Interleukin-1 and the NLRP3 inflammasome in COVID-19: Pathogenetic and therapeutic implications.

A hyperinflammatory response during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection crucially worsens clinical evolution of coronavirus disease 2019 (COVID-19). The interaction between SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) triggers the activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Enhanced inflammasome activity has been associated with increased disease severity and poor prognosis. Evidence suggests that inflammasome activation and interleukin-1ß (IL-1ß) release aggravate pulmonary injury and induce hypercoagulability, favoring progression to respiratory failure and widespread thrombosis eventually leading to multiorgan failure and death. Observational studies with the IL-1 blockers anakinra and canakinumab provided promising results. In the SAVE-MORE trial, early treatment with anakinra significantly shortened hospital stay and improved survival in patients with moderate-to-severe COVID-19. In this review, we summarize current evidence supporting the pathogenetic role of the NLRP3 inflammasome and IL-1ß in COVID-19, and discuss clinical trials testing IL-1 inhibition in COVID-19.

Gastrointestinal manifestations of SARS-CoV-2 infection in an Italian population of hospitalized patients.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters the cells via angiotensin-converting enzyme 2 receptor; therefore, tissues expressing this receptor are potential targets for infection. Although many studies have observed gastrointestinal (GI) symptoms in coronavirus disease 2019 (COVID-19) patients, prevalence and clinical impact are still uncertain due to the heterogeneity of reports and obstacles to generalization. Methods: In this cross-sectional study, we included symptomatic patients requiring hospital admission, with a confirmed diagnosis of COVID-19 by nasopharyngeal polymerase chain reaction test, between 18 March and 30 May 2020. Demographic data, symptoms at onset, vital signs, and laboratory tests at admission were recorded. Results: In all, 300 patients were included (57%M, 43%F). GI symptoms were mainly diarrhea (13%), anorexia (4.3%), vomiting (3%), and abdominal pain (2.3%). Overall, males were younger (68 years versus 76 years; p = 0.01); patients with GI manifestations at disease onset required significantly faster hospital admission and showed larger GI complication rates. GI symptoms were associated with abnormal high aspartate aminotransferase and alanine aminotransferase serum titers, especially in male patients. Conclusion: Our study on an Italian population during the outbreak of the COVID-19 pandemic shows that GI symptoms are part of the spectrum of the SARS-CoV-2 infection and could be the only manifestations at disease onset. Although patients with GI symptoms were associated with faster hospital admission and liver involvement, prognosis was not affected.

Direct oral anticoagulant plasma levels in hospitalized COVID-19 patients treated with dexamethasone.

Direct oral anticoagulants (DOACs) are not recommended in COVID-19 patients receiving dexamethasone because of potential drug-drug and drug-disease interactions affecting anticoagulant concentration and activity. To evaluate short- and long-term pharmacokinetic interactions, serial through and peak DOAC plasma levels were prospectively measured during and after dexamethasone therapy, as well as during the acute phase and after recovery from COVID-19 in hospitalized, non-critically ill patients undergoing treatment with DOACs. Thirty-three (18 males, mean age 79 years) consecutive patients received DOACs (17 apixaban, 12 rivaroxaban, 4 edoxaban) for atrial fibrillation (n = 22), venous thromboembolism (n = 10), and acute myocardial infarction (n = 1). Twenty-six patients also received dexamethasone at a dose of 6 mg once daily for a median of 14 days. Trough DOAC levels on dexamethasone were within and below expected reference ranges respectively in 87.5 and 8.3% of patients, with no statistically significant differences at 48-72 h and 14-21 days after dexamethasone discontinuation. Peak DOAC levels on dexamethasone were within expected reference ranges in 58.3% of patients, and below ranges in 33.3%, of whom over two thirds had low values also off dexamethasone. No significant differences in DOAC levels were found during hospitalization and after resolution of COVID-19. Overall, 28 patients were discharged alive, and none experienced thrombotic or bleeding events. In this study, dexamethasone administration or acute COVID-19 seemed not to affect DOAC levels in hospitalized, non-critically ill COVID-19 patients.

