Diagnostic Performance of Physician Gestalt for Bacteremia in Patients in the Process of Being Admitted With Suspected Infection.

BACKGROUND: Due to potentially fatal consequences of missed bacteremia, blood cultures are often overused. While there are several prediction models that can be used to identify patients who truly need blood cultures, physicians often rely on their gestalt. We evaluated the diagnostic performance of physician gestalt for bacteremia in comparison with 2 existing prediction models: Takeshima and Shapiro. METHODS: The study enrolled consecutive adult patients with suspected infection who were in the process of being admitted to the general medicine department at 2 hospitals between April 2017 and January 2019. Attending physicians provided gestalt regarding risk of bacteremia (0%-100%). Patients with a <10% risk estimated via each strategy (ie, physician gestalt or 2 existing models) were categorized as bacteremia excluded (ie, blood cultures were considered unnecessary). Strategies were compared in terms of safety (proportion of patients with bacteremia among those classified as bacteremia excluded) and efficiency (proportion of patients classified as bacteremia excluded among the total cohort). RESULTS: Among 2014 patients, 292 (14.5%) were diagnosed with bacteremia. The safety of physician gestalt and the Takeshima and Shapiro models was 3.7% (95% confidence interval [CI], 2.2% to 5.7%), 6.5% (95% CI, 5.0% to 7.9%), and 10.8% (95% CI, 9.4% to 12.3%), whereas the efficiency of each strategy was 22.4% (95% CI, 22.5% to 26.3%), 52.7% (95% CI, 50.5% to 54.9%), and 87.8% (95% CI, 86.3% to 89.2%), respectively. CONCLUSIONS: Physician gestalt was safer but less efficient than existing models. Clinical prediction models could help reduce the overuse of blood cultures.

Effect of histamine on intercellular adhesion molecule-1 expression and production of interferon-gamma and interleukin-12 in mixed lymphocyte reaction stimulated with interleukin-18.

BACKGROUND: Interleukin (IL)-18 was identified as an interferon (IFN)-gamma-inducing factor and was demonstrated to up-regulate the expression of intercellular adhesion molecule (ICAM)-1 on human monocytes. In organ transplantation, elevation of plasma IL-18 levels has been reported during acute rejection. In the present study, we examined the effect of IL-18 on human mixed lymphocyte reaction (MLR), an in vitro model of acute rejection after organ transplantation. We also investigated the modulatory effects of histamine on IL-18 action because histamine has been demonstrated to be a modulator of IL-18 effect and a mediator of inflammation. METHODS: We measured the expression of ICAM-1 on human monocytes in MLR in the presence or absence of IL-18 by flow cytometer and determined the associated production of IFN-gamma and IL-12 by ELISA. The modulatory effects of histamine and the relevant histamine receptor subtypes were characterized pharmacologically. RESULTS: The expression of ICAM-1 on monocytes in MLR was markedly enhanced by the addition of IL-18 in a concentration- and time-dependent manner. In parallel to ICAM-1 up-regulation, IL-18 significantly enhanced the production of IFN-gamma and IL-12 in MLR. Histamine concentration-dependently inhibited ICAM-1 expression and cytokine production in MLR stimulated with IL-18, whereas histamine alone did not show any effects on these responses in the absence of IL-18. The effects of histamine on both ICAM-1 expression and cytokine production were mimicked by the selective H2-receptor agonists 4-methylhistamine and dimaprit and were antagonized by the H2-receptor antagonist famotidine but not by H1- and H3-receptor antagonists. CONCLUSION: IL-18 strongly enhanced human MLR with respect to ICAM-1 expression and cytokine production. The fact that histamine could inhibit the IL-18-stimulated MLR implies that immunomodulation by histamine and selective H2-receptor agonists may have an important role in future immunosuppressive strategies.

Prostaglandin E(2) inhibits IL-18-induced ICAM-1 and B7.2 expression through EP2/EP4 receptors in human peripheral blood mononuclear cells.

