Protective effect of natural rotavirus infection in an Indian birth cohort.

BACKGROUND: More than 500,000 deaths are attributed to rotavirus gastroenteritis annually worldwide, with the highest mortality in India. Two successive, naturally occurring rotavirus infections have been shown to confer complete protection against moderate or severe gastroenteritis during subsequent infections in a birth cohort in Mexico. We studied the protective effect of rotavirus infection on subsequent infection and disease in a birth cohort in India (where the efficacy of oral vaccines in general has been lower than expected). METHODS: We recruited children at birth in urban slums in Vellore; they were followed for 3 years after birth, with home visits twice weekly. Stool samples were collected every 2 weeks, as well as on alternate days during diarrheal episodes, and were tested by means of enzyme-linked immunosorbent assay and polymerase-chain-reaction assay. Serum samples were obtained every 6 months and evaluated for seroconversion, defined as an increase in the IgG antibody level by a factor of 4 or in the IgA antibody level by a factor of 3. RESULTS: Of 452 recruited children, 373 completed 3 years of follow-up. Rotavirus infection generally occurred early in life, with 56% of children infected by 6 months of age. Levels of reinfection were high, with only approximately 30% of all infections identified being primary. Protection against moderate or severe disease increased with the order of infection but was only 79% after three infections. With G1P[8], the most common viral strain, there was no evidence of homotypic protection. CONCLUSIONS: Early infection and frequent reinfection in a locale with high viral diversity resulted in lower protection than has been reported elsewhere, providing a possible explanation why rotavirus vaccines have had lower-than-expected efficacy in Asia and Africa. (Funded by the Wellcome Trust.).

A systematic review on the excess health risk of antibiotic-resistant bloodstream infections for six key pathogens in Europe.

BACKGROUND: Antimicrobial resistance is a global threat, which requires novel intervention strategies, for which priority pathogens and settings need to be determined. OBJECTIVES: We evaluated pathogen-specific excess health burden of drug-resistant bloodstream infections (BSIs) in Europe. METHODS: A systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase, and grey literature for the period January 1990 to May 2022. STUDY ELIGIBILITY CRITERIA: Studies that reported burden data for six key drug-resistant pathogens: carbapenem-resistant (CR) Pseudomonas aeruginosa and Acinetobacter baumannii, third-generation cephalosporin or CR Escherichia coli and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Excess health outcomes compared with drug-susceptible BSIs or uninfected patients. For MRSA and third-generation cephalosporin E. coli and K. pneumoniae BSIs, five or more European studies were identified. For all others, the search was extended to high-income countries. PARTICIPANTS: Paediatric and adult patients diagnosed with drug-resistant BSI. INTERVENTIONS: Not applicable. ASSESSMENT OF RISK OF BIAS: An adapted version of the Joanna-Briggs Institute assessment tool. METHODS OF DATA SYNTHESIS: Random-effect models were used to pool pathogen-specific burden estimates. RESULTS: We screened 7154 titles, 1078 full-texts and found 56 studies on BSIs. Most studies compared outcomes of drug-resistant to drug-susceptible BSIs (46/56, 82.1%), and reported mortality (55/56 studies, 98.6%). The pooled crude estimate for excess all-cause mortality of drug-resistant versus drug-susceptible BSIs ranged from OR 1.31 (95% CI 1.03-1.68) for CR P. aeruginosa to OR 3.44 (95% CI 1.62-7.32) for CR K. pneumoniae. Pooled crude estimates comparing mortality to uninfected patients were available for vancomycin-resistant Enterococcus and MRSA BSIs (OR of 11.19 [95% CI 6.92-18.09] and OR 6.18 [95% CI 2.10-18.17], respectively). CONCLUSIONS: Drug-resistant BSIs are associated with increased mortality, with the magnitude of the effect influenced by pathogen type and comparator. Future research should address crucial knowledge gaps in pathogen- and infection-specific burdens to guide development of novel interventions.

Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia.

Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3(+)TCRα/ß(+)CD4(-)CD8(-) "double negative" T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool.

Development and validation of BLOOMY prediction scores for 14-day and 6-month mortality in hospitalised adults with bloodstream infections: a multicentre, prospective, cohort study.

