Low Rate of Infectious Enterocolitis in Allogeneic Stem Cell Transplant Recipients with Acute Diarrhea: A Prospective Study by the GETH-TC.

Acute diarrhea is a common and debilitating complication in recipients of allogeneic hematopoietic stem cell transplantation (HCT). In this prospective, observational, and multicenter study we examined all episodes occurring in the first 6 months of 142 consecutive adult patients who underwent a reduced-intensity conditioning HCT in 10 Spanish tertiary university hospitals. Fifty-four patients (38%) developed a total of 75 acute diarrhea episodes. The median time from HCT to the first episode was 38 days (4-157). The main cause of enterocolitis was lower GI-aGVHD (38%), followed by infections (21%) and drug-related toxicity (8%). Causative infectious causes were identified in only 16/75 episodes (21%). C. difficile-related infection was the most common infectious agent with an incidence and recurrence of 13% and 2%, respectively. With a median follow-up for survivors of 32 months, the non-relapse mortality (NRM) and the overall survival (OS) at 1 year, were 20% (95% C.I.: 14-28%) and 69% (95% C.I.: 61-77%), respectively. Development of enterocolitis was not associated with higher NRM (p = 0.37) or worse OS (p = 0.9). This real-life study confirms that the diagnosis and management of acute diarrhea in the early stages after HCT is challenging. Nosocomial infections seem to be relatively uncommon, probably due to more rational use of antibiotics.

Timing of neonatal mortality and severe morbidity during the postnatal period: a systematic review.

OBJECTIVE: The objective of this review was to determine the timing of overall and cause-specific neonatal mortality and severe morbidity during the postnatal period (1-28 days). INTRODUCTION: Despite significant focus on improving neonatal outcomes, many newborns continue to die or experience adverse health outcomes. While evidence on neonatal mortality and severe morbidity rates and causes are regularly updated, less is known on the specific timing of when they occur in the neonatal period. INCLUSION CRITERIA: This review considered studies that reported on neonatal mortality daily in the first week; weekly in the first month; or day 1, days 2-7, and days 8-28. It also considered studies that reported on timing of severe neonatal morbidity. Studies that reported solely on preterm or high-risk infants were excluded, as these infants require specialized care. Due to the available evidence, mixed samples were included (eg, both preterm and full-term infants), reflecting a neonatal population that may include both low-risk and high-risk infants. METHODS: MEDLINE, Embase, Web of Science, and CINAHL were searched for published studies on December 20, 2019, and updated on May 10, 2021. Critical appraisal was undertaken by 2 independent reviewers using standardized critical appraisal instruments from JBI. Quantitative data were extracted from included studies independently by 2 reviewers using a study-specific data extraction form. All conflicts were resolved through consensus or discussion with a third reviewer. Where possible, quantitative data were pooled in statistical meta-analysis. Where statistical pooling was not possible, findings were reported narratively. RESULTS: A total of 51 studies from 36 articles reported on relevant outcomes. Of the 48 studies that reported on timing of mortality, there were 6,760,731 live births and 47,551 neonatal deaths with timing known. Of the 34 studies that reported daily deaths in the first week, the highest proportion of deaths occurred on the first day (first 24 hours, 38.8%), followed by day 2 (24-48 hours, 12.3%). Considering weekly mortality within the first month (n = 16 studies), the first week had the highest mortality (71.7%). Based on data from 46 studies, the highest proportion of deaths occurred on day 1 (39.5%), followed closely by days 2-7 (36.8%), with the remainder occurring between days 8 and 28 (23.0%). In terms of causes, birth asphyxia accounted for the highest proportion of deaths on day 1 (68.1%), severe infection between days 2 and 7 (48.1%), and diarrhea between days 8 and 28 (62.7%). Due to heterogeneity, neonatal morbidity data were described narratively. The mean critical appraisal score of all studies was 84% (SD = 16%). CONCLUSION: Newborns experience high mortality throughout the entire postnatal period, with the highest mortality rate in the first week, particularly on the first day. Ensuring regular high-quality postnatal visits, particularly within the first week after birth, is paramount to reduce neonatal mortality and severe morbidity.

Incidence and predictors of severe acute malnutrition mortality in children aged 6-59 months admitted at Pawe general hospital, Northwest Ethiopia.

