Evaluation of spleen stiffness by 2D shear wave elastography for ruling out high risk varices in patients with chronic advanced liver disease. A systematic review and meta-analysis.

OBJECTIVES: To systematically review the accuracy of spleen stiffness measurement (SSM) by 2D- Shear Wave Elastography (2D-SWE) in predicting high risk for bleeding varices (HRV) in cirrhotic patients. METHODS: PubMed, Embase, Web of Science, Medline, Cochrane, and Google Scholar databases were searched up to 31/05/2023 for all human studies using 2D-SWE to estimate SSM and endoscopy to detect HRV. Meta-analysis was performed using a generalized linear mixed model. Publication bias was evaluated using the funnel plot asymmetry test. The Area Under the Summarized Receiver Operating Characteristic curve (AUSROC) was estimated using the "mada" package. RESULTS: A total of 13 studies and 1970 patients were included. Of them, 27.8 % had HRV. The pooled sensitivity and polled specificity of SSM in detecting HRV were 90 % (95 %CI:87-92 %) and 68 % (95 %CI:58-77 %), respectively, with an AUSROC at 0.86 (95 %CI:0.82-0.90). The median cutoff value of SSM in detecting HRV was 34.2 kPa. In studies including exclusively HBV cirrhotic patients, SSM's polled sensitivity and specificity in predicting HRV was 88 % (95 %CI:82-92 %) and 73 % (95 %CI:68-78 %), respectively. The AUSROC was 0.84 (95 %CI:0.81-0.87). The number of repeated measurements per patient (<5 or ≥ 5) did not affect the method's capability. Using Aixplorer to evaluate SSM had a higher sensitivity in ruling out HRV than other 2D-SWE devices. CONCLUSIONS: Our meta-analysis supports that SSM by 2D-SWE has a good diagnostic performance for ruling out HRV in cirrhosis.

Understanding the Role of Connexins in Hepatocellular Carcinoma: Molecular and Prognostic Implications.

Connexins, a family of tetraspan membrane proteins forming intercellular channels localized in gap junctions, play a pivotal role at the different stages of tumor progression presenting both pro- and anti-tumorigenic effects. Considering the potential role of connexins as tumor suppressors through multiple channel-independent mechanisms, their loss of expression may be associated with tumorigenic activity, while it is hypothesized that connexins favor the clonal expansion of tumor cells and promote cell migration, invasion, and proliferation, affecting metastasis and chemoresistance in some cases. Hepatocellular carcinoma (HCC), characterized by unfavorable prognosis and limited responsiveness to current therapeutic strategies, has been linked to gap junction proteins as tumorigenic factors with prognostic value. Notably, several members of connexins have emerged as promising markers for assessing the progression and aggressiveness of HCC, as well as the chemosensitivity and radiosensitivity of hepatocellular tumor cells. Our review sheds light on the multifaceted role of connexins in HCC pathogenesis, offering valuable insights on recent advances in determining their prognostic and therapeutic potential.

Prevalence of and Impact on the Outcome of Myosteatosis in Patients with Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Limited data exist on the prevalence of myosteatosis (i.e., excess accumulation of fat in skeletal muscles) in hepatocellular carcinoma (HCC) patients, and no systematic review or meta-analysis has been conducted in this context. METHODS: We searched for articles published from inception until November 2023 to assess the prevalence of myosteatosis in patients with HCC. RESULTS: Ten studies with 3316 patients focusing on myosteatosis and HCC were included. The overall prevalence of myosteatosis in HCC patients was 50% [95% Confidence Interval (CI): 35-65%]. Using the body mass index-based criteria (two studies), the prevalence was 34%, while gender-based criteria (eight studies) yielded 54% (p = 0.31). In Asian studies (n = 8), the prevalence was 45%, compared to 69% in non-Asian countries (two studies) (p = 0.02). For viral-associated HCC (eight studies), the prevalence was 49%, rising to 65% in non-alcoholic fatty liver disease-associated cases (three studies) and 86% in alcoholic liver disease-associated cases (three studies) (p < 0.01). The prevalence of myosteatosis was higher in Child-Pugh class C (3 studies, 91%) than in A (7 studies, 73%) or B (6 studies, 50%) (p = 0.02), but with no difference between Barcelona Clinic Liver Cancer stage A (3 studies, 66%), B (4 studies, 44%) and C (3 studies, 62%) (p = 0.80). Patients with myosteatosis had a significantly higher mortality (six studies) (Relative Risk: 1.35 (95%CI: 1.13-1.62, p < 0.01). CONCLUSION: The prevalence of myosteatosis is high in HCC patients and is associated with more severe liver disease and higher mortality rates.

