Network memory in the movement of hospital patients carrying antimicrobial-resistant bacteria

Hospitals constitute highly interconnected systems that bring into contact an abundance of infectious pathogens and susceptible individuals, thus making infection outbreaks both common and challenging. In recent years, there has been a sharp incidence of antimicrobial-resistance amongst healthcare-associated infections, a situation now considered endemic in many countries. Here we present network-based analyses of a data set capturing the movement of patients harbouring drug-resistant bacteria across three large London hospitals. We show that there are substantial memory effects in the movement of hospital patients colonised with drug-resistant bacteria. Such memory effects break first-order Markovian transitive assumptions and substantially alter the conclusions from the analysis, specifically on node rankings and the evolution of diffusive processes. We capture variable length memory effects by constructing a lumped-state memory network, which we then use to identify overlapping communities of wards. We find that these communities of wards display a quasi-hierarchical structure at different levels of granularity which is consistent with different aspects of patient flows related to hospital locations and medical specialties

Informing antimicrobial management in the context of COVID-19:Understanding the longitudinal dynamics of C-reactive protein and procalcitonin

Background: To characterise the longitudinal dynamics of C-reactive protein (CRP) and Procalcitonin (PCT) in a cohort of hospitalised patients with COVID-19 and support antimicrobial decision-making. Methods: Longitudinal CRP and PCT concentrations and trajectories of 237 hospitalised patients with COVID-19 were modelled. The dataset comprised of 2,021 data points for CRP and 284 points for PCT. Pairwise comparisons were performed between: (i) those with or without significant bacterial growth from cultures, and (ii) those who survived or died in hospital. Results: CRP concentrations were higher over time in COVID-19 patients with positive microbiology (day 9: 236 vs 123 mg/L, p < 0.0001) and in those who died (day 8: 226 vs 152 mg/L, p < 0.0001) but only after day 7 of COVID-related symptom onset. Failure for CRP to reduce in the first week of hospital admission was associated with significantly higher odds of death. PCT concentrations were higher in patients with COVID-19 and positive microbiology or in those who died, although these differences were not statistically significant. Conclusions: Both the absolute CRP concentration and the trajectory during the first week of hospital admission are important factors predicting microbiology culture positivity and outcome in patients hospitalised with COVID-19. Further work is needed to describe the role of PCT for co-infection. Understanding relationships of these biomarkers can support development of risk models and inform optimal antimicrobial strategies

Prediction of hospital-onset COVID-19 infections using dynamic networks of patient contact: an international retrospective cohort study.

BackgroundReal-time prediction is key to prevention and control of infections associated with health-care settings. Contacts enable spread of many infections, yet most risk prediction frameworks fail to account for their dynamics. We developed, tested, and internationally validated a real-time machine-learning framework, incorporating dynamic patient-contact networks to predict hospital-onset COVID-19 infections (HOCIs) at the individual level.MethodsWe report an international retrospective cohort study of our framework, which extracted patient-contact networks from routine hospital data and combined network-derived variables with clinical and contextual information to predict individual infection risk. We trained and tested the framework on HOCIs using the data from 51 157 hospital inpatients admitted to a UK National Health Service hospital group (Imperial College Healthcare NHS Trust) between April 1, 2020, and April 1, 2021, intersecting the first two COVID-19 surges. We validated the framework using data from a Swiss hospital group (Department of Rehabilitation, Geneva University Hospitals) during a COVID-19 surge (from March 1 to May 31, 2020; 40 057 inpatients) and from the same UK group after COVID-19 surges (from April 2 to Aug 13, 2021; 43 375 inpatients). All inpatients with a bed allocation during the study periods were included in the computation of network-derived and contextual variables. In predicting patient-level HOCI risk, only inpatients spending 3 or more days in hospital during the study period were examined for HOCI acquisition risk.FindingsThe framework was highly predictive across test data with all variable types (area under the curve [AUC]-receiver operating characteristic curve [ROC] 0·89 [95% CI 0·88-0·90]) and similarly predictive using only contact-network variables (0·88 [0·86-0·90]). Prediction was reduced when using only hospital contextual (AUC-ROC 0·82 [95% CI 0·80-0·84]) or patient clinical (0·64 [0·62-0·66]) variables. A model with only three variables (ie, network closeness, direct contacts with infectious patients [network derived], and hospital COVID-19 prevalence [hospital contextual]) achieved AUC-ROC 0·85 (95% CI 0·82-0·88). Incorporating contact-network variables improved performance across both validation datasets (AUC-ROC in the Geneva dataset increased from 0·84 [95% CI 0·82-0·86] to 0·88 [0·86-0·90]; AUC-ROC in the UK post-surge dataset increased from 0·49 [0·46-0·52] to 0·68 [0·64-0·70]).InterpretationDynamic contact networks are robust predictors of individual patient risk of HOCIs. Their integration in clinical care could enhance individualised infection prevention and early diagnosis of COVID-19 and other nosocomial infections.FundingMedical Research Foundation, WHO, Engineering and Physical Sciences Research Council, National Institute for Health Research (NIHR), Swiss National Science Foundation, and German Research Foundation

Development and delivery of a real-time hospital-onset COVID-19 surveillance system using network analysis

