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The reported estimates of bacterial co-infection in COVID-19 patients are highly variable. We aimed to determine the rates and risk factors of bacterial co-infection and develop a clinical prediction model to support early decision-making on antibiotic use. This is a retrospective cohort study conducted in a tertiary-level academic hospital in Israel between March 2020 and May 2022. All adult patients with severe COVID-19 who had a blood or lower respiratory specimen sent for microbiological analyses within 48 h of admission were included. The primary study endpoint was the prevalence of bacterial co-infection at the time of hospital admission. We created a prediction model using the R XGBoost package. The study cohort included 1,050 patients admitted with severe or critical COVID-19. Sixty-two patients (5.9%) had a microbiologically proven bacterial infection on admission. The variables with the greatest impact on the prediction model were age, comorbidities, functional capacity, and laboratory parameters. The model achieved perfect prediction on the training set (area under the curve = 1.0). When applied to the test dataset, the model achieved 56% and 78% specificity with the area under the receiver operating curve of 0.784. The negative and positive predictive values were 0.975 and 0.105, respectively. Applying the prediction model would have resulted in a 2.5-fold increase in appropriate antibiotic use and an 18% reduction in inappropriate use in patients with severe and critical COVID-19. The use of a clinical prediction model can support decisions to withhold empiric antimicrobial treatment at the time of hospital admission without adversely affecting patient outcomes., Importance: Estimates of bacterial coinfection in COVID-19 patients are highly variable and depend on many factors. Patients with severe or critical COVID-19 requiring intensive care unit admission have the highest risk of infection-related complications and death. Thus, the study of the incidence and risk factors for bacterial coinfection in this population is of special interest and may help guide empiric antibiotic therapy and avoid unnecessary antimicrobial treatment. The prediction model based on clinical criteria and simple laboratory tests may be a useful tool to predict bacterial co-infection in patients hospitalized with severe COVID-19., Competing Interests: The authors declare no conflict of interest.