BACKGROUND: Severe acute malnutrition (SAM) is defined as a weight-for-height < -3z scores of the median WHO growth standards, or visible severe wasting or the presence of nutritional edema. SAM related mortality rates in under-five children are well documented in Ethiopia but data on their predictors are limited. We aimed to document factors associated with SAM related mortality to inform better inpatient management. METHODS: A facility-based retrospective cohort study was conducted among children admitted due to SAM at Pawe General Hospital, Northwest Ethiopia, from the 1st of January 2015 to the 31st of December 2019. Data from the records of SAM children were extracted using a standardized checklist. Epi-Data version 3.2 was used for data entry, and Stata version 14 was used for analysis. Bi-variable and multivariable Cox regression analyses were conducted to identify predictors of mortality. Variables with P<0.05 were considered significant predictors of mortality. RESULTS: Five-hundred sixty-eight SAM cases were identified of mean age was 27.4 (SD± 16.5) months. The crude death rate was 91/568 (16.02%) and the mean time to death was determined as 13 (±8) days. Independent risk factors for death were: (i) vomiting AHR = 5.1 (1.35-21.1, p = 0.026), (ii) diarrhea AHR = 2.79 (1.46-5.4, p = 0.002), (iii) needing nasogastric therapy AHR = 3.22 (1.65-6.26, p = 0.001), (iv) anemia AHR = 1.89 (1.15-3.2, p = 0.012), and (v) being readmitted with SAM AHR = 1.7 (1.12-2.8, p = 0.037). CONCLUSION: SAM mortality was high in under-five children in our setting. The identified risk factors should inform treatment and prevention strategies. Improved community health education should focus on healthy nutrition and seeking early treatment. Inpatient mortality may be reduced by stricter adherence to treatment guidelines and recognizing early the key risk factors for death.

Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings: A Randomized Clinical Trial.

Importance: World Health Organization (WHO) guidelines do not recommend routine antibiotic use for children with acute watery diarrhea. However, recent studies suggest that a significant proportion of such episodes have a bacterial cause and are associated with mortality and growth impairment, especially among children at high risk of diarrhea-associated mortality. Expanding antibiotic use among dehydrated or undernourished children may reduce diarrhea-associated mortality and improve growth. Objective: To determine whether the addition of azithromycin to standard case management of acute nonbloody watery diarrhea for children aged 2 to 23 months who are dehydrated or undernourished could reduce mortality and improve linear growth. Design, Setting, and Participants: The Antibiotics for Children with Diarrhea (ABCD) trial was a multicountry, randomized, double-blind, clinical trial among 8266 high-risk children aged 2 to 23 months presenting with acute nonbloody diarrhea. Participants were recruited between July 1, 2017, and July 10, 2019, from 36 outpatient hospital departments or community health centers in a mixture of urban and rural settings in Bangladesh, India, Kenya, Malawi, Mali, Pakistan, and Tanzania. Each participant was followed up for 180 days. Primary analysis included all randomized participants by intention to treat. Interventions: Enrolled children were randomly assigned to receive either oral azithromycin, 10 mg/kg, or placebo once daily for 3 days in addition to standard WHO case management protocols for the management of acute watery diarrhea. Main Outcomes and Measures: Primary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment. Results: A total of 8266 children (4463 boys [54.0%]; mean [SD] age, 11.6 [5.3] months) were randomized. A total of 20 of 4133 children in the azithromycin group (0.5%) and 28 of 4135 children in the placebo group (0.7%) died (relative risk, 0.72; 95% CI, 0.40-1.27). The mean (SD) change in length-for-age z scores 90 days after enrollment was -0.16 (0.59) in the azithromycin group and -0.19 (0.60) in the placebo group (risk difference, 0.03; 95% CI, 0.01-0.06). Overall mortality was much lower than anticipated, and the trial was stopped for futility at the prespecified interim analysis. Conclusions and Relevance: The study did not detect a survival benefit for children from the addition of azithromycin to standard WHO case management of acute watery diarrhea in low-resource settings. There was a small reduction in linear growth faltering in the azithromycin group, although the magnitude of this effect was not likely to be clinically significant. In low-resource settings, expansion of antibiotic use is not warranted. Adherence to current WHO case management protocols for watery diarrhea remains appropriate and should be encouraged. Trial Registration: ClinicalTrials.gov Identifier: NCT03130114.

Taking care of a diarrhea epidemic in an urban hospital in Bangladesh: Appraisal of putative causes, presentation, management, and deaths averted.

