Reduced fixed dose tocilizumab 400 mg IV compared to weight-based dosing in critically ill patients with COVID-19: A before-after cohort study.

Background: Interleukin-6 inhibitors reduce mortality in severe COVID-19. British Columbia began using tocilizumab 8 mg/kg (maximum 800 mg) in January 2021 in critically ill patients with COVID-19, but due to drug shortages, decreased dosing to 400 mg IV fixed dose in April 2021. The aims of this study were twofold: to compare physiological responses and clinical outcomes of these two strategies, and examine the cost-effectiveness of treating all patients with 400 mg versus half the patients with 8 mg/kg and the other half without tocilizumab. Methods: This was a single-centre, before-after cohort study of critically ill COVID-19 patients treated with tocilizumab, and a control cohort treated with dexamethasone only. Physiological responses and clinical outcomes were compared between patients receiving both doses of tocilizumab and those receiving dexamethasone only. We built a decision tree model to examine cost-effectiveness. Findings: 152 patients were included; 40 received tocilizumab 8 mg/kg, 59 received 400 mg and 53 received dexamethasone only. Median CRP fell from 103 mg/L to 5.2 mg/L, 96 mg/L to 6.8 mg/L and from 81.3 mg/L to 48 mg/L in the 8 mg/kg, 400 mg tocilizumab, and dexamethasone only groups, respectively. 28-day mortality was 5% (n=2) vs 8% (n=5) vs 13% (n=7), with no significant difference in all pair-wise comparison. At an assumed willingness-to-pay threshold of $50,000 Canadian per life-year, utilizing 400 mg for all patients rather than 8 mg/kg for half the patients is cost-effective in 51.6% of 10,000 Monte Carlo simulations. Interpretation: Both doses of tocilizumab demonstrated comparable reduction of inflammation with similar 28-day mortality. Without consideration of equity, the net monetary benefits of providing 400 mg tocilizumab to all patients are comparable to 8 mg/kg to half the patients. In the context of ongoing drug shortages, fixed-dose 400 mg tocilizumab may be a practical, feasible and economical option. Funding: This work was supported by a gift donation from Hsu & Taylor Family to the VGH Foundation, and the Yale Bernard G. Forget Scholarship.

Clinical care pathway for the evaluation of patients with suspected VITT after ChAdOx1 nCoV-19 vaccination.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) adenoviral vector vaccination. In British Columbia (BC), Canada, a provincial clinical care pathway was developed to guide clinicians in evaluating for VITT among patients who present with thrombocytopenia or thrombosis symptoms within 4 to 28 days after adenoviral vector vaccine exposure. All patients had enzyme-linked immunosorbent assay (ELISA) testing for platelet factor 4 (PF4) antibodies, and all cases with positive PF4-ELISA or d-dimer levels ≥2.0 mg/L fibrinogen equivalent units (FEU) had further testing for platelet-activating PF4 antibodies using a modified serotonin release assay (SRA). Between 1 May and 30 June 2021, 37% of 68 patients investigated for VITT had thrombosis, but only 3 had VITT confirmed by PF4-ELISA and SRA. Platelet counts, d-dimer levels, and ELISA optical density values were significantly different between those with and without VITT. Three patients had thrombocytopenia and thrombosis with d-dimer levels >4.0 mg/L FEU but had negative PF4-ELISA and SRA results. Patients with VITT were treated successfully with IV immunoglobulin, nonheparin anticoagulants, and corticosteroids. Our pathway demonstrated that thrombosis is common among patients investigated for VITT and that PF4-ELISA testing is necessary to confirm VITT in those presenting with thrombosis and thrombocytopenia.

Soluble interleukin-6 receptor in the COVID-19 cytokine storm syndrome.

Data suggest that interleukin (IL)-6 blockade could reduce mortality in severe COVID-19, yet IL-6 is only modestly elevated in most patients. Chen et al. describe the role of soluble interleukin-6 receptor (sIL-6R) in IL-6 trans-signaling and how understanding the IL-6:sIL-6R axis might help define and treat COVID-19 cytokine storm syndrome.

Tocilizumab for hospitalized patients with COVID-19: CMAJ

Afra et al present several facts about the effectiveness of tocilizumab for patients with COVID-19. Among other things, tocilizumab is an immunomodulatory drug that blocks the activity of interleukin-6 (IL-6). Many patients with severe coronavirus disease 2019 have immune misfiring characterized by a defective interferon response followed by elevated inflammatory cytokines, notably IL-6. Tocilizumab is a monoclonal IL-6 receptor antibody that is approved for use in inflammatory conditions.

