Clinical research is necessary for an effective response to an emerging infectious disease outbreak. However, research efforts are often hastily organised and done using various research tools, with the result that pooling data across studies is challenging. In response to the needs of the rapidly evolving COVID-19 outbreak, the Clinical Characterisation and Management Working Group of the WHO Research and Development Blueprint programme, the International Forum for Acute Care Trialists, and the International Severe Acute Respiratory and Emerging Infections Consortium have developed a minimum set of common outcome measures for studies of COVID-19. This set includes three elements: a measure of viral burden (quantitative PCR or cycle threshold), a measure of patient survival (mortality at hospital discharge or at 60 days), and a measure of patient progression through the health-care system by use of the WHO Clinical Progression Scale, which reflects patient trajectory and resource use over the course of clinical illness. We urge investigators to include these key data elements in ongoing and future studies to expedite the pooling of data during this immediate threat, and to hone a tool for future needs.

Low-grade polymicrobial infection induced by cecal ligation and puncture is lethal in heme oxygenase-1-deficient mice (Hmox1(-/-)), but not in wild-type (Hmox1(+/+)) mice. Here we demonstrate that the protective effect of this heme-catabolizing enzyme relies on its ability to prevent tissue damage caused by the circulating free heme released from hemoglobin during infection. Heme administration after low-grade infection in mice promoted tissue damage and severe sepsis. Free heme contributed to the pathogenesis of severe sepsis irrespective of pathogen load, revealing that it compromised host tolerance to infection. Development of lethal forms of severe sepsis after high-grade infection was associated with reduced serum concentrations of the heme sequestering protein hemopexin (HPX), whereas HPX administration after high-grade infection prevented tissue damage and lethality. Finally, the lethal outcome of septic shock in patients was also associated with reduced HPX serum concentrations. We propose that targeting free heme by HPX might be used therapeutically to treat severe sepsis.

Background Most low-income and middle-income countries (LMICs) have little or no data integrated into a national surveillance system to identify characteristics or outcomes of COVID-19 hospital admissions and the impact of the COVID-19 pandemic on their national health systems. We aimed to analyse characteristics of patients admitted to hospital with COVID-19 in Brazil, and to examine the impact of COVID-19 on health-care resources and in-hospital mortality. MethodsWe did a retrospective analysis of all patients aged 20 years or older with quantitative RT-PCR (RT-qPCR)confirmed COVID-19 who were admitted to hospital and registered in SIVEP-Gripe, a nationwide surveillance database in Brazil, between Feb 16 and Aug 15, 2020 (epidemiological weeks 8-33). We also examined the progression of the COVID-19 pandemic across three 4-week periods within this timeframe (epidemiological weeks 8-12, 19-22, and 27-30). The primary outcome was in-hospital mortality. We compared the regional burden of hospital admissions stratified by age, intensive care unit (ICU) admission, and respiratory support. We analysed data from the whole country and its five regions: North, Northeast, Central-West, Southeast, and South. FindingsBetween Feb 16 and Aug 15, 2020, 254 288 patients with RT-qPCR-confirmed COVID-19 were admitted to hospital and registered in SIVEP-Gripe. The mean age of patients was 60 (SD 17) years, 119 657 (47%) of 254 288 were aged younger than 60 years, 143 521 (56%) of 254 243 were male, and 14 979 (16%) of 90 829 had no comorbidities. Case numbers increased across the three 4-week periods studied: by epidemiological weeks 19-22, cases were concentrated in the North, Northeast, and Southeast; by weeks 27-30, cases had spread to the Central-West and South regions. 232 036 (91%) of 254 288 patients had a defined hospital outcome when the data were exported; in-hospital mortality was 38% (87 515 of 232 036 patients) overall, 59% (47 002 of 79 687) among patients admitted to the ICU, and 80% (36 046 of 45 205) among those who were mechanically ventilated. The overall burden of ICU admissions per ICU beds was more pronounced in the North, Southeast, and Northeast, than in the Central-West and South. In the Northeast, 1545 (16%) of 9960 patients received invasive mechanical ventilation outside the ICU compared with 431 (8%) of 5388 in the South. In-hospital mortality among patients younger than 60 years was 31% (4204 of 13 468) in the Northeast versus 15% (1694 of 11 196) in the South.Interpretation We observed a widespread distribution of COVID-19 across all regions in Brazil, resulting in a high overall disease burden. In-hospital mortality was high, even in patients younger than 60 years, and worsened by existing regional disparities within the health system. The COVID-19 pandemic highlights the need to improve access to high-quality care for critically ill patients admitted to hospital with COVID-19, particularly in LMICs.