Metformin in Esophageal Carcinoma: Exploring Molecular Mechanisms and Therapeutic Insights.

Esophageal cancer (EC) remains a formidable malignancy with limited treatment options and high mortality rates, necessitating the exploration of innovative therapeutic avenues. Through a systematic analysis of a multitude of studies, we synthesize the diverse findings related to metformin's influence on EC. This review comprehensively elucidates the intricate metabolic pathways and molecular mechanisms through which metformin may exert its anti-cancer effects. Key focus areas include its impact on insulin signaling, AMP-activated protein kinase (AMPK) activation, and the mTOR pathway, which collectively contribute to its role in mitigating esophageal cancer progression. This review critically examines the body of clinical and preclinical evidence surrounding the potential role of metformin, a widely prescribed anti-diabetic medication, in EC management. Our examination extends to the modulation of inflammation, oxidative stress and angiogenesis, revealing metformin's potential as a metabolic intervention in esophageal cancer pathogenesis. By consolidating epidemiological and clinical data, we assess the evidence that supports metformin's candidacy as an adjuvant therapy for esophageal cancer. By summarizing clinical and preclinical findings, our review aims to enhance our understanding of metformin's role in EC management, potentially improving patient care and outcomes.

Prevalence and impact on the outcome of myosteatosis in patients with cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Myosteatosis in cirrhotic patients has been evaluated in limited studies with conflicting results and no systematic review or meta-analysis have been performed in this setting. METHODS: We searched for all articles published until June 2023 to evaluate the prevalence of myosteatosis in cirrhosis and chronic liver disease. RESULTS: Seventeen studies focused on cirrhosis and five studies in patients with chronic liver disease were included: the overall pooled prevalence of myosteatosis was 46% [95% Confidence Interval (CI) 36-57%] and 33% (95% CI 15-59%), respectively (p = 0.35). Among the studies with cirrhosis, the prevalence of myosteatosis was higher in those using the body mass index-based definition of myosteatosis (56%), than gender-based (36%) or other criteria (21%) (p < 0.01); was higher in women than in men (61% vs 45%), in Child-Pugh class C than A or B (57% vs 49% vs 50%), in non-alcoholic fatty liver disease (NAFLD)- than viral-associated cirrhosis (57% vs 43%), but these differences were not statistically significant (p > 0.05). Cirrhotic patients with myosteatosis, compared to those without myosteatosis, had more frequently a previous history of hepatic encephalopathy (32% vs 15%, p = 0.04), less frequently a previous history of variceal bleeding (46% vs 65%, p < 0.01), were more likely to suffer from diabetes mellitus (27% vs 18%, p < 0.01), while they had higher mortality rates (40% vs 14%, p = 0.02). CONCLUSION: Myosteatosis is highly prevalent in patients with cirrhosis, particularly in those with NAFLD-associated cirrhosis. Myosteatosis is associated with hepatic encephalopathy, while it seems to have a negative impact on the outcome.

qSOFA combined with suPAR for early risk detection and guidance of antibiotic treatment in the emergency department: a randomized controlled trial.

BACKGROUND: Sepsis guidelines suggest immediate start of resuscitation for patients with quick Sequential Organ Failure Assessment (qSOFA) 2 or 3. However, the interpretation of qSOFA 1 remains controversial. We investigated whether measurements of soluble urokinase plasminogen activator receptor (suPAR) may improve risk detection when qSOFA is 1. METHODS: The study had two parts. At the first part, the combination of suPAR with qSOFA was analyzed in a prospective cohort for early risk detection. At the second part, the double-blind, randomized controlled trial (RCT) SUPERIOR evaluated the efficacy of the suPAR-guided medical intervention. SUPERIOR took place between November 2018 and December 2020. Multivariate stepwise Cox regression was used for the prospective cohort, while univariate and multivariate logistic regression was used for the RCT. Consecutive admissions at the emergency department (ED) with suspected infection, qSOFA 1 and suPAR ≥ 12 ng/mL were allocated to single infusion of placebo or meropenem. The primary endpoint was early deterioration, defined as at least one-point increase of admission Sequential Organ Failure Assessment (SOFA) score the first 24 h. RESULTS: Most of the mortality risk was for patients with qSOFA 2 and 3. Taking the hazard ratio (HR) for death of patients with qSOFA = 1 and suPAR < 12 ng/mL as reference, the HR of qSOFA = 1 and suPAR ≥ 12 ng/mL for 28-day mortality was 2.98 (95% CI 2.11-3.96). The prospective RCT was prematurely ended due to pandemia-related ED re-allocations, with 91 patients enrolled: 47 in the placebo and 44 in the meropenem arm. The primary endpoint was met in 40.4% (n = 19) and 15.9% (n = 7), respectively (difference 24.5% [5.9-40.8]; odds ratio 0.14 [0.04-0.50]). One post hoc analysis showed significant median changes of SOFA score after 72 and 96 h equal to 0 and - 1, respectively. CONCLUSIONS: Combining qSOFA 1 with the biomarker suPAR improves its prognostic performance for unfavorable outcome and can help decision for earlier treatment. Trial registration EU Clinical Trials Register (EudraCT, 2018-001008-13) and Clinical-Trials.gov (NCT03717350). Registered 24 October 2018.

