Objectives: Cryoglobulinemia (CG) is marked by abnormal immunoglobulins (Ig) in serum, precipitating at temperatures below 37 °C. Current classification categorizes CG into three subtypes (types I, II, and III) based on Ig clonality. The features distinguishing patients with CG based on their etiology remain unidentified. Aiming to characterize clinical and serological profiles of CG individuals, we conducted an observational analysis of a large cohort of patients and compared their characteristics based on underlying causes: hepatovirus (HV) infections, rheumatic diseases (RD), hematological disorders, and unidentified etiology (essential CG). Methods: We analyzed 252 cryoglobulin-positive serum samples from 182 patients and classified these into the four etiological groups. A separate sub-analysis was carried out for 10 patients meeting criteria for multiple diseases. We collected demographic, clinical, and laboratory data: CG characterization, complement (C3 and C4) levels, antinuclear antibodies (ANA), and rheumatoid factor (RF). Kruskal-Wallis and Wilcoxon-Mann-Whitney U-tests were used for comparisons. Results: Most patients (93.3%) had mixed cryoglobulinemia (types II + III), with 6.7% having type I. HV infection, predominantly hepatitis C, was the main (52.9%) associated condition within the cohort, followed by rheumatic (27.3%) and hematological (9.8%) disorders. In our cohort, ANA were frequent (45.3%) and often associated with RF positivity (43.6%) and decreased complement levels (C3: 42.4%, C4: 32.5%). Essential CG and CG associated with RD had a higher prevalence of cutaneous manifestations (p < 0.01) and renal involvement (p = 0.017). Hematological disorder-related CG showed higher cryoglobulin and RF concentrations (p < 0.01), despite milder symptoms. Conclusions: Our study underscores a mixed prevalence of CG across disease subgroups, with hepatitis-C virus as the primary factor, followed by rheumatic and hematological disorders. Four clinical and serological profiles of CG were identified based on their etiologies.

Hepatitis C virus (HCV) has emerged as a major global health concern and, if left untreated, can lead to significant liver damage, including cirrhosis, decompensated liver disease, and hepatocellular carcinoma (HCC). Approximately 40% of patients with HCV infection experience extrahepatic manifestations, including renal involvement. HCV-related renal disease is of significant importance among patients with chronic kidney disease (CKD), leading to higher morbidity and mortality. The renal damage due to HCV infection primarily results from cryoglobulinemia and glomerulonephritis, with conditions such as membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy (MN) being most prevalent. Despite advancements in treatment, including the use of directly acting antiviral agents (DAAs), renal complications remain a significant burden in untreated patients. HCV-positive patients on hemodialysis (HD) or those who have undergone kidney transplantation face increased mortality rates compared to their HCV-negative counterparts. Managing HCV infection before kidney transplantation is crucial to mitigate the risk of HCV-related renal complications. Conversely, kidney transplantation from HCV-infected donors is well established, as post-transplant treatment for HCV is safe and effective, potentially reducing mortality and morbidity for patients on transplant waiting lists. This review aims to provide a comprehensive analysis of the renal manifestations of HCV, emphasizing the importance of early diagnosis and treatment to improve patient outcomes.

This case report describes a 66-year-old female with membranoproliferative glomerulonephritis (MPGN) with pulmonary involvement presumed secondary to Hepatitis C virus (HCV)-associated with mixed cryoglobulinemia. In this condition, pulmonary involvement is uncommon, and aggressive lung involvement can be associated with poor outcomes. Within eight weeks, the patient was hospitalized twice with acute pulmonary presentations and presented at a third hospitalization with dyspnea, chest pain, abdominal pain, and edema. Imaging revealed persistent and historically evolving lung consolidation, as well as a renal biopsy showing MPGN associated with mixed cryoglobulinemia. A lung biopsy revealed inflammation. Bronchoalveolar lavage did not show hemosiderin-laden macrophages and did not grow infectious agents. Serology revealed negative ANCAs and rheumatoid factor positive at 476 IU/ml (upper limit normal 14 IU/ml). Qualitative cryoglobulins were positive at 2 %ppt (reference range: negative %ppt) and Type II mixed cryoglobulinemia with IgM kappa plus polyclonal IgG. The treatment involved steroids and rituximab. The patient's clinical status deteriorated, and she elected to change her resuscitation status to comfort care measures. This case emphasizes that cryoglobulinemia can present with aggressive manifestations on a wide spectrum. Pulmonary manifestations are rare and were evident in this case (although without clear evidence of diffuse alveolar hemorrhage) and led to a complicated disease course and an unfavorable outcome. Overall, this case underscores the complexity of mixed cryoglobulinemia presentations and the challenges of managing severe cases with multi-organ involvement.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infect a significant number of individuals globally and their extra-hepatic manifestations, including glomerular disease, are well established. Additionally, liver disease-associated IgA nephropathy is the leading cause of secondary IgA nephropathy with disease course varying from asymptomatic urinary abnormalities to progressive kidney injury. Herein we provide an updated review on the epidemiology, pathogenesis, clinical manifestations, and treatment of HBV- and HCV-related glomerulonephritis as well as IgA nephropathy in patients with liver disease. The most common HBV-related glomerulonephritis is membranous nephropathy, although membranoproliferative glomerulonephritis and podocytopathies have been described. The best described HCV-related glomerulonephritis is cryoglobulinemic glomerulonephritis occurring in about 30% of patients with mixed cryoglobulinemic vasculitis. The mainstay of treatment for HBV-GN and HCV-GN is antiviral therapy, with significant improvement in outcomes since the emergence of the direct-acting antivirals. However, cases with severe pathology and/or a more aggressive disease trajectory can be offered a course of immunosuppression, commonly anti-CD20 therapy, particularly in the case of cryoglobulinemic glomerulonephritis.

