Bacterial pathogens and resistance causing community acquired paediatric bloodstream infections in low- and middle-income countries: a systematic review and meta-analysis

Background Despite a high mortality rate in childhood, there is limited evidence on the causes and outcomes of paediatric bloodstream infections from low- and middle-income countries (LMICs). We conducted a systematic review and meta-analysis to characterize the bacterial causes of paediatric bloodstream infections in LMICs and their resistance profile. Methods We searched Pubmed and Embase databases between January 1st 1990 and October 30th 2019, combining MeSH and free-text terms for “sepsis” and “low-middle-income countries” in children. Two reviewers screened articles and performed data extraction to identify studies investigating children (1 month-18 years), with at least one blood culture. The main outcomes of interests were the rate of positive blood cultures, the distribution of bacterial pathogens, the resistance patterns and the case-fatality rate. The proportions obtained from each study were pooled using the Freeman-Tukey double arcsine transformation, and a random-effect meta-analysis model was used. Results We identified 2403 eligible studies, 17 were included in the final review including 52,915 children (11 in Africa and 6 in Asia). The overall percentage of positive blood culture was 19.1% [95% CI: 12.0–27.5%]; 15.5% [8.4–24.4%] in Africa and 28.0% [13.2–45.8%] in Asia. A total of 4836 bacterial isolates were included in the studies; 2974 were Gram-negative (63.9% [52.2–74.9]) and 1858 were Gram-positive (35.8% [24.9–47.5]). In Asia, Salmonella typhi (26.2%) was the most commonly isolated pathogen, followed by Staphylococcus aureus (7.7%) whereas in Africa, S. aureus (17.8%) and Streptococcus pneumoniae (16.8%) were predominant followed by Escherichia coli (10.7%). S. aureus was more likely resistant to methicillin in Africa (29.5% vs. 7.9%), whereas E. coli was more frequently resistant to third-generation cephalosporins (31.2% vs. 21.2%), amikacin (29.6% vs. 0%) and ciprofloxacin (36.7% vs. 0%) in Asia. The overall estimate for case-fatality rate among 8 studies was 12.7% [6.6–20.2%]. Underlying conditions, such as malnutrition or HIV infection were assessed as a factor associated with bacteraemia in 4 studies each. Conclusions We observed a marked variation in pathogen distribution and their resistance profiles between Asia and Africa. Very limited data is available on underlying risk factors for bacteraemia, patterns of treatment of multidrug-resistant infections and predictors of adverse outcomes

Optimization of Cutting Parameters, Condition and Geometry in Turning AISI 316L Stainless Steel Using the Grey-Based Taguchi Method

In this study, experimental optimization of cutting forces, surface roughness and the hardness of material after turning of AISI 316L stainless steel, using conventional and wiper insert cutting tools under dry, CO2 and MQL cutting conditions, is presented. The influences of feed rate, cutting depth, and cooling system on surface roughness, cutting force and material hardness were examined. In order to optimize the turning process, Grey relational analysis optimization method was used. The optimal machinability parameters of AISI 316L stainless steel with coated carbide insert were successfully determined

Enteric fever among children: 50 cases in a French tertiary care centre.

Background: Enteric fever in France is primarily travel-associated. Characteristics of paediatric cases are scarce and information from field studies in endemic countries might not be generalizable to non-endemic countries. Methods: In this retrospective study, we reviewed all cases of typhoid and paratyphoid fever treated in a French paediatric tertiary care centre from 1993 through 2015. Results: Fifty cases of enteric fever due to Salmonella enterica serovar Typhi (n = 44) and Paratyphi (n = 6) were identified. Sixty-one percent of the children had travelled to Africa and 34 % to the Indian subcontinent. Among travel-associated cases, eighty-five percent were visiting friends and relatives (VFR). Ninety-six percent had high fever associated with gastrointestinal symptoms. Anaemia (66%), elevated CRP (80%), transaminitis (87%) and mild hyponatremia (50%) were the main biological findings. Blood cultures were positive in 90% of cases. Twelve strains (24%) were resistant at least to one antibiotic, and all of them had been isolated since 2003, increasing the resistance rate during this last period to 43% (12/28). Ceftriaxone was administered to 71 patients for a median duration of 6 days (IQR: 4‒8). The median time to apyrexia after onset of treatment was 4 days (IQR: 2‒5 days). Complications occurred in 9 children with 5 (10%) presenting neurologic disorders. All 50 patients recovered. Conclusion: In France, paediatric enteric fever is mainly a travel-associated disease and occurs in patients returning from a prolonged stay in an endemic area. Children VFR are at high risk and should be a priority target group for pre-travel preventive measures. The increase in antibiotic resistance reflects the situation in endemic countries and is a major concern