BACKGROUND: In April 2018, a diarrhea epidemic broke out in Dhaka city and adjoining areas, which continued through May. The Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), a dedicated diarrheal disease hospital, had a large upsurge in patient visits during the epidemic. An enhanced understanding of the epidemiology of this epidemic may help health-related professionals better prepare for such events in the future. This study examined the microbial etiology and non-pathogen factors associated with diarrhea during the epidemic. The study also evaluated the patients' presentation and clinical course and estimated the potential mortality averted by treating patients during the epidemic. METHODOLOGY/PRINCIPAL FINDINGS: Data from the patients who were treated at Dhaka Hospital during the diarrhea epidemic between April 2 and May 12, 2018 and were enrolled into the Diarrheal Disease Surveillance System (DDSS) at icddr,b were compared with the DDSS-enrolled patients treated during the seasonally-matched periods in the flanking years using logistic regression. icddr,b Dhaka Hospital treated 29,212 diarrheal patients during the 2018 epidemic period (and 25,950 patients per comparison period on average). Vibrio cholerae was the most common pathogen isolated (7,946 patients; 27%) and associated with diarrhea during the epidemic (adjusted odds ratio [AOR] 1.5, 95% CI: 1.1-2.0). The interaction of Vibrio cholerae with ETEC (AOR 2.7, 95% CI: 1.3-5.9) or Campylobacter (AOR 2.4, 95% CI: 1.1-5.1) was associated with further increased odds of diarrhea during the epidemic. In children under five years old, rotavirus was the most common pathogen (2,029 patients; 26%). Those who were adolescents (AOR 2.0, 95% CI: 1.3-3.1) and young adults (AOR 1.9, 95% CI: 1.4-2.5) compared to children younger than five years, resided within a 10 km radius of Dhaka Hospital (AOR 1.6, 95% CI: 1.1-2.2) compared to those living outside 20 km, borrowed money or relied on aid to pay for the transport to the hospital (AOR 1.6, 95% CI: 1.2-2.0), used tap water (AOR 1.8, 95% CI: 1.4-2.4) for drinking compared to tubewell water, and disposed of the solid waste directly outside the house (AOR 4.0, 95% CI: 2.7-5.9) were more likely to present with diarrhea during the epidemic. During the epidemic, patients were more likely to present with severe dehydration (odds ratio [OR] 1.6, 95% CI: 1.3-2.0) and require inpatient admission (OR 2.5, 95% CI: 1.9-3.3), intravenous rehydration (OR 1.7, 95% CI: 1.4-2.1), and antibiotics (OR 2.2, 95% CI: 1.8-2.7). The in-hospital case fatality rate was low (13 patients; 0.04%), and the hospital averted between 12,523 and 17,265 deaths during the epidemic. CONCLUSIONS/SIGNIFICANCE: Vibrio cholerae played the primary role in the 2018 diarrhea epidemic in Dhaka. Campylobacter, enterotoxigenic Escherichia coli, and rotavirus had a secondary role. Adolescents and adults, residents of the metropolitan area, and those who were relatively poor and lacked safe water, sanitation, and hygiene (WASH) practices comprised the most vulnerable groups. Despite the increased disease severity during the epidemic, the case fatality rate was less than 0.1%. icddr,b Dhaka Hospital saved as many as 17,265 lives during the epidemic.

Cost-effectiveness analysis of integrated community case management delivery models utilizing drug sellers and community health workers for treatment of under-five febrile cases of malaria, pneumonia, diarrhoea in rural Uganda.

BACKGROUND: Malaria, pneumonia and diarrhoea continue to be the leading causes of death in children under the age of five years (U5) in Uganda. To combat these febrile illnesses, integrated community case management (iCCM) delivery models utilizing community health workers (CHWs) or drug sellers have been implemented. The purpose of this study is to compare the cost-effectiveness of delivering iCCM interventions via drug sellers versus CHWs in rural Uganda. METHODS: This study was a cost-effectiveness analysis to compare the iCCM delivery model utilizing drug sellers against the model using CHWs. The effect measure was the number of appropriately treated U5 children, and data on effectiveness came from a quasi-experimental study in Southwestern Uganda and the inSCALE cross-sectional household survey in eight districts of mid-Western Uganda. The iCCM interventions were costed using the micro-costing (ingredients) approach, with costs expressed in US dollars. Cost and effect data were linked together using a decision tree model and analysed using the Amua modelling software. RESULTS: The costs per 100 treated U5 children were US$591.20 and US$298.42 for the iCCM trained-drug seller and iCCM trained-CHW models, respectively, with 30 and 21 appropriately treated children in the iCCM trained-drug seller and iCCM trained-CHW models. When the drug seller arm (intervention) was compared to the CHW arm (control), an incremental effect of 9 per 100 appropriately treated U5 children was observed, as well as an incremental cost of US$292.78 per 100 appropriately treated children, resulting in an incremental cost-effectiveness ratio (ICER) of US$33.86 per appropriately treated U5 patient. CONCLUSION: Since both models were cost-effective compared to the do-nothing option, the iCCM trained-drug seller model could complement the iCCM trained-CHW intervention as a strategy to increase access to quality treatment.

Causes of death after biannual azithromycin treatment: A community-level randomized clinical trial.