The innate immune system provides a first line of defense against invading pathogens by releasing multiple inflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, which directly combat the infectious agent and recruit additional immune responses. This exuberant cytokine release paradoxically injures the host by triggering leakage from capillaries, tissue edema, organ failure, and shock. Current medical therapies target individual pathogens with antimicrobial agents or directly either blunt or boost the host's immune system. We explored a third approach: activating with the soluble ligand Slit an endothelium-specific, Robo4-dependent signaling pathway that strengthens the vascular barrier, diminishing deleterious aspects of the host's response to the pathogen-induced cytokine storm. This approach reduced vascular permeability in the lung and other organs and increased survival in animal models of bacterial endotoxin exposure, polymicrobial sepsis, and H5N1

This large multicenter study reports encouraging survival rates for patients with cancer requiring intensive care. In these patients, mortality was mostly dependent on the severity of organ failures, performance status, and need for mechanical ventilation rather than cancer-related characteristics, such as the type of malignancy or the presence of neutropenia.

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Objective To describe quality of life (QoL) among sepsis survivors. Design Secondary analyses of 2 international, randomized clinical trials (ACCESS [derivation cohort] and PROWESS-SHOCK [validation cohort]). Patients Adults with severe sepsis admitted to the intensive care unit. We analyzed only patients who were functional and living at home without help before sepsis hospitalization (n=1,143 and 987 from ACCESS and PROWESS-SHOCK). Measurements and Main Results In ACCESS and PROWESS-SHOCK, the average age of patients living at home independently was 63 and 61 years; 400 (34.9%) and 298 (30.2%) died by 6 months. In ACCESS, 580 patients had a QoL measured using EQ-5D at 6 months. Of these, 41.6% could not live independently (22.7% were home but required help, 5.1% were in nursing home or rehabilitation facilities, and 5.3% were in acute care hospitals). Poor QoL at 6 months, as evidenced by problems in mobility, usual activities, and self-care domains were reported in 37.4%, 43.7%, and 20.5%, respectively, and the high incidence of poor QoL was also seen in patients in PROWESS-SHOCK. Over 45%of patients with mobility and self-care problems at 6 months in ACCESS died or reported persistent problems at 1 year. Conclusions Among individuals enrolled in a clinical trial who lived independently prior to severe sepsis, one third had died and of those who survived, a further one third had not returned to independent living by 6 months. Both mortality and QoL should be considered when designing new interventions and considering endpoints for sepsis trials.

Background As more patients are surviving intensive care, mental health concerns in survivors have become a research priority. Among these, post-traumatic stress disorder (PTSD) can have an important impact on the quality of life of critical care survivors. However, data on its burden are conflicting. Therefore, this systematic review and meta-analysis aimed to evaluate the prevalence of PTSD symptoms in adult critical care patients after intensive care unit (ICU) discharge. Methods We searched MEDLINE, EMBASE, LILACS, Web of Science, PsycNET, and Scopus databases from inception to September 2018. We included observational studies assessing the prevalence of PTSD symptoms in adult critical care survivors. Two reviewers independently screened studies and extracted data. Studies were meta-analyzed using a random-effects model to estimate PTSD symptom prevalence at different time points, also estimating confidence and prediction intervals. Subgroup and meta-regression analyses were performed to explore heterogeneity. Risk of bias was assessed using the Joanna Briggs Institute tool and the GRADE approach. Results Of 13,267 studies retrieved, 48 were included in this review. Overall prevalence of PTSD symptoms was 19.83% (95% confidence interval [CI], 16.72–23.13; I 2 = 90%, low quality of evidence). Prevalence varied widely across studies, with a wide range of expected prevalence (from 3.70 to 43.73% in 95% of settings). Point prevalence estimates were 15.93% (95% CI, 11.15–21.35; I 2 = 90%; 17 studies), 16.80% (95% CI, 13.74–20.09; I 2 = 66%; 13 studies), 18.96% (95% CI, 14.28–24.12; I 2 = 92%; 13 studies), and 20.21% (95% CI, 13.79–27.44; I 2 = 58%; 7 studies) at 3, 6, 12, and > 12 months after discharge, respectively. Conclusion PTSD symptoms may affect 1 in every 5 adult critical care survivors, with a high expected prevalence 12 months after discharge. ICU survivors should be screened for PTSD symptoms and cared for accordingly, given the potential negative impact of PTSD on quality of life. In addition, action should be taken to further explore the causal relationship between ICU stay and PTSD, as well as to propose early measures to prevent PTSD in this population. Trial registration PROSPERO, CRD42017075124 , Registered 6 December 2017. Electronic supplementary material The online version of this article (10.1186/s13054-019-2489-3) contains supplementary material, which is available to authorized users.