The infection caused by the hepatitis C virus (HCV) is a significant global health concern. The prevailing genotype of HCV in Egypt is 4a, commonly referred to as GT-4a. A significant proportion exceeding 50% of patients infected with HCV experience extrahepatic manifestations (EHMs), encompassing a diverse range of clinical presentations. These manifestations, including essential mixed cryoglobulinemia (MC), can serve as initial and solitary indicators of the disease. The complete understanding of the pathogenesis of EHM remains unclear, with autoimmune phenomena being recognized as the primary causative factor. In this study, we examined the predictive significance of T-cell subpopulations in relation to the occurrence and prognosis of cryoglobulinemia in HCV patients. A total of 450 CHC genotype four treatment naïve patients were enrolled in this analytic cross-sectional study after thorough clinical, laboratory, and radiological examinations. All patients underwent laboratory investigations, including testing for cryoglobulin antibodies and measurements of CD4 and CD8 levels; two groups were described according to their test results: Group 1 consists of patients who have tested positive for cryoglobulin antibodies and Group 2 consists of patients who have tested negative for cryoglobulin antibodies. The exclusion criteria encompassed individuals with HIV infection or chronic HBV infection. Additionally, pelvi-abdominal ultrasonography was performed. Our study included 450 treatment naïve CHC patients (59% male, mean age 50.8 years). The patients were categorized according to their cryoglobulin antibodys test results into two groups: group A, CHC patients with cryoglobulin antibodies (Abs) negative (364 patients), and group B, CHC patients with cryoglobulin Ab positive (86 patients). Group B demonstrated a higher average age, elevated international normalized ratio, more prolonged duration of HCV infection, lower albumin, higher alanine aminotransferase, higher aspartate aminotransferase, higher bilirubin, lower CD8, lower CD4, and lower CD4:CD8 ratio. In contrast, 27 out of 86 (31.40%) patients in group B had symptoms; 85.8% had purpura and arthralgia, 74.3% had paresthesias, 86.7% had weakness, and 12.2% had non-Hodgkin's lymphoma. The levels of CD4 and CD8 were found to be decreased in chronic HCV patients with MC. T-cell subpopulation serves as a reliable indicator for assessing the prevalence and prognosis of MC in individuals with genotype 4 chronic hepatitis C. However, additional research is needed to further understand the development and spread of various emerging infectious diseases. Nevertheless, it is noteworthy that a critical threshold may exist beyond which EHM reaches a point of no return.

(1) Background. Hepatitis C infection often leads to extrahepatic manifestations, including cryoglobulinemic vasculitis. This systematic review aimed to assess the efficacy and safety of rituximab in treating hepatitis C-associated cryoglobulinemic vasculitis. (2) Methods. Following PRISMA guidelines, databases were searched for relevant studies. Eligibility criteria included studies on hepatitis C-associated cryoglobulinemic vasculitis treated with rituximab. (3) Results. Nine studies met the eligibility criteria and were included in this analysis. Rituximab was commonly administered at 375 mg/m2 weekly for one month. The results consistently demonstrated the efficacy of rituximab, whether as a standalone treatment or as part of a therapeutic regimen. The combination of rituximab with Peg-IFN-α and ribavirin significantly increased the complete response rate compared to Peg-IFN-α and ribavirin alone (54.5% vs. 33.3%, p < 0.05). The 3-year sustained response rate was notably higher in the rituximab combination group (83.3% vs. 40%). In another trial, rituximab achieved remission in 83.3% of patients at 6 months, compared to only 8.3% in the control group. The efficacy of rituximab was supported by long-term experience, with clinical benefits in patients with severe cryoglobulinemic vasculitis, including those resistant to standard therapies. Mild adverse events were generally reported, with rare severe reactions in some studies. (4) Conclusions: In conclusion, rituximab appeared to be effective and safe in managing hepatitis C-associated cryoglobulinemic vasculitis, either alone or with antiviral therapy.

Egypt used to have one of the highest prevalences of HCV infection worldwide. The Egyptian Ministry of Health launched a national campaign for the detection and management of HCV to reduce its burden. This study aims to carry out a cost-effectiveness analysis to evaluate the costs and benefits of the Egyptian national screening and treatment programme.

A disease burden and economic impact model was populated with the Egyptian national screening and treatment programme data to assess direct medical costs, health effects measured in disability-adjusted life years and the incremental cost-effectiveness ratio. The scenario was compared to a historical base case, which assumed that no programme had been conducted.

Total number of viremic cases is expected to decrease in 2030 by 86% under the national screening and treatment programme, versus by 41% under the historical base case. Annual discounted direct medical costs are expected to decrease from $178 million in 2018 to $81 million by 2030 under the historical base case, while annual direct medical costs are estimated to have peaked in 2019 at $312 million before declining to $55 million by 2030 under the national screening and treatment programme. Under the programme, annual disability-adjusted life years are expected to decline to 127 647 by 2030, leading to 883 333 cumulative disability-adjusted life years averted over 2018-2030.

The national screening and treatment programme is highly cost-effective by the year 2021, cost-saving by 2029 and expected to save about $35 million in direct costs and $4705 million in indirect costs by 2030.

Mixed cryoglobulinemia (MC) is a hepatitis C virus (HCV)-related extrahepatic manifestation that is characterized by the abnormal presence of immune complexes (ICs). This may be due to the reduced uptake and clearance of ICs. The C-type lectin member 18A (CLEC18A) is a secretory protein that is expressed abundantly in hepatocytes. We previously observed that CLEC18A increased significantly in the phagocytes and sera of patients with HCV, particularly those with MC. Herein, we explored the biological functions of CLEC18A in the MC syndrome development of patients with HCV by using an in vitro cell-based assay with quantitative reverse transcription-PCR, immunoblotting, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent assays. HCV infection or Toll-like receptor 3/7/8 activation could induce CLEC18A expression in Huh7.5 cells. Upregulated CLEC18A interacts with Rab5 and Rab7 and enhances type I/III interferon production to inhibit HCV replication in hepatocytes. However, overexpressed CLEC18A suppressed phagocytic activity in phagocytes. Significantly decreased levels of the Fc gamma receptor (FcγR) IIA were found in the neutrophils of HCV patients, particularly in those with MC (P < 0.005). We demonstrated that CLEC18A could inhibit FcγRIIA expression in a dose-dependent manner through the production of NOX-2-dependent reactive oxygen species to impair the uptake of ICs. Additionally, CLEC18A suppresses the Rab7 expression that is induced by starvation. Overexpressed CLEC18A does not affect autophagosome formation but does reduce the recruitment of Rab7 to autophagosomes, thereby retarding the maturation of autophagosomes and affecting autophagosome-lysosome fusion. We offer a novel molecular machinery with which to understand the association of HCV infection with autoimmunity and propose that CLEC18A may act as a candidate biomarker for HCV-associated MC. IMPORTANCE During infection, the host immune system produces cellular factors to protect against pathogen invasion. However, when the immune response overreacts and there is dysregulated cytokine homeostasis, autoimmunity occurs following an infection. We identified a cellular factor that is involved in HCV-related extrahepatic manifestation, namely, CLEC18A, which is expressed abundantly in hepatocytes and phagocytes. It inhibits HCV replication in hepatocytes by interacting with Rab5/7 and enhancing type I/III IFN expression. However, overexpressed CLEC18A inhibited FcγRIIA expression in phagocytes to impair phagocytosis. Furthermore, the interaction between CLEC18A and Rab5/7 may reduce the recruitment of Rab7 to autophagosomes and thereby retard autophagosome maturation and cause immune complex accumulation. A decreasing trend in CLEC18A levels that was accompanied by reduced HCV RNA titers and diminished cryoglobulin was observed in the sera of HCV-MC patients after direct-acting antiviral therapy. CLEC18A may be used for the evaluation of anti-HCV therapeutic drug effects and could be a potential predisposing factor for the development of MC syndrome.