Natural history of metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD), which has been the term for non-alcoholic fatty liver disease (NAFLD) since June 2023, represents the most common liver disease worldwide and is a leading cause of liver-related morbidity and mortality. A thorough knowledge of the disease's natural history is required to promptly stratify patients' risks, since MASLD is a multifaceted disorder with a broad range of clinical phenotypes. The histological disease spectrum ranges from isolated hepatic steatosis, currently named as metabolic dysfunction-associated steatotic liver (MASL), to metabolic dysfunction-associated steatohepatitis (MASH) and eventually may accumulate hepatic fibrosis and develop cirrhosis and/or hepatocellular carcinoma (HCC). Several risk factors for fibrosis progression have been identified, while the disease's progression displays notable dynamism and bidirectionality. When compared to the general population, all MASLD histological stages are substantially related with greater overall mortality, and this association exhibits a disease severity-dependent pattern. Interestingly, the fibrosis stage is the most accurate predictor of mortality among MASLD patients. The mortality attributed to MASLD predominantly stems from issues linked with the liver and cardiovascular system, as well as HCC and extrahepatic cancers. In light of the disease natural course, it is crucial to prioritize the identification of at-risk patients for disease progression in order to effectively address and change modifiable risk factors, hence mitigating disease complications. Further investigation is required to define the phenotype of rapid progressors more precisely as well as to improve risk stratification for HCC in non-cirrhotic individuals.

Immunogenicity and safety of vaccines in multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Seroconversion rate of vaccines varies and requires further elucidation in patients with multiple sclerosis (MS) under treatment with disease-modifying therapies (DMTs). We aimed to investigate this in a systematic review and meta-analysis. METHODS: MEDLINE(PubMed) and Cochrane databases were searched based on a pre-specified protocol (PROSPERO: CRD42020202018). Studies reporting on patients with MS, diagnosed with McDonald criteria getting vaccinated with any type of vaccine were included in the analysis. The primary endpoint was the incidence of patients being seropositive and experience adverse events after vaccination. Outcomes were expressed as proportions with respective 95% confidence interval (CI). Two reviewers independently screened and reviewed existing literature and assessed study quality with the Methodological index for non-randomized studies. RESULTS: Of 295 articles, 45 studies were analyzed. Seroconversion after COVID-19 vaccines was 76% (95% CI, 70-80; I2 = 95%; 20 studies including 5601 patients. Protection was lower in patients treated with anti-CD20 antibodies and sphingosine-1-phosphate receptor (S1PR) modulators compared to untreated patients or treatment with other DMTs. Relapse occurred in 2% (95% CI, 1-3; I2 = 86%; 16 studies including 7235 patients). Seroconversion after seasonal influenza vaccines was 82% (95% CI, 65-91; I2 = 90%; 6 studies including 490 patients). Relapse rate was similar to this after COVID-19 vaccination. CONCLUSION: The majority of MS patients vaccinated for COVID-19 or seasonal influenza mount an adequate immune response without safety concerns. Data on other vaccines are limited.

Meeting at the Crossroad between Obesity and Hepatic Carcinogenesis: Unique Pathophysiological Pathways Raise Expectations for Innovative Therapeutic Approaches.

The escalating global prevalence of obesity and its intricate association with the development of hepatocellular carcinoma (HCC) pose a substantial challenge to public health. Obesity, acknowledged as a pervasive epidemic, is linked to an array of chronic diseases, including HCC, catalyzing the need for a comprehensive understanding of its molecular underpinnings. Notably, HCC has emerged as a leading malignancy with rising incidence and mortality. The transition from viral etiologies to the prominence of metabolic dysfunction-associated fatty liver disease (MAFLD)-related HCC underscores the urgent need to explore the intricate molecular pathways linking obesity and hepatic carcinogenesis. This review delves into the interwoven landscape of molecular carcinogenesis in the context of obesity-driven HCC while also navigating using the current therapeutic strategies and future prospects for combating obesity-related HCC. We underscore the pivotal role of obesity as a risk factor and propose an integrated approach encompassing lifestyle interventions, pharmacotherapy, and the exploration of emerging targeted therapies. As the obesity-HCC nexus continues to challenge healthcare systems globally, a comprehensive understanding of the intricate molecular mechanisms and innovative therapeutic strategies is imperative to alleviate the rising burden of this dual menace.