The MORDOR study, a masked, community-level randomized clinical trial conducted in Niger, Malawi and Tanzania (2015 to 2017), showed that biannual administration of single-dose azithromycin to preschool children reduced all-cause mortality. We sought to evaluate its impact on causes of death in children aged 1-59 months in Tanzania. A random sampling of 614 communities was conducted in Kilosa District, Tanzania, with simple random assignment of communities to receive either azithromycin or placebo. In these communities, a census was carried out every 6 months and children aged 1-59 months received biannual (every 6 months), single-dose azithromycin (~20mg/kg) or placebo depending on community assignment, over a 2-year period. Mortality was determined at the time of the biannual census. For child deaths, a verbal autopsy was performed to ascertain the cause using a standardized diagnostic classification. A total of 190- (0.58 /100 person-years) and 200 deaths (0.59/100 person-years) were reported in the azithromycin and placebo arms, respectively. Malaria, pneumonia and diarrhea, accounted for 71% and 68% of deaths in the respective arms. Overall, the mortality was not different by treatment arm, nor were the distribution of causes of death after adjusting for community clustering. The cause-specific mortality for diarrhea/pneumonia was no different over time. In children aged 1-5 months, 32 deaths occurred in the placebo arm and 25 deaths occurred in the azithromycin arm; 20 (62.5%) deaths in the placebo- and 10 (40%) in the azithromycin arm were attributed to diarrhea or pneumonia. Neither differences in the number of deaths nor the diarrhea/pneumonia attribution was statistically significant after adjusting for community clustering. In conclusion, azithromycin was not associated with a significant decline in deaths by specific causes compared to placebo. The non-significant lower rates of diarrhea or pneumonia in children <6 months who received azithromycin merit further investigation in high-mortality settings. Trial registration: NCT02048007.

Serum Albumin to Creatinine Ratio as Predictor for 30-Day All-Cause Mortality in Patients with Clostridium Di!cile-Associated Diarrhea.

BACKGROUND: Clostridium difficile-associated diarrhea (CDAD) is a significant cause of mortality and morbidity in hospitalized patients. Several scores have developed in order to assess the severity of CDAD. OBJECTIVE: To determine the role of the serum albumin to creatinine ratio (sACR) in predicting the 30-day all-cause mortality of patients with CDAD in comparison with other known severity scores of CDAD. METHODS: A retrospective study was conducted at Baruch-Padeh Medical Center from January 2014 to December 2019. Patients with CDAD were recruited from Internal Medicine Departments, Intensive Care Units, and Surgical Departments. Data on demographic characteristics, clinical signs, underlying conditions, and several risk factors for CD infection were collected. We compared between severity scores of CDAD, such as ATLAS, the CDAD severity score, and the sACR in predicting the 30-day all-cause mortality in hospitalized patients with CDAD. RESULTS: 116 patients with CDAD were included. The ATLAS, CDAD scores, and sACR were calculated for all patients. The mean age of the participants was 71.4±16.4 years. 57.7% were of female gender. Fifty-two (44.8%) died within 30 days. An ATLAS score of ≥8 points had a 3.6-fold higher risk of 30-day all-cause mortality in hospitalized patients with CDAD (HR 3.6, 95% CI 3.28-3.99, p=0.001), a CDAD score of ≥5 points (HR 1.1, 95% CI 0.91-1.42, p=0.05), and a sACR≤3.4 (HR 1.5, 95%CI 1.25-1.82, p=0.04). CONCLUSION: In this study, it was found that a sACR≤3.4 could predict the 30-day all-cause mortality in patients with CDAD.

Outcomes of Immune Checkpoint Inhibitor-related Diarrhea or Colitis in Cancer Patients With Superimposed Gastrointestinal Infections.

BACKGROUND AND OBJECTIVE: Immune-mediated diarrhea and colitis (IMDC) is a common adverse event in cancer patients receiving immune checkpoint inhibitors (ICIs). Gastrointestinal (GI) infections can co-occur with IMDC, and its impact on the course and outcome of IMDC remains unclear. PATIENTS AND METHODS: We retrospectively reviewed cancer patients who received ICIs and developed IMDC between January 2015 and September 2019. GI multiplex panel is used to assess GI infection. The study group included patients with positive infection except those who are only positive for Clostridioides difficile or cytomegalovirus. The control group is IMDC patients with negative infection using frequency matching. Patients' disease course and outcome were compared between groups. RESULTS: A total of 72 patients with IMDC were included: 22 in the study group and 50 as control. Escherichia coli of different pathotypes was observed in 17 patients. Five patients had viral infections, for example, adenovirus, norovirus, and sapovirus. Patients with GI infections more frequently had grade 3 or 4 colitis (43% vs. 18%, P=0.041). Overall, GI infections were not associated with different risks of IMDC recurrence or overall survival. Antibiotics treatment did not affect the requirement for infliximab or vedolizumab but relate to a higher risk of IMDC recurrence (50.0% vs. 0.0%, P=0.015). CONCLUSIONS: In our study, concomitant GI infections are associated with more severe symptoms in IMDC patients. Antimicrobial treatment did not circumvent the need for immunosuppressive therapy for IMDC or improve the clinical outcome. Concomitant GI infection was not associated with a higher risk of IMDC recurrence or poor overall survival.

Deprived areas and community water fluoridation in Brazil: a multilevel approach for refocusing public policy.

