Stratified Management for Bacterial Infections in Late Preterm and Term Neonates:Current Strategies and Future Opportunities Toward Precision Medicine

Bacterial infections remain a major cause of morbidity and mortality in the neonatal period. Therefore, many neonates, including late preterm and term neonates, are exposed to antibiotics in the first weeks of life. Data on the importance of inter-individual differences and disease signatures are accumulating. Differences that may potentially influence treatment requirement and success rate. However, currently, many neonates are treated following a “one size fits all” approach, based on general protocols and standard antibiotic treatment regimens. Precision medicine has emerged in the last years and is perceived as a new, holistic, way of stratifying patients based on large-scale data including patient characteristics and disease specific features. Specific to sepsis, differences in disease susceptibility, disease severity, immune response and pharmacokinetics and -dynamics can be used for the development of treatment algorithms helping clinicians decide when and how to treat a specific patient or a specific subpopulation. In this review, we highlight the current and future developments that could allow transition to a more precise manner of antibiotic treatment in late preterm and term neonates, and propose a research agenda toward precision medicine for neonatal bacterial infections.</p

Growth and CD4 patterns of adolescents living with perinatally acquired HIV worldwide, a CIPHER cohort collaboration analysis.

INTRODUCTION Adolescents living with HIV are subject to multiple co-morbidities, including growth retardation and immunodeficiency. We describe growth and CD4 evolution during adolescence using data from the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) global project. METHODS Data were collected between 1994 and 2015 from 11 CIPHER networks worldwide. Adolescents with perinatally acquired HIV infection (APH) who initiated antiretroviral therapy (ART) before age 10 years, with at least one height or CD4 count measurement while aged 10-17 years, were included. Growth was measured using height-for-age Z-scores (HAZ, stunting if <-2 SD, WHO growth charts). Linear mixed-effects models were used to study the evolution of each outcome between ages 10 and 17. For growth, sex-specific models with fractional polynomials were used to model non-linear relationships for age at ART initiation, HAZ at age 10 and time, defined as current age from 10 to 17 years of age. RESULTS A total of 20,939 and 19,557 APH were included for the growth and CD4 analyses, respectively. Half were females, two-thirds lived in East and Southern Africa, and median age at ART initiation ranged from 7 years in sub-Saharan African regions. At age 10, stunting ranged from 6% in North America and Europe to 39% in the Asia-Pacific; 19% overall had CD4 counts <500 cells/mm3 . Across adolescence, higher HAZ was observed in females and among those in high-income countries. APH with stunting at age 10 and those with late ART initiation (after age 5) had the largest HAZ gains during adolescence, but these gains were insufficient to catch-up with non-stunted, early ART-treated adolescents. From age 10 to 16 years, mean CD4 counts declined from 768 to 607 cells/mm3 . This decline was observed across all regions, in males and females. CONCLUSIONS Growth patterns during adolescence differed substantially by sex and region, while CD4 patterns were similar, with an observed CD4 decline that needs further investigation. Early diagnosis and timely initiation of treatment in early childhood to prevent growth retardation and immunodeficiency are critical to improving APH growth and CD4 outcomes by the time they reach adulthood

Identification of amino acid residues critical for catalysis of holliday junction resolution by Mycoplasma genitalium RecU

The RecU protein from Mycoplasma genitalium, RecU Mge, is a 19.4-kDa Holliday junction (HJ) resolvase that binds in a nonspecific fashion to HJ substrates and, in the presence of Mn 2+, cleaves these substrates at a specific sequence (5'-G/TC2C/TTA/GG-3'). To identify amino acid residues that are crucial for HJ binding and/or cleavage, we generated a series of 16 deletion mutants (9 N- and 7 C-terminal deletion mutants) and 31 point mutants of RecU Mge. The point mutations were introduced at amino acid positions that are highly conserved among bacterial RecU-like sequences. All mutants were purified and tested for the ability to bind to, and cleave, HJ substrates. We found the five N-terminal and three C-terminal amino acid residues of RecU Mge to be dispensable for its catalytic activities. Among the 31 point mutants, 7 mutants were found to be inactive in both HJ binding and cleavage. Interestingly, in 12 other mutants, these two activities were uncoupled; while these proteins displayed HJ-binding characteristics similar to those of wild-type RecU Mge, they were unable to cleave HJ substrates. Thus, 12 amino acid residues were identified (E11, K31, D57, Y58, Y66, D68, E70, K72, T74, K76, Q88, and L92) that may play either a direct or indirect role in the catalysis of HJ resolution.</p

