Neutrophil activation and neutrophil extracellular traps (NETs) in COVID-19 ARDS and immunothrombosis.

Acute respiratory distress syndrome (ARDS) is an acute inflammatory condition with a dramatic increase in incidence since the beginning of the coronavirus disease 19 (COVID-19) pandemic. Neutrophils play a vital role in the immunopathology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by triggering the formation of neutrophil extracellular traps (NETs), producing cytokines including interleukin-8 (CXCL8), and mediating the recruitment of other immune cells to regulate processes such as acute and chronic inflammation, which can lead to ARDS. CXCL8 is involved in the recruitment, activation, and degranulation of neutrophils, and therefore contributes to inflammation amplification and severity of disease. Furthermore, activation of neutrophils also supports a prothrombotic phenotype, which may explain the development of immunothrombosis observed in COVID-19 ARDS. This review aims to describe hyperinflammatory ARDS due to SARS-CoV-2 infection. In addition, we address the critical role of polymorphonuclear neutrophils, inflammatory cytokines, and the potential targeting of CXCL8 in treating the hyperinflammatory ARDS population.

Current Perspectives of Anticoagulation in Patients With COVID-19.

Thromboembolism and myocardial injury is common in patients with COVID-19. Low-molecular-weight heparin appears to be associated with a good prognosis in patients with COVID-19 and has the ability to reduce coagulation and inflammation markers. Hospitalized patients with COVID-19 should be placed on thromboprophylaxis with the option of full therapeutic anticoagulation or tissue plasminogen activator in high-risk or mechanically ventilated patients. Thromboprophylaxis should also be considered at hospital discharge for high-risk patients. Clinical judgment should be used to evaluate the bleeding and safety risk of anticoagulation in patients with COVID-19 without confirmed data.

Pyoderma Gangrenosum and Superimposed Infection: A Case Report.

Pyoderma gangrenosum (PG) is a rare, ulcerating, inflammatory disease that is often misdiagnosed as a skin and soft tissue infection. If PG is identified, it is treated with topical or systemic immunosuppressants to reduce inflammation and induce remission. However, the use of immunosuppressants has been linked to a higher risk of superimposed infections. The authors report the case of a 24-year-old female patient with bilateral lower extremity PG with a superimposed infection of Pseudomonas aeruginosa and Bacteroides fragilis after intralesional corticosteroid therapy.

Efficacy and Safety of Reparixin in Patients with Severe COVID-19 Pneumonia: A Phase 3, Randomized, Double-Blind Placebo-Controlled Study.

INTRODUCTION: Polymorphonuclear cell influx into the interstitial and bronchoalveolar spaces is a cardinal feature of severe coronavirus disease 2019 (COVID-19), principally mediated by interleukin-8 (IL-8). We sought to determine whether reparixin, a novel IL-8 pathway inhibitor, could reduce disease progression in patients hospitalized with severe COVID-19 pneumonia. METHODS: In this Phase 3, randomized, double-blind, placebo-controlled, multicenter study, hospitalized adult patients with severe COVID-19 pneumonia were randomized 2:1 to receive oral reparixin 1200 mg three times daily or placebo for up to 21 days or until hospital discharge. The primary endpoint was the proportion of patients alive and free of respiratory failure at Day 28, with key secondary endpoints being the proportion of patients free of respiratory failure at Day 60, incidence of intensive care unit (ICU) admission by Day 28 and time to recovery by Day 28. RESULTS: Of 279 patients randomized, 182 received at least one dose of reparixin and 88 received placebo. The proportion of patients alive and free of respiratory failure at Day 28 was similar in the two groups {83.5% versus 80.7%; odds ratio 1.63 [95% confidence interval (CI) 0.75, 3.51]; p = 0.216}. There were no statistically significant differences in the key secondary endpoints, but a numerically higher proportion of patients in the reparixin group were alive and free of respiratory failure at Day 60 (88.7% versus 84.6%; p = 0.195), fewer required ICU admissions by Day 28 (15.8% versus 21.7%; p = 0.168), and a higher proportion recovered by Day 28 compared with placebo (81.6% versus 74.9%; p = 0.167). Fewer patients experienced adverse events with reparixin than placebo (45.6% versus 54.5%), most mild or moderate intensity and not related to study treatment. CONCLUSIONS: This trial did not meet the primary efficacy endpoints, yet reparixin showed a trend toward limiting disease progression as an add-on therapy in COVID-19 severe pneumonia and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04878055, EudraCT: 2020-005919-51.

Coronavirus disease 2019 (COVID-19): Secondary bacterial infections and the impact on antimicrobial resistance during the COVID-19 pandemic.