OBJECTIVES: The aim of this study was to determine whether geographic location, socioeconomic status, infant mortality, and mortality from diarrheal disease in health regions are associated with the provision of community water fluoridation (CWF) in Brazilian municipalities. METHODS: A multilevel ecological study was conducted based on data from the National Survey of Basic Sanitation and Human Development Atlas. A multilevel analysis was carried out considering Brazilian municipalities as the first level and health regions as the second level, comprising sanitation, demographic, socioeconomic, and health characteristics. RESULTS: The observation units comprised 5,565 municipalities clustered in 438 health regions in Brazil. The lack of CWF provision was positively associated with the following municipal characteristics: a below-median proportion of inhabitants covered by the sewage network, medium to very low human development index, below-median per capita gross domestic product, and an above-median percentage of expenditures on sanitation. In relation to the health regions, the likelihood of a lack of CWF provision was greater in the municipalities belonging to the health regions located in the Northern and Northeastern areas of Brazil and in those where child mortality due to acute diarrheal disease and the proportion of people with low income were higher when adjusted by municipal indicators. CONCLUSIONS: Information on the characteristics associated with CWF provision constitutes important input for refocusing public policy to reduce inequalities among Brazilian municipalities and health regions. These findings may help policy-makers to understand the challenges facing CWF expansion in low-, middle-, and high-income countries.

Prevalence of common symptoms of neonatal illness in Northwest Ethiopia: A repeated measure cross-sectional study.

BACKGROUND: The neonatal period is the most vulnerable stage of life. In Ethiopia, neonatal illness is common and the reduction in neonatal mortality is not as significant as for under-five mortality. OBJECTIVES: To determine the prevalence and factors associated with neonatal illness symptoms reported by mothers delivering in health facilities in Northwest Ethiopia. METHODS: A repeated measure cross-sectional study design was employed to collect data from 358 randomly selected deliveries in 11 health facilities from November 2018 to March 2019. A pretested and interviewer-administered structured questionnaire adapted from the literature was employed to record neonatal outcomes (illnesses and/or deaths) at birth, 24 hours, 7th, 14th and 28th day from birth. Cleaned data was exported to STATA version 14 software for analysis. Multilevel analysis was used to identify individual and facility-level characteristics associated with neonatal illness symptoms. RESULTS: The prevalence of neonatal illness symptoms was 27.8% (95% CI; 23.2, 32.8) of the 338 babies born alive and the neonatal mortality rate was 41/1000 live births (14/338). The most common symptoms or conditions of neonatal illness reported by mothers' in the study area were possible serious bacterial infections (95.8%, 90/94), localized bacterial infections (43.6%, 41/94), low birth weight (23.4%, 22/94), diarrhea (18.1%, 17/94), prematurity (14.9%, 14/94), and jaundice (7.5%, 7/94). Among the babies who died, neonates who had possible serious bacterial infections, low birth weight, localized bacterial infections, and prematurity took the highest proportions with 100% (14/14), 64.3% (9/14), 50% (7/14), and 42.9% (6/14), respectively. Having a maximum of 3 children (AOR = 1.96; 95% CI = 1.1-3.6), having twins or triplets during pregnancy (AOR = 2.43; 95% CI = 1.1-6.1), and lack of antenatal counseling (AOR = 1.83; 95% CI = 1.1-3.3) were among the maternal factors associated with neonatal illness. Having low birth length (AOR = 7.93; 95% CI = 3.6-17.3), and having a poor breastfeeding quality (AOR = 2.37; 95% CI = 1.4-4.0) were found to be the neonatal factors associated with neonatal illness. CONCLUSIONS: This study indicated a high prevalence of neonatal illness symptoms in Northwest Ethiopia. Therefore, early detection, referral and better management of symptoms or conditions with a high mortality, like sepsis and low birth weight are compulsory to save the lives of many neonates. Strengthening the health extension programme to improve antenatal care service utilization and breastfeeding quality of neonates among postpartum women is crucial.

Causes of neonatal calf diarrhea and mortality in pasture-based dairy herds in Uruguay: a farm-matched case-control study.

