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Background and Aims: We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility. Methods: This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model. Results: Of 5492 HBsAg-positive enrolled patients, 4152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age ≤ 40 years vs. 2.1%; P < 0.001), more often females (males 43.0% vs. 68.6%; P < 0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care. Conclusions: CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN.

Introduction: The impact of COVID-19 pandemic represents a serious challenge for ‘frail’ patients' populations with inflammatory autoimmune systemic diseases such as systemic sclerosis (SSc). We investigated the prevalence and severity of COVID-19, as well the effects of COVID-19 vaccination campaign in a large series of SSc patients followed for the entire period (first 38 months) of pandemic. Patients and method: This prospective survey study included 1755 unselected SSc patients (186 M, 1,569F; mean age 58.7 ± 13.4SD years, mean disease duration 8.8 ± 7.3SD years) recruited in part by telephone survey at 37 referral centers from February 2020 to April 2023. The following parameters were carefully evaluated: i. demographic, clinical, serological, and therapeutical features; ii. prevalence and severity of COVID-19; and iii. safety, immunogenicity, and efficacy of COVID-19 vaccines. Results: The prevalence of COVID-19 recorded during the whole pandemic was significantly higher compared to Italian general population (47.3 % vs 43.3 %, p

Objectives: The study measures trends in the profile of patients with chronic hepatitis B virus linked to care in Italy. Methods: A cross-sectional, multicenter, observational cohort (PITER cohort) of consecutive patients with hepatitis B surface antigen (HBsAg) over the period 2019-2021 from 46 centers was evaluated. The reference was the MASTER cohort collected over the years 2012-2015. Standard statistical methods were used. Results: The PITER cohort enrolled 4583 patients, of whom 21.8% were non-Italian natives. Compared with those in MASTER, the patients were older and more often female. The prevalence of hepatitis B e antigen (HBeAg) declined (7.2% vs 12.3; P

Background: Patients with autoimmune systemic diseases (ASDs) represent a frail population during the ongoing COVID-19 pandemic. The vaccination is the major preventive measure; however, a significant number of ASD patients show an impaired production of anti-COVID-19 neutralizing antibodies (NAb), possibly counterbalanced by adequate T-cell response. The present study aimed at evaluating both humoral and cellular response to COVID-19 vaccine booster dose in this particular setting. Patients and methods: Serum NAb titer and T-cell response (measuring interferon gamma –IFN–γ- release) were evaluated 3 weeks after the COVID-19 vaccine booster dose, in 17 patients (12 F, mean age 68.8 ± 15.3 SD yrs) with different ASDs, compared to 17 healthy controls (HCs). Results: The analysis excluded one patient reporting symptoms of COVID-19 only after the immunogenicity tests had been performed.The NAb levels were significantly lower in ASD compared to HCs (p

