diarrheal Disease Hospital in Bangladesh.

BACKGROUND: Non-typhoidal Salmonella (NTS) and Salmonella enterica serovar Typhi bacteremia are the causes of significant morbidity and mortality worldwide. There is a paucity of data regarding NTS bacteremia in South Asia, a region with a high incidence of typhoidal bacteremia. We sought to determine clinical predictors and outcomes associated with NTS bacteremia compared with typhoidal bacteremia. METHODOLOGY: We performed a retrospective age-matched case-control study of patients admitted to the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh, between February 2009 and March 2013. We compared demographic, clinical, microbiological, and outcome variables of NTS bacteremic patients with age-matched S. Typhi bacteremic patients, and a separate comparison of patients with NTS bacteremia and patients with NTS gastroenteritis. PRINCIPAL FINDINGS: Of 20 patients with NTS bacteremia, 5 died (25% case fatality), compared to none of 60 age-matched cases of S. Typhi bacteremia. In univariate analysis, we found that compared with S. Typhi bacteremia, cases of NTS bacteremia had more severe acute malnutrition (SAM) in children under five years of age, less often presented with a duration of fever ≥ 5 days, and were more likely to have co-morbidities on admission such as pneumonia and clinical signs of sepsis (p<0.05 in all cases). In multivariable logistic regression, SAM, clinical sepsis, and pneumonia were independent risk factors for NTS bacteremia compared with S. Typhi bacteremia (p<0.05 in all cases). Notably, we found marked differences in antibiotic susceptibilities, including NTS strains resistant to antibiotics commonly used for empiric therapy of patients suspected to have typhoid fever. CONCLUSIONS/SIGNIFICANCE: Diarrheal patients with NTS bacteremia more often presented with co-morbidities and had a higher case fatality rate compared to those with typhoidal bacteremia. Clinicians in regions where both typhoid and NTS bacteremia are prevalent need to be vigilant about the possibility of both entities, especially given notable differences in antibiotic susceptibility patterns.

Sociodemographic, Epidemiological, and Clinical Risk Factors for Childhood Pulmonary Tuberculosis in Severely Malnourished Children Presenting With Pneumonia: Observation in an Urban Hospital in Bangladesh.

We aimed to evaluate sociodemographic, epidemiological, and clinical risk factors for pulmonary tuberculosis (PTB) in children presenting with severe acute malnutrition (SAM) and pneumonia. Children aged 0 to 59 months with SAM and radiologic pneumonia from April 2011 to July 2012 were studied in Bangladesh. Children with confirmed PTB (by culture and/or X-pert MTB/RIF) (cases = 27) and without PTB (controls = 81; randomly selected from 378 children) were compared. The cases more often had the history of contact with active PTB patient (P < .01) and exposure to cigarette smoke (P = .04) compared with the controls. In logistic regression analysis, after adjusting for potential confounders, the cases were independently associated with working mother (P = .05) and positive tuberculin skin test (TST; P = .02). Thus, pneumonia in SAM children is a common presentation of PTB and further highlights the importance of the use of simple TST and/or history of contact with active TB patients in diagnosing PTB in such children, especially in resource-limited settings.

Treatment Failure and Mortality amongst Children with Severe Acute Malnutrition Presenting with Cough or Respiratory Difficulty and Radiological Pneumonia.

BACKGROUND: Appropriate intervention is critical in reducing deaths among under-five, severe acutely malnourished (SAM) children with danger signs of severe pneumonia; however, there is paucity of data on outcome of World Health Organisation (WHO) recommended interventions of SAM children with severe pneumonia. We sought to evaluate outcome of the interventions in such children. METHODS: We prospectively enrolled SAM children aged 0-59 months, admitted to the Intensive Care Unit (ICU) or Acute Respiratory Infection (ARI) ward of the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), between April 2011 and June 2012 with cough or respiratory difficulty and radiological pneumonia. All the enrolled children were treated with ampicillin and gentamicin, and micronutrients as recommended by the WHO. Comparison was made among pneumonic children with (n = 111) and without WHO defined danger signs of severe pneumonia (n = 296). The outcomes of interest were treatment failure (if a child required changing of antibiotics) and deaths during hospitalization. Further comparison was also made among those who developed treatment failure and who did not and among the survivors and deaths. RESULTS: SAM children with danger signs of severe pneumonia more often experienced treatment failure (58% vs. 20%; p<0.001) and fatal outcome (21% vs. 4%; p<0.001) compared to those without danger signs. Only 6/111 (5.4%) SAM children with danger signs of severe pneumonia and 12/296 (4.0%) without danger signs had bacterial isolates from blood. In log-linear binomial regression analysis, after adjusting for potential confounders, danger signs of severe pneumonia, dehydration, hypocalcaemia, and bacteraemia were independently associated both with treatment failure and deaths in SAM children presenting with cough or respiratory difficulty and radiological pneumonia (p<0.01). CONCLUSION AND SIGNIFICANCE: The result suggests that SAM children with cough or respiratory difficulty and radiologic pneumonia who had WHO-defined danger signs of severe pneumonia more often had treatment failure and fatal outcome compared to those without the danger signs. In addition to danger signs of severe pneumonia, other common causes of both treatment failure and deaths were dehydration, hypocalcaemia, and bacteraemia on admission. The result underscores the importance for further research especially a randomized, controlled clinical trial to validate standard WHO therapy in SAM children with pneumonia especially with danger signs of severe pneumonia to reduce treatment failures and deaths.

Severe Sepsis in Severely Malnourished Young Bangladeshi Children with Pneumonia: A Retrospective Case Control Study.

BACKGROUND: In developing countries, there is no published report on predicting factors of severe sepsis in severely acute malnourished (SAM) children having pneumonia and impact of fluid resuscitation in such children. Thus, we aimed to identify predicting factors for severe sepsis and assess the outcome of fluid resuscitation of such children. METHODS: In this retrospective case-control study SAM children aged 0-59 months, admitted to the Intensive Care Unit (ICU) of the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh from April 2011 through July 2012 with history of cough or difficult breathing and radiologic pneumonia, who were assessed for severe sepsis at admission constituted the study population. We compared the pneumonic SAM children with severe sepsis (cases = 50) with those without severe sepsis (controls = 354). Severe sepsis was defined with objective clinical criteria and managed with fluid resuscitation, in addition to antibiotic and other supportive therapy, following the standard hospital guideline, which is very similar to the WHO guideline. RESULTS: The case-fatality-rate was significantly higher among the cases than the controls (40% vs. 4%; p<0.001). In logistic regression analysis after adjusting for potential confounders, lack of BCG vaccination, drowsiness, abdominal distension, acute kidney injury, and metabolic acidosis at admission remained as independent predicting factors for severe sepsis in pneumonic SAM children (p<0.05 for all comparisons). CONCLUSION AND SIGNIFICANCE: We noted a much higher case fatality among under-five SAM children with pneumonia and severe sepsis who required fluid resuscitation in addition to standard antibiotic and other supportive therapy compared to those without severe sepsis. Independent risk factors and outcome of the management of severe sepsis in our study children highlight the importance for defining optimal fluid resuscitation therapy aiming at reducing the case fatality in such children.