Use of radiolabeled hyaluronic acid for preclinical assessment of inflammatory injury and acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is accompanied by a dramatic increase in lung hyaluronic acid (HA), leading to a dose-dependent reduction of pulmonary oxygenation. This pattern is associated with severe infections, such as COVID-19, and other important lung injury etiologies. HA actively participates in molecular pathways involved in the cytokine storm of COVID-19-induced ARDS. The objective of this study was to evaluate an imaging approach of radiolabeled HA for assessment of dysregulated HA deposition in mouse models with skin inflammation and lipopolysaccharide (LPS)-induced ARDS using a novel portable intensified Quantum Imaging Detector (iQID) gamma camera system. METHODS: HA of 10 kDa molecular weight (HA10) was radiolabeled with 125I and 99mTc respectively to produce [125I]I-HA10 and [99mTc]Tc-HA10, followed by comparative studies on stability, in vivo biodistribution, and uptake at inflammatory skin sites in mice with 12-O-tetradecanoylphorbol-13-acetate (TPA)-inflamed ears. [99mTc]Tc-HA10 was used for iQID in vivo dynamic imaging of mice with ARDS induced by intratracheal instillation of LPS. RESULTS: [99mTc]Tc-HA10 and [125I]I-HA10 had similar biodistribution and localization at inflammatory sites. [99mTc]Tc-HA10 was shown to be feasible in measuring skin injury and monitoring skin wound healing. [99mTc]Tc-HA10 dynamic pulmonary images yielded good visualization of radioactive uptake in the lungs. There was significantly increased lung uptake and slower lung washout in mice with LPS-induced ARDS than in control mice. Postmortem biodistribution measurement of [99mTc]TcHA10 (%ID/g) was 11.0 ± 3.9 vs. 1.3 ± 0.3 in the ARDS mice (n = 6) and controls (n = 6) (P < 0.001), consistent with upregulated HA expression as determined by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) staining. CONCLUSIONS: [99mTc]Tc-HA10 is promising as a biomarker for evaluating HA dysregulation that contributes to pulmonary injury in ARDS. Rapid iQID imaging of [99mTc]Tc-HA10 clearance from injured lungs may provide a functional template for timely assessment and quantitative monitoring of pulmonary pathophysiology and intervention in ARDS.

Safety and Efficacy of Tocilizumab 4 or 8 mg/kg in Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019 Pneumonia: A Randomized Clinical Trial.

BACKGROUND: Tocilizumab, an interleukin 6 receptor (IL-6R) antagonist monoclonal antibody, has shown efficacy in patients with coronavirus disease 2019 (COVID-19) pneumonia, but the optimal dose is unknown. METHODS: Patients hospitalized for moderate to severe COVID-19 pneumonia were randomized 1:1 to receive standard of care treatment and 1-2 doses of intravenous tocilizumab 4 mg/kg or 8 mg/kg (open-label). Primary pharmacokinetic and pharmacodynamic end points were serum concentrations of tocilizumab and soluble interleukin 6 receptor (sIL-6R), IL-6, ferritin, and C-reactive protein (CRP), from baseline to day 60. The secondary end point was safety. Key exploratory efficacy end points included clinical status, time to discharge, mortality rate, and incidence of mechanical ventilation. RESULTS: Of 100 patients randomized, 49 received tocilizumab 4 mg/kg and 48 received 8 mg/kg. In pharmacokinetic and sIL-6R assessments, dose-dependent differences were seen in patients who received 1 or 2 doses of 4 or 8 mg/kg. Serum concentrations of IL-6, ferritin, and CRP and safety outcomes were comparable between groups. Through day 60, serious adverse events were reported in 30.6% and 25.0% of patients in the 4- and 8-mg/kg groups, respectively. Eight patients (16.3%) in the 4-mg/kg group and 6 (12.5%) in the 8-mg/kg group died. Exploratory time-to-event outcomes favored 8 mg/kg within the first 2 weeks. CONCLUSIONS: In patients with moderate to severe COVID-19 pneumonia who received tocilizumab 4 or 8 mg/kg, pharmacokinetic and sIL-6R assessments showed expected dose-dependent effects; pharmacodynamic assessments and safety were comparable, with no new safety signals. Further study is required before a lower dose of tocilizumab can be recommended in patients with COVID-19 pneumonia. CLINICAL TRIALS REGISTRATION: NCT04363736.

Clinical Outcomes Following Tocilizumab Administration in Mechanically Ventilated Coronavirus Disease 2019 Patients.

