Safety of Tocilizumab in COVID-19 Patients and Benefit of Single-Dose: The Largest Retrospective Observational Study.

Severe acute respiratory coronavirus-2 (SARS-CoV-2) still presents a public threat and puts extra strain on healthcare facilities. Without an effective antiviral drug, all available treatment options are considered supportive. Tocilizumab as a treatment option has to date shown variable results. In this retrospective study, we aimed to assess predictors of mortality of COVID-19 patients (n = 300) on tocilizumab and the clinical effectiveness of this drug. The results showed that ICU admission OR = 64.6 (95% CI: 8.2, 507.4); age of the patient OR = 1.1 (95% CI: 1.0, 1.1); and number of tocilizumab doses administered by the patient OR(two doses) = 4.0 (95% CI: 1.5, 10.9), OR(three doses) = 1.5 (95% CI: 0.5, 5.1), and OR(four doses or more) = 7.2 (95% CI: 2.0, 25.5) presented strong correlation factors that may be linked to COVID-19 mortality. Furthermore, our study showed the beneficial effects of early administration of tocilizumab OR = 1.2 (95% CI: 1.1, 1.4) and longer hospital length of stay OR = 0.974 (95% CI: 0.9, 1.0) in reducing COVID-19 mortalities. High blood D-dimer concentration OR = 1.1 (95% CI: 1.0, 1.2) and reciprocal blood phosphate concentration OR = 0.008 (95% CI: 0.0, 1.2) were correlated to high mortality under SARS-CoV-2 infection. The short-term effect of a single dose of tocilizumab was a significant increase in blood BUN and liver enzymes (ALT, AST, and LDH) above their normal ranges. Furthermore, it significantly reduced CRP blood concentration, but not to normal levels (13.90 to 1.40 mg/dL, p < 0.001). Assessing the effect of different doses of tocilizumab (in terms of the number of doses, total mg, and total mg/kg administered by the patients) indicated that administering more than one dose may lead to increases in ICU length of stay and hospital length of stay of up to 14 and 22 days after the last dose of tocilizumab (6 to 14, p = 0.06, and 10 to 22, p < 0.001), with no improvement in 28- and 90-day mortality, as confirmed by Kaplan-Meier analysis. There were also clear correlations and trends between the number of doses of tocilizumab and increased blood CO2, MCV, RDW, and D-dimer concentrations and between number of doses of tocilizumab and decreased CRP, AST, and hemoglobin concentrations. Microbiology analysis showed a significant increase in the incidence of infection after tocilizumab administration (28 to 119, p < 0.001) with a median time of incidence within 6 days of the first dose of tocilizumab. A significant correlation was also found between the number of tocilizumab doses and the number of incidences of infections after tocilizumab administration r (298) = 0.396, p = 1.028 × 10-12. Based on these results and depending on the pharmacokinetic parameters of the drug, we recommend single-dose administration of tocilizumab as the optimal dosage for COVID-19 patients who do not have active bacterial infection or liver diseases, to be administered as soon as the patient is admitted to the hospital.

Thymus Gland: A Double Edge Sword for Coronaviruses.

The thymus is the main lymphoid organ that regulates the immune and endocrine systems by controlling thymic cell proliferation and differentiation. The gland is a primary lymphoid organ responsible for generating mature T cells into CD4+ or CD8+ single-positive (SP) T cells, contributing to cellular immunity. Regarding humoral immunity, the thymic plasma cells almost exclusively secrete IgG1 and IgG3, the two main complement-fixing effector IgG subclasses. Deformity in the thymus can lead to inflammatory diseases. Hassall's corpuscles' epithelial lining produces thymic stromal lymphopoietin, which induces differentiation of CDs thymocytes into regulatory T cells within the thymus medulla. Thymic B lymphocytes produce immunoglobulins and immunoregulating hormones, including thymosin. Modulation in T cell and naive T cells decrement due to thymus deformity induce alteration in the secretion of various inflammatory factors, resulting in multiple diseases. Influenza virus activates thymic CD4+ CD8+ thymocytes and a large amount of IFNγ. IFNs limit virus spread, enhance macrophages' phagocytosis, and promote the natural killer cell restriction activity against infected cells. Th2 lymphocytes-produced cytokine IL-4 can bind to antiviral INFγ, decreasing the cell susceptibility and downregulating viral receptors. COVID-19 epitopes (S, M, and N proteins) with ≥90% identity to the SARS-CoV sequence have been predicted. These epitopes trigger immunity for antibodies production. Boosting the immune system by improving thymus function can be a therapeutic strategy for preventing virus-related diseases. This review aims to summarize the endocrine-immunoregulatory functions of the thymus and the underlying mechanisms in the prevention of COVID-19.

Diverse Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses.

