Seroconversion following a booster dose of COVID-19 vaccine in liver transplant recipients. A systematic review and meta-analysis.

INTRODUCTION: Although it is well established that two doses of COVID-19 vaccines are associated with reduced immune responses in liver transplant recipients [LTRs], studies regarding their immunogenicity and tolerability after a booster dose are limited. OBJECTIVES: We aimed to review the available literature data regarding antibody responses and safety of the third dose of COVID-19 vaccines in LTRs. METHODS: We searched PubMed for eligible studies. The primary outcome was to compare the rates of seroconversion after the second and third COVID-19 vaccine dose in LTRs. Meta-analysis was performed using a generalized linear mixed model (GLMM) and the Clopper and Pearson method was used to calculate the two-sided confidence intervals (CI). RESULTS:  Six prospective studies involving 596 LTRs met the inclusion criteria. The pooled rate of antibody response before the third dose was 71% (95%CI:56-83%; heterogeneity: I2=90%, p<0.001), while after the third dose was 94% (95%CI:91-96%; heterogeneity: I2=17%, p=0.31). There was no difference in antibody responses after the third dose in relation to the use, or not, of calcineurin inhibitors (p=0.44) or mammalian target of rapamycin inhibitors (p=0.33), while the pooled rate of antibody responses in those under mycophenolate mofetil (MMF) was 88% (95%CI:83-92%; heterogeneity: I2=0%, p=0.57), significantly lower (p<0.001), compared to those under MMF-free immunosuppression [pooled rate:97%, 95%CI:95-98%; heterogeneity: I2=30%, p=0.22]. No safety concerns of the booster dose were reported. CONCLUSIONS: Our meta-analysis demonstrated that the third dose of COVID-19 vaccines induced adequate humoral and cellular immune responses in LTRs, while MMF remained a negative predictor of immunological responses.

COVID-19 and liver injury in individuals with obesity.

Coronavirus disease 2019 is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 that manifests as a variety of clinical manifestations, including liver damage commonly detected by a hepatocellular pattern from liver function tests. Liver injury is associated with a worse prognosis overall. Conditions associated with the severity of the disease include obesity and cardiometabolic comorbidities, which are also associated with nonalcoholic fatty liver disease (NAFLD). The presence of NAFLD, similarly to obesity, is associated with an unfavourable impact on the coronavirus disease 2019 outcome. Individuals with these conditions could present with liver damage and elevated liver function tests due to direct viral cytotoxicity, systemic inflammation, ischemic or hypoxic liver damage or drug side effects. However, liver damage in the setting of NAFLD could also be attributed to a pre-existing chronic low-grade inflammation associated with surplus and dysfunctional adipose tissue in these individuals. Here we investigate the hypothesis that a pre-existing inflammatory status is exacerbated after severe acute respiratory syndrome coronavirus 2 infection, which embodies a second hit to the underestimated liver damage.

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure.

Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7-8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation.