Hemophagocytic syndrome following alemtuzumab treatment for multiple sclerosis: A case report.

BACKGROUND: Alemtuzumab is a monoclonal antibody targeting CD-52, used for treating relapsing-remitting multiple sclerosis (RRMS). METHODS: We present a case of a 44-year-old male with RRMS who was admitted due to fever and jaundice after starting treatment with alemtuzumab 12 months ago. RESULTS: He was diagnosed with hemophagocytic syndrome (HS). Liver biopsy revealed images of hemophagocytosis in Kupffer cells of lobular sinusoid. Management consisted of treatment with corticosteroids. CONCLUSION: HS is a severe condition marked by an excessive activation of the immune system that leads to a rapid and progressive multi-organ failure, so it is important to consider it in the differential diagnosis of a fever syndrome following the administration of alemtuzumab.

Hepatitis E virus infection in acute hepatitis in Spain.

In order to study the prevalence of hepatitis E virus (HEV) infection in developed countries, IgG and IgM anti-HEV were determined in serum samples from 382 patients with acute viral hepatitis (244 hepatitis A, 48 hepatitis B and/or D, and 90 non-A, non-B, non-C hepatitis), 76 healthy subjects, 55 hemophiliacs and 50 patients on hemodialysis. IgG anti-HEV antibodies were detected and confirmed by a synthetic peptide-based EIA in 5 (5.6%) non-A, non-B, non-C acute hepatitis, in 3 (6.5%) B and D acute hepatitis, in 10 (4%) acute A hepatitis, in 3 (5.5%) of 54 healthy adults in none of the hemophiliacs and in 3 (6%) patients on hemodialysis. IgM anti-HEV antibodies were only detected in two cases of acute hepatitis B and/or D. Analysis of serial serum samples demonstrated IgG anti-HEV seroconversion in 3 of the 18 confirmed cases; one of them was also positive for IgM anti-HEV. All 3 acute anti-HEV-positive hepatitis cases occurred in adults, were community-acquired (two of them were intravenous drug addicts) and had a self-limited course. These results demonstrate that HEV is a minor cause of acute hepatitis in Spain. A similar low rate of IgG anti-HEV antibodies was detected in patients with different diseases, suggesting that HEV has a very low epidemiological impact. An apparent association of HEV infection with hepatitis B and D suggests a possible parenteral transmission of a mainly enteral pathogen.

Evaluation of hepatitis C virus RNA RT/PCR qualitative and quantitative second generation assays.

Hepatitis C virus (HCV) RNA qualitative and quantitative second generation assays (Amplicor HCV v2.0 and Amplicor HCV Monitor v2.0, respectively) were evaluated by testing serum samples from 132 blood donors anti-HCV positive HCV RNA negative by first generation qualitative assay and 326 viremic patients. An HCV RNA transcript was synthesized and ten-fold dilutions were used to assess sensitivity. Second generation assays were one log more sensitive than their respective first generation tests (10(2) copies per ml vs. 10(3) for the qualitative tests; 10(3) copies per ml vs. 10(4) for the quantitative tests). From the 132 anti-HCV positive RNA negative subjects, 6 (5%) were positive by Amplicor v2.0. Quantification figures by Monitor v2.0 were similar in genotypes 1, 2 and 3, whereas Monitor 1.0 values were higher in genotype 1 than in genotype 2 or 3. In 114 patients, branched-DNA v2.0 obtained higher values than Monitor v2.0 and Monitor v1.0 (6.6+/-0.6 log RNA copies per ml, 6.4+/-0.6, and 5.3+/-0.7, respectively, P<0.001). HCV RNA qualitative and quantitative second generation assays are more sensitive and genotype independent than first generation assays.

Hepatitis C virus markers in patients with acute post-transfusion hepatitis treated with interferon alfa-2b.

This trial was undertaken to establish the long term biochemical and serological outcome of patients with acute post-transfusion hepatitis C virus infection after treatment with interferon alfa-2b. After 12 months, 12 patients (eight treated, four controls) had self limited disease and 16 patients (seven treated, nine controls) had chronic disease. After a total mean 31 months of follow up in 23 patients, nine (six treated, three controls) had self limited disease while 14 (five treated, nine controls) developed chronic liver disease; all patients with spontaneous or self limited hepatitis C (HCV) infection maintained normal serum alanine amino-transferase activity and absence of HCV-RNA, and tended to lose anti-HCV antibodies.

Hepatitis B virus infection: precore mutants and its relation to viral genotypes and core mutations.

