The CHARTER-Ireland trial: can nebulised heparin reduce acute lung injury in patients with SARS-CoV-2 requiring advanced respiratory support in Ireland: a study protocol and statistical analysis plan for a randomised control trial.

BACKGROUND: COVID-19 pneumonia is associated with the development of acute respiratory distress syndrome (ARDS) displaying some typical histological features. These include diffuse alveolar damage with extensive pulmonary coagulation activation. This results in fibrin deposition in the microvasculature, leading to the formation of hyaline membranes in the air sacs. Well-conducted clinical trials have found that nebulised heparin limits pulmonary fibrin deposition, attenuates progression of ARDS, hastens recovery and is safe in non-COVID ARDS. Unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents entry into mammalian cells. Nebulisation of heparin may therefore limit fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. Based on these findings, we designed the CHARTER-Ireland Study, a phase 1b/2a randomised controlled study of nebulised heparin in patients requiring advanced respiratory support for COVID-19 pneumonia. METHODS: This is a multi-centre, phase 1b/IIa, randomised, parallel-group, open-label study. The study will randomise 40 SARs-CoV-2-positive patients receiving advanced respiratory support in a critical care area. Randomisation will be via 1:1 allocation to usual care plus nebulised unfractionated heparin 6 hourly to day 10 while receiving advanced respiratory support or usual care only. The study aims to evaluate whether unfractionated heparin will decrease the procoagulant response associated with ARDS up to day 10. The study will also assess safety and tolerability of nebulised heparin as defined by number of severe adverse events; oxygen index and respiratory oxygenation index of intubated and unintubated, respectively; ventilatory ratio; and plasma concentration of interleukin (IL)-1ß, IL6, IL-8, IL-10 and soluble tumour necrosis factor receptor 1, C-reactive protein, procalcitonin, ferritin, fibrinogen and lactate dehydrogenase as well as the ratios of IL-1ß/IL-10 and IL-6/IL-10. These parameters will be assessed on days 1, 3, 5 and 10; time to separation from advanced respiratory support, time to discharge from the intensive care unit and number tracheostomised to day 28; and survival to days 28 and 60 and to hospital discharge, censored at day 60. Some clinical outcome data from our study will be included in the international meta-trials, CHARTER and INHALE-HEP. DISCUSSION: This trial aims to provide evidence of potential therapeutic benefit while establishing safety of nebulised heparin in the management of ARDS associated with SARs-CoV-2 infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT04511923 . Registered on 13 August 2020. Protocol version 8, 22/12/2021 Protocol identifier: NUIG-2020-003 EudraCT registration number: 2020-003349-12 9 October 2020.

The Outcomes of Patients Incidentally Confirmed with Covid-19 After Cardiac Surgery.

BACKGROUND: The aim of this study was to investigate the clinical outcomes of cardiac surgery in patients who were incidentally diagnosed with Covid-19 in the postoperative period. PATIENTS AND METHODS: We performed 826 open cardiac surgeries in five tertiary centers. Most of the surgeries were elective coronary artery bypass grafting (CABG) (93.8%). A preoperative RT-PCR test and transcutaneous oxygen saturation were routinely investigated prior to surgery. We also investigated whether the patients already received Covid-19 treatment or had any contact with a Covid-19 patient in the last two weeks. We analyzed high sensitive C-reactive protein (hs-CRP), d-dimer, and fibrinogen, which plays a main role in the activation of procoagulant state after surgeries. RESULTS: Acute lung injury related to Covid-19 activation was observed in 48 out of 826 patients (5.8%). The median age of 48 patients was 63.9±12.4 years. Euro-Score and body mass index (BMI) were 6.1±1.1 and 29.2±4.1kg/m², respectively. RT-PCR test results were positive in 29 patients (60.4%). We performed thoracic computed tomography (CT) in all patients with or without positive RT-PCR test results. Thoracic CT images showed that there was a different degree of ARDS (mild, moderate, and serious). The median time of extracorporeal circulation (ECC) was 93.2±14.6 min. in on-pump surgery (IQR, 68-155 min.). Common symptoms included dyspnea (N = 22; 45.8%) and fever (N = 12; 25%). Eleven patients needed readmission to ICU. Compared with non-admitted to ICU patients, ICU patients were higher comorbidities and severe laboratory abnormalities (eg, high blood d-dimer and fibrinogen). We also detected significantly low oxygen saturation, hypercapnia, and severe acidosis in readmitted patients. Radiologic investigations showed that there were severe ARDS with bilateral pneumonic infiltration resistant to medical treatment in 6 out of 11 patients who died (54.5%). CONCLUSION: Diffuse pneumonic infiltration related to Covid-19 may develop in asymptomatic cardiac surgery patients with negative RT-PCR test results. Immunologic disorders resulting from ECC, physiologic distress, and anesthesia may activate Covid-19 during the incubation period. We need randomized clinical trials to explain Covid-19 activation in the latent period of the virus, and clinical outcomes in cardiac surgery.

