Evangelos J Giamarellos-Bourboulis’s research while affiliated with National and Kapodistrian University of Athens and other places

Infections, cancer, and trauma can cause life-threatening hyperinflammation. In the present study, using single-cell RNA sequencing of circulating immune cells, we found that the mammalian target of rapamycin (mTOR) pathway plays a critical role in myeloid cell regulation in COVID-19 patients. Previously, we developed an mTOR-inhibiting nanobiologic (mTORi-nanobiologic) that efficiently targets myeloid cells and their progenitors in the bone marrow. In vitro, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the in vivo effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using ¹⁸F-FDG uptake and flow cytometry readouts, we found mTORi-nanobiologic therapy to efficiently reduce hematopoietic organ metabolic activity and inflammation to levels comparable to those of healthy control animals. Together, we show that regulating myelopoiesis with mTORi-nanobiologics is a compelling therapeutic strategy to prevent deleterious organ inflammation in infection-related complications.

Recent studies argue for a novel concept of the role of chromatin as a carrier of epigenetic memory through cellular and organismal generations, defining and coordinating gene activity states and physiological functions. Environmental insults, such as exposures to unhealthy diets, smoking, toxic compounds, and infections, can epigenetically reprogram germ-line cells and influence offspring phenotypes. This review focuses on intergenerational and transgenerational epigenetic inheritance in different plants, animal species and humans, presenting the up-to-date evidence and arguments for such effects in light of Darwinian and Lamarckian evolutionary theories. An overview of the epigenetic changes induced by infection or other immune challenges is presented, and how these changes, known as epimutations, contribute to shaping offspring phenotypes. The mechanisms that mediate the transmission of epigenetic alterations via the germline are also discussed. Understanding the relationship between environmental fluctuations, epigenetic changes, resistance, and susceptibility to diseases is critical for unraveling disease etiology and adaptive evolution.

Precision immunotherapy signifies the administration of the required type of immune intervention tailored to the state of immune activation at the appropriate time window. The classification of patients into the different states of immune activation is usually done by either a protein blood biomarker or a molecular blood endotype which is diagnostic of the precise immune state. Evidence coming from trials of the last decade suggests that immune interventions should be split into strategies aiming to attenuate the exaggerated immune responses, strategies aiming to restore sepsis-induced immunoparalysis (SII) and strategies aiming to restore the vascular tone. Suggested strategies to attenuate the immune responses are anakinra, nangibotide and tocilizumab. Biomarkers which guide their use are ferritin and sTREM-1 (soluble triggering receptor expressed on myeloid cells-1). Suggested strategies to restore SII are nivolumab, recombinant human interferon-gamma, CYT107 and GM-CSF (granulocyte macrophage colony stimulating factor). Biomarkers which guide their use are the expression of the human leukocyte antigen DR on blood monocytes, the absolute lymphocyte count, and blood levels of IgM. One recently suggested strategy to restore vascular tone is adrecizumab, the use is guided by the blood levels of bio-adrenomedulin. The use of these precision treatment strategies is still hampered by the need of large scale randomized controlled trials.

Rationale: Early detection, standardized therapy, adequate infrastructure, and strategies for quality improvement should constitute essential components of every hospital's sepsis plan. Objectives: To investigate the extent to which recommendations from the sepsis guidelines are implemented and the availability of infrastructure for the care of patients with sepsis in acute-care hospitals. Methods: A multidisciplinary cross-sectional questionnaire was used to investigate sepsis care in hospitals. This included the use of sepsis definitions, the implementation of sepsis guideline recommendations, diagnostic and therapeutic infrastructure, antibiotic stewardship, and quality improvement initiatives (QIIs) in hospitals. Measurements and Main Results: A total of 1,023 hospitals in 69 countries were included. Most of them, 835 (81.6%), were in Europe. Sepsis screening was used in 54.2% of emergency departments (EDs), 47.9% of wards, and 61.7% of ICUs. Sepsis management was standardized in 57.3% of EDs, 45.2% of wards, and 70.7% of ICUs. The implementation of comprehensive QIIs was associated with increased screening (EDs, +33.3%; wards, +44.4%; ICUs, +23.8% absolute difference) and increased standardized sepsis management (EDs, +33.6%; wards, +40.0%; ICUs, +17.7% absolute difference) compared with hospitals without QIIs. A total of 9.8% of hospitals had implemented ongoing QIIs, and 4.6% had invested in sepsis programs. Conclusions: The findings indicate that there is considerable room for improvement in a large number of mainly European hospitals, particularly with regard to early identification and standardized management of sepsis, the availability of guidelines, diagnostic and therapeutic infrastructure, and the implementation of QIIs. Further efforts are required to implement a more comprehensive and appropriate quality of care.

This JAMA Viewpoint explores the addition of host-directed therapy using immunotherapeutic agents to pandemic preparedness programs.

Purpose of review Define the utility of adjunctive macrolide therapy in patients with more severe forms of community-acquired pneumonia (CAP). Recent findings Guidelines recommend adjunctive macrolide therapy as an option for patients with CAP, admitted to the hospital. A large data set collected both retrospectively and prospectively, including several recent randomized controlled trials (RCTs) have shown that adjunctive macrolide therapy can reduce mortality and improve outcomes in patients with severe CAP, more effectively than other alternative therapies. This effect appears to be most evident in those with severe illness and appears to be independent of direct antimicrobial effects and may be a result of the immunomodulatory properties of macrolides. A recent RCT, the ACCESS study, showed a clinical benefit of macrolides in severe CAP patients, but this may have been the result of a reversal of infection-related immunoparalysis. Macrolides appear to be valuable for patients with more severe CAP, but their therapeutic value is being challenged by the recent emergence of macrolide-resistant Mycoplasma pneumoniae; however, the optimal therapy for this pathogen still needs to be defined. Summary New evidence has further advanced the role of macrolides as preferred adjunctive therapy for patients with severe CAP.