BACKGROUND: The burden of bloodstream infections remains high worldwide and cannot be confined to short-term in-hospital mortality. We aimed to develop scores to predict short-term and long-term mortality in patients with bloodstream infections. METHODS: The Bloodstream Infection due to Multidrug-resistant Organisms: Multicenter Study on Risk Factors and Clinical Outcomes (BLOOMY) study is a prospective, multicentre cohort study at six German tertiary care university hospitals to develop and validate two scores assessing 14-day and 6-month mortality in patients with bloodstream infections. We excluded patients younger than 18 years or who were admitted to an ophthalmology or psychiatry ward. Microbiological, clinical, laboratory, treatment, and survival data were prospectively collected on day 0 and day 3 and then from day 7 onwards, weekly. Participants were followed up for 6 months. All patients in the derivation cohort who were alive on day 3 were included in the analysis. Predictive scores were developed using logistic regression and Cox proportional hazards models with a machine-learning approach. Validation was completed using the C statistic and predictive accuracy was assessed using sensitivity, specificity, and predictive values. FINDINGS: Between Feb 1, 2017, and Jan 31, 2019, 2568 (61·5%) of 4179 eligible patients were recruited into the derivation cohort. The in-hospital mortality rate was 23·75% (95% CI 22·15-25·44; 610 of 2568 patients) and the 6-month mortality rate was 41·55% (39·54-43·59; 949 of 2284). The model predictors for 14-day mortality (C statistic 0·873, 95% CI 0·849-0·896) and 6-month mortality (0·807, 0·784-0·831) included age, body-mass index, platelet and leukocyte counts, C-reactive protein concentrations, malignancy (ie, comorbidity), in-hospital acquisition, and pathogen. Additional predictors were, for 14-day mortality, mental status, hypotension, and the need for mechanical ventilation on day 3 and, for 6-month mortality, focus of infection, in-hospital complications, and glomerular filtration rate at the end of treatment. The scores were validated in a cohort of 1023 patients with bloodstream infections, recruited between Oct 9, 2019, and Dec 31, 2020. The BLOOMY 14-day score showed a sensitivity of 61·32% (95% CI 51·81-70·04), a specificity of 86·36% (83·80-88·58), a positive predictive value (PPV) of 37·57% (30·70-44·99), and a negative predictive value (NPV) of 94·35% (92·42-95·80). The BLOOMY 6-month score showed a sensitivity of 69·93% (61·97-76·84), a specificity of 66·44% (61·86-70·73), a PPV of 40·82% (34·85-47·07), and a NPV of 86·97% (82·91-90·18). INTERPRETATION: The BLOOMY scores showed good discrimination and predictive values and could support the development of protocols to manage bloodstream infections and also help to estimate the short-term and long-term burdens of bloodstream infections. FUNDING: DZIF German Center for Infection Research. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.

Burden of illness in the first 3 years of life in an Indian slum.

The morbidity and mortality in a cohort of 452 children followed up from birth up to 3 years of age, in an urban slum in India, is described. These children were recruited and followed from March 2002 to September 2006. A prospective morbidity survey was established. There were 1162 child-years of follow-up. The average morbidity rate was 11.26 episodes/child-year. Respiratory infections caused 58.3 and diarrheal disease 18.4% of the illnesses. Respiratory illnesses resulted in 48, 67.5 and 50 days of illnesses, and there were 3.6, 1.64 and 1.16 diarrheal episodes per child in the 3 years, respectively. There were five deaths in the cohort in the 3 years of follow-up. Of the 77 drop-outs 44 were contacted for mortality data. The morbidity in the area is high, comparable to other studies. The mortality is low, and is attributed to the facilitated access to care.

Chronic growth faltering amongst a birth cohort of Indian children begins prior to weaning and is highly prevalent at three years of age.