Ruxolitinib as adjunctive therapy for secondary hemophagocytic lymphohistiocytosis: A case series.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a cytokine storm syndrome associated with mortality rates of up to 88%. Standard therapy with high-dose glucocorticoids and etoposide used in adults is extrapolated from pediatric trials, with significant toxicity in older patients and those with poor performance status. The JAK1/2 inhibitor ruxolitinib has recently gained attention as a treatment option for HLH due to its broad cytokine-modulating abilities and safety profile. Herein we report our center's experience using ruxolitinib in the treatment of adult-onset secondary HLH. CASE SERIES: We report four patients with profound secondary HLH provoked by diverse triggers, including invasive pulmonary aspergillosis on background systemic lupus erythematosus, disseminated tuberculosis, and T-cell lymphoma treated with ruxolitinib as monotherapy or combination therapy in upfront and salvage settings. RESULTS: All four patients had rapid, sustained improvement in clinical status, inflammatory markers, and hematological cell counts followed by durable remission. Three patients developed manageable infectious complications postruxolitinib. CONCLUSIONS: This series demonstrates the effective use of JAK inhibition with ruxolitinib to control pathological immune activation in critically ill patients with secondary HLH and otherwise limited therapeutic options. JAK inhibition is also an area of urgent investigation for the treatment of cytokine storm associated with COVID-19.

The association of ABO blood group with indices of disease severity and multiorgan dysfunction in COVID-19.

Studies on severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) suggest a protective effect of anti-A antibodies against viral cell entry that may hold relevance for SARS-CoV-2 infection. Therefore, we aimed to determine whether ABO blood groups are associated with different severities of COVID-19. We conducted a multicenter retrospective analysis and nested prospective observational substudy of critically ill patients with COVID-19. We collected data pertaining to age, sex, comorbidities, dates of symptom onset, hospital admission, intensive care unit (ICU) admission, mechanical ventilation, continuous renal replacement therapy (CRRT), standard laboratory parameters, and serum inflammatory cytokines. National (N = 398 671; P = .38) and provincial (n = 62 246; P = .60) ABO blood group distributions did not differ from our cohort (n = 95). A higher proportion of COVID-19 patients with blood group A or AB required mechanical ventilation (P = .02) and CRRT (P = .004) and had a longer ICU stay (P = .03) compared with patients with blood group O or B. Blood group A or AB also had an increased probability of requiring mechanical ventilation and CRRT after adjusting for age, sex, and presence of ≥1 comorbidity. Inflammatory cytokines did not differ between patients with blood group A or AB (n = 11) vs O or B (n = 14; P > .10 for all cytokines). Collectively, our data indicate that critically ill COVID-19 patients with blood group A or AB are at increased risk for requiring mechanical ventilation, CRRT, and prolonged ICU admission compared with patients with blood group O or B. Further work is needed to understand the underlying mechanisms.

The Association of Inflammatory Cytokines in the Pulmonary Pathophysiology of Respiratory Failure in Critically Ill Patients With Coronavirus Disease 2019.

OBJECTIVES: The majority of coronavirus disease 2019 mortality and morbidity is attributable to respiratory failure from severe acute respiratory syndrome coronavirus 2 infection. The pathogenesis underpinning coronavirus disease 2019-induced respiratory failure may be attributable to a dysregulated host immune response. Our objective was to investigate the pathophysiological relationship between proinflammatory cytokines and respiratory failure in severe coronavirus disease 2019. DESIGN: Multicenter prospective observational study. SETTING: ICU. PATIENTS: Critically ill patients with coronavirus disease 2019 and noncoronavirus disease 2019 critically ill patients with respiratory failure (ICU control group). INTERVENTIONS: Daily measurement of serum inflammatory cytokines. MEASUREMENTS AND MAIN RESULTS: Demographics, comorbidities, clinical, physiologic, and laboratory data were collected daily. Daily serum samples were drawn for measurements of interleukin-1ß, interleukin-6, interleukin-10, and tumor necrosis factor-α. Pulmonary outcomes were the ratio of Pao2/Fio2 and static lung compliance. Twenty-six patients with coronavirus disease 2019 and 22 ICU controls were enrolled. Of the patients with coronavirus disease 2019, 58% developed acute respiratory distress syndrome, 62% required mechanical ventilation, 12% underwent extracorporeal membrane oxygenation, and 23% died. A negative correlation between interleukin-6 and Pao2/Fio2 (rho, -0.531; p = 0.0052) and static lung compliance (rho, -0.579; p = 0.033) was found selectively in the coronavirus disease 2019 group. Diagnosis of acute respiratory distress syndrome was associated with significantly elevated serum interleukin-6 and interleukin-1ß on the day of diagnosis. CONCLUSIONS: The inverse relationship between serum interleukin-6 and Pao2/Fio2 and static lung compliance is specific to severe acute respiratory syndrome coronavirus 2 infection in critically ill patients with respiratory failure. Similar observations were not found with interleukin-ß or tumor necrosis factor-α.