Patients infected with the hepatitis C virus (HCV) have high complication rates following total hip arthroplasty (THA). Advances in HCV therapy now enable clinicians to eradicate the disease, however, its cost effectiveness from an orthopaedic perspective remains to be demonstrated. We sought to conduct a cost effectiveness analysis comparing no therapy to direct acting antiviral therapy (DAA) prior to THA among HCV positive patients.

A Markov model was utilized to evaluate the cost-effectiveness of treating HCV with DAA prior to THA. The model was powered with event probabilities, mortality, cost and quality adjusted life-year values for patients with and without HCV that were obtained from the published literature. This included treatment costs, successes of HCV eradication, incidences of superficial or periprosthetic joint infection (PJI), probabilities of utilizing various PJI treatment modalities, PJI treatment success/failures, and mortality rates. The incremental cost-effectiveness ratio (ICER) was compared to a willingness-to-pay threshold of $50,000/QALY.

Our Markov model indicates that in comparison to no therapy, DAA prior to THA is cost-effective for HCV positive patients. THA in the setting of no therapy and DAA added 8.06 and 14.39 QALYs at a mean cost of $28,800 and $115,800. The ICER associated with HCV DAA in comparison to no therapy was $13,800/QALY, below the willingness-to-pay threshold of $50,000/QALY.

Hepatitis-C treatment with DAA prior to THA is cost-effective at all current drug list prices. Given these findings, strong consideration should be given to treating patients for HCV prior to elective THA.

Diabetes mellitus (DM) and hepatitis C virus (HCV) infection are prevalent diseases globally and emerging evidence demonstrates the bidirectional association between the two diseases. Direct-acting antivirals (DAAs) for HCV have a high treatment success rate and can significantly reduce the risks of short and long-term complications of HCV infection. However, despite the evidence of the association between diabetes and HCV and the benefits of anti-HCV treatment, previously published guidelines did not focus on the universal HCV screening for patients with diabetes and their subsequent management once confirmed as having HCV viremia. Nonetheless, screening for HCV among patients with diabetes will contribute to the eradication of HCV infection. Thus, the three major Taiwan medical associations of diabetes and liver diseases endorsed a total of 14 experts in the fields of gastroenterology, hepatology, diabetology, and epidemiology to convene and formulate a consensus statement on HCV screening and management among patients with diabetes. Based on recent studies and guidelines as well as from real-world clinical experiences, the Taiwan experts reached a consensus that provides a straightforward approach to HCV screening, treatment, and monitoring of patients with diabetes.

The association between viral infections and glomerular diseases, commonly known as "viral glomerulopathies," has been described in various clinical scenarios for decades. Despite advancements in diagnostic tools, it remains challenging to establish a causative link fully.

Data from mouse models have substantiated clinical observations and implicate direct viral infection in the pathogenesis of viral glomerulopathy, particularly in human immunodeficiency virus-associated nephropathy. In addition to the traditional concept of direct viral effects on kidneys, other factors such as APOL1 risk alleles can further modify the clinical outcomes or presentations of different viral glomerulopathies. Newly developed antiviral drugs are now applicable to a wider range of patients with lower kidney function and fewer side effects.

Efforts focusing on vaccines and antiviral treatments have significantly reduced the incidence of viral glomerulopathies. However, the most recent pandemic caused by severe acute respiratory syndrome coronavirus 2 infection complicated by COVID-associated nephropathy illustrates our susceptibility to novel viruses. Ongoing research is pivotal to deciphering the mechanisms behind viral glomerulopathies and discovering therapeutics in a collaborative approach.

Hepatitis C virus (HCV) is a common cause of liver disease and is associated with various extrahepatic manifestations (EHMs). This mini-review outlines the currently available treatments for HCV infection and their prognostic effect on hepatic manifestations and EHMs. Direct-acting antiviral (DAA) regimens are considered pan-genotypic as they achieve a sustained virological response (SVR) > 85% after 12 wk through all the major HCV genotypes, with high percentages of SVR even in advanced fibrosis and cirrhosis. The risk factors for DAA failure include old males, cirrhosis, and the presence of resistance-associated substitutions (RAS) in the region targeted by the received DAAs. The effectiveness of DAA regimens is reduced in HCV genotype 3 with baseline RAS like A30K, Y93H, and P53del. Moreover, the European Association for the Study of the Liver recommended the identification of baseline RAS for HCV genotype 1a. The higher rate of hepatocellular carcinoma (HCC) after DAA therapy may be related to the fact that DAA regimens are offered to patients with advanced liver fibrosis and cirrhosis, where interferon was contraindicated to those patients. The change in the growth of pre-existing subclinical, undetectable HCC upon DAA treatment might be also a cause. Furthermore, after DAA therapy, the T cell-dependent immune response is much weaker upon HCV clearance, and the down-regulation of TNF-α or the elevated neutrophil to lymphocyte ratio might increase the risk of HCC. DAAs can result in reactivation of hepatitis B virus (HBV) in HCV co-infected patients. DAAs are effective in treating HCV-associated mixed cryoglobulinemia, with clinical and immunological responses, and have rapid and high effectiveness in thrombocytopenia. DAAs improve insulin resistance in 90% of patients, increase glomerular filtration rate, and decrease proteinuria, hematuria and articular manifestations. HCV clearance by DAAs allows a significant improvement in atherosclerosis and metabolic and immunological conditions, with a reduction of major cardiovascular events. They also improve physical function, fatigue, cognitive impairment, and quality of life. Early therapeutic approach with DAAs is recommended as it cure many of the EHMs that are still in a reversible stage and can prevent others that can develop due to delayed treatment.