The role of IL-6 and IL-6 blockade in COVID-19.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a dysregulated hyperinflammatory response. AREAS COVERED: Authors review evidence on IL-6 and IL-6 blockade in coronavirus disease 2019 (COVID-19) and discuss the pathophysiological and prognostic roles of this cytokine and the clinical impact of pharmacological blockade of IL-6 . The material includes original articles and reviews published from March 2020 to March 2021 and searched on PubMed, medRxiv, and bioRxiv. EXPERT OPINION: IL-6 is one of the most prominent pro-inflammatory cytokines. Increased levels are recorded in COVID-19 patients, especially those with severe-to-critical disease. Evidence is accumulating on the relevance of IL-6 as a prognostic marker in COVID-19. Since IL-6 is a druggable target for several inflammatory diseases, pharmacological blockers of the IL-6 signaling pathway were repurposed to blunt the abnormal SARS-CoV-2-induced cytokine release. Data are limited to few randomized controlled trials that reported encouraging, though not conclusive, results, indicating the usefulness of IL-6 blockade early in the course of the disease in patients with hyperinflammation and no or limited organ damage. Further research is warranted to explore the role of IL-6 in different COVID-19 phenotypes and identify subgroups of patients who may mostly benefit from IL-6 pathway inhibition.

Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19.

BACKGROUND: Many COVID-19 patients develop a hyperinflammatory response which activates blood coagulation and may contribute to the occurrence of thromboembolic complications. Blockade of interleukin-6, a key cytokine in COVID-19 pathogenesis, may improve the hypercoagulable state induced by inflammation. The aim of this study was to evaluate the effects of subcutaneous tocilizumab, a recombinant humanized monoclonal antibody against the interleukin-6 receptor on coagulation parameters. METHODS: Hospitalized adult patients with laboratory-confirmed moderate to critical COVID-19 pneumonia and hyperinflammation, who received a single 324 mg subcutaneous dose of tocilizumab on top of standard of care were enrolled in this analysis. Coagulation parameters were measured before tocilizumab and at day 1, 3, and 7 after treatment. All patients were followed-up for 35 days after admission or until death. RESULTS: 70 patients (mean age 60 years, interquartile range 52-75) were included. Treatment with tocilizumab was associated with a reduction in D-dimer levels (-56%; 95% confidence interval [CI], -68% to -44%), fibrinogen (-48%; 95%CI, -60% to -35%), C-reactive protein (-93%; 95%CI, -99% to -87%), prothrombin time (-4%; 95%CI,-9% to 0.8%), and activated thromboplastin time (-4%; 95%CI,-8.7% to 0.8%), and an increase in platelet count (34%; 95%CI, 23% to 45%). These changes occurred already one day after treatment with sustained reductions throughout day 7. The improvement in coagulation was consistently observed in patients receiving prophylactic or therapeutic dose anticoagulants, and was paralleled by a rapid improvement in respiratory function. CONCLUSIONS: Subcutaneous tocilizumab was associated with significant improvement of blood coagulation parameters independently of thromboprophylaxis dose.

Smell and Taste in Severe CoViD-19: Self-Reported vs. Testing.