Galacto-Oligosaccharides as an Anti-Infective and Anti-Microbial Agent for Macrolide-Resistant and -Sensitive Mycoplasma pneumoniae

The worldwide increase in the incidence of antibiotic resistance of the atypical bacterium Mycoplasma pneumoniae (MP) challenges the treatment of MP infections, especially in children. Therefore, alternative strategies for the treatment of MP infections are warranted. Galacto- and fructo-oligosaccharides (GOS and FOS) are a specific group of complex carbohydrates that were recently shown to possess direct anti-pathogenic properties. In this study, we assessed whether GOS and FOS exert anti-microbial and anti-infective effects against MP and, especially, macrolide-resistant MP (MRMP) in vitro. The MIC values of GOS for MP and MRMP were 4%. In contrast, the MIC values of FOS for both MP and MRMP were 16%. A time-kill kinetic assay showed that FOS possess bacteriostatic properties, while for GOS, a bactericidal effect against MP and MRMP was observed after 24 h at a concentration of 4x MIC. In co-cultures with human alveolar A549 epithelial cells, GOS killed adherent MP and MRMP and also concentration-dependently inhibited their adherence to A549 cells. Further, GOS suppressed (MR)MP-induced IL-6 and IL-8 in A549 cells. None of the aforementioned parameters were affected when FOS were added to these co-cultures. In conclusion, the anti-infective and anti-microbial properties of GOS could provide an alternative treatment against MRMP and MP infections

School functioning of children with perinatal HIV-infection in high-income countries: A systematic review

Introduction Since the introduction of combination antiretroviral therapy, human immunodeficiency virus (HIV) infection is a manageable chronic disease. However, school-age children (4-18 years) living with HIV could still experience problems with functioning at school, due to the impact of the virus itself, medication, comorbidities and social stigma. School functioning covers academic achievement, school attendance, and social relationships and is of utmost importance to optimize normal participation. Methods To gain insight in school functioning problems of perinatally HIV-infected children, we performed a systematic review of the literature in multiple databases from January 1997 up to February 2019. Studies were included if they described outcomes of school functioning of school-age children perinatally infected with HIV, in high-income countries. Meta-analyses were performed for sufficiently comparable studies. Results and discussion Results from 32 studies show that HIV-infected children experience more problems in various areas of school functioning in comparison with national norms, matched healthy controls, siblings and HIV-exposed uninfected (HEU) children. The most pronounced differences concerned the usage of special educational services, general learning problems, and mathematics and reading performance scores. Comparisons with both national norms and siblings/HEU children show that the differences between HIV-infected children and siblings/HEU children were less pronounced. Moreover, siblings/HEU children also reported significantly worse outcomes compared to national norms. This suggests that problems in school functioning cannot be solely attributed to the HIV-infection, but that multiple socio-economic and cultural factors may play a role herein. Conclusion Perinatally HIV-infected children seem vulnerable to problems in various areas of school functioning. Therefore, monitoring of school functioning should be an important aspect in the care for these children. A family-focused approach with special attention to a child's socio-environmental context and additional attention for siblings and HEU children, is therefore recommended

Human autoinflammatory disease reveals ELF4 as a transcriptional regulator of inflammation

Transcription factors specialized to limit the destructive potential of inflammatory immune cells remain ill-defined. We discovered loss-of-function variants in the X-linked ETS transcription factor gene ELF4 in multiple unrelated male patients with early onset mucosal autoinflammation and inflammatory bowel disease (IBD) characteristics, including fevers and ulcers that responded to interleukin-1 (IL-1), tumor necrosis factor or IL-12p40 blockade. Using cells from patients and newly generated mouse models, we uncovered ELF4-mutant macrophages having hyperinflammatory responses to a range of innate stimuli. In mouse macrophages, Elf4 both sustained the expression of anti-inflammatory genes, such as Il1rn, and limited the upregulation of inflammation amplifiers, including S100A8, Lcn2, Trem1 and neutrophil chemoattractants. Blockade of Trem1 reversed inflammation and intestine pathology after in vivo lipopolysaccharide challenge in mice carrying patient-derived variants in Elf4. Thus, ELF4 restrains inflammation and protects against mucosal disease, a discovery with broad translational relevance for human inflammatory disorders such as IBD