In this article we review complications to the peripheral nervous system that occur as a consequence of viral infections, with a special focus on complications of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We discuss neuromuscular complications in three broad categories; the direct consequences of viral infection, autoimmune neuromuscular disorders provoked by viral infections, and chronic neurodegenerative conditions which have been associated with viral infections. We also include discussion of neuromuscular disorders that are treated by immunomodulatory therapies, and how this affects patient susceptibility in the current context of the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 is associated with direct consequences to the peripheral nervous system via presumed direct viral injury (dysgeusia/anosmia, myalgias/rhabdomyolysis, and potentially mononeuritis multiplex) and autoimmunity (Guillain Barré syndrome and variants). It has important implications for people receiving immunomodulatory therapies who may be at greater risk of severe outcomes from COVID-19. Thus far, chronic post-COVID syndromes (a.k.a: long COVID) also include possible involvement of the neuromuscular system. Whether we may observe neuromuscular degenerative conditions in the longer term will be an important question to monitor in future studies.

Elevated rheumatoid factor (RF) levels and systemic immune activation are highly prevalent during chronic hepatitis C virus (HCV) infection. Direct-acting antiviral (DAA) therapy has been associated with normalization of various soluble immune activation parameters. Whether the RF levels relate to soluble immune activation markers during chronic HCV infection, and over what time frame RF levels normalize during and after DAA treatment is unknown and was investigated here.

In a longitudinal study, plasma and serum was obtained from HCV infected RF positive (RF+) and RF negative (RF-) participants. The levels of RF, HCV RNA and soluble markers of inflammation were determined before (week 0), during (weeks 4, 8 and 12) and after (week 24) treatment with HCV DAA therapy. In a subset of RF+ participants, the analysis was extended to over 70 weeks after therapy initiation. Hepatic and other clinical parameters were determined at baseline (week 0) in all participants.

Before therapy, transient elastography (TE) score was greater in RF+ compared to RF- HCV infected participants, while the systemic levels of soluble inflammatory markers were comparable. Following DAA therapy initiation, HCV RNA levels became undetectable within 4 weeks in both the RF+ and RF- groups. RF levels declined in the first 6 months in most RF+ persons but most commonly remained positive. The levels of some soluble inflammatory markers declined, mainly within 4 weeks of DAA therapy start, in both the RF+ and RF- groups. The baseline (week 0) TE score correlated with RF levels before, during and after DAA therapy, while plasma IL-18 levels correlated with RF level after DAA therapy.

During chronic HCV infection, TE score is elevated in RF+ HCV infected individuals and factors other than HCV viremia (including liver stiffness or fibrosis and select markers of inflammation) likely contribute to persistence of RF after treatment of HCV with DAA.

Coronavirus disease 2019 (COVID-19) may cause a wide spectrum of kidney pathologies. The impact of COVID-19 is unclear in the context of the complement system abnormalities, including C3 glomerulopathy (C3G). In this report, we describe a young adult receiving a kidney transplant for C3 glomerulopathy (C3G), a disorder of the alternative complement pathway. The patient developed a recurrent C3G ~7 months after transplantation. His post-transplant course was complicated by SARS-CoV-2 infection. There was a progression of glomerulonephritis, characterized by de novo immune-complex mediated membranoproliferative glomerulonephritis pattern of injury with crescentic and necrotizing features, along with positive immunoglobulins, persistent IgM staining and the presence of cryoglobulinemia. COVID-19 may have aggravated the inherent complement dysregulation and contributed to cryoglobulinemia observed in this patient. Our study of 5 sequential kidney allograft biopsy series implicates that COVID-19 in this patient promoted a superimposed immune complex-mediated glomerulonephritis with membranoproliferative glomerulonephritis (MPGN) pattern and cryoglobulinemia, which was a potentiating factor in allograft loss. This work represents the first report of cryoglobulinemic GN after COVID-19.

Skin manifestations of systemic disorders give a clue to the organ involved and help identify the possible disease-causing injury. Skin changes of liver cirrhosis are not specific, as they may be seen in disorders not involving the liver. Thus, a constellation of skin changes along with systemic features may help us to identify the disease-causing liver cirrhosis. Pruritus is one of the most common and distressful symptoms of liver cirrhosis, severely affecting the quality of life, which further necessitates understanding cutaneous manifestations of cirrhosis. Other nonspecific cutaneous manifestations include spider telangiectasia, palmar erythema, paper money skin, xanthomas, pigmentation changes, nutritional deficiencies, hair changes, and nail changes. This review discusses the nonspecific skin manifestations associated with liver cirrhosis followed by specific cutaneous findings seen in common diseases causing liver cirrhosis, such as viral infections, biliary tract disorders, chronic alcoholism, and metabolic disorders. Early recognition of cutaneous features can help prevent or delay the development of complications and end-stage disease, decreasing morbidity and mortality.

A small yet growing subset of total joint arthroplasty (TJA) candidates are diagnosed with the hepatitis C virus (HCV), which is a known risk factor for periprosthetic joint infections. Given the poor outcomes associated with TJA infection, we recommend that candidates with HCV receive treatment prior to elective TJA.

Interferon and ribavirin have historically been the standard treatment regimen for the management of HCV; however, adverse events and an inconsistent viral response have limited the efficacy of these therapies. The advent of direct-acting antivirals has resolved many of the issues associated with interferon and ribavirin regimens.

Despite the success of direct-acting antivirals, there are still barriers to seeking treatment for TJA candidates with HCV. Many patients are faced with financial burdens, as insurance coverage of direct-acting antiviral therapies is inconsistent and varies by the patient's state of residence and specific treatment regimen.

TJA candidates with HCV present health-care providers with a unique set of challenges, often encompassing economic, psychosocial, and complex medical concerns. Multidisciplinary care teams can be beneficial when caring for and optimizing this patient cohort.

Management of HCV prior to elective TJA is associated with higher up-front costs but ultimately reduces long-term patient morbidity as well as associated direct and indirect health-care expenditures.