One of the most striking reported symptoms in CoViD-19 is loss of smell and taste. The frequency of these impairments and their specificity as a potential central nervous system function biomarker are of great interest as a diagnostic clue for CoViD-19 infection as opposed to other similar symptomatologic diseases and because of their implication in viral pathogenesis. Here severe CoViD-19 was investigated by comparing self-report vs. testing of smell and taste, thus the objective severity of olfactory impairment and their possible correlation with other symptoms. Because a significant discrepancy between smell and taste testing vs. self-report results (p < 0.001) emerges in our result, we performed a statistical analysis highlighting disagreement among normosmia (p < 0.05), hyposmia, severe hyposmia, and anosmia (p < 0.001) and, in hypogeusia and severe hypogeusia, while no differences are observed in normogeusia and ageusia. Therefore, we analyzed the olfactory threshold by an objective test revealing the distribution of hyposmic (34%), severe hyposmic (48%), and anosmic (13%) patients in severe CoViD-19. In severe CoViD-19 patients, taste is lost in 4.3% of normosmic individuals, 31.9% of hyposmic individuals, 46.8% of severe hyposmic individuals, and 17% of anosmic individuals. Moreover, 95% of 100 CoViD-19 patients objectively tested were affected by smell dysfunction, while 47% were affected by taste dysfunction. Furthermore, analysis by objective testing also highlighted that the severity of smell dysfunction in CoViD-19 subjects did not correlate with age and sex. In conclusion, we report by objective testing that the majority of CoViD-19 patients report severe anosmia, that most of the subjects have olfactory impairment rather than taste impairment, and, finally, that the olfactory impairment correlate with symptom onset and hospitalization (p < 0.05). Patients who exhibit severe olfactory impairment had been hospitalized for about a week from symptom onset; double time has taken place in subjects with normosmia. Our results may be limited by the relatively small number of study participants, but these suggest by objective testing that hyposmia, severe hyposmia, and anosmia may relate directly to infection severity and neurological damage. The smell test assessment could be a potential screening symptom that might contribute to the decision to test suspected cases or guide quarantine instructions, further therapeutic approach, and evaluation of neurological damage.

Low-dose subcutaneous tocilizumab to prevent disease progression in patients with moderate COVID-19 pneumonia and hyperinflammation.

AIM: This study aimed to evaluate the safety and efficacy profile of low-dose tocilizumab (TCZ), to prevent disease progression, subcutaneously administered to patients with moderate COVID-19 pneumonia and hyperinflammation. METHODS: Clinical characteristics and outcomes were retrospectively analysed of patients - with laboratory-confirmed bilateral COVID-19 pneumonia, hyperinflammation (C-reactive protein (CRP) ≥20 mg/dL), no hypoxaemia (oxygen saturation >90%), and no contraindications to TCZ - who were treated with subcutaneous TCZ (324 mg) administered within 48 h from hospitalization on top of standard of care (SOC). They were compared with matched controls treated with SOC only before TCZ was available at the institution. Clinical data were available for all patients until death or until day 35 for those discharged from hospital. FINDINGS: Ten consecutive patients (six males, median age 55 years) treated with TCZ on top of SOC, and ten patients (six males, median age 56 years) treated with SOC only were included. TCZ was well-tolerated with no clinically relevant adverse events. TCZ was associated with a reduction in CRP at day 1 (-50%, IQR -28 to -80) and day 3 (-89%, IQR -79 to -96; p = 0.005 for within-group), whereas there was no significant change in CRP values in the SOC group (p < 0.001 for between-group comparisons at both time points). TCZ resulted in a parallel improvement in oxygenation, as assessed by the ratio of partial pressure of oxygen to fraction of inspired oxygen (P/F) ratio, which increased at day 1 (+11%, IQR +6 to +16; p = 0.005 for within-group and p = 0.006 for between-group comparisons), and day 3 (+23%, IQR +16 to +34; p = 0.005 for within-group and p = 0.003 for between-group comparisons). None of the TCZ-treated patients had disease progression, defined as requirement of oxygen therapy or mechanical ventilation, whereas progression occurred in five (50%) patients among the SOC group. CONCLUSIONS: Low-dose subcutaneous TCZ may be a safe and promising therapeutic option administered on top of SOC to prevent disease progression in hospitalised patients with moderate COVID-19 and hyperinflammation.

Venous thromboembolism in patients with COVID-19: Systematic review and meta-analysis.