Current and Past Infections of HBV Do Not Increase Mortality in Patients With COVID-19.

BACKGROUND AND AIMS: We compared risk of acute liver injury and mortality in patients with COVID-19 and current, past, and no HBV infection. APPROACH AND RESULTS: This was a territory-wide retrospective cohort study in Hong Kong. Patients with COVID-19 between January 23, 2020, and January 1, 2021, were identified. Patients with hepatitis C or no HBsAg results were excluded. The primary outcome was mortality. Acute liver injury was defined as alanine aminotransferase or aspartate aminotransferase ≥2 × upper limit of normal (ULN; i.e., 80 U/L), with total bilirubin ≥2 × ULN (i.e., 2.2 mg/dL) and/or international normalized ratio ≥1.7. Of 5,639 patients included, 353 (6.3%) and 359 (6.4%) had current and past HBV infection, respectively. Compared to patients without known HBV exposure, current HBV-infected patients were older and more likely to have cirrhosis. Past HBV-infected patients were the oldest, and more had diabetes and cardiovascular disease. At a median follow-up of 14 (9-20) days, 138 (2.4%) patients died; acute liver injury occurred in 58 (1.2%), 8 (2.3%), and 11 (3.1%) patients with no, current, and past HBV infection, respectively. Acute liver injury (adjusted HR [aHR], 2.45; 95% CI, 1.52-3.96; P < 0.001), but not current (aHR, 1.29; 95% CI, 0.61-2.70; P = 0.507) or past (aHR, 0.90; 95% CI, 0.56-1.46; P = 0.681) HBV infection, was associated with mortality. Use of corticosteroid, antifungal, ribavirin, or lopinavir-ritonavir (adjusted OR [aOR], 2.55-5.63), but not current (aOR, 1.93; 95% CI, 0.88-4.24; P = 0.102) or past (aOR, 1.25; 95% CI, 0.62-2.55; P = 0.533) HBV infection, was associated with acute liver injury. CONCLUSION: Current or past HBV infections were not associated with more liver injury and mortality in COVID-19.

Key Pathogenic Factors in Coronavirus Disease 2019-Associated Coagulopathy and Acute Lung Injury Highlighted in a Patient With Copresentation of Acute Myelocytic Leukemia: A Case Report.

The role of concurrent illness in coronavirus disease 2019 (COVID-19) is unknown. Patients with leukemia may display altered thromboinflammatory responses. We report a 53-year-old man presenting with acute leukemia and COVID-19 who developed thrombotic complications and acute respiratory distress syndrome. Multiple analyses, including rotational thromboelastometry and flow cytometry on blood and bronchoalveolar lavage, are reported to characterize coagulation and immune profiles. The patient developed chemotherapy-induced neutropenia that may have protected his lungs from granulocyte-driven hyperinflammatory acute lung injury. However, neutropenia also alters viral clearing, potentially enabling ongoing viral propagation. This case depicts a precarious equilibrium between leukemia and COVID-19.

Study on Laboratory Indicators Related to Lung Injury of Corona Virus Disease 2019.

BACKGROUND: Since December 2019, a series of pneumonia cases caused by COVID-19 emerged in Wuhan, Hubei Province, China. People are generally susceptible to COVID-19 because people lack immunity to this new virus. With the spread of this epidemic disease from Wuhan, a national outbreak soon appeared, and now many countries have this disease. Unfortunately, no effective drug for COVID-19 treatment has been found so far. METHODS: We designed a retrospective study based on patients admitted to The Affiliated Infectious Hospital of Soochow University from January 22, 2020, to February 25, 2020, with diagnosed COVID-19. We analyzed correlations between RT-PCR negative time and laboratory indicators, then divided all cases into 2 groups according to oxygenation index, data of RT-PCR negative time and related laboratory indicators of the two groups were com-pared. RESULTS: We collected 84 confirmed patients whose RT-PCR had turned negative, including 23 patients with the lowest oxygenation index ≤ 300 mmHg and 61 patients had > 300 mmHg. There was a positive correlation between the RT-PCR negative time and age, WBC count, LDH, SCr. There were statistically significant differences in fever numbers, WBC count, lymphocyte count, CRP, ALT, AST, albumin, LDH, SCr, D-dimer, and fibrinogen between the two groups based on the oxygenation index. CONCLUSIONS: Age, WBC count, LDH, and SCr may be related to the duration of COVID-19 disease. Fever, WBC count, lymphocyte count, CRP, ALT, AST, albumin, LDH, SCr, D-dimer, and fibrinogen are related to the severity of acute lung injury.