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

SARS-CoV-2 Seroconversion and Viral Clearance in Patients Hospitalized With COVID-19: Viral Load Predicts Antibody Response.

BACKGROUND: The interdependencies of viral replication and the host immune response in patients with coronavirus disease 2019 (COVID-19) remain to be defined. We investigated the viral determinants of antibody response, the predictors of nonseroconversion, and the role of antibodies on viral dynamics. METHODS: This was a prospective study in patients hospitalized with COVID-19 that was microbiologically confirmed by real-time polymerase chain reaction (RT-PCR). Serial nasopharyngeal and oropharyngeal swabs and plasma samples were obtained for measuring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antibodies (total and S-IgG/N-IgG), respectively. RESULTS: Of 132 patients included, 99 (75%) showed positive antibody titers after a median (Q1-Q3) of 11 (8-14) days. The median (Q1-Q3) follow-up was 74.5 (63.0-87.0) days. In an adjusted linear regression model, time to seropositivity was inversely associated with peak log SARS-CoV-2 viral load (P = .009) and positively with time to viral clearance (P = .004). Adjusted predictors of S-IgG levels were time to viral clearance (P < .001), bilateral lung infiltrates on admission (P = .011), and the time-dependent SARS-CoV-2 RNA (P < .001) and SARS-CoV-2 RNA area under the curve (P = .001). Thirty-three (25%) patients showed undetectable antibody titers. Patients who did not seroconvert had higher cycle threshold values of RT-PCR (38.0 vs 28.0; P < .001), had shorter time to viral clearance (3.0 vs 41.0; P < .001), and were more likely to have SARS-CoV-2 only detected on fecal samples (P < .001). Nonseroconvertors had also lower levels of blood inflammatory biomarkers on admission and lower disease severity. CONCLUSIONS: Viral replication determines the magnitude of antibody response to SARS-CoV-2, which, in turn, contributes to viral clearance. COVID-19 patients who do not seroconvert exhibit a differential virological and clinical profile.

COVID-19-associated encephalitis successfully treated with combination therapy.

BACKGROUND: Acute encephalitis can occur in different viral diseases due to infection of the brain or by an immune mechanism. Severe novel coronavirus disease 2019 (COVID-19) is associated with a major immune inflammatory response with cytokine upregulation including interleukin 6 (IL-6). We report a case presenting with acute encephalitis that was diagnosed as having severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection with hyperinflammatory systemic response and recovered after therapy with immunoglobulins and cytokine blockade. CASE REPORT: A 39-year-old-man was brought to the Emergency Department with drowsiness, mental disorientation, intermittent fever and headache. A brain magnetic resonance imaging showed extensive involvement of the brain including cortical and subcortical right frontal regions, right thalamus, bilateral temporal lobes and cerebral peduncles, with no leptomeningeal enhancement. Cerebrospinal fluid (CSF) showed a leukocyte count of 20/µL (90% lymphocytes), protein level of 198 mg/dL, and glucose of 48 mg/dL. SARS-CoV-2 was detected in nasopharyngeal swabs by reverse-transcriptase-PCR (RT-PCR) but it was negative in the CSF. Remarkable laboratory findings in blood tests included low lymphocyte count and elevated ferritin, IL-6 and D-dimer. He had a complicated clinical course requiring mechanical ventilation. Intravenous immunoglobulins and cytokine blockade with tocilizumab, an IL-6 receptor antagonist, were added considering acute demyelinating encephalomyelitis. The patient made a full recovery, suggesting that it could have been related to host inflammatory response. CONCLUSION: This case report indicates that COVID-19 may present as an encephalitis syndrome mimicking acute demyelinating encephalomyelitis that could be amenable to therapeutic modulation.

Predictive factors for cardiac conduction abnormalities with hydroxychloroquine-containing combinations for COVID-19.