Effective treatments for the critically ill patient with novel coronavirus disease 2019 are desperately needed. Given the role of cytokine release syndrome in the pathogenesis of coronavirus disease 2019-associated respiratory distress, therapies aimed at mitigating cytokine release, such as the interleukin-6 receptor-inhibiting monoclonal antibody tocilizumab, represent potential treatment strategies. Therefore, we examined the outcomes of critically ill coronavirus disease 2019 patients treated with tocilizumab and factors associated with clinical improvement. DESIGN: A retrospective cohort analysis of 21-day outcomes for consecutive mechanically ventilated patients treated with tocilizumab from March 24, 2020, to May 4, 2020. SETTING: Nine ICUs at six hospitals within a hospital system in Houston, Texas, United States. PATIENTS: The first 62 coronavirus disease 2019 patients on invasive mechanical ventilation who were treated with tocilizumab, which was considered for all patients with severe disease. INTERVENTIONS: Tocilizumab was administered either at a weight-based dose of 4-8 mg/kg or at a flat dose of 400 mg, with repeat administration in some patients at the physician's discretion. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were mortality and clinical improvement, defined as extubation. By day 21 post-tocilizumab, clinical improvement occurred in 36 patients (58%) and 13 patients (21%) died. In both univariable and multivariable analyses, age less than 60 years was associated with clinical improvement. Transient transaminitis was the most common adverse reaction, occurring in 25 patients (40%). CONCLUSIONS: Based on clinical outcomes and mortality rates seen in previous reports of mechanically ventilated patients, tocilizumab, as part of the management strategy for severe coronavirus disease 2019, represents a promising option. These findings support the need for evaluation of tocilizumab in a randomized controlled trial.

Sepsis outcomes in solid organ transplant recipients.

BACKGROUND: We present data on a cohort of patients diagnosed with sepsis over a 10-year period comparing outcomes in solid organ transplant (SOT) and non-solid organ transplant (non-SOT) recipients. METHODS: This is a retrospective single-center study of patients with diagnosis of sepsis from 1/1/06 to 6/30/16. Cases and controls were matched by year of sepsis diagnosis with propensity score matching. Conditional logistic regression and repeated measurement models were performed for binary outcomes. Trends over time for in-hospital mortality were determined using the Cochran-Armitage test. A gamma-distributed model was performed on the continuous variables. RESULTS: Overall, there were 18 632 admission encounters with a discharge diagnosis of sepsis in 14 780 unique patients. Of those admissions, 1689 were SOT recipients. After 1:1 matching by year, there were three thousand three hundred and forty patients (1670 cases; 1670 controls) diagnosed with sepsis. There was a decreasing trend for in-hospital mortality for sepsis over time in SOT patients and non-SOT patients (P < .05) due to early sepsis recognition and improved standard of care. Despite higher comorbidities in the SOT group, conditional logistic regression showed that in-hospital mortality for sepsis in SOT patients was similar compared with non-SOT patients (odds ratio [OR] =1.14 [95% confidence interval {CI}, 0.95-1.37], P = .161). However, heart and lung SOT subgroups had higher odds of dying compared with the non-SOT group (OR = 1.83 [95% CI, 1.30-2.57], P < .001 and OR = 1.77 [95% CI, 1.34-2.34], P < .001). On average, SOT patients had 2 days longer hospital length of stay compared with non-SOT admissions (17.00 ± 19.54 vs 15.23 ± 17.07, P < .05). Additionally, SOT patients had higher odds of hospital readmission within 30 days (OR = 1.25 [95% CI, 1.06-1.51], P = .020), and higher odds for DIC compared with non-SOT patients (OR = 1.76 [95% CI, 1.10-2.86], P = .021). CONCLUSION: Sepsis in solid organ transplants and non-solid organ transplant patients have similar mortality; however, the subset of heart and lung transplant recipients with sepsis has a higher rate of mortality compared with the non-solid organ transplant recipients. SOT with sepsis as a group has a higher hospital readmission rate compared with non-transplant sepsis patients.

Sepsis in a Panorama: What the Cardiovascular Physician Should Know.

Sepsis accounts for an estimated 30 million cases and 6 million deaths globally each year. According to a multidisciplinary task force convened by the Society of Critical Care Medicine and European Society of Intensive Care Medicine, sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Sepsis is a medical emergency, so much so that the World Health Organization made it a global health priority. Since patients with cardiovascular diseases have unique risk factors for sepsis, prompt and accurate diagnosis is critical. In this regard, the sepsis-specific Sequential Organ Failure Assessment (SOFA) helps clinicians identify the organ dysfunction and predict outcomes. Sepsis management is grouped into specific interventions called bundles, and completion of each bundle element is time sensitive. The U.S. Centers for Medicaid and Medicare Services and some state-specific regulations have made compliance with these bundles reportable as a quality measure. The updated Surviving Sepsis Campaign Hour-1 bundle recommends that lactate measurement, blood cultures procurement, broad spectrum antibiotics administration, resuscitation with 30 mL/kg crystalloid, and vasopressor initiation for hypotension all be initiated within 1 hour of time zero, which is from the time of triage in the emergency department or from sepsis diagnosis. Septic shock is defined as hypotension with a mean arterial pressure less than 65 mm Hg, requiring vasopressors despite adequate fluid resuscitation and/or lactic acid levels above 2 mmol/L. Both fluid resuscitation and clinical re-evaluation with lactate measurement guide the fluid and vasopressor therapy. Specific guidelines exist for organ support that address mechanical ventilation, blood transfusions, vasopressor choices, and nutrition.