Objective: Mixed cryoglobulinemia syndrome (MCs) is a systemic vasculitis characterized by multiple organ involvement due to the vascular deposition of immune-complexes, mainly the cryoglobulins. B-lymphocyte expansion represents the underlying pathological alteration frequently triggered by hepatitis C virus (HCV) infection. The treatment of MCs syndrome is generally based on antiviral drugs and/or immunosuppressors, among which rituximab, an anti-CD20 monoclonal antibody, has been usefully employed for both cutaneous and visceral MCs organ involvement. This multicenter study retrospectively evaluated the effects of rituximab in a large series of patients with active MCs. The observed results were compared to those emerging from the updated review of the literature on this topic., Methods: The study included 87 patients (male/female 19/68, mean age 62.3±11.4SD years, mean disease duration 9±6.2SD years, HCV infection in 92% of cases) with active cryoglobulinemic vasculitis evaluated before rituximab monotherapy and after 6-month follow-up by means of main clinico-serological parameters. A PubMed search up to May 31, 2011, was done to find published clinical studies, including case reports of MCs treated with rituximab., Results: A significant clinical improvement was observed in a relevant percentage of cases, regardless the presence/absence of associated HCV infection; namely, complete/partial remission of pre-treatment active manifestations was observed in 74% of skin purpuric lesions, up to 87% of non-healing vasculitic leg ulcers, and 44% of the peripheral neuropathy, mainly paresthesias (patient's visual analogical scale from 62±25 to 37±27; p≤.0001). Moreover, cryoglobulinemic nephropathy, observed in 38 patients, significantly improved in 95% of cases (serum creatinine from 1.8±1.1SD to 1.4±0.8SD mg/dl, p≤.0001; 24-hour proteinuria from 2.2±2.1SD to 0.9±1.7SD g/24h, p≤.0001), with complete remission in the 50%. Among 6 patients with complicating non-Hodgkin's B-cell lymphoma a complete or partial remission was observed in 5/6. A complete remission of abdominal vasculitis was also observed in one patient. These beneficial effects were mirrored by the improvement of cryoglobulinemic serological hallmarks, namely cryocrit and low complement C4, in half cases. The safety of rituximab was confirmed by the small number of side effects recorded during the 6-month follow-up. On the whole, the results of the present study are in keeping with those reported in 39 papers present in world literature, including a total of 279 MCs patients., Conclusions: Rituximab may be regarded as useful and safe pathogenetic treatment of cryoglobulinemic vasculitis. The actual role of this drug should be definitely confirmed by randomized controlled trials, as well as its position in the therapeutical strategy, mainly with respect to antiviral treatment in HCV-associated MCs., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The fibrogenic evolution of chronic viral hepatitis B and C towards cirrhosis represents a key issue in clinical Hepatology whose monitoring still relies on liver biopsy and consequent histopathological staging. In the last decade, non-invasive methodologies have been proposed to predict the presence of fibrosis in chronic liver disease. Most of these methods are based on algorithms, including biochemical parameters, which have demonstrated an acceptable diagnostic accuracy towards the two extremities of the fibrogenetic process. The introduction of transient elastography has represented a further advancement in clinical Hepatology and it seems that the combination of different non-invasive methodologies will provide an improvement in the clinical management of disease progression in viral chronic hepatitis. Studies, conducted especially in chronic viral hepatitis C, suggest that transient elastography is a useful technique for the detection of severe fibrosis-cirrhosis and for the exclusion of significant fibrosis (>or=F2), that could be employed as "diagnostic discriminator" for establishing clinical priorities and reducing the number of liver biopsies. This review article will focus on the clinical utility of this novel methodology for the assessment of liver fibrosis in chronic viral hepatitis and will highlight potential further advantages.

Background: No study evaluates serum levels of CXCL10 and CCL2 chemokines in patients with hepatitis C associated mixed cryoglobulinaemia., Aims: To measure circulating CXCL10 and CCL2 in cryoglobulinaemic patients., Patients and Methods: Serum CXCL10 and CCL2 were assayed in 70 consecutive cryoglobulinaemic patients, and in 2 control groups (1:1, gender- and age-matched) of healthy (controls), or of chronic hepatitis C subjects without cryoglobulinaemia., Results: Cryoglobulinaemic patients showed higher CXCL10 serum levels than controls (p<0.0001), or hepatitis C patients (p=0.001) (389 +/- 141, 91 +/- 51, 311 +/- 142 pg/ml, respectively). By defining a "high CXCL10" as a value at least 2 S.D. above the mean value of the control group (>193 pg/ml), 79% of cryoglobulinaemic patients, 5% of the controls and 69% of hepatitis C patients had high CXCL10 (p<0.0001). CXCL10 levels were (p<0.01) increased in cryoglobulinaemic patients with active vasculitis, with respect to those without (445+/-108, 339 +/- 161 pg/ml, respectively). Cryoglobulinaemic patients showed significantly higher CCL2 serum level than controls (p<0.01), but not than hepatitis C patients (541 +/- 493, 387 +/- 173 and 451 +/- 281 pg/ml, respectively)., Conclusion: Our study first demonstrates high serum levels of CXCL10 and CCL2 chemokines in cryoglobulinaemic patients. Circulating CXCL10 is higher overall in cryoglobulinaemic patients with active vasculitis, suggesting a prevalence of the Th1 immune response in this phase.

The possibility that HCV infects lymphoid cells has been widely discussed. Evidence in favor of HCV tropism for lymphoid cells derives from a series of data including: (1) the higher sensitivity of testing HCVRNA in PBMC than in serum or plasma samples, with possible detection of HCV RNA-positive PBMC in the absence of HCV viremia; (2) short-term cultures of PBMC which yield a significant increase in the amount of viral RNA on stimulation by mitogens; (3) results of "in situ" methods (i.e. in situ hybridization, immunofluorescence); (4) efficient infection of lymphoid cell lines or PBMC from normal individuals; (5) the persistence of HCV RNA in PBMC obtained from HCV-positive subjects and injected into SCID mice; (6) the long-term persistence of HCV RNA in PBMC in spite of HCV RNA negativity of serum and liver in sustained responder patients after therapy. The principal criticisms concerning effective HCV infection of lymphoid cells arise from technical difficulty in identifying HCV RNA replicative intermediate in these elements. Conflicting data may also result from differences in PBMC infection by different genotypes, samples taken at different stages in the disease process and differences in the sensitivity of detection methods, as well as low replication levels and/or proportion of infected PBMC. Interesting available data about HCV lymphotropism, which is possibly important in influencing the natural history of infection, include: (1) possible preferential viral tropism for specific PBMC subsets; (2) different lymphotropism of different viral strains; (3) selection of distinctive viral strains; (4) identification of putative HCV cell receptors; (5) association between determination of HCV lymphatic infection and t(14; 18) translocation. The clinical correlates of HCV lymphotropism are potentially very numerous, including, first, its role in determining HCV-related lymphoproliferative disorders.