This longitudinal, prospective cohort study aimed to assess risk of QTc interval prolongation and its predicting factors in subjects treated with combinations containing hydroxychloroquine (HCQ) for COVID-19. Moderate-to-severe QTc prolongation during therapy was defined as a QTc interval >470 ms in men or >480 ms in women. Patients were treated under strict cardiac supervision. A total of 105 adults were included [56% male; median (IQR) age 69 (57-79) years]. All patients received therapy with HCQ in combination with azithromycin (AZM), and 95 (90%) also with lopinavir/ritonavir (LPV/r). Concomitant medications classified as having risk of developing torsades de pointes (TdP) were simultaneously used in 81 patients (77%). Moderate-to-severe QTc prolongation was observed in 14 patients (13%), mostly at Days 3-5 from baseline, with 6 (6%) developing severe prolongation (>500 ms). There was no evidence of TdP arrhythmia or TdP-associated death. Adding LPV/r to HCQ+AZM did not significantly prolong the QTc interval. Multivariable Cox regression revealed that comedications with known risk of TdP (HR = 11.28, 95% CI 1.08-117.41), higher neutrophil-to-lymphocyte (NLR) ratio (HR = 1.10, 95% CI 1.03-1.18 per unit increase) and higher serum hs-cardiac troponin I (HR = 4.09, 95% CI 1.36-12.2 per unit increase) were major contributors to moderate-to-severe QTc prolongation. In this closely screened and monitored cohort, no complications derived from QTc prolongation were observed during pharmacological therapy containing HCQ for COVID-19. Evidence of myocardial injury with elevated troponin and strong inflammatory response, specifically higher NLR, are conditions requiring careful QTc interval monitoring.

Impact of interleukin-6 blockade with tocilizumab on SARS-CoV-2 viral kinetics and antibody responses in patients with COVID-19: A prospective cohort study.

BACKGROUND: The virological and immunological effects of the immunomodulatory drugs used for COVID-19 remain unknown. We evaluated the impact of interleukin (IL)-6 blockade with tocilizumab on SARS-CoV-2 viral kinetics and the antibody response in patients with COVID-19. METHODS: Prospective cohort study in patients admitted with COVID-19. Serial nasopharyngeal and plasma samples were measured for SARS-CoV-2 RNA and S-IgG/N-IgG titers, respectively. FINDINGS: 138 patients with confirmed infection were included; 76 (55%) underwent IL-6 blockade. Median initial SOFA (p = 0•016) and SARS-CoV-2 viral load (p<0•001, Mann-Whitney-Wilcoxon test) were significantly higher among anti-IL-6 users. Patients under IL-6 blockade showed delayed viral clearance in the Kaplan-Meier curves (HR 0•35 [95%CI] [0•15-0•81], log-rank p = 0•014), but an adjusted propensity score matching model did not demonstrate a significant relationship of IL-6 blockade with viral clearance (HR 1•63 [0•35-7•7]). Cox regression showed an inverse association between SARS-CoV-2 RNA clearance and the initial viral load (HR 0•35 [0•11-0•89]). Patients under the IL-6 blocker showed shorter median time to seropositivity, higher peak antibody titers, and higher cumulative proportion of seropositivity in the Kaplan Meier curves (HR 3•1 [1•9-5] for S-IgG; and HR 3•0 [1•9-4•9] for N-IgG; log-rank p<0•001 for both). However, no significant differences between groups were found in either S-IgG (HR 1•56 [0•41-6•0]) nor N-IgG (HR 0•96 [0•26-3•5]) responses in an adjusted propensity score analysis. INTERPRETATION: Our results suggest that in patients infected with SARS-CoV-2, IL-6 blockade does not impair the viral specific antibody responses. Although a delayed viral clearance was observed, it was driven by a higher initial viral load. The study supports the safety of this therapy in patients with COVID-19. FUNDING: Instituto de salud Carlos III (Spain).

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

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.

Dyspnea and pleuritic chest pain during the COVID-19 pandemic / Disnea y dolor torácico pleurítico durante la pandemia de la COVID-19

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