Patients with hepatitis C virus (HCV) have an increased risk of complications after total joint arthroplasty (TJA). There is a limited but growing body of evidence on the benefit of preoperative antiviral treatment to reduce complications after TJA. What has not been well established is the effect of preoperative antiviral treatment among those with advanced disease as indicated by hepatic fibrosis.

In total, 270 patients at 2 urban medical centers were reviewed for patient demographics, comorbidities, HCV treatment, hepatic fibrosis status, surgical information, and postoperative complications. Patients were divided into 2 groups based on their antiviral treatment status prior to TJA: Treated (n = 129) and Untreated (n = 141). Pearson's chi-squared test, Student's t-test, and multivariate logistic regressions were used to analyze complications between groups.

Patients in the Treated group had significantly fewer all-type complications (4.7% vs 14.9%, P = .007), infections (2.3% vs 12.1%, P = .002), and reoperations (0.8% vs 9.9%, P = .001) compared to the Untreated group. After controlling for hepatic fibrosis, we found that Treated patients still had significantly lower odds of experiencing all-type complications (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.10-0.88; P = .028), infection (OR 0.19, 95% CI 0.04-0.87; P = .033), and reoperation (OR 0.11, 95% CI 0.01-0.90; P = .039) following TJA.

HCV antiviral treatment reduces postoperative complications after primary TJA, even among those who have progressed to hepatic fibrosis. Surgeons can use this information in shared decision making prior to TJA to counsel patients about the benefits of preoperative antiviral treatment even in the presence of hepatic fibrosis.

Human hepatitis viruses (HHVs) include hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus, and hepatitis E virus and can cause liver inflammation in their common human host. Usually, HHV is rapidly cleared by the immune system, following acute HHV invasion. The morbidities associated with hepatitis A virus and hepatitis E virus infection occur shortly after their intrusion, in the acute stage. Nevertheless, the viral infectious process can persist for a long period of time, especially in HBV and HCV infection, leading to chronic hepatitis and further progressing to hepatic cirrhosis and liver cancer. HHV infection brings about complications in other organs, and both acute and chronic hepatitis have been associated with clinical presentations outside the liver. Vascular involvement with cutaneous and systemic vasculitis is a well-known extrahepatic presentation; moreover, there is growing evidence for a possible causal relationship between viral pathogens and vasculitis. Except for hepatitis delta virus, other HHVs have participated in the etiopathogenesis of cutaneous and systemic vasculitis via different mechanisms, including direct viral invasion of vascular endothelial cells, immune complex-mediated vessel wall damage, and autoimmune responses with stimulation of autoreactive B-cells and impaired regulatory T-cells. Cryoglobulinemic vasculitis and polyarteritis nodosa are recognized for their association with chronic HHV infection. Although therapeutic guidelines for HHV-associated vasculitis have not yet been established, antiviral therapy should be initiated in HBV and HCV-related systemic vasculitis in addition to the use of corticosteroids. Plasma exchange and/or combined cyclophosphamide and corticosteroid therapy can be considered in patients with severe life-threatening vasculitis manifestations.

Non-human primate models will expedite therapeutics and vaccines for coronavirus disease 2019 (COVID-19) to clinical trials. Here, we compare acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old rhesus macaques, baboons and old marmosets. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies, and both age groups recovered in two weeks. Baboons had prolonged viral RNA shedding and substantially more lung inflammation compared with macaques. Inflammation in bronchoalveolar lavage was increased in old versus young baboons. Using techniques including computed tomography imaging, immunophenotyping, and alveolar/peripheral cytokine response and immunohistochemical analyses, we delineated cellular immune responses to SARS-CoV-2 infection in macaque and baboon lungs, including innate and adaptive immune cells and a prominent type-I interferon response. Macaques developed T-cell memory phenotypes/responses and bystander cytokine production. Old macaques had lower titres of SARS-CoV-2-specific IgG antibody levels compared with young macaques. Acute respiratory distress in macaques and baboons recapitulates the progression of COVID-19 in humans, making them suitable as models to test vaccines and therapies.

Exhaustion of Hepatitis C Virus (HCV)-specific T cells and abnormal B cell function is a hallmark of chronic HCV infection. Direct-acting antiviral (DAA) therapies are effective in achieving sustained virologic response (SVR), however, whether successful DAA treatment reconstitute T follicular helper (T_FH)-B cell axis in HCV patients is unclear. Here, we aimed to evaluate the immunological changes in global and HCV-specific CD4 + CXCR5 + T_FH, CD4 + CXCR5-T and B cells in 20 HCV patients who achieved SVR with Sofosbuvir and Ledipasvir for 12 weeks and compared with 15 healthy controls (HC). Global and HCV-specific CD4 + CXCR5 + T_FH, CD4 + CXCR5-T and CD19 + B cells had significant phenotypic and functional reconstitution post DAA therapy. Reconstitution of effector, central and terminally differentiated memory cell population and increased ICOS and BCL6 expression was seen in HCV patients at SVR12. HCV-specific cytokines were also improved post DAA. Exhausted and regulatory B cells were declined whereas memory B cells were expanded post DAA therapy. Importantly, frequencies of T_FH cells were significantly associated with HCV RNA reduction, expansion of memory B and plasmablasts, while negatively associated with exhausted/regulatory B cells. Our results demonstrate that SVR with DAA therapy is effective in the reconstitution of phenotypic and functional abnormalities of T_FH-B cell axis.

Cryoglobulinemia is one of the most frequent extrahepatic manifestations of chronic hepatitis C virus (HCV) infection and it may evolve to cryoglobulinemic vasculitis (CryoVas) which is a systemic vasculitis that affects small-sized vessels. The objective of this study was to evaluate the prevalence of cryoglobulinemia and CryoVas in HCV patients in São Paulo, Brazil.

A cross-sectional study was conducted and included sixty-eight viremic HCV patients, without HIV or hepatitis B coinfection. A thorough clinical and laboratory evaluation was performed including the detection of serum cryoglobulins and measurement of serum complement components. The classification criteria for CryoVas were applied.