Secondary bacterial infections and bacterial coinfections are an important complication of coronavirus disease 2019 (COVID-19), leading to antibiotic overuse and increased rates of antimicrobial resistance (AMR) during the COVID-19 pandemic. In this literature review, we summarize the reported rates of secondary bacterial infections and bacterial coinfections in patients with COVID-19, the impact on patient outcomes, the antibiotic treatment approaches employed, and the resistance patterns observed. The reported data suggest that although the incidence of secondary bacterial infections or bacterial coinfections is relatively low, they are associated with worse outcomes such as prolonged hospitalization, intensive care unit admission, mechanical ventilator use, and increased mortality. Interestingly, antibiotic prescription rates are typically higher than secondary bacterial and bacterial coinfection rates, and reports of AMR are common. These findings highlight the need for an improved understanding of secondary bacterial and bacterial coinfection in patients with COVID-19, as well as improved treatment options, to mitigate inappropriate antibiotic prescribing and AMR.

A Multicenter Phase 2 Randomized Controlled Study on the Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients with COVID-19 Pneumonia.

INTRODUCTION: Acute lung injury and acute respiratory distress syndrome are common complications in patients with coronavirus disease 2019 (COVID-19). Poor outcomes in patients with COVID-19 are associated with cytokine release syndrome. Binding of interleukin-8 (CXCL8/IL-8) to its chemokine receptors, CXCR1/2, may mediate this inflammatory process. The aim of this clinical trial was to determine if CXCR1/2 blockade with reparixin can improve clinical outcomes in hospitalized patients with severe COVID-19 pneumonia. The dose and safety of reparixin have been investigated in clinical trials of patients with metastatic breast cancer. METHODS: This was a phase 2, open-label, multicenter, randomized study in hospitalized adult patients with severe COVID-19 pneumonia from May 5, 2020 until November 27, 2020. Patients were randomized 2:1 to receive 1200 mg reparixin orally three times daily or standard of care (SOC) for up to 21 days. The primary endpoint was defined as a composite of clinical events: use of supplemental oxygen, need for mechanical ventilation, intensive care unit admission, and/or use of rescue medication. RESULTS: Fifty-five patients were enrolled between reparixin (n = 36) and SOC (n = 19). The rate of clinical events was statistically significantly lower in the reparixin group compared with the SOC group (16.7% [95% CI 6.4-32.8%] vs. 42.1% [95% CI 20.3-66.5%], P = 0.02). The sensitivity analysis based on the Cox regression model provided an adjusted hazard ratio of 0.33 with statistical significance lower than 0.05 (95% CI 0.11-0.99; P = 0.047). Reparixin treatment appeared to be well tolerated. CONCLUSION: In patients with severe COVID-19, reparixin led to an improvement in clinical outcomes when compared with the SOC. A larger phase 3 clinical study is needed to confirm these results. TRIAL REGISTRATION: EudraCT identifier, 2020-001645-40; registered May 6, 2020 (retrospectively registered), and clinicaltrials.gov (NCT04794803) on March 8, 2021.

The Risk of QTc Prolongation with Antiemetics in the Palliative Care Setting: A Narrative Review.

Nausea and vomiting are common within the palliative care population. Antiemetic agents may help control symptoms, but may also place patients at risk for QTc prolongation. This article reviews pharmacotherapy agents including anticholinergics, antihistamines, antidopaminergics, 5-HT3 receptor antagonists, dronabinol, and medical marijuana and their associated risk of QTc prolongation. A clinical treatment pathway is provided to help guide clinicians in choosing the most appropriate antiemetic based upon patient specific factors for QTc prolongation.

Staphylococcus aureus Bacteremia in Patients Infected With COVID-19: A Case Series.

BACKGROUND: Previous viral pandemics have shown that secondary bacterial infections result in higher morbidity and mortality, with Staphylococcus aureus being the primary causative pathogen. The impact of secondary S. aureus bacteremia on mortality in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unknown. METHODS: This was a retrospective observational case series of patients with coronavirus disease 2019 (COVID-19) who developed secondary S. aureus bacteremia across 2 New York City hospitals. The primary end point was to describe 14-day and 30-day hospital mortality rates of patients with COVID-19 and S. aureus bacteremia. Secondary end points included predictors of 14-day and 30-day hospital mortality in patients with COVID-19 and S. aureus bacteremia. RESULTS: A total of 42 patients hospitalized for COVID-19 with secondary S. aureus bacteremia were identified. Of these patients, 23 (54.8%) and 28 (66.7%) died at 14 days and 30 days, respectively, from their first positive blood culture. Multivariate analysis identified hospital-onset bacteremia (≥4 days from date of admission) and age as significant predictors of 14-day hospital mortality and Pitt bacteremia score as a significant predictor of 30-day hospital mortality (odds ratio [OR], 11.9; 95% CI, 2.03-114.7; P = .01; OR, 1.10; 95% CI, 1.03-1.20; P = .02; and OR, 1.56; 95% CI, 1.19-2.18; P = .003, respectively). CONCLUSIONS: Bacteremia with S. aureus is associated with high mortality rates in patients hospitalized with COVID-19. Further investigation is warranted to understand the impact of COVID-19 and secondary S. aureus bacteremia.