Background: Coronavirus disease 2019 (COVID-19) is a newly emerging infectious disease and rapidly escalating epidemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The pathogenesis of COVID-19 remains to be elucidated. We aimed to clarify correlation of systemic inflammation with disease severity and outcomes in COVID-19 patients. Methods: In this retrospective study, baseline characteristics, laboratory findings, and treatments were compared among 317 laboratory-confirmed COVID-19 patients with moderate, severe, or critically ill form of the disease. Moreover, the longitudinal changes of serum cytokines, lactate dehydrogenase (LDH), high-sensitivity C-reactive protein (hsCRP), and hsCRP to lymphocyte count ratio (hsCRP/L) as well as their associations with disease severity and outcomes were investigated in 68 COVID-19 patients. Results: Within 24 h of admission, the critically ill patients showed higher concentrations of inflammatory markers including serum soluble interleukin (IL)-2 receptor, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), ferritin, procalcitonin, LDH, hsCRP, and hsCRP/L than patients with severe or moderate disease. The severe cases displayed the similar response patterns when compared with moderate cases. The longitudinal assays showed the levels of pro-inflammatory cytokines, LDH, hsCRP, and hsCRP/L gradually declined within 10 days post admission in moderate, severe cases or those who survived. However, there was no significant reduction in cytokines, LDH, hsCRP, and hsCRP/L levels in critically ill or deceased patients throughout the course of illness. Compared with female patients, male cases showed higher serum concentrations of soluble IL-2R, IL-6, ferritin, procalcitonin, LDH, and hsCRP. Multivariate logistic regression analysis revealed that IL-6 > 50 pg/mL and LDH > 400 U/L on admission were independently associated with disease severity in patients with COVID-19. Conclusion: Exuberant inflammatory responses within 24 h of admission in patients with COVID-19 may correlate with disease severity. SARS-CoV-2 infection appears to elicit a sex-based differential immune response. IL-6 and LDH were independent predictive parameters for assessing the severity of COVID-19. An early decline of these inflammation markers may be associated with better outcomes.

The role of liver NK cells in virus-induced severe viral hepatitis and, subsequently, hepatic failure is not well defined. In this study, we investigated the role of liver NK cells in the development of hepatocyte necrosis in fulminant hepatic failure (FHF)and acute-on-chronic liver failure (ACLF) because of viral infection. A mouse model of FHF induced by murine hepatitis virus strain 3 (MHV-3) was used to study the role of liver NK cells. Samples from patients with hepatitis B virus-related ACLF (HBV-ACLF) were examined. After MHV-3 infection, the number of NK cells in livers of BALB/cJ mice increased markedly, peaked at 48 h postinfection, and remained at a high level until sacrifice. In peripheral blood, spleen, and bone marrow, this number decreased significantly. Expression of CD69, cytotoxic activity, and intracellular IFN-γ and TNF-α production by liver NK cells at 48 h postinfection were all significantly upregulated. Depletion of NK cells 24 h post-MHV-3 infection increased the mice survival from 0 of 18 (0%) to 4 of 18 (22.2%). Highly activated liver NK cells were cytotoxic to MHV-3-infected hepatocytes and this effect was markedly inhibited by anti-Fas ligand (FasL) plus anti-NKG2D mAbs. Furthermore, the accumulation of hepatic NK cells and increased expression of FasL and natural cytotoxicity receptors (NKp30 and NKp46) on the peripheral NK cells from patients with HBV-ACLF were correlated with disease progression. These results indicate NK cells play a pivotal role in the pathogenesis of FHF and HBV-ACLF, in which process Fas/FasL and NKG2D/NKG2D ligand pathway contribute to the liver NK cell-mediated hepatocyte injury.

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.

Background: In the OSST study, hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients who switched from long-term entecavir (ETV) therapy to pegylated interferon-α2a (PEG-IFN-α2a; 40 kDa) achieved higher rates of HBeAg seroconversion and hepatitis B surface antigen (HBsAg) loss than those who continued ETV. Herein we report the sustainability of serological responses during 1 year of untreated follow-up in patients who switched from ETV to PEG-IFN-α2a therapy. Methods: A total of 62 patients who completed 48 weeks of PEG-IFN-α2a therapy were followed-up for 48 weeks off treatment. Primary end points were HBeAg seroconversion and maintenance of HBeAg seroconversion at 48 weeks post-treatment. Secondary end points included HBsAg loss, HBV DNA <1,000 copies/ml and alanine aminotransferase normalization (<1 x upper limit of normal). Results: The HBeAg seroconversion rate increased from 17.7% (11/62) at the end of treatment to 38.7% (24/62) 1 year post-treatment. Sustained HBeAg seroconversion was achieved by 63.6% (7/11) patients with end-of-treatment responses, while late HBeAg seroconversion was achieved by 33.3% (17/51) of patients who did not have end-of-treatment responses. Sustained HBsAg loss was documented in 6 of 7 patients, and sustained HBV DNA suppression was achieved in 60% (27/45) of patients with an end-of-treatment response. Conclusions: In patients who do not achieve HBeAg sero-conversion during long-term ETV therapy, switching to finite treatment with PEG-IFN-α2a produces HBeAg sero-conversion in a substantial proportion of patients at end of treatment and during 1 year of follow-up. Moreover, HBeAg seroconversion and HBsAg loss are sustained in most patients during 1 year of untreated follow-up.