The prevalence of serious bacterial infections in neutropenic immunocompetent febrile children.

CONTEXT: Febrile neutropenic immunocompromised children are at a high risk of Serious Bacterial Infections (SBI). OBJECTIVE: This systematic review and meta-analysis report the prevalence of SBI in healthy children with febrile neutropenia. DATA SOURCE: PubMed, EMBASE, and Web of Science from their inception to August 2020. STUDY SELECTION: Patients with an Absolute Neutrophil Count (ANC) <1000 cells/mm3 up to 18 years of age presenting to the ED with a chief complaint of fever (temperature > 38°C) and who had a workup for SBI as defined by each study. DATA ABSTRACTION: Data from individual studies was abstracted by a subset of the authors and checked independently by the senior author. Any discrepancies were adjudicated by the joint agreement of all the authors. We calculated the prevalence of SBI by using the number of SBI's as the numerator and the total number of febrile events in patients as the denominator. Bias in our studies was quantified by the Newcastle Ottawa Scale. RESULTS: We identified 2066 citations of which five studies (1693 patients) our inclusion criteria. None of our reviewed studies consistently tested every included patient for SBI. Spectrum bias in every study resulted in a wide range of the SBI prevalence of 1.9% (<0.01% - 11%) similar to non-neutropenic children. LIMITATIONS: All of our studies were retrospective and many did not consistently screen all subjects for SBI. CONCLUSION: If the clinical suspicion is low, the risk for SBI is similar between febrile healthy neutropenic and non-neutropenic children.

Sufficient production of geranylgeraniol is required to maintain endotoxin tolerance in macrophages.

Endotoxin tolerance allows macrophages to produce large quantities of proinflammatory cytokines immediately after their contact with lipopolysaccharides (LPSs), but prevents their further production after repeated exposure to LPSs. While this response is known to prevent overproduction of proinflammatory cytokines, the mechanism through which endotoxin tolerance is established has not been identified. In the current study, we demonstrate that sufficient production of geranylgeraniol (GGOH) in macrophages is required to maintain endotoxin tolerance. We show that increased synthesis of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) protein following LPS treatment is required to produce enough GGOH to inhibit expression of Malt1, a protein known to stimulate expression of proinflammatory cytokines, in macrophages repeatedly exposed to LPSs. Depletion of GGOH caused by inhibition of HMGCR led to increased Malt1 expression in macrophages subjected to repeated exposure to LPSs. Consequently, endotoxin tolerance was impaired, and production of interleukin 1-ß and other proinflammatory cytokines was markedly elevated in these cells. These results suggest that insufficient production of GGOH in macrophages may cause autoinflammatory diseases.