Background Understanding nosocomial acquisition, outbreaks, and transmission chains in real time will be fundamental to ensuring infection-prevention measures are effective in controlling coronavirus disease 2019 (COVID-19) in healthcare. We report the design and implementation of a hospital-onset COVID-19 infection (HOCI) surveillance system for an acute healthcare setting to target prevention interventions. Methods The study took place in a large teaching hospital group in London, United Kingdom. All patients tested for SARS-CoV-2 between 4 March and 14 April 2020 were included. Utilizing data routinely collected through electronic healthcare systems we developed a novel surveillance system for determining and reporting HOCI incidence and providing real-time network analysis. We provided daily reports on incidence and trends over time to support HOCI investigation and generated geotemporal reports using network analysis to interrogate admission pathways for common epidemiological links to infer transmission chains. By working with stakeholders the reports were co-designed for end users. Results Real-time surveillance reports revealed changing rates of HOCI throughout the course of the COVID-19 epidemic, key wards fueling probable transmission events, HOCIs overrepresented in particular specialties managing high-risk patients, the importance of integrating analysis of individual prior pathways, and the value of co-design in producing data visualization. Our surveillance system can effectively support national surveillance. Conclusions Through early analysis of the novel surveillance system we have provided a description of HOCI rates and trends over time using real-time shifting denominator data. We demonstrate the importance of including the analysis of patient pathways and networks in characterizing risk of transmission and targeting infection-control interventions

Integrated analysis of patient networks and plasmid genomes reveals a regional, multi-species outbreak of carbapenemase-producing Enterobacterales carrying both blaIMP and mcr-9 genes

Background Carbapenemase-producing Enterobacterales (CPE) are challenging in healthcare, with resistance to multiple classes of antibiotics. This study describes the emergence of IMP-encoding CPE amongst diverse Enterobacterales species between 2016 and 2019 across a London regional network. Methods We performed a network analysis of patient pathways, using electronic health records, to identify contacts between IMP-encoding CPE positive patients. Genomes of IMP-encoding CPE isolates were overlayed with patient contacts to imply potential transmission events. Results Genomic analysis of 84 Enterobacterales isolates revealed diverse species (predominantly Klebsiella spp, Enterobacter spp, E. coli); 86% (72/84) harboured an IncHI2 plasmid carrying blaIMP and colistin resistance gene mcr-9 (68/72). Phylogenetic analysis of IncHI2 plasmids identified three lineages showing significant association with patient contacts and movements between four hospital sites and across medical specialities, which was missed on initial investigations. Conclusions Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of blaIMPCPE, which remained unidentified during standard investigations. With DNA sequencing and multi-modal data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Plasmid-level outbreak analysis reveals that resistance spread may be wider than suspected, allowing more interventions to stop transmission within hospital networks

Identifying robust biomarkers of infection through an omics-based meta-analysis

AbstractA fundamental problem for disease treatment is that while antibiotics are a powerful counter to bacteria, they are ineffective against viruses. To ensure a given individual receives optimal treatment given their disease state and to reduce over-prescription of antibiotics leading to antimicrobial resistance, the host response can be measured to distinguish between the two states. To establish a predictive biomarker panel of disease state we conducted a meta-analysis of human blood infection studies using Machine Learning (ML). We focused on publicly available gene expression data from two widely used platforms, Affymetrix and Illumina microarrays, and integrated over 2000 samples for each platform to develop optimal gene panels. On average our models predicted 80% of bacterial and 85% viral samples correctly by class of infection type. For our best performing model, identified with an evolutionary algorithm, 93% of bacterial and 89% of viral samples were classified correctly. To enable comparison between the two differing microarray platforms, we reverse engineered the underlying molecular regulatory network and overlay the identified models. This revealed that although the exact gene-level overlap between models generated from the two technologies was relatively low, both models contained genes in the same areas of the network, indicating that the same functional changes in host biology were being detected, providing further confidence in the robustness of our models. Specifically, this convergence was to pathways including the Type I interferon Signalling Pathway, Chemotaxis, Apoptotic Processes, and Inflammatory / Innate Response. Amongst and related to these pathways we found three genes,IFI27, LY6E, andCD177, particularly prevalent throughout our analysis.Author summaryBacterial and viral disease require specific treatments, and whilst there are various treatment options for specific infection types, rapid diagnosis and identification of the optimal treatment remains challenging. Even in wealthier countries with developed healthcare systems, unnecessary prescription of antibiotics to patients with viral infections is causing phenomena such as multi-drug resistent bacteria. One way to distinguish a viral from bacterial infection is to measure an individual’s responses, for example by measuring the expression of particular genes in a blood sample, as different types of infections trigger different types of responses. In our study we analysed thousands of previously collected data sets from human blood, where individuals had either viral, bacterial or no infection (control). We used machine learning to identify “signatures” – small sets of genes that are indicative of the type of infection (if any) carried by an individual. Within data sets we used two different technology platforms had been used to collect data. We demonstrated that their gene-level signatures do not overlap perfectly when derived from the different platforms, the biological networks from which those genes were derived, however, had a high overlap – giving confidence that our models are robust against technology artefacts or bias. We have identified a small set of genes that serve as strong biomarkers of infection status in humans.</jats:sec

Network memory in the movement of hospital patients carrying antimicrobial-resistant bacteria

AbstractHospitals constitute highly interconnected systems that bring into contact an abundance of infectious pathogens and susceptible individuals, thus making infection outbreaks both common and challenging. In recent years, there has been a sharp incidence of antimicrobial-resistance amongst healthcare-associated infections, a situation now considered endemic in many countries. Here we present network-based analyses of a data set capturing the movement of patients harbouring antibiotic-resistant bacteria across three large London hospitals. We show that there are substantial memory effects in the movement of hospital patients colonised with antibiotic-resistant bacteria. Such memory effects break first-order Markovian transitive assumptions and substantially alter the conclusions from the analysis, specifically on node rankings and the evolution of diffusive processes. We capture variable length memory effects by constructing a lumped-state memory network, which we then use to identify individually import wards and overlapping communities of wards. We find these wards align closely to known hotspots of transmission and commonly followed pathways patients. Our framework provides a means to focus infection control efforts and cohort outbreaks of healthcare-associated infections.</jats:p