Serum Sodium, Patient Symptoms, and Clinical Outcomes in Hospitalized Patients with COVID-19.

INTRODUCTION: Disorders of serum sodium (SNa) are common in hospitalized patients with COVID-19 and may reflect underlying disease severity. However, the association of SNa with patient-reported outcomes is not clear. METHODS: The Brigham and Women's Hospital COVID-19 Registry is a prospective cohort study of consecutively admitted adult patients with confirmed SARS-CoV-2 infection (n = 809). We examined the associations of SNa (continuous and tertiles) on admission with: (1) patient symptoms obtained from detailed chart review; and (2) in-hospital mortality, length of stay, and intensive care unit (ICU) admission using unadjusted and adjusted logistic regression models. Covariates included demographic data and comorbidities. RESULTS: Mean age was 60 years, 48% were male, and 35% had diabetes. The most frequent symptoms were cough (64%), fever (60%), and shortness of breath (56%). In adjusted models, higher SNa (per mmol/L) was associated with lower odds of GI symptoms (OR 0.96; 95% CI 0.92-0.99), higher odds of confusion (OR 1.08; 95% CI 1.04-1.13), in-hospital mortality (OR 1.06; 95% CI 1.02-1.11), and ICU admission (OR 1.09; 95% CI 1.05-1.13). The highest sodium tertile (compared with the middle tertile) showed similar associations, in addition to lower odds of either anosmia or ageusia (OR 0.30; 95% CI 0.12-0.74). CONCLUSION: In this prospective cohort study of hospitalized patients with COVID-19, hypernatremia was associated with higher odds of confusion and in-hospital mortality. These findings may aid providers in identifying high-risk patients who warrant closer attention, thereby furthering patient-centered approaches to care.

Plasma from patients with bacterial sepsis or severe COVID-19 induces suppressive myeloid cell production from hematopoietic progenitors in vitro.

Bacterial sepsis and severe COVID-19 share similar clinical manifestations and are both associated with dysregulation of the myeloid cell compartment. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis and validated expansion of this cell subpopulation in publicly available transcriptomics data. Here, using published datasets, we show that the gene expression program associated with MS1 correlated with sepsis severity and was up-regulated in monocytes from patients with severe COVID-19. To examine the ontogeny and function of MS1 cells, we developed a cellular model for inducing CD14+ MS1 monocytes from healthy bone marrow hematopoietic stem and progenitor cells (HSPCs). We found that plasma from patients with bacterial sepsis or COVID-19 induced myelopoiesis in HSPCs in vitro and expression of the MS1 gene program in monocytes and neutrophils that differentiated from these HSPCs. Furthermore, we found that plasma concentrations of IL-6, and to a lesser extent IL-10, correlated with increased myeloid cell output from HSPCs in vitro and enhanced expression of the MS1 gene program. We validated the requirement for these two cytokines to induce the MS1 gene program through CRISPR-Cas9 editing of their receptors in HSPCs. Using this cellular model system, we demonstrated that induced MS1 cells were broadly immunosuppressive and showed decreased responsiveness to stimulation with a synthetic RNA analog. Our in vitro study suggests a potential role for systemic cytokines in inducing myelopoiesis during severe bacterial or SARS-CoV-2 infection.

Induction of a regulatory myeloid program in bacterial sepsis and severe COVID-19.

A recent estimate suggests that one in five deaths globally are associated with sepsis 1 . To date, no targeted treatment is available for this syndrome, likely due to substantial patient heterogeneity 2,3 and our lack of insight into sepsis immunopathology 4 . These issues are highlighted by the current COVID-19 pandemic, wherein many clinical manifestations of severe SARS-CoV-2 infection parallel bacterial sepsis 5-8 . We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis or non-infectious critical illness, and validated its expansion in sepsis across thousands of patients using public transcriptomic data 9 . Despite its marked expansion in the circulation of bacterial sepsis patients, its relevance to viral sepsis and association with disease outcomes have not been examined. In addition, the ontogeny and function of this monocyte state remain poorly characterized. Using public transcriptomic data, we show that the expression of the MS1 program is associated with sepsis mortality and is up-regulated in monocytes from patients with severe COVID-19. We found that blood plasma from bacterial sepsis or COVID-19 patients with severe disease induces emergency myelopoiesis and expression of the MS1 program, which are dependent on the cytokines IL-6 and IL-10. Finally, we demonstrate that MS1 cells are broadly immunosuppressive, similar to monocytic myeloid-derived suppressor cells (MDSCs), and have decreased responsiveness to stimulation. Our findings highlight the utility of regulatory myeloid cells in sepsis prognosis, and the role of systemic cytokines in inducing emergency myelopoiesis during severe bacterial and SARS-CoV-2 infections.

Leukocyte function assessed via serial microlitre sampling of peripheral blood from sepsis patients correlates with disease severity.

Dysregulated leukocyte responses underlie the pathobiology of sepsis, which is a leading cause of death. However, measures of leukocyte function are not routinely available in clinical care. Here we report the development and testing of an inertial microfluidic system for the label-free isolation and downstream functional assessment of leukocytes from 50 µl of peripheral blood. We used the system to assess leukocyte phenotype and function in serial samples from 18 hospitalized patients with sepsis and 10 healthy subjects. The sepsis samples had significantly higher levels of CD16dim and CD16- neutrophils and CD16+ 'intermediate' monocytes, as well as significantly lower levels of neutrophil-elastase release, O2- production and phagolysosome formation. Repeated sampling of sepsis patients over 7 days showed that leukocyte activation (measured by isodielectric separation) and leukocyte phenotype and function were significantly more predictive of the clinical course than complete-blood-count parameters. We conclude that the serial assessment of leukocyte function in microlitre blood volumes is feasible and that it provides significantly more prognostic information than leukocyte counting.