Costimulatory molecules play important roles in immune responses. In the present study we investigated the effects of PGE(2) on the expression of ICAM-1, B7.1, and B7.2 on monocytes in IL-18-stimulated PBMC using FACS analysis. Addition of PGE(2) to PBMC inhibited ICAM-1 and B7.2 expression elicited by IL-18 in a concentration-dependent manner. We examined the involvement of four subtypes of PGE(2) receptors, EP1, EP2, EP3, and EP4, in the modulatory effect of PGE(2) on ICAM-1 and B7.2 expression elicited by IL-18, using subtype-specific agonists. ONO-AE1-259-01 (EP2R agonist) inhibited IL-18-elicited ICAM-1 and B7.2 expression in a concentration-dependent manner with a potency slightly less than that of PGE(2), while ONO-AE1-329 (EP4R agonist) was much less potent than PGE(2). The EP2/EP4R agonist 11-deoxy-PGE(1) mimicked the effect of PGE(2) with the same potency. ONO-D1-004 (EP1R agonist) and ONO-AE-248 (EP3R agonist) showed no effect on IL-18-elicited ICAM-1 or B7.2 expression. These results indicated that EP2 and EP4Rs were involved in the action of PGE(2). Dibutyryl cAMP and forskolin down-regulated ICAM-1 and B7.2 expression in IL-18-stimulated monocytes. As EP2 and EP4Rs are coupled to adenylate cyclase, we suggest that PGE(2) down-regulates IL-18-induced ICAM-1 and B7.2 expression in monocytes via EP2 and EP4Rs by cAMP-dependent signaling pathways. The fact that anti-B7.2 as well as anti-ICAM-1 Ab inhibited IL-18-induced cytokine production implies that PGE(2) may modulate the immune response through regulation of the expression of particular adhesion molecules on monocytes via EP2 and EP4Rs.

Essential role of ICAM-1/LFA-1 interaction in synergistic effect of IL-18 and IL-12 on IFN-gamma production in human PBMC.

IL-18 (0-100 ng/ml) specifically upregulated ICAM-1 expression on monocytes in human PBMC as demonstrated in our previous study. In the present study, we examined whether the synergistic upregulation of ICAM-1 occurred after the stimulation with the combination of IL-18 and IL-12 and whether the synergistic production of IFN-gamma was dependent on the interaction between ICAM-1 on monocytes and LFA-1 on NK/T cells. The effect of IL-12 on ICAM-1 expression on monocytes was marginal even at the highest concentration (100 ng/ml). However, in the presence of IL-12 (100 ng/ml), the expression of ICAM-1 induced by IL-18 was significantly enhanced as compared with that obtained by IL-18 alone. In addition to the expression of ICAM-1 on monocytes, IFN-gamma production was synergistically stimulated by IL-18 and IL-12. Anti-ICAM-1 and anti-LFA-1 Abs exhibited significant inhibitory effect on enhanced production of IFN-gamma by the combination of two cytokines, in particular, anti-ICAM-1 showing the complete inhibition. These results as a whole indicated that synergistic effect of IL-18 and IL-12 on IFN-gamma production in human PBMC is ascribed to the synergism of the effect of two cytokines on ICAM-1 expression on monocytes and that the subsequent ICAM-1/LFA-1 interaction plays an important role in the enhanced production of IFN-gamma.

Histamine regulation of interleukin-18-initiating cytokine cascade is associated with down-regulation of intercellular adhesion molecule-1 expression in human peripheral blood mononuclear cells.

In the previous study, we demonstrated that interleukin (IL)-18 up-regulated intercellular adhesion molecule-1 (ICAM-1) expression on monocytes in human peripheral blood mononuclear cells (PBMC) and that heterotypic interaction between monocytes/T or NK cells through ICAM-1/LFA-1 intensified the production of IL-12, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) in PBMC. In the present study, we demonstrate that histamine inhibited the ICAM-1 expression in monocytes induced by IL-18 using flow cytometry and that the responses of IL-12, IFN-gamma, and TNF-alpha induced by IL-18 were concentration dependently inhibited by coexisting histamine, whereas IL-18-inhibited IL-10 production was reversed by the same concentrations of histamine. The modulatory effects of histamine on ICAM-1 expression and cytokine production were all concentration dependently antagonized by famotidine but not by d-chlorpheniramine and thioperamide, and were mimicked by selective H(2)-receptor agonists but not by H(1)- and H(3)-receptor agonists, indicating the involvement of H(2)-receptors in histamine action. The inhibition of IL-18-induced IFN-gamma by histamine was ascribed to the strong inhibition of IL-12 production by histamine. Histamine thus operates the negative feedback mechanism against IL-18-activated cytokine cascade through the strong inhibitory effect on ICAM-1 expression and IL-12 production in monocytes, contributing to the formation of diverse pattern of cytokine activation from Th1 to Th2, depending on the monocyte/macrophage activation and cytokine environment.