Neonatal calf diarrhea (NCD) and mortality cause significant losses to the dairy industry. The preweaning dairy calf mortality risk in Uruguay is high (15.2%); however, causes for these losses are largely unknown. This study aimed to assess whether various pathogens were associated with NCD and death in Uruguayan dairy calves and whether these infections, diarrhea, or deaths were associated with the failure of transfer of passive immunity (FTPI). Contemporary diarrheic (n = 264,) and non-diarrheic (n = 271) 1- to 30-day-old calves from 27 farms were sampled. Feces were analyzed by antigen-capture ELISA for Cryptosporidium spp., rotavirus, bovine coronavirus, and Escherichia coli F5+, RT-PCR for bovine astrovirus (BoAstV), and bacterial cultures for Salmonella enterica. Blood/serum was analyzed by RT-PCR or antigen-capture ELISA for bovine viral diarrhea virus (BVDV). Serum of ≤ 8-day-old calves (n = 95) was assessed by refractometry to determine the concention of serum total proteins (STP) as an indicator of FTPI. Whether the sampled calves died before weaning was recorded. At least one pathogen was detected in 65.4% of the calves, and this percentage was significantly higher in diarrheic (83.7%) versus non-diarrheic (47.6%) calves. Unlike the other pathogens, Cryptosporidium spp. and rotavirus were associated with NCD. Diarrheic calves, calves infected with any of the pathogens, and calves infected with rotavirus had significantly lower concentrations of STP. Diarrheic calves had higher chances of dying before weaning than non-diarrheic calves. Diarrheic calves infected with S. enterica were at increased risk of mortality. Controlling NCD, salmonellosis, cryptosporidiosis, and rotavirus infections, and improving colostrum management practices would help to reduce calf morbi-mortality in dairy farms in Uruguay.

Association between pertuzumab-associated diarrhoea and rash and survival outcomes in patients with HER2-positive metastatic breast cancer: Exploratory analysis from the CLEOPATRA trial.

BACKGROUND: Skin rash and diarrhoea are known side-effects of pertuzumab. Studies with other anti-HER2 agents suggested that adverse events correlate with patient outcomes. In this exploratory cohort of patients with metastatic HER2-positive breast cancer included in the CLEOPATRA trial we evaluated the value of rash and diarrhoea as prognostic markers and as predictors of pertuzumab benefit. METHODS: This is a retrospective analysis of the multicenter, prospective, randomised CLEOPATRA trial. We defined two analytic cohorts: cohort 1 (C1) included patients from treatment initiation, and cohort 2 (C2) included patients after discontinuation of docetaxel. A landmark analysis was introduced to deal with immortal-time bias. Study endpoints were progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox proportional hazards models were used. RESULTS: Of the 808 patients and after application of the landmark analysis, C1 and C2 included 777 and 518 patients, respectively. In C1, rash occurred in 271 patients (34.9%) and diarrhoea in 470 (60.5%). Rash was prognostic for PFS and OS (C1: adjusted hazard ratio [aHR] = 0.66 [95% CI = 0.48-0.91], p = 0.010]; C2: aHR 0.52 [95% CI = 0.30-0.89], p = 0.018) in both cohorts, while diarrhoea was only prognostic for PFS in cohort 2 (aHR = 0.65 [95% CI = 0.46-0.91], p = 0.011). Rash and diarrhoea were not predictive of pertuzumab benefit (in terms of PFS/OS) in the two cohorts. CONCLUSIONS: In patients treated with pertuzumab, trastuzumab, and docetaxel, rash is prognostic whenever it occurs during treatment, while diarrhoea only has prognostic value when occurring after docetaxel discontinuation. However, neither rash nor diarrhoea predict pertuzumab benefit.

Prevalence and clustering of diarrhoea within households in India: some evidence from NFHS-4, 2015-16.

Diarrhoeal disease is one of the major causes of morbidity and mortality in children and is usually measured at individual level. Shared household attributes, such as improved water supply and sanitation, expose those living in the same household to these same risk factors for diarrhoea. The occurrence of diarrhoea in two or more children in the same household is termed 'diarrhoea clustering'. The aim of this study was to examine the role of improved water supply and sanitation in the occurrence of diarrhoea, and the clustering of diarrhoea in households, among under-five children in India. Data were taken from the fourth round of the National Family and Health Survey (NFHS-4), a nationally representative survey which interviewed 699,686 women from 601,509 households in the country. If any child was reported to have diarrhoea in a household in the 2 weeks preceding the survey, the household was designated a diarrhoeal household. Household clustering of diarrhoea was defined the occurrence of diarrhoea in more than one child in households with two or more children. The analysis was done at the household level separately for diarrhoeal households and clustering of diarrhoea in households. The presence of clustering was tested using a chi-squared test. The overall prevalences of diarrhoea and clustering of diarrhoea were examined using exogenous variables. Odds ratios, standardized to allow comparison across categories, were computed. The household prevalence of diarrhoea was 12% and that of clustering of diarrhoea was 2.4%. About 6.5% of households contributed 12.6% of the total diarrhoeal cases. Access to safe water and sanitation was shown to have a great impact on reducing diarrhoeal prevalence and clustering across different household groups. Safe water alone had a greater impact on reducing the prevalence in the absence of improved sanitation when compared with the presence of improved sanitation. It may be possible to reduce the prevalence of diarrhoea in households by targeting those households with more than one child in the under-five age group with the provision of safe water and improved sanitation.

Diarrhea and altered inflammatory cytokine pattern in severe coronavirus disease 2019: Impact on disease course and in-hospital mortality.