BACKGROUND: Venous thromboembolism (VTE) may complicate the course of Coronavirus Disease 2019 (COVID-19). OBJECTIVES: To evaluate the incidence of VTE in patients with COVID-19. METHODS: MEDLINE, EMBASE, and PubMed were searched up to 24th June 2020 for studies that evaluated the incidence of VTE, including pulmonary embolism (PE) and/or deep vein thrombosis (DVT), in patients with COVID-19. Pooled proportions with corresponding 95% confidence intervals (CI) and prediction intervals (PI) were calculated by random-effect meta-analysis. RESULTS: 3487 patients from 30 studies were included. Based on very low-quality evidence due to heterogeneity and risk of bias, the incidence of VTE was 26% (95% PI, 6%-66%). PE with or without DVT occurred in 12% of patients (95% PI, 2%-46%) and DVT alone in 14% (95% PI, 1%-75%). Studies using standard algorithms for clinically suspected VTE reported PE in 13% of patients (95% PI, 2%-57%) and DVT in 6% (95% PI, 0%-60%), compared to 11% (95% PI, 2%-46%) and 24% (95% PI, 2%-85%) in studies using other diagnostic strategies or patient sampling. In patients admitted to intensive care units, VTE occurred in 24% (95% PI, 5%-66%), PE in 19% (95% PI, 6%-47%), and DVT alone in 7% (95% PI, 0%-69%). Corresponding values in general wards were respectively 9% (95% PI, 0%-94%), 4% (95% PI, 0%-100%), and 7% (95% CI, 1%-49%). CONCLUSIONS: VTE represents a frequent complication in hospitalized COVID-19 patients and often occurs as PE. The threshold for clinical suspicion should be low to trigger prompt diagnostic testing.

Acute complications and mortality in hospitalized patients with coronavirus disease 2019: a systematic review and meta-analysis.

BACKGROUND: The incidence of acute complications and mortality associated with COVID-19 remains poorly characterized. The aims of this systematic review and meta-analysis were to summarize the evidence on clinically relevant outcomes in hospitalized patients with COVID-19. METHODS: MEDLINE, EMBASE, PubMed, and medRxiv were searched up to April 20, 2020, for studies including hospitalized symptomatic adult patients with laboratory-confirmed COVID-19. The primary outcomes were all-cause mortality and acute respiratory distress syndrome (ARDS). The secondary outcomes included acute cardiac or kidney injury, shock, coagulopathy, and venous thromboembolism. The main analysis was based on data from peer-reviewed studies. Summary estimates and the corresponding 95% prediction intervals (PIs) were obtained through meta-analyses. RESULTS: A total of 44 peer-reviewed studies with 14,866 COVID-19 patients were included. In general, risk of bias was high. All-cause mortality was 10% overall (95% PI, 2 to 39%; 1687/14203 patients; 43 studies), 34% in patients admitted to intensive care units (95% PI, 8 to 76%; 659/2368 patients; 10 studies), 83% in patients requiring invasive ventilation (95% PI, 1 to 100%; 180/220 patients; 6 studies), and 75% in patients who developed ARDS (95% PI, 35 to 94%; 339/455 patients; 11 studies). On average, ARDS occurred in 14% of patients (95% PI, 2 to 59%; 999/6322 patients; 23 studies), acute cardiac injury in 15% (95% PI, 5 to 38%; 452/2389 patients; 10 studies), venous thromboembolism in 15% (95% PI, 0 to 100%; patients; 3 studies), acute kidney injury in 6% (95% PI, 1 to 41%; 318/4682 patients; 15 studies), coagulopathy in 6% (95% PI, 1 to 39%; 223/3370 patients; 9 studies), and shock in 3% (95% PI, 0 to 61%; 203/4309 patients; 13 studies). CONCLUSIONS: Mortality was very high in critically ill patients based on very low-quality evidence due to striking heterogeneity and risk of bias. The incidence of clinically relevant outcomes was substantial, although reported by only one third of the studies suggesting considerable underreporting. TRIAL REGISTRATION: PROSPERO registration ID for this study is CRD42020177243 ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=177243 ).