The study population comprised mainly women (61.8%) with long term HCV infection (median 11.0 years). Advanced hepatic fibrosis was detected in 20.6% (14/68) of cases. Cryoglobulins were detected in 48.5% (33/68) of HCV-patients with type III cryoglobulinemia being the most frequent. CryoVas was present in 10.3% (7/68) and the main manifestations were peripheral neuropathy (85.7%), palpable purpura (42.8%), arthralgias (42.8%) and renal involvement (42.8%). Life-threatening manifestations were rare. Low hemolytic C2, C4 and total hemolytic complement (CH100) levels were common findings in the cryoglobulinemia group. Low C4 levels were independently associated with the development of CryoVas.

A high prevalence of cryoglobulinemia and CryoVas was found in Brazilian HCV-patients. CryoVas patients mostly presented non-life-threatening manifestations, especially peripheral neuropathy. Complement abnormalities were common in patients with cryoglobulinemia and low serum C4 levels were associated with CryoVas.

Hepatitis C virus (HCV) infection remains a major public health issue with high prevalence in Taiwan. Recently, the advent of direct-acting antiviral (DAA) agents, with higher efficacy, excellent safety profile, and truncated treatment duration, has revolutionized the paradigm of hepatitis C treatment and made HCV elimination possible. To provide timely guidance for optimal hepatitis C management, the Taiwan Association for the Study of the Liver (TASL) established an expert panel to publish a 2-part consensus statement on the management of hepatitis C in the DAA era. After comprehensive literature review and a consensus meeting, patient-oriented, genotype-guided recommendations on hepatitis C treatment for the general and special populations have been provided based on the latest indications and scientific evidence. In the first part of this consensus, we present the epidemiology and treatment situation of hepatitis C in Taiwan, the development of DAA, pre-treatment evaluation, post sustained virologic response (SVR) monitoring, and most importantly the treatment recommendations for the general population with compensated liver disease. The second part will focus on the treatment recommendations for the special populations.

The prevalence and associations of mixed cryoglobulinemia (MC) in patients with spontaneous clearance of hepatitis C virus (HCV) remain elusive.

A 13-year prospective cohort study of patients with spontaneous HCV clearance was conducted in a tertiary care centre. Baseline characteristics, incident cardiovascular and neurologic events and cancers were analysed.

Of 104 consecutive patients (mean age: 54.08 years old; females: 71 [68%]), 37 (34.6%) had MC and 6 (5.8%) had cirrhosis. MC (+) patients were more female (86% vs 58%, P = .002), had higher rate of cirrhosis (14% vs 1.5%, P = .012), higher levels of Immunoglobulin G (IgG; P = .001), IgM (P = .002) and fibrosis-4 (FIB-4) (P = .004), but lower levels of complement C4 (P = .034) than the MC (-) patients. Female gender (95% confidence interval [CI] of odds ratio: 1.402-26.715), levels of IgG (1.000-1.004), IgM (1.009-1.037) and FIB-4 (1.217-3.966) were independently associated with MC. Baseline rheumatoid factor (RF) levels were independently associated with incident cancer (95% CI hazard ratio [HR]: 1.001-1.030 [HR: 1.015], P = .039). With a cut-off value of 11.3 IU/mL, RF levels significantly predicted incident cancer (area under curve: 0.865, P = .002). No different cumulative incidences of cardiovascular and neurologic events, cancers or mortalities were identified between MC (+) and MC (-) patient.

Approximately 1/3 of patients with spontaneous HCV clearance yielded MC, which harboured similar characteristics of MC in patients with chronic hepatitis C. Despite the negligible role of MC in the prognosis of patients with spontaneous HCV clearance, the connection between RF and incident cancer demands further investigation.

Previous reports establish that infection with hepatitis C virus (HCV) predisposes total joint arthroplasty (TJA) recipients to poor postoperative outcomes. The purpose of the present study is to assess whether variation in HCV VL influences perioperative outcomes following TJA.

A multicenter retrospective review of all patients diagnosed with HCV who underwent primary TJA between January 2005 and April 2018 was conducted. Patients were stratified into 2 cohorts: (1) patients with an undetectable VL (U-VL) and (2) patients with a detectable VL (D-VL). Kaplan-Meier survivorship analysis was calculated with revision TJA as the end point. Subanalysis on the VL profile was done.

A total of 289 TJAs were included (U-VL:118 TJAs; D-VL:171 TJAs). Patients in the D-VL cohort had longer operative times (133.9 vs 109.2 minutes), higher intraoperative blood loss (298.4 vs 219.5 mL), longer inpatient hospital stays (4.0 vs 2.9 days), more postoperative infections (11.7% vs 4.2%), and an increased risk for revision TJA (12.9% vs 5.1%). Kaplan-Meier demonstrated that the U-VL cohort trended toward better survivorship (P = .17). On subanalysis of low and high VL, no difference in outcomes was appreciated.

TJA recipients with a detectable HCV VL have longer operative times, experience more intraoperative blood loss, have longer hospital length of stay, and are more likely to experience infection and require revision TJA. The blood loss, hospital length of stay, and revision rate findings should be interpreted with caution, however, as there are confounding factors. Our findings suggest that HCV VL is a modifiable risk factor that, can reduce the risk of infection and revision surgery. Additionally, serum HCV VL was not correlated with outcomes.

Cryoglobulins are immunoglobulins with the ability to precipitate at temperatures <37 °C. They are related to hematological disorders, infections [especially hepatitis C virus (HCV)], and autoimmune diseases. In this article, the state of the art on Cryoglobulinemic Vasculitis (CV), in a helpful and schematic way, with a special focus on HCV related Mixed Cryoglobulinemia treatment are reviewed.

Direct - acting antivirals (DAA) against HCV have emerged as an important key in HCV treatment to related Cryoglobulinemic Vasculitis, and should be kept in mind as the initial treatment in non-severe manifestations. On the other hand, a recent consensus panel has published their recommendations for treatment in severe and life threatening manifestations of Mixed Cryoglobulinemias. HCV-Cryoglobulinemic vasculitis is the most frequent form of CV. There are new treatment options in HCV-CV with DAA, with an important number of patients achieving complete response and sustained virologic response (SVR). In cases of severe forms of CV, treatment with Rituximab and PLEX are options. The lack of data on maintenance therapy could impulse future studies in this setting.

hepatitis C virus (HCV) has several extra-hepatic manifestations including cryoglubulinemia. Cryoglobulinemia is defined as the abnormal presence in the blood of one or several proteins (cryoglobulins) that can precipitate at low temperatures.