Objective: Mean arterial pressure (MAP) plays a significant role in regulating tissue perfusion and urine output (UO). The optimal MAP target in critically ill patients remains a subject of debate. We aimed to explore the relationship between MAP and UO., Design: A retrospective observational study., Setting: A general ICU in a tertiary medical center., Patients: All critically ill patients admitted to the ICU for more than 10 hours., Interventions: None., Measurements and Main Results: MAP values and hourly UO were collected in 5,207 patients. MAP levels were categorized into 10 groups of 5 mm Hg (from MAP < 60 mm Hg to MAP > 100 mg Hg), and 656,423 coupled hourly mean MAP and UO measurements were analyzed. Additionally, we compared the UO of individual patients in each MAP group with or without norepinephrine (NE) support or diuretics, as well as in patients with acute kidney injury (AKI).Hourly UO rose incrementally between MAP values of 65-100 mm Hg. Among 2,226 patients treated with NE infusion, mean UO was significantly lower in the MAP less than 60 mm Hg group (53.4 mL/hr; 95% CI, 49.3-57.5) compared with all other groups (p < 0.001), but no differences were found between groups of 75 less than or equal to MAP. Among 2500 patients with AKI, there was a linear increase in average UO from the MAP less than 60 mm Hg group (57.1 mL/hr; 95% CI, 54.2-60.0) to the group with MAP greater than or equal to 100 mm Hg (89.4 mL/hr; 95% CI, 85.7-93.1). When MAP was greater than or equal to 65 mm Hg, we observed a statistically significant trend of increased UO in periods without NE infusion., Conclusions: Our analysis revealed a linear correlation between MAP and UO within the range of 65-100 mm Hg, also observed in the subgroup of patients treated with NE or diuretics and in those with AKI. These findings highlight the importance of tissue perfusion to the maintenance of diuresis and achieving adequate fluid balance in critically ill patients., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: The exposure of blood to the artificial circuit during extracorporeal membrane oxygenation (ECMO) can induce an inflammatory response. C-reactive protein (CRP) is a commonly used biomarker of systemic inflammation., Methods: In this retrospective observational study, we analyzed results of daily plasma CRP measurements in 110 critically ill patients, treated with ECMO. We compared CRP levels during the first 5 days of ECMO operation, between different groups of patients according to ECMO configurations, Coronavirus disease 2019 (COVID-19) status, and mechanical ventilation parameters., Results: There was a statistically significant decrease in CRP levels during the first 5 days of veno-venous (VV) ECMO (173 ± 111 mg/L, 154 ± 107 mg/L, 127 ± 97 mg/L, 114 ± 100 mg/L and 118 ± 90 mg/L for days 1-5 respectively, p  < 0.001). Simultaneously, there was a significant reduction in ventilatory parameters, as represented by the mechanical power (MP) calculation, from 24.02 ± 14.53 J/min to 6.18 ± 4.22 J/min within 3 h of VV ECMO initiation ( p  < 0.001). There was non-significant trend of increase in CRP level during the first 5 days of veno arterial (VA) ECMO (123 ± 80 mg/L, 179 ± 91 mg/L, 203 ± 90 mg/L, 179 ± 95 mg/L and 198 ± 93 for days 1-5 respectively, p  = 0.126) and no significant change in calculated MP (from 14.28 ± 8.56 J/min to 10.81 ± 8.09 J/min within 3 h if ECMO initiation, p  = 0.071)., Conclusions: We observed a significant decrease in CRP levels during the first 5 days of VV ECMO support, and suggest that the concomitant reduction in ventilatory MP may have mitigated the degree of alveolar stress and strain that could have contributed to a decrease in the systemic inflammatory process., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor known to be involved in macrophage differentiation and function, steatohepatitis and liver fibrosis., Methods: Immune restricted C/EBPβ deficient and control mice were investigated in steady-state and in the CDA-HFD steatohepatitis model. Mice were assessed for weight change, liver biochemical profile, histology and hepatic phagocytes composition., Results: Flow cytometry analysis of hepatic nonparenchymal cells revealed reduced numbers of hepatic monocytes and Kupffer cells and an increase in hepatic MHC class II positive myeloid cells in immune cells restricted C/EBPβ deficient mice. Immune-restricted C/EBPβ deficiency resulted in decreased weight gain and appearance of mild spontaneous liver inflammation. Nevertheless, In the CDA-HFD steatohepatitis model, immune restricted C/EBPβ deficient and proficient mice exhibit similar grade of hepatic steatosis, liver enzymes levels and fibrosis stage., Conclusions: Immune-restricted C/EBPβ deficiency leads to significant alteration in hepatic mononuclear phagocytes composition associated with spontaneous mild hepatitis. Steatohepatitis associated fibrosis is not dependent on C/EBPβ expression by immune cells., (© 2022 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Liver-resident macrophages Kupffer cells (KCs) and infiltrating Ly6C hi monocytes both contribute to liver tissue regeneration in various pathologies but also to disease progression upon disruption of orderly consecutive regeneration cascades. Little is known about molecular pathways that regulate their differentiation, maintenance, or inflammatory behavior during injury. Here, we show that copper metabolism MURR1 domain (COMMD)10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10 deficiency in KCs and in other tissue-resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6C hi monocytes. While COMMD10 deficiency in KCs mildly worsens acetaminophen-induced liver injury (AILI), its deficiency in Ly6C hi monocytes results in exacerbated and sustained hepatic damage. Monocytes display unleashed inflammasome activation and a reduced type I interferon response and acquire "neutrophil-like" and lipid-associated macrophage differentiation fates. Collectively, COMMD10 appears indispensable for KC and other tissue-resident macrophage survival and is an important regulator of Ly6C hi monocyte fate decisions and reparative behavior in the diseased liver., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The therapy of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases despite significant improvements in our understanding of both immunological and molecular events that lead to loss of tolerance to the E2 component of pyruvate dehydrogenase, the immunodominant autoepitope of PBC. It is well known that Ly6C hi monocytes are innate immune cells infiltrating inflammatory sites that are dependent on the expression of C-C motif chemokine receptor 2 (CCR2) for emigration from bone marrow. Importantly, humans with PBC have a circulating monocyte pro-inflammatory phenotype with macrophage accumulation in portal tracts. We have taken advantage of an inducible chemical xenobiotic model of PBC and recapitulated the massive infiltration of monocytes to portal areas. To determine the clinical significance, we immunized both CCR2-deficient mice and controls with 2OA-BSA and noted that CCR2 deficiency is protective for the development of autoimmune cholangitis. Importantly, because of the therapeutic potential, we focused on inhibiting monocyte infiltration through the use of cenicriviroc (CVC), a dual chemokine receptor CCR2/CCR5 antagonist shown to be safe in human trials. Importantly, treatment with CVC resulted in amelioration of all aspects of disease severity including serum total bile acids, histological severity score, and fibrosis stage. In conclusion, our results indicate a major role for Ly6C hi monocytes and for CCR2 in PBC pathogenesis and suggest that inhibition of this axis by CVC should be explored in humans through the use of clinical trials.