Machine Learning Used to Compare the Diagnostic Accuracy of Risk Factors, Clinical Signs and Biomarkers and to Develop a New Prediction Model for Neonatal Early-onset Sepsis

BACKGROUND: Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs. STUDY DESIGN: Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier. RESULTS: One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (±8.8%) and an area-under-the-precision-recall-curve of 28.42% (±11.5%). The predictive performance of the model with RFs alone was comparable with random. CONCLUSIONS: Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics

C-Reactive Protein, Procalcitonin, and White Blood Count to Rule Out Neonatal Early-onset Sepsis Within 36 Hours: A Secondary Analysis of the Neonatal Procalcitonin Intervention Study

BACKGROUND: Neonatal early-onset sepsis (EOS) is one of the main causes of global neonatal mortality and morbidity, and initiation of early antibiotic treatment is key. However, antibiotics may be harmful. METHODS: We performed a secondary analysis of results from the Neonatal Procalcitonin Intervention Study, a prospective, multicenter, randomized, controlled intervention study. The primary outcome was the diagnostic accuracy of serial measurements of C-reactive protein (CRP), procalcitonin (PCT), and white blood count (WBC) within different time windows to rule out culture-positive EOS (proven sepsis). RESULTS: We analyzed 1678 neonates with 10 899 biomarker measurements (4654 CRP, 2047 PCT, and 4198 WBC) obtained within the first 48 hours after the start of antibiotic therapy due to suspected EOS. The areas under the curve (AUC) comparing no sepsis vs proven sepsis for maximum values of CRP, PCT, and WBC within 36 hours were 0.986, 0.921, and 0.360, respectively. The AUCs for CRP and PCT increased with extended time frames up to 36 hours, but there was no further difference between start to 36 hours vs start to 48 hours. Cutoff values at 16 mg/L for CRP and 2.8 ng/L for PCT provided a sensitivity of 100% for discriminating no sepsis vs proven sepsis. CONCLUSIONS: Normal serial CRP and PCT measurements within 36 hours after the start of empiric antibiotic therapy can exclude the presence of neonatal EOS with a high probability. The negative predictive values of CRP and PCT do not increase after 36 hours

Multisystem Inflammatory Syndrome in Children in Western Countries? Decreasing Incidence as the Pandemic Progresses?: An Observational Multicenter International Cross-sectional Study

BACKGROUND: SARS-CoV-2 variations as well as immune protection after previous infections and/or vaccination may have altered the incidence of multisystemic inflammatory syndrome in children (MIS-C). We aimed to report an international time-series analysis of the incidence of MIS-C to determine if there was a shift in the regions or countries included into the study. METHODS: This is a multicenter, international, cross-sectional study. We collected the MIS-C incidence from the participant regions and countries for the period July 2020 to November 2021. We assessed the ratio between MIS-C cases and COVID-19 pediatric cases in children <18 years diagnosed 4 weeks earlier (average time for the temporal association observed in this disease) for the study period. We performed a binomial regression analysis for 8 participating sites [Bogotá (Colombia), Chile, Costa Rica, Lazio (Italy), Mexico DF, Panama, The Netherlands and Catalonia (Spain)]. RESULTS: We included 904 cases of MIS-C, among a reference population of 17,906,432 children. We estimated a global significant decrease trend ratio in MIS-C cases/COVID-19 diagnosed cases in the previous month ( P < 0.001). When analyzing separately each of the sites, Chile and The Netherlands maintained a significant decrease trend ( P < 0.001), but this ratio was not statistically significant for the rest of sites. CONCLUSIONS: To our knowledge, this is the first international study describing a global reduction in the trend of the MIS-C incidence during the pandemic. COVID-19 vaccination and other factors possibly linked to the virus itself and/or community transmission may have played a role in preventing new MIS-C cases