We conducted a cross-sectional analytical study in the Laboratory of Biology and in the Unit of Hepatology of the General Hospital in Douala (HGD) over a period of 6 months. All patients agreeing to participate to the study and with anti-hepatitis-C antibodies under treatment or not were enrolled. Cryoglobulins were detected using biuret method and the classification was performed using Brouet immunoelectrophoresis. A multivariate analysis was conducted, confounding factors such as age, sex and the length of time after Hepatitis C Virus screening were adjusted.

The study enrolled 116 patients. The average age of patients was 58.47±9.95 years. Male sex accounted for 50.86% of cases. Arthralgia was found in 69.80% of cases. Cryoglobulin was found in 63.80% of patients. After adjustment, female sex (OR =2.18; CI 95% [0,97-4,90]; p= 0.059), asthenia alone (OR =2.45;CI 95% [1,04-5,80]; p= 0.041), asthenia combined with arthralgia (OR =2.84;CI 95% [1,13-7, 10]; p= 0.026) and the presence of HCV RNA (OR =2.84;CI 95% [1,13-7,10]; p= 0.028) were factors independently associated with the presence of cryoglobulin.

The prevalence of cryoglobubin is high in patients with anti-hepatitis-C antibodies at the HGD. Simple biological methods are used to detect it. Cryoglobulin test in patients with HCV is essential in resource-limited countries.

The prevalence and factors of hepatitis C virus (HCV) -associated mixed cryoglobulinaemia in Asia remain elusive, and we aimed to investigate these topics.

An 8-year prospective cohort study was conducted in 678 consecutive Taiwanese individuals with chronic HCV infection (438 completed an anti-HCV therapy course).

Of 678 individuals, 437 (64.5%) had mixed cryoglobulinaemia and 20 (2.9%) had mixed cryoglobulinaemic syndrome. At baseline, IgM (cut-off >122 mg/dL), triglycerides and IgG levels, and HCV genotype 3 were independently associated with mixed cryoglobulinaemia. Rheumatoid factor (RF) levels were associated with mixed cryoglobulinaemic syndrome (cut-off >12.2 IU/mL). At 24 weeks post-therapy, the 362 individuals with a sustained virological response (SVR) had higher cured (106/362 (29.3%) versus 10/76 (13.2%), p = 0.003) and lower persistent (100/362 (27.6%) versus 33/76 (43.4%), p = 0.003) mixed cryoglobulinaemia rates than non-SVR patients. Among SVR patients, compared with baseline levels, RF, IgG and IgM levels decreased, except in individuals with new mixed cryoglobulinaemia. Pre-therapy IgM levels were associated with 24-week post-therapy new (95% CI of OR 1.002-1.023) and persistent (95% CI of OR 1.004-1.015) mixed cryoglobulinaemia in SVR patients. After up to 8 years, 24-week post-therapy IgM levels were associated with mixed cryoglobulinaemia in SVR patients (9/51; 17.64%; 95% CI of HR 1.004-1.011). Among 17 SVR patients with pre-therapy mixed cryoglobulinaemic syndrome, 5 (29.4%) had long-term mixed cryoglobulinaemia and 4 (23.5%) had mixed cryoglobulinaemic syndrome.

Over 60% of chronic HCV-infected individuals had mixed cryoglobulinaemia, and 17.64% of SVR patients had mixed cryoglobulinaemia 8 years post-therapy. Pre-therapy RF and IgM levels marked HCV-associated mixed cryoglobulinaemic syndrome and mixed cryoglobulinaemia, respectively.

With an ageing population of patients who are infected with hepatitis C virus (HCV), the demand for total knee arthroplasty (TKA) in this high-risk group continues to grow. It has previously been shown that HCV infection predisposes to poor outcomes following TKA. However, there is little information about the outcome of TKA in patients with HCV who have been treated successfully. The purpose of this study was to compare the outcomes of TKA in untreated HCV patients and those with HCV who have been successfully treated and have a serologically confirmed remission.

A retrospective review of all patients diagnosed with HCV who underwent primary TKA between November 2011 and April 2018 was conducted. HCV patients were divided into two groups: 1) those whose HCV was cured (HCV-C); and 2) those in whom it was untreated (HCV-UT). All variables including demographics, HCV infection characteristics, surgical details, and postoperative medical and surgical outcomes were evaluated. There were 64 patients (70 TKAs) in the HCV-C group and 63 patients (71 TKAs) in the HCV-UT cohort. The mean age at the time of surgery was 63.0 years (sd 7.5; 44 to 79) in the HCV-C group and 61.7 years (sd 6.9; 47 to 88) in the HCV-UT group.

HCV-UT patients had a significantly longer mean hospital stay (3.4 days vs 2.9 days; p = 0.04), were more likely to be transferred to the intensive care unit (14.1% vs 4.3%; p = 0.04), and were significantly more often discharged to a post-acute care facility (39.4% vs 14.3%; p < 0.01). HCV-UT patients had significantly more postoperative infections (15.5% vs 4.3%; p = 0.03), surgical complications (21.1% vs 7.1%; p = 0.02), and revision TKA (12.7% vs 1.4%; p < 0.01) than HCV-C patients.

The preoperative treatment of HCV can reduce the risk of complications, including prosthetic joint infection and revision TKA. We recommend that HCV treatment regimens should be integrated into the preoperative optimization protocol for this high-risk group of patients. Cite this article: Bone Joint J 2019;101-B:667-674.