The pathogenesis of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still not fully unraveled. Though preventive vaccines and treatment methods are out on the market, a specific cure for the disease has not been discovered. Recent investigations and research studies primarily focus on the immunopathology of the disease. A healthy immune system responds immediately after viral entry, causing immediate viral annihilation and recovery. However, an impaired immune system causes extensive systemic damage due to an unregulated immune response characterized by the hypersecretion of chemokines and cytokines. The elevated levels of cytokine or hypercytokinemia leads to acute respiratory distress syndrome (ARDS) along with multiple organ damage. Moreover, the immune response against SARS-CoV-2 has been linked with race, gender, and age; hence, this viral infection's outcome differs among the patients. Many therapeutic strategies focusing on immunomodulation have been tested out to assuage the cytokine storm in patients with severe COVID-19. A thorough understanding of the diverse signaling pathways triggered by the SARS-CoV-2 virus is essential before contemplating relief measures. This present review explains the interrelationships of hyperinflammatory response or cytokine storm with organ damage and the disease severity. Furthermore, we have thrown light on the diverse mechanisms and risk factors that influence pathogenesis and the molecular pathways that lead to severe SARS-CoV-2 infection and multiple organ damage. Recognition of altered pathways of a dysregulated immune system can be a loophole to identify potential target markers. Identifying biomarkers in the dysregulated pathway can aid in better clinical management for patients with severe COVID-19 disease. A special focus has also been given to potent inhibitors of proinflammatory cytokines, immunomodulatory and immunotherapeutic options to ameliorate cytokine storm and inflammatory responses in patients affected with COVID-19.

Genome composition and genetic characterization of SARS-CoV-2.

SARS-CoV-2 is a type of Betacoronaviruses responsible for COVID-19 pandemic disease, with more than 1.745 million fatalities globally as of December-2020. Genetically, it is considered the second largest genome of all RNA viruses with a 5' cap and 3' poly-A tail. Phylogenetic analyses of coronaviruses reveal that SARS-CoV-2 is genetically closely related to the Bat-SARS Like-Corona virus (Bat-SL-Cov) with 96% whole-genome identity. SARS-CoV-2 genome consists of 15 ORFs coded into 29 proteins. At the 5' terminal of the genome, we have ORF1ab and ORF1a, which encode the 1ab and 1a polypeptides that are proteolytically cleaved into 16 different nonstructural proteins (NSPs). The 3' terminal of the genome represents four structural (spike, envelope, matrix, and nucleocapsid) and nine accessory (3a, 3b, 6, 7a, 7b, 8b, 9a, 9b, and orf10) proteins. As the number of COVID-19 patients increases dramatically worldwide, there is an urgent need to find a quick and sensitive diagnostic tool for controlling the outbreak of SARS-CoV-2 in the community. Today, molecular testing methods utilizing viral genetic material (e.g., PCR) represent the crucial diagnostic tool for the SARS-CoV-2 virus despite its low sensitivity in the early stage of viral infection. This review summarizes the genome composition and genetic characterization of the SARS-CoV-2.

Recent advances in vaccine and immunotherapy for COVID-19.

The COVID-19 pandemic caused by SARS-CoV-2 has resulted in millions of cases and hundreds of thousands of deaths. Beyond there being no available antiviral therapy, stimulating protective immunity by vaccines is the best option for managing future infections. Development of a vaccine for a novel virus is a challenging effort that may take several years to accomplish. This mini-review summarizes the immunopathological responses to SARS-CoV-2 infection and discusses advances in the development of vaccines and immunotherapeutics for COVID-19.

Structural and operational redesigning of patient-centered ambulatory care pharmacy services and its effectiveness during the COVID-19 pandemic.

BACKGROUND: The newly emerged coronavirus pandemic (COVID-19) has collapsed the entire global health care system. Due to these settings, a lot of strategic changes are adopted by healthcare facilities to ensure continuity in patient-centered services. OBJECTIVE: This study aims to evaluate the effectiveness of structural and operational changes made in ambulatory care pharmacy services during the COVID-19 pandemic. METHODS: A retrospective comparative study was conducted to evaluate the impact and effectiveness of patient-centered interventions and consequent access to medication management care within Johns Hopkins Aramco Health Care ambulatory care pharmacy services during the COVID-19 pandemic by comparing patient-centered key performance indicators before and during COVID-19 pandemic for a total of 4 months. RESULTS: As a result of the structural and operational changes made in patient-centered ambulatory care pharmacy services during the COVID-19 pandemic, a 48% prescriptions requests and 90% prescriptions fills are increased through online health portal application. A three-fold increase in the pharmacy call center utilization resulted in around 10% abandoned calls. In the number of physical visits to ambulatory care pharmacies, a 37% reduction was also noted. The decrease in staff schedule efficiency and an increase in average prescription waiting time were also noticed. The prescription collection through remote area pick up locations, and medication home delivery services were successful during COVID-19 pandemic as supported by statistical data. CONCLUSION: The access to ambulatory care pharmacy services during COVID-19 pandemic has been successfully maintained via medication home delivery, remote area pickup locations, pharmacy call-center consultations and refill requests, online health portal application services, and other measures, while reducing the number of physical visits to the JHAH hospital/clinic to ensure compliance with infection control and prevention measures.