The CD300 family of receptors is an evolutionary conserved receptor family that belongs to the Ig superfamily and is expressed predominantly by the myeloid lineage. Over the past couple of years, accumulating data have shown that eosinophils express various Ig superfamily receptors that regulate key checkpoints in their biology including their maturation, transition from the bone marrow to the peripheral blood, migration, adhesion, survival, and effector functions in response to numerous activating signals such as IL-4, IL-33, and bacteria. In this review, we will present the emerging roles of CD300 family receptors and specifically CD300a and CD300f in the regulation of these eosinophil activities. The structure and expression pattern of these molecules will be discussed and their involvement in suppressing or co-activating eosinophil functions in health and disease will be illustrated., (©2017 Society for Leukocyte Biology.)

Eosinophils are bone marrow-derived cells that have been largely implicated in Th2-associated diseases. Recent data highlights a key role for eosinophils in mucosal innate immune responses especially in the gastrointestinal (GI) tract, which is one of the largest eosinophil reservoirs in the body. Although eosinophils express and synthesize a plethora of proteins that can mediate their effector activities, the transcriptome signature of eosinophils in mucosal inflammation and subsequent repair has been considerably overlooked. We demonstrate that eosinophils are recruited to the colon in acute inflammatory stages where they promote intestinal inflammation and remain in substantial numbers throughout the mucosal healing process. Microarray analysis of primary colonic eosinophils that were sorted at distinct stages of mucosal inflammation and repair revealed dynamic regulation of colonic eosinophil mRNA expression. The clinically relevant genes s100a8 and s100a9 were strikingly increased in colonic eosinophils (up to 550-fold and 80-fold, respectively). Furthermore, local and systemic expression of s100a8 and s100a9 were nearly diminished in eosinophil-deficient ΔdblGATA mice, and were re-constituted upon adoptive transfer of eosinophils. Taken together, these data may provide new insight into the involvement of eosinophils in colonic inflammation and repair, which may have diagnostic and therapeutic implications.

The function of NCR1 was studied in a model of experimental asthma, classified as a type 1 hypersensitivity reaction, in mice. IgE levels were significantly increased in the serum of OVA immunized NCR1 deficient (NCR1gfp/gfp) mice in comparison to OVA immunized wild type (NCR1+/+) and adjuvant immunized mice. Histological analysis of OVA immunized NCR1gfp/gfp mice revealed no preservation of the lung structure and overwhelming peribronchial and perivascular granulocytes together with mononuclear cells infiltration. OVA immunized NCR+/+ mice demonstrated preserved lung structure and peribronchial and perivascular immune cell infiltration to a lower extent than that in NCR1gfp/gfp mice. Adjuvant immunized mice demonstrated lung structure preservation and no immune cell infiltration. OVA immunization caused an increase in PAS production independently of NCR1 presence. Bronchoalveolar lavage (BAL) revealed NCR1 dependent decreased percentages of eosinophils and increased percentages of lymphocytes and macrophages following OVA immunization. In the OVA immunized NCR1gfp/gfp mice the protein levels of eosinophils' (CCL24) and Th2 CD4+ T-cells' chemoattractants (CCL17, and CCL24) in the BAL are increased in comparison with OVA immunized NCR+/+ mice. In the presence of NCR1, OVA immunization caused an increase in NK cells numbers and decreased NCR1 ligand expression on CD11c+GR1+ cells and decreased NCR1 mRNA expression in the BAL. OVA immunization resulted in significantly increased IL-13, IL-4 and CCL17 mRNA expression in NCR1+/+ and NCR1gfp/gfp mice. IL-17 and TNFα expression increased only in OVA-immunized NCR1+/+mice. IL-6 mRNA increased only in OVA immunized NCR1gfp/gfp mice. Collectively, it is demonstrated that NCR1 dampens allergic eosinophilic airway inflammation., Competing Interests: The authors have declared that no competing interests exist.