The ability of the immune system to distinguish between self and non-self is critical to the functioning of the immune response. A breakdown in these mechanisms can lead to the onset of autoimmune disease. Clinical and molecular data suggest that shared immunogenetic mechanisms lead to the autoimmune process. The most studied part of the autoimmune process is the human leukocyte antigen (HLA) region. Recently, progress has been made in narrowing down HLA cluster classifications based on structural and functional features of HLA alleles. Using this approach we have investigated 175 patients with hepatitis C virus (HCV)-induced type II cryoglobulinemia (MC), and compared them to a control group of 14,923 bone marrow donors. Additionally, we investigated the frequency of HLA homozygosity in the same groups of subjects. Our results provide evidence of a role for DR5 and DQ3 HLA class II clusters and a higher frequency of HLA homozygous leading to the clinical outcome of type II mixed cryoglobulinemic autoimmune disease. The DR5 cluster is characterized by a Glu in beta 9 and its polymorphism is connected with preferred anchors at beta 9 of the binding peptide, while the DQ3 cluster is characterized by Glu B86 and Leu B87, which allows the binding of large hydrophobic amino acids at p1 of the binding peptide. The mechanisms by which variations in HLA lead to autoimmunity remain unknown, although they are likely to be mediated by continuous presentation of HCV epitopes to T cells and a genetic background that limits the effective clearance of HCV. The results presented in this paper have increased our knowledge of the mechanism of autoimmune disease and B-cell lymphoproliferation during HCV infection. The work was performed in accordance with the principles of the 1983 Declaration of Helsinki. There is no conflict of interest.

Hepatitis C virus (HCV) chronic infection may be associated with a great number of both hepatic and extrahepatic manifestations. HCV lymphotropism is responsible for poly-oligoclonal B-lymphocyte expansion, which is the common underlying alteration in a significant percentage of HCV-infected individuals. The consequent production of different autoantibodies and immune-complexes, including cryoglobulins, may lead to organ- and non-organ-specific immunological alterations. Mixed cryoglobulinemia, a small-vessel systemic vasculitis, is characterized by the coexistence of autoimmune and lymphoproliferative alterations; therefore, it represents the prototype of HCV-associated disorders. Moreover, HCV shows an oncogenic potential; several studies support its pathogenetic link with some malignancies, mainly hepatocellular carcinoma and B-cell lymphomas. On the whole, HCV-related disorders present a heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. While the majority of HCV-infected individuals is asymptomatic or may develop only liver manifestations, a significant percentage of them may develop a variable combination of autoimmune lymphoproliferative disorders. The resulting multiform clinico-pathological condition can be termed HCV syndrome. The natural history of HCV syndrome is the expression of multifactorial and multistep pathogenetic process, which usually proceeds from mild, often isolated manifestations to systemic immune-mediated disorders, and less frequently to overt malignancies.

HCV chronic infection leads to liver diseases and also to a wide range of extrahepatic disorders including benign, but pre-lymphomatous forms (mixed cryoglobulinemia) to frank hematological neoplasia (non-Hodgkin's lymphoma). Recent data showed the involvement of p53 superfamily members in the pathogenesis of different lymphatic malignancies. In fact, tymomas and a subset of non-Hodgkin's lymphomas (NHLs) express high levels of p63. Thus, we analyzed whether alterations in p53 superfamily gene expression are observable in B lymphocytes isolated from HCV-infected patients with and without lymphoproliferative disorders. We showed, by real-time PCR, a significant induction of DNp63 mRNAs in B lymphocytes obtained from HCV-positive low grade non-Hodgkin's lymphoma patients. Since our current understanding of HCV proteins emphasizes the ability of the HCV core protein to deregulate the expression and activity of p53-related proteins, we established different B lymphocyte cell lines (Wil2-ns, Daudi and Ramos) stably expressing HCV core protein, in order to investigate the possible involvement of the viral protein in the upregulation of DNp63 in B lymphocytes. The analysis of p63 family transcripts showed no transcriptional changes for the p63 TA isoforms, whereas an increase (>5 times) of DNp63 mRNA occurred. In all cell lines, this abnormal expression was associated with a significant increase of cell proliferation that was specifically inhibited by silencing DNp63 mRNA. These findings suggest a pathogenetic role of the HCV core in HCV-related lymphomagenesis, through the induction of DNp63's pro-proliferative effects.

