Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis.

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-CoV-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homolog in myeloid cells triggered a STAT3-linked, progressive, and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury, and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.

[Reorganization and public health management by the Department of Prevention during the COVID-19 emergency. An experience of integration between prevention and primary care in the proactive management of possible cases]. / Riorganizzazione e management di sanità pubblica del dipartimento di prevenzione nell'emergenza COVID-19. Un'esperienza di integrazione tra prevenzione e cure primarie nella gestione proattiva dei casi possibili.

OBJECTIVES: to describe the organisation and the role of the Department of Prevention of the Local Health Unit (APSS) of Trento (Trentino-Alto Adige Region, Northern Italy) against the spread of COVID-19 in the population, in the management of possible cases (with only clinical criteria of influenza-like illness, ILI, without diagnostic swab) reported by General practitioners (GPs) and by Family paediatricians (FPs) during the initial phase of the pandemic COVID-19 in Trentino-Alto Adige Region. DESIGN: descriptive study. SETTING AND PARTICIPANTS: this study analysed the reports of patients with ILI sent to the Healthcare company from 17 March to 17 April 2020 by their GPs or FP and subsequently classified into: redundant reports (people already known to the healthcare company as confirmed or probable case COVID-19); reports inconsistent with ILI criteria (patients not known to APSS as probable/confirmed case; without ILI criteria); appropriate reports (patients not known to APSS as probable/confirmed case; with ILI criteria). MAIN OUTCOME MEASURES: proportion of GPs and FPs who participated to report system reporting at least one patient, out of the total number of GPs and FPs; frequency of patients reported as ILI; time (in days) to manage reported patients. The cumulative weekly rate of "non-redundant" (not already known to APSS as probable/confirmed case) reports per thousand inhabitants was also calculated. RESULTS: over 80% of GPs and FPs voluntary participated into the reporting system of patients with COVID-19 clinical criteria. Overall, 4,270 patients were reported; of these, 2,865 (67%) were not known to APSS as probable/confirmed case. Response time in days decrease progressively during the period of activity (from a mean of 6 days to 0.4 days during the 12th and 16th week of 2020, respectively). The cumulative weekly rate of client reports which were not already known as probable or confirmed cases (per 1,000 population) ranges from 3.54 to 6.84 cases in the 12th and 16th week, respectively. Among the 4,270 reports, 1,471 patients considered possible COVID-19 cases were identified due to the presence of ILI symptoms, even in the absence of a swab or a positive history for close contact with COVID-19 case. From the epidemiological investigation into the 1,471 possible cases, 2,514 close contacts were identified and quarantined at home. Of the 2,514 close contacts, 127 (5.05%) people developed symptoms during quarantine. CONCLUSIONS: the integration among primary care, GPs and FPS, and the Department of Prevention could be an element of success in the management of the COVID-19 emergency and in the return to a normal phase. However, further assessments are required on the effectiveness and impact of the adopted model, especially in relation to the exit from phase 1 and phase 2 of the pandemic emergency.