IL-4 receptor (R) α, the common receptor chain for IL-4 and IL-13, is a critical component in IL-4- and IL-13-mediated signaling and subsequent effector functions such as those observed in type 2 inflammatory responses. Nonetheless, the existence of intrinsic pathways capable of amplifying IL-4Rα-induced responses remains unknown. In this study, we identified the myeloid-associated Ig receptor CD300f as an IL-4-induced molecule in macrophages. Subsequent analyses demonstrated that CD300f was colocalized and physically associated with IL-4Rα. Using Cd300f(-/-) cells and receptor cross-linking experiments, we established that CD300f amplified IL-4Rα-induced responses by augmenting IL-4/IL-13-induced signaling, mediator release, and priming. Consistently, IL-4- and aeroallergen-treated Cd300f(-/-) mice displayed decreased IgE production, chemokine expression, and inflammatory cell recruitment. Impaired responses in Cd300f(-/-) mice were not due to the inability to generate a proper Th2 response, because IL-4/IL-13 levels were markedly increased in allergen-challenged Cd300f(-/-) mice, a finding that is consistent with decreased cytokine consumption. Finally, CD300f expression was increased in monocytes and eosinophils obtained from allergic rhinitis patients. Collectively, our data highlight a previously unidentified role for CD300f in IL-4Rα-induced immune cell responses. These data provide new insights into the molecular mechanisms governing IL-4Rα-induced responses, and may provide new therapeutic tools to target IL-4 in allergy and asthma.

Eosinophilia is a hallmark characteristic of T helper type 2 (TH2) cell-associated diseases and is critically regulated by the central eosinophil growth factor interleukin 5 (IL-5). Here we demonstrate that IL-5 activity in eosinophils was regulated by paired immunoglobulin-like receptors PIR-A and PIR-B. Upon self-recognition of β₂-microglobulin (β₂M) molecules, PIR-B served as a permissive checkpoint for IL-5-induced development of eosinophils by suppressing the proapoptotic activities of PIR-A, which were mediated by the Grb2-Erk-Bim pathway. PIR-B-deficient bone marrow eosinophils underwent compartmentalized apoptosis, resulting in decreased blood eosinophilia in naive mice and in mice challenged with IL-5. Subsequently, Pirb(-/-) mice displayed impaired aeroallergen-induced lung eosinophilia and induction of lung TH2 cell responses. Collectively, these data uncover an intrinsic, self-limiting pathway regulating IL-5-induced expansion of eosinophils, which has broad implications for eosinophil-associated diseases.

Macrophages are lung-resident cells that play key roles in fibrosis. Surprisingly, pathways that inhibit macrophage functions, especially in idiopathic pulmonary fibrosis (IPF), receive little attention. The cell-surface molecule paired immunoglobulin-like receptor B (PIR-B) can suppress macrophage activation. However, its role in pulmonary fibrosis remains unknown. We sought to define the role of PIR-B in IPF. The expression of PIR-B was assessed (by quantitative PCR and flow cytometry) after bleomycin treatment. Differential cell counts, histopathology, and profibrogenic-mediator expression, for example, collagen, α-smooth muscle actin, resistin-like molecule-α (Relm-α), matrix metalloproteinase (MMP)-12, and tissue inhibitor of metalloproteinase (TIMP)-1, were determined (by ELISA quantitative PCR and flow cytometry) in the lungs of wild-type and Pirb(-/-) mice after bleomycin or IL-4 treatment. Bone marrow-derived wild-type and Pirb(-/-) macrophages were stimulated with IL-4 and assessed for Relm-α and MMP-12 expression. PIR-B was up-regulated in lung myeloid cells after bleomycin administration. Bleomycin-treated Pirb(-/-) mice displayed increased lung histopathology and an increased expression of collagen and of the IL-4-associated profibrogenic markers Relm-α, MMP-12, TIMP-1, and osteopontin, which were localized to alveolar macrophages. Increased profibrogenic mediator expression in Pirb(-/-) mice was not attributable to increased IL-4/IL-13 concentrations, suggesting that PIR-B negatively regulates IL-4-induced macrophage activation. Indeed, IL-4-treated Pirb(-/-) mice displayed increased Relm-α expression and Relm-α(+) macrophage concentrations. IL-4-activated Pirb(-/-) macrophages displayed increased Relm-α and MMP-12 induction. Finally, leukocyte immunoglobulin-like receptor subfamily B member 3 (LILRB3)/immunoglobulin-like transcript-5, the human PIR-B orthologue, was expressed and up-regulated in lung biopsies from patients with IPF. Our results establish a key role for PIR-B in IPF, likely via the regulation of macrophage activation. Therefore, PIR-B/LILRB3 may offer a possible target for suppressing macrophage profibrogenic activity in IPF.