Hepatitis C Virus is associated with a wide series of extrahepatic manifestations. Based on available data the link between the virus and some of these extrahepatic diseases is only suggested and needs further confirmation. Hepatitis C Virus-related lymphoproliferative disorders, whose prototype is mixed cryoglobulinaemia, represent the most closely related extrahepatic manifestations of Hepatitis C Virus. Other Hepatitis C Virus-associated disorders include nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, porphyria cutanea tarda, lichen planus, diabetes, chronic polyarthritis, cardiopathy and atherosclerosis. A pathogenetic link between Hepatitis C Virus and some extrahepatic manifestations was confirmed by their responsiveness to antiviral therapy, which is now deemed the first therapeutic option to consider. By contrast, there are diseases where treatment with interferon was ineffective or dangerous. The aim of the present paper is to outline the most recent evidence concerning extrahepatic disorders that are possibly associated with Hepatitis C Virus infection. Special emphasis will be given to discussion of the most appropriate clinical approaches to be adopted in order to diagnose, treat (possibly prevent) and follow-up extrahepathic diseases in patients with Hepatitis C Virus infection.

Background: Patients with chronic hepatitis C infected by hepatitis A virus have a substantial risk of fulminant hepatitis or death, while the course of hepatitis A virus is uncomplicated in most subjects with chronic hepatitis B., Aim: To evaluate the prevalence of anti-hepatitis A virus antibodies and the incidence of hepatitis A virus seroconversion in a nationwide sample of 530 patients with chronic hepatitis B and/or hepatitis C infection initially susceptible to this infection after a follow-up of some years., Results: The overall anti-hepatitis A virus prevalence was 85.7%, with no difference between males and females. By the age of 50 years, almost all patients were found to have been exposed to hepatitis A virus. After a mean follow-up period of 76 months the overall anti-hepatitis A virus seroconversion rate in the 76 initially susceptible individuals was 1.2 per 100 person/years. However, it was 0.3 per 100 person/years in those hepatitis B surface antigen positive but 3.36 per 100 person/years in those anti-hepatitis C virus positive. None of the seroconverters was affected by a clinically evident disease or showed deterioration of underlying chronic liver disease., Conclusions: The present study shows that Italian patients >50 years of age with chronic liver disease have already been exposed to hepatitis A virus suggesting that anti-hepatitis A virus screening is not advisable in these subjects.

Multiple infection by different hepatitis C virus (HCV) genotypes may be of great clinico-pathologic interest. In this study we determined the effective prevalence of coinfections by two or more HCV genotypes in 213 subjects with HCV-positive chronic hepatitis by using genotype-specific polymerase chain reaction (PCR), genotype-specific probe hybridization, and direct sequencing. The most prevalent genotype was HCV-1b (54%). HCV-2 (a/c) was also prevalent (27%), and types 1a and 3a were found in 5% and 3% of patients, respectively. A mixed infection was detected in 23 patients (10.8%): 4 out of 23 were coinfected by types 1a + 1b, while the remaining 19 patients had a b + 2 (a/c) mixed infection. Further analysis based on restriction fragment length polymorphism (RFLP) on type-specific PCR products was used to verify genotyping results. Only four coinfections (1a + 1b in 2 patients and 1b + 2 (a/c) in the remaining 2 patients, respectively) were confirmed by enzyme cleavage. All patients with true coinfection had long-lasting infection and liver cirrhosis. Both true and false mixed infections resulting from RFLP analysis were confirmed by direct sequencing of type-specific amplification products. We also determined a recurrent C/T transversion at position 618 in all sequenced samples. In 4 cases another point mutation (G/A at position 626) was found, reducing the number of mismatches between HCV-2 and HCV-1b from 4 to 3 (or 2). Interestingly, all HCV-2 isolates sequenced showed the highest degree of nucleotide homology with HCV-2 subtype c, confirming the relatively high prevalence of this subtype in Italy. In conclusion, we showed the possibility of multiple infection by different HCV types in the general population of chronically infected patients without particular risk factors, even if in a low percentage of cases. Further studies are needed to assess the clinical relevance of chronic HCV infection with multiple genotypes.

