Michael T. McCurdy

Sepsis stands apart from the other emergencies that define time-critical care. While trauma, stroke, and STEMI are anchored by a discrete lesion and a confirmatory test, sepsis offers no such certainty – no single biomarker, no clear identifiable moment of onset, no clean diagnostic threshold. Clinicians are instead asked to recognize a shifting constellation of signs that vary by both pathogen and a fluid host immune response, often without the reassurance of positive cultures. This review examines the paradox at the heart of emergency sepsis care, which is the demand for immediate, decisive treatment of a syndrome that resists reliable, timely characterization.

Background: Critical illness in coronavirus disease 2019 may require extracorporeal membrane oxygenation support. We quantified immunothrombotic markers in patients with COVID-19 receiving ECMO and evaluated their predictive capacity for death. Methods: We performed a retrospective analysis of 74 consecutive patients with COVID-19 on ECMO at a single academic medical center between March 2020 and February 2021. Severe acute respiratory syndrome coronavirus-2 nucleocapsid RNA and 16 immunothrombotic biomarkers were longitudinally quantified and their trajectories were used to predict death and decannulation across multiple models. Results: Male sex, smoking, serum bilirubin levels, and low partial arterial oxygen pressure–fraction of inspired oxygen ratio were associated with increased risk of death. Plasma levels of 10 immunothrombotic markers were significantly elevated in fatal cases and some were associated with an increased hazard of death (eg, interleukin 8, von Willebrand factor) or decreased hazard for decannulation (eg, angiopoietin 2, interleukin 1β) when adjusting for sex, smoking status, and time to cannulation. Predictive models incorporating biomarkers were superior to demographics alone and equivalent to models including clinical information. Conclusions: We found that male sex, smoking, and select clinical variables and immunothrombotic markers were risk factors for death in patients with COVID-19 on ECMO informing pathogenesis and prognostication of severe COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) causes coronavirus disease 2019 (COVID‐19) and has been related to more than 7 million deaths globally since 2019. The association of high levels of IL‐6 with severe cases led to the early evaluation of the anti‐IL6 inhibitor tocilizumab as a potential treatment, which unfortunately failed to improve survival in many trials. Moreover, little is known about the development of COVID‐19 sequelae, and biomarkers are needed to understand and anticipate these processes. Because extracellular vesicles (EVs) play an important role in viral infection and immune response, they could potentially serve as predictive and prognostic biomarkers. We isolated EVs from 39 patients with severe COVID‐19, from which 29 received tocilizumab and 10 were considered controls. Blood samples, which were collected at hospitalisation before treatment, at Day 7, and Day 15 during follow‐up, were assessed by immunoblot for longitudinal expression of spike (S) and nucleocapsid (N) proteins. Dynamic expression was calculated and compared with clinicopathological and experimental variables. Expression of EV S was validated by immunogold and imaging flow‐cytometry, revealing an enrichment in CD9+ EVs. As a result, decreasing expression of EV viral proteins was observed in patients treated with tocilizumab. Moreover, higher increase in EV S was observed in patients with lower antibody response, hyperfibrinogenemia, lower respiratory function, higher blood pressure and shorter outcomes. These findings lay the foundation for future studies characterizing the role of EVs in multiorgan assessment and identifying biomarkers in patients with severe COVID‐19 and possible long COVID.

Septic shock management in the cardiac intensive care unit (CICU) is challenging due to the complex interaction of pathophysiology between vasodilatory and cardiogenic shock, complicating how to optimally deploy fluid resuscitation, vasopressors, and mechanical circulatory support devices. Because mixed shock portends high mortality and morbidity, familiarity with quality, contemporary clinical evidence surrounding available therapeutic tools is needed to address the resultant wide range of complications that can arise. This review integrates pathophysiology principles and clinical recommendations to provide an organized, topic-based review of the nuanced intricacies of managing sepsis in the CICU.

Bacterial and fungal co-infections are reported complications of coronavirus disease 2019 (COVID-19) in critically ill patients but may go unrecognized premortem due to diagnostic limitations. We compared the premortem with the postmortem detection of pulmonary co-infections in 55 fatal COVID-19 cases from March 2020 to March 2021. The concordance in the premortem versus the postmortem diagnoses and the pathogen identification were evaluated. Premortem pulmonary co-infections were extracted from medical charts while applying standard diagnostic definitions. Postmortem co-infection was defined by compatible lung histopathology with or without the detection of an organism in tissue by bacterial or fungal staining, or polymerase chain reaction (PCR) with broad-range bacterial and fungal primers. Pulmonary co-infection was detected premortem in significantly fewer cases (15/55, 27%) than were detected postmortem (36/55, 65%; p < 0.0001). Among cases in which co-infection was detected postmortem by histopathology, an organism was identified in 27/36 (75%) of cases. Pseudomonas, Enterobacterales, and Staphylococcus aureus were the most frequently identified bacteria both premortem and postmortem. Invasive pulmonary fungal infection was detected in five cases postmortem, but in no cases premortem. According to the univariate analyses, the patients with undiagnosed pulmonary co-infection had significantly shorter hospital (p = 0.0012) and intensive care unit (p = 0.0006) stays and significantly fewer extra-pulmonary infections (p = 0.0021). Bacterial and fungal pulmonary co-infection are under-recognized complications in critically ill patients with COVID-19.

Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction^1,2,3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. ^4,5). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain^{3,6,7,8,9,10,11,12,13,14}. Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.