Effects of TNFalpha, NOS3, MDR1 gene polymorphisms on clinical parameters, prognosis and survival of multiple myeloma cases

It is not clear how gene polymorphisms affecting drugs can contributes totheir efficacy in multiple myeloma (MM). We here aimed to explore associations among gene polymorphisms of tumor necrosis factor alpha (TNFalpha), nitric oxide synthesis 3 (NOS3) and multi-drug resistance 1 (MDR1), clinical parameters, prognosis and survival in MM patients treated with VAD (vincristine-adriamycine-dexamethasone), MP (mephalane-prednisolone), autolougus stem cell transplantation (ASCT), BODEC (bortezomib-dexamethasonecyclophosphamide) and TD (thalidomide-dexamethasone). We analyzed TNFalpha, NOS 3 and MDR1 in 77 patients with MM and 77 healthy controls. The genotyping was performed with PCR and/or PCR-RFLP. There was no clinically significant difference between MM and control groups when TNFalpha (-238) and (-857) and MDR1 gene polymorphisms were studied. However, the TNFalpha gene polymorphism (-308) GG genotype (p=0.012) and NOS3 (+894) TT genotype (p=0.008) were more common in the MM group compared to healthy controls. NOS3 (VNTR) AA (p=0.007) and NOS3 (+894) GG genotypes (p=0.004) were decreased in the MM group in contrast. In conclusion, the NOS3 (+894) TT and TNFalpha (-308) GG genotypes may have roles in myeloma pathogenesis

Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study.

OBJECTIVES: To describe the characteristics of children and adolescents affected by an outbreak of Kawasaki-like multisystem inflammatory syndrome and to evaluate a potential temporal association with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DESIGN: Prospective observational study. SETTING: General paediatric department of a university hospital in Paris, France. PARTICIPANTS: 21 children and adolescents (aged ≤18 years) with features of Kawasaki disease who were admitted to hospital between 27 April and 11 May 2020 and followed up until discharge by 15 May 2020. MAIN OUTCOME MEASURES: The primary outcomes were clinical and biological data, imaging and echocardiographic findings, treatment, and outcomes. Nasopharyngeal swabs were prospectively tested for SARS-CoV-2 using reverse transcription-polymerase chain reaction (RT-PCR) and blood samples were tested for IgG antibodies to the virus. RESULTS: 21 children and adolescents (median age 7.9 (range 3.7-16.6) years) were admitted with features of Kawasaki disease over a 15 day period, with 12 (57%) of African ancestry. 12 (57%) presented with Kawasaki disease shock syndrome and 16 (76%) with myocarditis. 17 (81%) required intensive care support. All 21 patients had noticeable gastrointestinal symptoms during the early stage of illness and high levels of inflammatory markers. 19 (90%) had evidence of recent SARS-CoV-2 infection (positive RT-PCR result in 8/21, positive IgG antibody detection in 19/21). All 21 patients received intravenous immunoglobulin and 10 (48%) also received corticosteroids. The clinical outcome was favourable in all patients. Moderate coronary artery dilations were detected in 5 (24%) of the patients during hospital stay. By 15 May 2020, after 8 (5-17) days of hospital stay, all patients were discharged home. CONCLUSIONS: The ongoing outbreak of Kawasaki-like multisystem inflammatory syndrome among children and adolescents in the Paris area might be related to SARS-CoV-2. In this study an unusually high proportion of the affected children and adolescents had gastrointestinal symptoms, Kawasaki disease shock syndrome, and were of African ancestry

COVID-19 pandemic: Impact caused by school closure and national lockdown on pediatric visits and admissions for viral and non-viral infections, a time series analysis.