A striking association between hepatitis C virus (HCV) infection and mixed cryoglobulinemia (MC) has been shown; thus, HCV seems to play an important etiopathogenetic role in this lymphoproliferative disorder. Because HCV is both a hepatotropic and lymphotropic virus, this study aimed to investigate the prevalence of HCV infection of peripheral blood mononuclear cells (PBMCs) in a series of 16 patients with type II (IgMk) MC. Antibodies against HCV were detected by commercially available kits (Second Generation Chiron enzyme-linked immunosorbent assay [ELISA] and recombinant-based immunoblot assay [RIBA]), and the presence of HCV RNA was evaluated in both sera and isolated PBMCs using the polymerase chain reaction technique. A previous exposure to HCV was shown by ELISA and confirmed by RIBA in all cases (100%). Moreover, HCV RNA was present in the sera of 8 of 16 patients (50%), whereas its frequency markedly increased (13 of 16 [81%]) when genomic sequences were detected in peripheral lymphocytes. HCV RNA was never detected in the PBMCs of 20 control subjects. These findings showed that HCV infection, alone or in combination with other factors, may be responsible for the clonal B-cell expansion underlying the systemic manifestations of MC, and may explain the appearance of a malignant non-Hodgkin's lymphoma in some subjects.

The effects of interferon-alpha (IFN-alpha) on clinical and serologic manifestations of mixed cryoglobulinemia (MC) were investigated by randomized, crossover-controlled trial in 26 patients. The trial alternated 6 months with and 6 months without IFN-alpha therapy (2 x 10(6) IU daily for a month, then every other day for 5 months). In 22 patients, pretreatment steroid dosage remained unchanged during the study. Six patients dropped out (three because of side effects), whereas another 20 patients experienced a significant improvement of purpura (P < .02) and serum transaminases (P < .005) during IFN-alpha treatment. The presence of clinical improvement was supported by the outcome measurements of several immunologic parameters. In particular, serum cryoglobulins were significantly reduced (P < .04) during IFN-alpha therapy. A rebound phenomenon of clinical and serologic parameters was observed after IFN-alpha discontinuation. In addition, no variations were recorded during 6 months without therapy. Hepatitis C virus (HCV) RNA was detected in 91% (20/22) of our MC patients; in 2/13 cases HCV RNA was no longer detectable in serum samples after IFN-alpha therapy. Thus, IFN-alpha could be considered as treatment for MC in patients with HCV seropositivity.

We investigated the infection of peripheral blood mononuclear cells (PBMNC) by hepatitis C virus (HCV) in 5 patients with HCV-related chronic hepatitis. The presence of HCV-RNA-positive and -negative strands was tested with the polymerase chain reaction (PCR) method. In all subjects, HCV-RNA was shown in PBMNC. In 3 cases, HCV-RNA was shown in the T- and B-cell populations, with viral RNA also present in the monocyte-macrophage fraction of two of these. HCV-RNA-negative stranded molecules, indicative of the viral multiplication, were significantly increased in cells maintained in cultures with PHA/PMA stimulation. The results indicate that HCV infect blood mononuclear cells, thus suggesting that this cellular tropism may play a role in HCV infection.

We have investigated the usefulness of serum hepatitis delta virus (HDV) RNA detection using a slot hybridization analysis of serum samples from ten patients with acute hepatitis and delta markers (group I), from 28 patients with chronic delta hepatitis (group II) and from seven liver graft recipients with hepatitis B virus (HBV) and HDV related cirrhosis or fulminant hepatitis (group III). The slot-blots were hybridized with both HDV-complementary DNA and single-stranded RNA probes. With the single-stranded RNA probe, HDV RNA was detected in the first serum sample available in 9/10 of the patients with acute hepatitis (group I). In addition, HDV RNA was detected in 8/9 and 7/8 of the samples obtained within and after 1 month of the onset of hepatitis. Five of the ten patients scored positive for HDV RNA and negative for hepatitis delta antigen (HDAg) while one was negative for HDV RNA and positive for HDAg. The same RNA probe enabled the detection of serum HDV RNA in 21/28 chronic hepatitis patients (liver HDAg and/or IgM anti-HD positive) (group II). Among the liver graft recipients (group III), 7/7 had a recurrent delta infection. Serum HDAg, liver HDAg and anti-HD IgM were identified in 3/7, 6/7 and 5/7 of the patients, respectively. HDV RNA was detected in the seven patients with either persistent (4/7) or transient (3/7) positivity. In addition, HBsAg and HBV RNA were persistently shown in 4/7 patients with continuous HDV replication. In the remaining three patients, HDV RNA was detectable despite the absence of HBsAg.(ABSTRACT TRUNCATED AT 250 WORDS)