Background To explore and describe the current literature surrounding bacterial/fungal coinfection in patients with coronavirus infection. Methods MEDLINE, EMBASE, and Web of Science were searched using broad-based search criteria relating to coronavirus and bacterial coinfection. Articles presenting clinical data for patients with coronavirus infection (defined as SARS-1, MERS, SARS-CoV-2, and other coronavirus) and bacterial/fungal coinfection reported in English, Mandarin, or Italian were included. Data describing bacterial/fungal coinfections, treatments, and outcomes were extracted. Secondary analysis of studies reporting antimicrobial prescribing in SARS-CoV-2 even in absence of coinfection was performed. Results 1007 abstracts were identified. Eighteen full texts reporting bacterial/fungal coinfection were included. Most studies did not identify or report bacterial/fungal coinfection (85/140; 61%). Nine of 18 (50%) studies reported on COVID-19, 5/18 (28%) on SARS-1, 1/18 (6%) on MERS, and 3/18 (17%) on other coronaviruses. For COVID-19, 62/806 (8%) patients were reported as experiencing bacterial/fungal coinfection during hospital admission. Secondary analysis demonstrated wide use of broad-spectrum antibacterials, despite a paucity of evidence for bacterial coinfection. On secondary analysis, 1450/2010 (72%) of patients reported received antimicrobial therapy. No antimicrobial stewardship interventions were described. For non–COVID-19 cases, bacterial/fungal coinfection was reported in 89/815 (11%) of patients. Broad-spectrum antibiotic use was reported. Conclusions Despite frequent prescription of broad-spectrum empirical antimicrobials in patients with coronavirus-associated respiratory infections, there is a paucity of data to support the association with respiratory bacterial/fungal coinfection. Generation of prospective evidence to support development of antimicrobial policy and appropriate stewardship interventions specific for the COVID-19 pandemic is urgently required.

The innate immune system is absolutely required for host defence, but, uncontrolled, it leads to inflammatory disease. This control is mediated, in part, by cytokines that are secreted by macrophages. Immune regulation is extraordinarily complex, and can be best investigated with systems approaches (that is, using computational tools to predict regulatory networks arising from global, high-throughput data sets). Here we use cluster analysis of a comprehensive set of transcriptomic data derived from Toll-like receptor (TLR)-activated macrophages to identify a prominent group of genes that appear to be regulated by activating transcription factor 3 (ATF3), a member of the CREB/ATF family of transcription factors. Network analysis predicted that ATF3 is part of a transcriptional complex that also contains members of the nuclear factor (NF)-kappaB family of transcription factors. Promoter analysis of the putative ATF3-regulated gene cluster demonstrated an over-representation of closely apposed ATF3 and NF-kappaB binding sites, which was verified by chromatin immunoprecipitation and hybridization to a DNA microarray. This cluster included important cytokines such as interleukin (IL)-6 and IL-12b. ATF3 and Rel (a component of NF-kappaB) were shown to bind to the regulatory regions of these genes upon macrophage activation. A kinetic model of Il6 and Il12b messenger RNA expression as a function of ATF3 and NF-kappaB promoter binding predicted that ATF3 is a negative regulator of Il6 and Il12b transcription, and this hypothesis was validated using Atf3-null mice. ATF3 seems to inhibit Il6 and Il12b transcription by altering chromatin structure, thereby restricting access to transcription factors. Because ATF3 is itself induced by lipopolysaccharide, it seems to regulate TLR-stimulated inflammatory responses as part of a negative-feedback loop.