The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks?

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Immunotherapy has emerged as the mainstay treatment option for unresectable HCC. Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune response by recognizing and responding primarily to bacterial lipopolysaccharides. In addition to its role in the innate immune system, TLR4 has also been implicated in adaptive immunity, including specific anti-tumor immune responses. In particular, the TLR4 signaling pathway seems to be involved in the regulation of several cancer hallmarks, such as the continuous activation of cellular pathways that promote cell division and growth, the inhibition of programmed cell death, the promotion of several invasion and metastatic mechanisms, epithelial-to-mesenchymal transition, angiogenesis, drug resistance, and epigenetic modifications. Emerging evidence further suggests that TLR4 signaling holds promise as a potential immunotherapeutic target in HCC. The aim of this review was to explore the multilayer aspects of the TLR4 signaling pathway, regarding its role in liver diseases and HCC, as well as its potential utilization as an immunotherapy target for HCC.

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 2 doses of COVID­19 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 COVID­19 vaccines in LTRs. METHODS: We searched PubMed and Google Scholar for eligible studies. The primary outcome was to compare the rates of seroconversion after the second and third dose of COVID­19 vaccine in LTRs. This meta­analysis was performed using a generalized linear mixed model and the Clopper and Pearson method was employed to calculate the 2­sided CIs. 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 it 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 of calcineurin inhibitors (P = 0.44) or mammalian target of rapamycin inhibitors (P = 0.33), while the pooled rate of antibody responses in the patients on mycophenolate mofetil (MMF) was 88% (95% CI, 83%-92%; heterogeneity, I2 = 0%; P = 0.57). It was significantly lower (P <0.001), as compared with those on MMF­free immunosuppression (pooled rate, 97%; 95% CI, 95%-98%; heterogeneity, I2 = 30%; P = 0.22). No safety concerns were reported for the booster dose. CONCLUSIONS: Our meta­analysis demonstrated that the third dose of COVID­19 vaccines induced adequate humoral and cellular immune responses in LTRs, while MMF remained a negative predictor of immunologic 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.

The Lyon Consensus Criteria for GERD Diagnosis in a Greek Population: The Clinical Impact and Changes in GERD Diagnosis in a Real-World, Retrospective Study.

(1) Introduction/aim: Gastroesophageal reflux disease (GERD) affects 8−33% globally. The gold standard examination technique in diagnosing GERD is 24 h pHmetry ± impedance. Recently, new diagnostic criteria were introduced by the Lyon Consensus for GERD diagnosis. Our aim was to investigate the diagnostic yield of pHmetry + impedance using the Lyon Consensus criteria in a real-world study. (2) Patients and methods: Our study included 249 consecutive patients (M/F: 120/129, mean age 50 ± 15 years) who underwent 24 h pH+ impedance monitoring in our department, during a 5-year period. Epidemiological, endoscopic, clinical, and 24 h pH+ impedance data were retrospectively collected. (3) Results: Typical GERD symptoms were reported by 140/249 (56.2%) patients, whereas 99/249 (39.6%) patients reported various extraesophageal symptoms. Endoscopic findings supportive of GERD based on the Lyon Consensus were present in 42/185 (22.7%). An AET value of >6% was observed in 60/249 (24.1%). GERD diagnosis according to the Lyon Consensus criteria was set in 63/249 (25.3%) patients; a rate significantly lower than that observed by implementing the older criteria (32.1%), p < 0.001. In the multivariate analysis, the existence of endoscopic findings supportive of GERD diagnosis as defined by the Lyon Consensus (p = 0.036), a De Meester score of over 14.7, and the presence of typical GERD symptoms were correlated to GERD diagnosis (p < 0.001, respectively) using the criteria defined for pH−impedance monitoring. (4) Conclusions: Changes in the diagnostic criteria concerning the 24 h pH−impedance monitoring of GERD based on the Lyon Consensus led to a conclusive GERD diagnosis in approximately 25% of the patients. This rate of GERD diagnosis is reduced in comparison to the one confirmed with the use of previously established criteria.