A time series analysis of 871,543 pediatric emergency visits revealed that the COVID-19 lockdown and school closure were associated with a significant decrease in infectious diseases disseminated through airborne or fecal-oral transmissions: common cold, gastro-enteritis, bronchiolitis, acute otitis. No change was found for urinary tract infections

Research priorities for European paediatric emergency medicine

Objective Research in European Paediatric Emergency Medicine (REPEM) network is a collaborative group of 69 paediatric emergency medicine (PEM) physicians from 20 countries in Europe, initiated in 2006. To further improve paediatric emergency care in Europe, the aim of this study was to define research priorities for PEM in Europe to guide the development of future research projects. Design and Setting We carried out an online survey in a modified three-stage Delphi study. Eligible participants were members of the REPEM network. In stage 1, the REPEM steering committee prepared a list of research topics. In stage 2, REPEM members rated on a 6-point scale research topics and they could add research topics and comment on the list for further refinement. Stage 3 included further prioritisation using the Hanlon Process of Prioritisation (HPP) to give more emphasis to the feasibility of a research topic. Results Based on 52 respondents (response rates per stage varying from 41% to 57%), we identified the conditions 'fever', 'sepsis' and 'respiratory infections', and the processes/interventions 'biomarkers', 'risk stratification' and 'practice variation' as common themes of research interest. The HPP identified highest priority for 4 of the 5 highest prioritised items by the Delphi process, incorporating prevalence and severity of each condition and feasibility of undertaking such research. Conclusions While the high diversity in emergency department (ED) populations, cultures, healthcare systems and healthcare delivery in European PEM prompts to focus on practice variation of ED conditions, our defined research priority list will help guide further collaborative research efforts within the REPEM network to improve PEM care in Europe.publishersversionPeer reviewe

Presentations of children to emergency departments across Europe and the COVID-19 pandemic: A multinational observational study

BACKGROUND: During the initial phase of the Coronavirus Disease 2019 (COVID-19) pandemic, reduced numbers of acutely ill or injured children presented to emergency departments (EDs). Concerns were raised about the potential for delayed and more severe presentations and an increase in diagnoses such as diabetic ketoacidosis and mental health issues. This multinational observational study aimed to study the number of children presenting to EDs across Europe during the early COVID-19 pandemic and factors influencing this and to investigate changes in severity of illness and diagnoses. METHODS AND FINDINGS: Routine health data were extracted retrospectively from electronic patient records of children aged 18 years and under, presenting to 38 EDs in 16 European countries for the period January 2018 to May 2020, using predefined and standardized data domains. Observed and predicted numbers of ED attendances were calculated for the period February 2020 to May 2020. Poisson models and incidence rate ratios (IRRs), using predicted counts for each site as offset to adjust for case-mix differences, were used to compare age groups, diagnoses, and outcomes. Reductions in pediatric ED attendances, hospital admissions, and high triage urgencies were seen in all participating sites. ED attendances were relatively higher in countries with lower SARS-CoV-2 prevalence (IRR 2.26, 95% CI 1.90 to 2.70, p < 0.001) and in children aged <12 months (12 to <24 months IRR 0.86, 95% CI 0.84 to 0.89; 2 to <5 years IRR 0.80, 95% CI 0.78 to 0.82; 5 to <12 years IRR 0.68, 95% CI 0.67 to 0.70; 12 to 18 years IRR 0.72, 95% CI 0.70 to 0.74; versus age <12 months as reference group, p < 0.001). The lowering of pediatric intensive care admissions was not as great as that of general admissions (IRR 1.30, 95% CI 1.16 to 1.45, p < 0.001). Lower triage urgencies were reduced more than higher triage urgencies (urgent triage IRR 1.10, 95% CI 1.08 to 1.12; emergent and very urgent triage IRR 1.53, 95% CI 1.49 to 1.57; versus nonurgent triage category, p < 0.001). Reductions were highest and sustained throughout the study period for children with communicable infectious diseases. The main limitation was the retrospective nature of the study, using routine clinical data from a wide range of European hospitals and health systems. CONCLUSIONS: Reductions in ED attendances were seen across Europe during the first COVID-19 lockdown period. More severely ill children continued to attend hospital more frequently compared to those with minor injuries and illnesses, although absolute numbers fell. TRIAL REGISTRATION: ISRCTN91495258 https://www.isrctn.com/ISRCTN91495258

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population