The burden of bacterial antimicrobial resistance in the WHO European region in 2019: a cross-country systematic analysis

Background: Antimicrobial resistance (AMR) represents one of the most crucial threats to public health and modern health care. Previous studies have identified challenges with estimating the magnitude of the problem and its downstream effect on human health and mortality. To our knowledge, this study presents the most comprehensive set of regional and country-level estimates of AMR burden in the WHO European region to date.  Methods: We estimated deaths and disability-adjusted life-years attributable to and associated with AMR for 23 bacterial pathogens and 88 pathogen–drug combinations for the WHO European region and its countries in 2019. Our methodological approach consisted of five broad components: the number of deaths in which infection had a role, the proportion of infectious deaths attributable to a given infectious syndrome, the proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antimicrobial drug of interest, and the excess risk of mortality (or duration of an infection) associated with this resistance. These components were then used to estimate the disease burden by using two counterfactual scenarios: deaths attributable to AMR (considering an alternative scenario where infections with resistant pathogens are replaced with susceptible ones) and deaths associated with AMR (considering an alternative scenario where drug-resistant infections would not occur at all). Data were solicited from a wide array of international stakeholders; these included research hospitals, surveillance networks, and infection databases maintained by private laboratories and medical technology companies. We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity.  Findings: We estimated 541 000 deaths (95% UI 370 000–763 000) associated with bacterial AMR and 133 000 deaths (90 100–188 000) attributable to bacterial AMR in the whole WHO European region in 2019. The largest fatal burden of AMR in the region came from bloodstream infections, with 195 000 deaths (104 000–333 000) associated with resistance, followed by intra-abdominal infections (127 000 deaths [81 900–185 000]) and respiratory infections (120 000 deaths [94 500–154 000]). Seven leading pathogens were responsible for about 457 000 deaths associated with resistance in 53 countries of this region; these pathogens were, in descending order of mortality, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecium, Streptococcus pneumoniae, and Acinetobacter baumannii. Methicillin-resistant S aureus was shown to be the leading pathogen–drug combination in 27 countries for deaths attributable to AMR, while aminopenicillin-resistant E coli predominated in 47 countries for deaths associated with AMR.  Interpretation: The high levels of resistance for several important bacterial pathogens and pathogen–drug combinations, together with the high mortality rates associated with these pathogens, show that AMR is a serious threat to public health in the WHO European region. Our regional and cross-country analyses open the door for strategies that can be tailored to leading pathogen–drug combinations and the available resources in a specific location. These results underscore that the most effective way to tackle AMR in this region will require targeted efforts and investments in conjunction with continuous outcome-based research endeavours. </p

Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19

COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells of hospitalized patients during the peak of the COVID-19 pandemic in the United Kingdom. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1, and IP-10 and modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, and enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of patients with COVID-19 and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission, suggesting that immunomodulating therapies would be most beneficial at early time points