Hepatitis B virus reactivation associated with new classes of immunosuppressants and immunomodulators: A systematic review, meta-analysis, and expert opinion.

HBV reactivation (HBVr) can be prevented by nucleos(t)ide analogues (NAs). We conducted a systematic review and meta-analysis on the risk of HBVr associated with new classes of immunosuppressive and immunomodulatory therapies and developed guidance on NA prophylaxis. An expert panel reviewed the data and categorised the risk of HBVr associated with each class of drugs into low (<1%), intermediate (1-10%), and high (>10%). Our search uncovered 59 studies, including 3,424 HBsAg+ and 5,799 HBsAg-/anti-HBc+ patients, which met our eligibility criteria. Based on medium-high quality evidence, immune checkpoint inhibitors, tyrosine kinase inhibitors, cytokine inhibitors, chimeric antigen receptor T-cell immunotherapies, and corticosteroids were associated with high HBVr risk in HBsAg+ patients; cytokine inhibitors, chimeric antigen receptor T-cell immunotherapies, and corticosteroids with intermediate risk in HBsAg-/anti-HBc+ patients; and anti-tumour necrosis factor agents and immune checkpoint inhibitors with low risk in HBsAg-/anti-HBc+ patients. Provisional recommendations are provided for drugs with low quality evidence. NA prophylaxis is recommended when using drugs associated with a high HBVr risk, while monitoring with on-demand NAs is recommended for low-risk drugs - either approach may be appropriate for intermediate-risk drugs. Consensus on definitions and methods of reporting HBVr, along with inclusion of HBsAg+, and HBsAg-/anti-HBc+ patients in clinical trials, will be key to gathering reliable data on the risk of HBVr associated with immunosuppressive or immunomodulatory therapies.

The impact of emricasan on chronic liver diseases: current data.

Immoderate caspase-mediated apoptosis in chronic liver injury is a crucial driver of sustained HSC activation and worsening hepatic inflammation as well as fibrosis, with the ultimate outcome of liver cirrhosis and its consequences. Therefore, the inhibition of hepatocyte apoptosis by caspase cascade blockage may be a promising therapeutic strategy to achieve fibrosis regression in chronic liver diseases. Emricasan is a broad-spectrum, liver-targeted caspase inhibitor with a favorable pharmacokinetic profile, characterized by prolonged retention in the liver and low systemic exposure after oral administration. In animal models, emricasan had a clear intrahepatic anti-apoptotic effect with consequent elimination of circulating pro-inflammatory cytokines and favorable impact in liver fibrogenesis and portal pressure. Even though, this intrahepatic drug effect confirmed in human clinical trials, no clear linkage was emerged with portal hypertension, liver function or liver histology in both non-cirrhotic and cirrhotic patients except from a subgroup of patients with high MELD score (> 15) or severe HVPG (> 16 mmHg). As emricasan treatment appeared safe and well-tolerated, irrespective the severity of liver disease, more studies are required to clarify better these subgroups of patients who may benefit most from this drug.

BioFire® FilmArray® Pneumonia Panel for Severe Lower Respiratory Tract Infections: Subgroup Analysis of a Randomized Clinical Trial.

INTRODUCTION: The epidemiology of severe lower respiratory tract infections (LRTI) is constantly changing. We aimed to describe it using the BioFire® FilmArray® Pneumonia plus (PNplus) Panel. METHODS: In a sub-study of the PROGRESS trial, sputum samples of 90 patients with sepsis and LRTI were retrospectively studied. The primary endpoint was the comparative detection rate of pathogens between conventional microbiology and PNplus Panel; secondary endpoints were microbiology and the association with the inflammatory host response. RESULTS: Fifty-six patients with community-acquired pneumonia without risk factors for multidrug-resistant (MDR) pathogens and another 34 patients with risk factors for MDR were studied; median pneumonia severity index (PSI) was 113 (88-135). PNplus detection rate was 72.2% compared to 10% by conventional microbiology (p < 0.001); Streptococcus pneumoniae was the most common pathogen. PSI and procalcitonin were greater among patients with bacterial pathogens than viral pathogens. Median procalcitonin was 0.49 ng/ml and 0.18 ng/ml among patients with ≥ 105 and < 105 copies/ml of detected bacteria, respectively (p = 0.004). Resistance reached 14.4%. CONCLUSION: PNplus detects severe pneumonia pathogens at a greater rate than conventional microbiology. High levels of inflammation accompany bacterial detection. TRIAL REGISTRATION: PROGRESS, ClinicalTrials.gov NCT03333304, 06/11/2017.

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.