BACKGROUND AND AIM: Dynamic changes of immunocyte subsets and inflammatory profiles in coronavirus disease 2019 (COVID-19) patients with gastrointestinal symptoms were undetermined. METHODS: A single-center retrospective analysis of 409 severe, hospitalized COVID-19 patients from 20 January to 29 February 2020 was performed. The longitudinal characteristics of immune inflammatory cytokines in patients with/without diarrhea were analyzed. The relations of diarrhea and immuno-inflammatory factors with illness course and clinical outcomes were further explored. RESULTS: Diarrhea was more common and more serious with longer duration (4.9 ± 1.5 vs 4.2 ± 1.5 days, P = 0.039) and higher frequency (5.5 ± 2.1 vs 4.0 ± 2.0 times/day, P = 0.001) in deceased patients than in the survivors. Also, diarrhea patients were more inclined to develop multi-organ damage: survivors have longer illness course (media 41.0 vs 36.0 days, P = 0.052) and hospital stays (media 27.0 vs 23.0 days, P = 0.041), and the deceased patients had higher mortality (33.0% vs 22.6%, P = 0.045) and earlier death (media 20.0 vs 25.0 days, P = 0.038). Progressively, neutrophilia and lymphopenia, especially the declined CD8+ T cells, were demonstrated in diarrhea patients relative to the non-diarrhea cases. The inflammatory cytokines including IL-6, IL-10, and TNF-α were intensively increased in patients with diarrhea. The multivariable logistic analysis showed longer duration of diarrhea (P = 0.036), higher neutrophil counts (P = 0.011), and lower lymphocyte counts (P < 0.001) were independent risk factors of in-hospital death. The proportional hazards model indicated that longer duration of diarrhea (P = 0.002), higher frequency of diarrhea (P = 0.058), higher neutrophil counts (P = 0.001), lower lymphocyte counts (P = 0.035), and decreased proportion of CD8+ T cells (P < 0.001) were independently associated with longer illness course of the survivors. CONCLUSIONS: Diarrhea patients were more likely to present with neutrophilia, lymphopenia, and cytokine storm and to develop multi-organ damage. The inflammatory patterns were independent factors associated with illness course of the survivors and in-hospital death of severe COVID-19.

Diarrheal Deaths After the Introduction of Rotavirus Vaccination in 4 Countries.

BACKGROUND: We aim in our analysis to estimate the reduction of diarrhea-related mortality rates after introduction of a rotavirus vaccine in subregions of 4 Latin American countries. METHODS: We selected diarrhea-related deaths from individual-level data from death certificates in Brazil, Colombia, Ecuador, and Mexico. Counts were aggregated by region, year and month, and age group for each country. We ran an interrupted time-series analysis using Poisson regression to obtain seasonal and trend-adjusted estimates of impact. Results are reported as percentages (1 - mortality rate ratio). RESULTS: We found a reduction in diarrhea-related mortality in children <5 years old of 18% (95% confidence interval [CI], 15 to 20) for Mexico, 39% (95% CI, 35 to 44) for Colombia, 19 (95% CI, 17 to 22) for Brazil, and -26% (95% CI, -40 to -14) for Ecuador. Using wavelet analyses, we found a reduction of 6- and 12-month seasonality in Brazil, Colombia, and Mexico. We also found that the increased reduction of diarrhea-related deaths was larger with greater prevaccine burden of diarrhea in infants. CONCLUSIONS: Our findings and available evidence support the recommendation from the World Health Organization for the monovalent and/or pentavalent rotavirus vaccine in countries worldwide. We found an increased benefit in those settings with a higher burden of infant diarrhea-related deaths.

A preliminary study of bowel rest strategy in the management of Clostridioides difficile infection.

Clostridioides difficile infection (CDI) is an important nosocomial infection and is the leading cause of infectious diarrhea in hospitalized patients. We aimed to assess the effect of bowel rest on the management of CDI. A single-center retrospective cohort study was conducted. The primary outcome was the composite of the all-cause mortality and CDI recurrence within 30 days. The main secondary outcome was switching from metronidazole to vancomycin. Of the 91 patients with CDI enrolled as the full cohort, 63 patients (69%) and 28 patients (31%) constituted the control group and the bowel rest group, respectively. After one-to-one propensity score matching, a total of 46 patients were included as the matched cohort. In the full cohort, the composite outcome occurred in 19.0% and 14.3% of the patients in the control and the bowel rest group, respectively (p = 0.768). In the matched cohort, it was 17.4% in each group. Although there was no statistically significant difference, the trend of switching was lower in the bowel rest group. The bowel rest may not affect the all-cause mortality and CDI recurrence within 30 days. However, in those prescribed bowel rest, switching from metronidazole to vancomycin may reduce.

Socio-demographic and environmental factors associated with diarrhoeal disease among children under five in India.

BACKGROUND: Globally, diarrhoea is the second leading cause of death in children under five and a major public health problem. Despite several health care initiatives taken by the government, a large proportion of children still experience diarrhoeal diseases which cause high childhood death in India. This study aims to examine the socio-demographic and environmental factors associated with diarrhoea in children under five in India. METHODS: A cross-sectional study was designed using secondary data from the recent round of the National Family Health Survey (NFHS-4), conducted in 2015-16. A total of 247,743 living children below 5 years of age were included in the analysis. Bivariate and multivariate logistic regression models were carried out to assess the factors associated with childhood diarrhoeal disease. RESULTS: In India, about 9% of under-five children experience diarrhoeal disease in the past 2 weeks preceding the survey. Children living in rural areas (Adjusted odds ratio [aOR]: 1.05; 95% CI: 1.01, 1.09), children belonged to scheduled tribe (aOR: 0.83; 95% CI: 0.79, 0.89) and other castes (aOR: 0.92; 95% CI: 0.88, 0.97), Muslim children (aOR: 1.18; 95% CI: 1.13, 1.24), and children resided in the central (aOR: 1.61; 95% CI: 1.52, 1.70) and west (aOR: 1.08; 95% CI: 1.01, 1.15) regions were significantly associated with higher likelihood of diarrhoea in the past 2 weeks. Concerning environmental factors, child stool disposal (aOR: 1.06; 95% CI: 0.98, 1.09), floor materials (aOR: 1.08; 95% CI: 1.03, 1.12) and roof materials (aOR: 1.08; 95% CI: 1.04, 1.13) of the household were found to be significant predictors of childhood diarrhoea occurrence. CONCLUSIONS: Diarrhoeal disease is common among children who lived in rural areas, scheduled castes, Muslims, and children from poor families. Regarding environmental factors, stool disposal practices in the household, dirt floor, and thatch roof materials of the household unit are risk factors for diarrhoeal disease. Targeted approach should be initiated to mitigate the problem of the poor health status of children by providing adequate health care. The policy-makers and stakeholders should address adverse environmental conditions by the provision of latrine and improved housing facilities.

Clinical and laboratory characteristics of children under five hospitalized with diarrhea and bacteremia.

BACKGROUND: Diarrhea is one of the leading causes of mortality in children under five globally. When it is associated with bacteremia, mortality is even higher. However, bacteraemia in diarrheal children has gained little attention in spite of its deleterious impact in under-five mortality. So, we aimed to evaluate associated clinical and laboratory factors for death in under-five children hospitalized with both diarrhea and bacteremia. METHODS: In this retrospective cross-sectional study, we used patients' electronic database of Dhaka Hospital of 'icddr,b', and enrolled all under-five children with diarrhea and bacterial growth in their blood samples on admission between June-2014 and May-2017. Clinical and laboratory characteristics were compared between those who died and who survived with a special attention to bacterial pathogens related to deaths and their sensitivity pattern. RESULTS: In a total of 401 diarrheal children with bacteraemia, 45 (11%) died. Although Salmonella Typhi (34%) was the most predominant isolate followed by Staphylococcus species (16%) and Pseudomonas species (9%), children who died more often had E. coli (OR = 5.69, 95% CI = 2.42-13.39, p = <0.001) and Klebsiella bacteraemia (OR = 4.59, 95% CI = 1.84-11.46, p = 0.001) compared to those who survived. However, none of them was significantly associated with deaths in regression analysis when adjusted with other potential confounders. E. coli was 100% resistant to ampicillin, 41% to gentamicin, and 73% to ceftriaxone and Klebsiella species was 96% resistant to ampicillin, 42% to gentamicin, and 62% to ceftriaxone. Study children who died had significantly higher overall resistance pattern shown in World Health Organization (WHO) recommended one of the first line antibiotics in treating childhood sepsis such as ampicillin (80% vs. 50%, p = 0.001) and in second line antibiotic such as ceftriaxone (49% vs. 22%, p = 0.001) compared to the survivors. In logistic regression analysis, after adjusting for potential confounders, we found that clinical sepsis (aOR 3.79, 95% CI 1.60-8.96, p = 0.002), hypoxemia (aOR 4.20, 95% CI 1.74-10.12, p = 0.001), and hyperkalaemia (aOR 2.69, 95% CI 1.05-6.91, p = 0.039) were found to be independent predictors of deaths and receipt of sensitive antibiotic (aOR 0.42, 95% CI 0.18-0.99, p = 0.048) was revealed as the independent protective factor for deaths in this population. CONCLUSION AND SIGNIFICANCE: The results of our data suggest that diarrheal children with bacteremia who died more often had gram negative bacteremia compared to those who survived and these pathogens are highly resistant to WHO recommended first line and second line antibiotics. The results further emphasize the critical importance of early identification of important clinical problems such as clinical sepsis, hypoxemia and hyperkalaemia in diarrheal children and treat them with potential sensitive antibiotic(s) in order to reduce bacteremia related mortality in children with diarrhea, especially in resource limited settings.