Newer treatment protocols involving direct-acting antiviral agents (DAAs) have been associated with high rates of sustained virologic response (SVR) and clinical remission in patients with hepatitis C virus (HCV) associated cryoglobulinemic vasculitis (HCV-CV), but clinical response in those with renal involvement is less clear. Our goal was to evaluate the clinical course following DAA therapy in one of the largest cohorts of patients with HCV-associated cryoglobulinemic glomerulonephritis (HCV-GN) reported to date. This is an observational study of patients with chronic HCV infection and circulating cryoglobulins (CC) treated with DAAs in our department from January 2015 to January 2019. We identified a total of 67 patients with HCV and CC out of which nine patients fulfilled the criteria of HCV-GN and had adequate clinical follow-up time. We describe a cohort of nine patients with a mean age of 57 years and known duration of HCV infection ranging 3-20 years (four with evidence of compensated cirrhosis). All patients received the ritonavir-boosted paritaprevir/ombitasvir/dasabuvir regimen for 12 weeks and achieved SVR without subsequent viral relapse. Following DAAs completion, one patient developed "new-onset" cryoglobulinemic glomerulonephritis, six showed either persistent or worsening glomerulonephritis, and only two patients had a complete clinical response (CCR). Of the six patients with either persistent or worsening CV, 67% received additional immunosuppressive (IS) therapy for uncontrolled CV. Of the two patients that had a CCR, one patient received prior IS therapy while the other one improved without any additional intervention. Newer HCV treatment protocols involving DAAs are highly successful in eradication of HCV infection; however, in our experience, DAA treatment alone is insufficient in improving the renal outcomes of patients with HCV-GN and additional IS therapies should be considered.

Mixed cryoglobulinemia (MC) is well known for its association with chronic hepatitis C virus (HCV) infection. However, it has also been linked to autoimmune disorders and hematological malignancies, particularly of B-cell lymphoid origin. Association with solid malignancies is poorly described in the literature. Non-HCV-related MC, in the setting of prostate cancer, has been reported only twice. Here, we describe a case of MC in a prostate cancer patient complicated by membranoproliferative glomerulonephritis (MPGN) that responded well to plasma exchange therapy and treatment with both corticosteroids and rituximab.

Clinical spectrum of hepatitis C virus (HCV)-related cryoglobulinemia varies from an asymptomatic presentation to severe vasculitis and lymphoma. A recent study in HCV-negative patients suggests that low cryoglobulins (CGs) levels are responsible for severe renal and neurological complications. The aim of this study was to identify a panel of serological biomarkers associated with low levels of CGs in HCV-positive patients. We studied a population of 79 untreated patients with chronic HCV infection: 13 naïve patients without CGs; 28 patients with asymptomatic mixed cryoglobulinemia (MC) and low levels of CGs (16/28 with polyclonal type III and 12/28 with microheterogeneous type III CGs); 38 patients with symptomatic MC and high levels of type II CGs. Serum samples were collected and examined for rheumatoid factor (RF) IgG and IgM, free light chains (FLCs) and C3 and C4 complement components. We found that RF-IgG and IgM, free k chains and k+λ were increased while C4 component was reduced, both in symptomatic and asymptomatic patients. Our results suggest that, even in absence of MC symptoms, the low levels of CGs may represent a trigger of activation for immune system in course of HCV infection. The identification of a correlated biomarkers panel could improve the clinical management of these patients and pave the way for target treatment strategies. © 2018 BioFactors, 45(3):318-325, 2019.

Infection by the hepatitis C virus (HCV) is currently considered to be a global health issue, with a high worldwide prevalence and causing chronic disease in afflicted individuals. The disease largely involves the liver but it can affect other organs, including the skin. While leukocytoclastic vasculitis has been reported as one of the dermatologic manifestations of HCV infection, there are no reports of this condition as the first symptom of HCV recurrence after liver transplantation.

We report here a case of leukocytoclastic vasculitis in a liver transplant recipient on maintenance immunosuppression. The condition presented as a palpable purpura in both lower extremities. Blood and urine cultures were negative and all biochemical tests were normal, excepting evidence of anemia and hypocomplementemia. Imaging examination by computed tomography showed a small volume of ascites, diffuse thickening of bowel walls, and a small bilateral pleural effusion. Skin biopsy showed leukocytoclasia and fibrinoid necrosis. Liver biopsy was suggestive of HCV recurrence in the graft, and HCV polymerase chain reaction yielded 11460 copies/mL and identified the genotype as 1A. Treatment of the virus with a 12-wk direct-acting antiviral regimen of ribavirin, sofosbuvir and daclatasvir led to regression of the symptoms within the first 10 d and subsequent complete resolution of the symptoms.

This case highlights the difficulties of diagnosing skin lesions caused by HCV infection in immunosuppressed patients.

A 65-year-old male patient with nephrotic syndrome was admitted to our hospital due to worsening systemic edema and purpura on the limbs. He had an impaired renal function, low serum complement level, and elevated rheumatoid factor level. He was positive for cryoglobulin (monoclonal IgM-κ and polyclonal mixed-type IgG), and the results of his kidney biopsy showed a tissue profile of membranoproliferative glomerulonephritis (MPGN). Due to the fact that the secondary cause was unclear, he was diagnosed with MPGN due to essential mixed cryoglobulinemia. On hospital day 20, he was initiated on 50 mg/day prednisolone (PSL). On hospital day 43, oral mizoribine (MZR) at a dose of 150 mg/day was prescribed. On hospital day 49, cryofiltration was performed because the disease was steroid resistant. The treatment promptly decreased urine protein levels. Serum albumin and serum complement levels increased, and complete remission was achieved approximately three months after the initiation of treatment. The PSL and MZR doses were gradually reduced to 2 mg/day and 100 mg/day, respectively, without any reemergence of the symptoms of cryoglobulinemia or relapse of the nephrotic syndrome for three years. Here, we report this case with essential mixed cryoglobulinemia in whom we could achieve complete remission of the disease by adding cryofiltration to the oral corticosteroid and immunosuppressant therapy with mizoribine and could maintain for a long time.

Chronic hepatitis C virus (HCV) infection is common among patients with chronic kidney disease (CKD) and those on hemodialysis due to nosocomial infections and past blood transfusions. While a majority of HCV-infected patients with end-stage renal disease are asymptomatic, some may ultimately experience decompensated liver diseases and hepatocellular carcinoma. Administration of a combination of elbasvir/grazoprevir for 12 weeks leads to high sustained virologic response (SVR) rates in patients with HCV genotypes (GTs) 1a, 1b or 4 and stage 4 or 5 CKD. Furthermore, a combination of glecaprevir/pibrentasvir for 8-16 weeks also results in high SVR rates in patients with all HCV GTs and stage 4 or 5 CKD. However, these regimens are contraindicated in the presence of advanced decompensated cirrhosis. Although sofosbuvir and/or ribavirin are not generally recommended for HCV-infected patients with severe renal impairment, sofosbuvir-based regimens may be appropriate for those with mild renal impairment. To eliminate HCV worldwide, HCV-infected patients with renal impairment should be treated with interferon-free therapies.