Nathan I. Shapiro

Prolonged symptom duration and disability are common in adults hospitalized with severe coronavirus disease 2019 (COVID-19). Characterizing return to baseline health among outpatients with milder COVID-19 illness is important for understanding the full spectrum of COVID-19-associated illness and tailoring public health messaging, interventions, and policy. During April 15-June 25, 2020, telephone interviews were conducted with a random sample of adults aged ≥18 years who had a first positive reverse transcription-polymerase chain reaction (RT-PCR) test for SARS-CoV-2, the virus that causes COVID-19, at an outpatient visit at one of 14 U.S. academic health care systems in 13 states. Interviews were conducted 14-21 days after the test date. Respondents were asked about demographic characteristics, baseline chronic medical conditions, symptoms present at the time of testing, whether those symptoms had resolved by the interview date, and whether they had returned to their usual state of health at the time of interview. Among 292 respondents, 94% (274) reported experiencing one or more symptoms at the time of testing; 35% of these symptomatic respondents reported not having returned to their usual state of health by the date of the interview (median = 16 days from testing date), including 26% among those aged 18-34 years, 32% among those aged 35-49 years, and 47% among those aged ≥50 years. Among respondents reporting cough, fatigue, or shortness of breath at the time of testing, 43%, 35%, and 29%, respectively, continued to experience these symptoms at the time of the interview. These findings indicate that COVID-19 can result in prolonged illness even among persons with milder outpatient illness, including young adults. Effective public health messaging targeting these groups is warranted. Preventative measures, including social distancing, frequent handwashing, and the consistent and correct use of face coverings in public, should be strongly encouraged to slow the spread of SARS-CoV-2.

INTRODUCTION: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. METHODS: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. RESULTS: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. CONCLUSIONS: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. TRIAL REGISTRATION: ClinicalTrials.gov number NCT01209169.

The glycocalyx is a gel-like layer covering the luminal surface of vascular endothelial cells. It is comprised of membrane-attached proteoglycans, glycosaminoglycan chains, glycoproteins, and adherent plasma proteins. The glycocalyx maintains homeostasis of the vasculature, including controlling vascular permeability and microvascular tone, preventing microvascular thrombosis, and regulating leukocyte adhesion.During sepsis, the glycocalyx is degraded via inflammatory mechanisms such as metalloproteinases, heparanase, and hyaluronidase. These sheddases are activated by reactive oxygen species and pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-1beta. Inflammation-mediated glycocalyx degradation leads to vascular hyper-permeability, unregulated vasodilation, microvessel thrombosis, and augmented leukocyte adhesion. Clinical studies have demonstrated the correlation between blood levels of glycocalyx components with organ dysfunction, severity, and mortality in sepsis.Fluid resuscitation therapy is an essential part of sepsis treatment, but overaggressive fluid therapy practices (leading to hypervolemia) may augment glycocalyx degradation. Conversely, fresh frozen plasma and albumin administration may attenuate glycocalyx degradation. The beneficial and harmful effects of fluid and plasma infusion on glycocalyx integrity in sepsis are not well understood; future studies are warranted.In this review, we first analyze the underlying mechanisms of glycocalyx degradation in sepsis. Second, we demonstrate how the blood and urine levels of glycocalyx components are associated with patient outcomes. Third, we show beneficial and harmful effects of fluid therapy on the glycocalyx status during sepsis. Finally, we address the concept of glycocalyx degradation as a therapeutic target.

Importance: A comprehensive understanding of the benefits of COVID-19 vaccination requires consideration of disease attenuation, determined as whether people who develop COVID-19 despite vaccination have lower disease severity than unvaccinated people. Objective: To evaluate the association between vaccination with mRNA COVID-19 vaccines-mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech)-and COVID-19 hospitalization, and, among patients hospitalized with COVID-19, the association with progression to critical disease. Design, Setting, and Participants: A US 21-site case-control analysis of 4513 adults hospitalized between March 11 and August 15, 2021, with 28-day outcome data on death and mechanical ventilation available for patients enrolled through July 14, 2021. Date of final follow-up was August 8, 2021. Exposures: COVID-19 vaccination. Main Outcomes and Measures: Associations were evaluated between prior vaccination and (1) hospitalization for COVID-19, in which case patients were those hospitalized for COVID-19 and control patients were those hospitalized for an alternative diagnosis; and (2) disease progression among patients hospitalized for COVID-19, in which cases and controls were COVID-19 patients with and without progression to death or mechanical ventilation, respectively. Associations were measured with multivariable logistic regression. Results: Among 4513 patients (median age, 59 years [IQR, 45-69]; 2202 [48.8%] women; 23.0% non-Hispanic Black individuals, 15.9% Hispanic individuals, and 20.1% with an immunocompromising condition), 1983 were case patients with COVID-19 and 2530 were controls without COVID-19. Unvaccinated patients accounted for 84.2% (1669/1983) of COVID-19 hospitalizations. Hospitalization for COVID-19 was significantly associated with decreased likelihood of vaccination (cases, 15.8%; controls, 54.8%; adjusted OR, 0.15; 95% CI, 0.13-0.18), including for sequenced SARS-CoV-2 Alpha (8.7% vs 51.7%; aOR, 0.10; 95% CI, 0.06-0.16) and Delta variants (21.9% vs 61.8%; aOR, 0.14; 95% CI, 0.10-0.21). This association was stronger for immunocompetent patients (11.2% vs 53.5%; aOR, 0.10; 95% CI, 0.09-0.13) than immunocompromised patients (40.1% vs 58.8%; aOR, 0.49; 95% CI, 0.35-0.69) (P < .001) and weaker at more than 120 days since vaccination with BNT162b2 (5.8% vs 11.5%; aOR, 0.36; 95% CI, 0.27-0.49) than with mRNA-1273 (1.9% vs 8.3%; aOR, 0.15; 95% CI, 0.09-0.23) (P < .001). Among 1197 patients hospitalized with COVID-19, death or invasive mechanical ventilation by day 28 was associated with decreased likelihood of vaccination (12.0% vs 24.7%; aOR, 0.33; 95% CI, 0.19-0.58). Conclusions and Relevance: Vaccination with an mRNA COVID-19 vaccine was significantly less likely among patients with COVID-19 hospitalization and disease progression to death or mechanical ventilation. These findings are consistent with risk reduction among vaccine breakthrough infections compared with absence of vaccination.