BACKGROUND: Poor growth of children in developing countries is a major public health problem associated with mortality, morbidity and developmental delay. We describe growth up to three years of age and investigate factors related to stunting (low height-for-age) at three years of age in a birth cohort from an urban slum. METHODS: 452 children born between March 2002 and August 2003 were followed until their third birthday in three neighbouring slums in Vellore, South India. Field workers visited homes to collect details of morbidity twice a week. Height and weight were measured monthly from one month of age in a study-run clinic. For analysis, standardised z-scores were generated using the 2006 WHO child growth standards. Risk factors for stunting at three years of age were analysed in logistic regression models. A sensitivity analysis was conducted to examine the effect of missing values. RESULTS: At age three years, of 186 boys and 187 girls still under follow-up, 109 (66%, 95% Confidence interval 58-73%) boys and 93 (56%, 95% CI 49-64%) girls were stunted, 14 (8%, 95% CI 4-13%) boys and 12 (7%, 95% CI 3-11%) girls were wasted (low weight-for-height) and 72 (43%, 95% CI 36-51) boys and 66 (39%, 95% CI 31-47%) girls were underweight (low weight-for-age). In total 224/331 (68%) children at three years had at least one growth deficiency (were stunted and/or underweight and/or wasted); even as early as one month of age 186/377 (49%) children had at least one growth deficiency. Factors associated with stunting at three years were birth weight less than 2.5 kg (OR 3.63, 95% CI 1.36-9.70) 'beedi-making' (manual production of cigarettes for a daily wage) in the household (OR 1.74, 95% CI 1.05-2.86), maternal height less than 150 cm (OR 2.02, 95% CI 1.12-3.62), being stunted, wasted or underweight at six months of age (OR 1.75, 95% CI 1.05-2.93) and having at least one older sibling (OR 2.00, 95% CI 1.14-3.51). CONCLUSION: A high proportion of urban slum dwelling children had poor growth throughout the first three years of life. Interventions are needed urgently during pregnancy, early breastfeeding and weaning in this population.

Rotavirus infections in a community based cohort in Vellore, India.

INTRODUCTION: The burden of infection in communities determines the spread of rotavirus infection and disease in susceptible populations. This study reports rotavirus infection and disease in a community based birth cohort in Vellore. METHODS: Bimonthly surveillance and diarrheal stool were collected from 452 children enrolled at birth, of whom 373 completed three years of follow up. Samples were screened for rotavirus by an ELISA and genotyped by reverse transcription polymerase chain reaction for VP7 and VP4 genes. Rotavirus incidence rates were calculated using Poisson regression equations. Risk factors associated with symptomatic and asymptomatic rotavirus infections were compared using multiple logistic regression. RESULTS: A total of 1149 episodes of rotavirus infections occurred in 94.4% children in the cohort. Incidence of rotavirus infection was 1.04 (0.97-1.1) per child-year with 0.75 asymptomatic and 0.29 symptomatic infections per child-year. About 18% of the children were infected in the first month, mainly with the G10P[11] strain. Rotavirus infections were more prevalent during October-March, but seasonality was not as marked in rotavirus disease. Rotavirus was associated with 15.1% of mild diarrhea, 38.9% of moderate/severe diarrhea and 66.7% of very severe diarrhea. Four common G types - G1 (26.8%), G2 (16%), G10 (11.2%) and G9 (9.6%) were seen, with high rates of mixed infections and untypable samples. Male gender, presence of siblings and low maternal education were associated with rotavirus disease. CONCLUSION: This study demonstrates that rotavirus is the most common cause of gastroenteritis in the community, and indicates that since rotavirus caused the greatest proportion of moderate and severe disease, targeted interventions such as vaccines are needed for rotavirus, in addition to health education, sanitation and appropriate treatment to decrease diarrheal disease in communities.

Giardia duodenalis assemblages associated with diarrhea in children in South India identified by PCR-RFLP.

Giardial diarrhea in a birth cohort of 452 children in an urban slum in South India was characterized. Of the 155 episodes that occurred in 99 children, 73% were acute diarrhea. Children with better educated mothers and a toilet at home had lower odds of acquiring giardial diarrhea, whereas low socioeconomic status and drinking municipal water were associated with greater risk. Children with co-infections tended to have a slightly longer duration of diarrhea (P = 0.061) and showed significantly more wasting after an episode than children with diarrhea resulting from Giardia alone (P = 0.032). Among the 99 cases, 50 diarrheal and 51 asymptomatic Giardia positive samples were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) at the triose phosphate isomerase gene. Assemblage B was predominant both in giardial diarrhea (80%) and asymptomatic giardiasis (94%). Children with Assemblage A subgroup-II alone or dual infections with both assemblage A and B had diarrhea more frequently (P = 0.07).