Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients and experimentally infected animals indicate a critical role for augmented expression of proinflammatory chemokines and cytokines in severe disease. Here, we demonstrate that SARS-CoV-2 infection of human monocyte-derived macrophages (MDMs) and monocyte-derived dendritic cells was abortive, but induced the production of multiple antiviral and proinflammatory cytokines (interferon-α, interferon-β, tumor necrosis factor, and interleukins 1β, 6, and 10) and a chemokine (CXCL10). Despite the lack of efficient replication in MDMs, SARS-CoV-2 induced profound interferon-mediated cell death of host cells. Macrophage activation and death were not enhanced by exposure to low levels of convalescent plasma, suggesting that antibody-dependent enhancement of infection does not contribute to cell death. Together, these results indicate that infection of macrophages and dendritic cells potentially plays a major role in coronavirus disease 2019 pathogenesis, even in the absence of productive infection.

Severe Acute Respiratory Syndrome Coronavirus 2-Induced Immune Activation and Death of Monocyte-Derived Human Macrophages and Dendritic Cells.

Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context.

The recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the cause of coronavirus disease (COVID-19) and the associated ongoing pandemic, frequently leads to severe respiratory distress syndrome and pneumonia with fatal consequences. Although several factors of this infection and its consequences are not completely clear, the presence and involvement of specific chemokines is undoubtedly crucial for the development and progression of COVID-19. Cytokine storm and the often-resulting cytokine release syndrome (CRS) are pathophysiological hallmarks in COVID-19 infections related to its most severe and fatal cases. In this hyperinflammatory event, chemokines and other cytokines are highly upregulated and are therefore not fulfilling their beneficial function in the host response anymore but causing harmful effects. Here, we present the recent views on the involvement of chemokines and selected cytokines in COVID-19 and the therapeutics currently in clinical development targeting or interfering with them, discussing their potentials in the treatment of COVID-19 infections.

https://www.mdpi.com/2218-273X/11/1/91/pdf

Cytokines and Chemokines in SARS-CoV-2 Infections-Therapeutic Strategies Targeting Cytokine Storm.

Introduction The results of studies of tocilizumab (TCZ) in COVID-19 are contradictory. Our study aims to update medical evidence from controlled observational studies and randomized clinical trials (RCTs) on the use of TCZ in hospitalized patients with COVID-19. Methods We searched the following databases from January 1, 2020 to April 13, 2021 (date of the last search): MEDLINE database through the PubMed search engine and Scopus, using the terms ("COVID-19" [Supplementary Concept]) AND "tocilizumab" [Supplementary Concept]). Results Sixty four studies were included in the present study: 54 were controlled observational studies (50 retrospective and 4 prospective) and 10 were RCTs. The overall results provided data from 20,616 hospitalized patients with COVID-19: 7668 patients received TCZ in addition to standard of care (SOC) (including 1915 patients admitted to intensive care units (ICU) with reported mortality) and 12,948 patients only receiving SOC (including 4410 patients admitted to the ICU with reported mortality). After applying the random-effects model, the hospital-wide (including ICU) pooled mortality odds ratio (OR) of patients with COVID-19 treated with TCZ was 0.73 (95% confidence interval (CI) = 0.56-0.93). The pooled hospital-wide mortality OR was 1.25 (95% CI = 0.74-2.18) in patients admitted at conventional wards versus 0.66 (95% CI = 0.59-0.76) in patients admitted to the ICU. The pooled OR of hospital-wide mortality (including ICU) of COVID-19 patients treated with TCZ plus corticosteroids (CS) was 0.67 (95% CI = 0.54-0.84). The pooled in-hospital mortality OR was 0.71 (95% CI = 0.35-1.42) when TCZ was early administered (≤10 days from symptom onset) versus 0.83 (95% CI 0.48-1.45) for late administration (>10 days from symptom onset). The meta-analysis did not find significantly higher risk for secondary infections in COVID-19 patients treated with TCZ. Conclusions TCZ prevented mortality in patients hospitalized for COVID-19. This benefit was seen to a greater extent in patients receiving concomitant CS and when TCZ administration occurred within the first 10 days after symptom onset.

Beneficial and Harmful Outcomes of Tocilizumab in Severe COVID-19: A Systematic Review and Meta-Analysis

Excessive interleukin-6 signaling is a key factor contributing to the cytokine release syndrome implicated in clinical manifestations of COVID-19. Preliminary results suggest that tocilizumab, a humanized monoclonal anti-interleukin-6 receptor antibody, may be beneficial in severely ill patients, but no data are available on earlier stages of disease. An anticipated blockade of interleukin-6 might hypothetically prevent the catastrophic consequences of the overt cytokine storm. We evaluated early-given tocilizumab in patients hospitalized with COVID-19, and identified outcome predictors. Consecutive patients with initial Sequential-Organ-Failure-Assessment (SOFA) score < 3 fulfilling pre-defined criteria were treated with tocilizumab. Serial plasma biomarkers and nasopharyngeal swabs were collected. Of 193 patients admitted with COVID-19, 64 met the inclusion criteria. After tocilizumab, 49 (76.6%) had an early favorable response. Adjusted predictors of response were gender, SOFA score, neutrophil/lymphocyte ratio, Charlson comorbidity index and systolic blood pressure. At week-4, 56.1% of responders and 30% of non-responders had cleared the SARS-CoV-2 from nasopharynx. Temporal profiles of interleukin-6, C-reactive protein, neutrophil/lymphocyte ratio, NT-ProBNP, D-dimer, and cardiac-troponin-I differed according to tocilizumab response and discriminated final in-hospital outcome. No deaths or disease recurrences were observed. Preemptive therapy with tocilizumab was safe and associated with favorable outcomes in most patients. Biological and clinical markers predicted outcomes.

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Preemptive interleukin-6 blockade in patients with COVID-19.

Background: Baricitinib is a Janus kinase (JAK) inhibitor with a broader anti-inflammatory activity than tocilizumab and an antiviral potential although no head-to-head trials are available. The benefits of adding baricitinib to patients with COVID-19 experiencing clinical progression despite the standard of care (SOC), including corticosteroids and tocilizumab, are also unknown. Methods: A cohort study included microbiologically confirmed COVID-19 hospitalizations. The primary outcome was 28-day mortality. Secondary outcomes were 60- and 90-day mortality, the composite outcome "28-day invasive mechanical ventilation (IMV) or death" and the safety of the combination. Propensity score (PS) matching was used to identify the association between baricitinib use and the outcomes of interest. Results: Of 1,709 admissions, 994 patients received corticosteroids and tocilizumab and 110 of them received baricitinib after tocilizumab. PS matched 190 (95:95) patients with baricitinib + SOC vs. SOC, of whom 69.5% received remdesivir. No significant effect of baricitinib was observed on 28-day [39 events; adjusted hazard ratio (aHR), 0.76; 95% CI, 0.31-1.86], 60-day (49 events, aHR, 1.17; 95% CI, 0.55-2.52), or 90-day mortality (49 events; aHR, 1.14; 95% CI, 0.53-2.47), or on the composite outcome 28-day IMV/death (aHR, 0.88; 95% CI, 0.45-1.72). Secondary infections during hospitalization were not different between groups (17.9 vs. 10.5%, respectively; p = 0.212) and thromboembolic events were higher with baricitinib (11.6% vs. 3.2%; p = 0.048), but differences vanished after the adjustment [aHR 1.89 (0.31-11.57), p = 0.490]. Conclusion: The addition of baricitinib did not substantially reduce mortality in hospitalized patients with COVID-19 having clinical progression despite the therapy with tocilizumab and corticosteroids. The combination of baricitinib and tocilizumab was not associated with an increased risk of secondary infections or thromboembolic events.

Impact of the Addition of Baricitinib to Standard of Care Including Tocilizumab and Corticosteroids on Mortality and Safety in Severe COVID-19.

http://www.thelancet.com/article/S2352396422003346/pdf

Robust long-term immunity to SARS-CoV-2 in patients recovered from severe COVID-19 after interleukin-6 blockade

/pdf/dyspnea-and-pleuritic-chest-pain-during-the-covid-19-4lye7lvwd4.pdf

Dyspnea and pleuritic chest pain during the COVID-19 pandemic.

Abstract Background Mycobacterium africanum is a member of the Mycobacterium tuberculosis complex (MTBC) and is endemic in West Africa, where it causes up to half of all cases of pulmonary tuberculosis. Here, we report the first isolation of Mycobacterium africanum from the pericardial effusion culture of a patient with tuberculous pericarditis. Case presentation A 31-year-old man, native from Senegal, came to the emergency room with massive pericardial effusion and cardiac tamponade requiring pericardiocentesis. M. africanum subtype II was identified in the pericardial fluid. The patient completed 10 months of standard treatment, with a favorable outcome. Conclusions We report the first case of tuberculous pericarditis caused by Mycobacterium africanum , which provide evidence that this microorganism can cause pericardial disease and must be considered in patients from endemic areas presenting with pericardial effusion. 

/pdf/pericarditis-caused-by-mycobacterium-africanum-case-report-3h4mzcza.pdf

Ángela Botella

Papers

Preemptive interleukin-6 blockade in patients with COVID-19.

Impact of the Addition of Baricitinib to Standard of Care Including Tocilizumab and Corticosteroids on Mortality and Safety in Severe COVID-19.

Robust long-term immunity to SARS-CoV-2 in patients recovered from severe COVID-19 after interleukin-6 blockade

Dyspnea and pleuritic chest pain during the COVID-19 pandemic.

Pericarditis caused by Mycobacterium africanum: case report