The precore-core gene of hepatitis B virus (HBV) was directly sequenced from serum samples of 42 patients with chronic B hepatitis (19 hepatitis B e antigen [HBeAg]+ and 23 anti-HBE+). Viral genotypes were determined by comparison with 11 reference sequences and by restriction analysis. Genotype A was identified in 16 cases, genotype D in 24 cases, and other genotypes in 2 cases. Precore mutations, mainly M1 (stop at codon 28), were differently distributed among the viral genotypes: 3 cases (18.8%) with genotype A and 18 cases (75%) with genotype D. In sequences with precore mutants, the encapsidation signal was more stable (negative stabilization energy) than in sequences without precore mutants. In genotype A, the M1 mutation coexisted with a second mutation (C-->T at position 1858 in codon 15), and both mutations were paired in the secondary structure of the RNA encapsidation signal, which justified the rare presence of precore mutants in this genotype. The analysis showed different distribution of mutations depending on the viral genotype; patients with genotype D were more likely to have persistent HBV infection by selection of precore mutants. Multiple amino acid substitutions were detected in the core region, mainly in two subsequences that have been previously described as epitopes (flanked by codons 11 to 27 and 74 to 83); the presence of these mutations was significantly related to the presence of precore variants which abolished the expression of HBeAg.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term immunogenicity and efficacy of hepatitis B vaccine in hemodialysis patients.

Although the efficacy of hepatitis B vaccines in patients under chronic hemodialysis treatment has been well documented, the persistence of immunity in this population remains largely unknown. In this study we have followed 60 hemodialysis patients up to 3 years after primary hepatitis B vaccination (four doses of recombinant hepatitis B vaccine; Engerix B, 20 mg/dose) to evaluate the persistence of immunity (as indicated by serum levels of antibody to hepatitis B surface antigen-anti-HBs-higher than or equal to 10 mIU/ml). Fourty-four (73%) patients developed anti-HBs levels above 10 mIU/ml after vaccination; the remaining 16 (27%) vaccinees were considered nonresponders and were given a booster dose that again failed to elicit an immunoresponse. After 3 years of follow-up, 18 out of 44 (41%) responders had no detectable anti-HBs levels in the serum (antibody loss occurring within 8 and 12 months in 3 cases, within 1 and 2 years in 13, and within 2 and 3 years in 2 other cases). When compared with the responders that lost their antibodies during the follow-up period, those who remained immunoreactive 3 years after vaccination was initiated were younger and had higher anti-HBs levels at 8 months of follow-up. Two hepatitis B virus infections were detected among nonresponders during the follow-up period. Based on these data, we conclude that patients undergoing chronic hemodialysis therapy not only have lower response rates to hepatitis B vaccination than healthy adults, but also that these are frequently transient.(ABSTRACT TRUNCATED AT 250 WORDS)

Utility of early testing for HCV viremia as predictive factor of sustained response during interferon or interferon plus ribavirin treatment.

BACKGROUND/AIM: To evaluate the utility of early testing for hepatitis C viremia as a predictor of treatment outcome during interferon or combination therapy. METHODS: We studied 184 patients with chronic hepatitis C who received interferon and were monitored for HCV RNA. Sixty-two patients received interferon alone for 12 months and 122 patients, who were still HCV RNA positive at 2 months, received an additional 12-month course of interferon and ribavirin combination therapy. RESULTS: Using this strategy, sustained response occurred in a total of 34 patients (18.5%). Independent variables associated with sustained response were HCV genotype (p=0.06), viral load < or = 5.1 logs/ml (p= 0.005) and negative HCV RNA at 1 month (p<0.0001) in the interferon group, and female sex (p=0.04), genotype (p=0.03), viral load < or = 5.5 logs/ml (p=0.01), normal ALT (p=0.001) and decline in viral load > or = 1.2 logs/ml after 2 months of interferon monotherapy (p<0.001) and negative viremia at 5 months of ribavirin onset (p<0.0001) in the combination therapy group. Persistence of viremia at 1 month of interferon monotherapy and at 5 months of combination therapy were the strongest predictors of non-response (negative predictive value of 100% and 99%, respectively). CONCLUSIONS: Qualitative assessment of HCV RNA during treatment is the strongest predictor of sustained response during interferon or combination therapy for chronic hepatitis C.

Chronic delta hepatitis: is the prognosis worse when associated with hepatitis C virus and human immunodeficiency virus infections?

Eighty-six patients were followed for 6.5 years to study the epidemiological, virological, and histological course of chronic delta hepatitis and the relationship of this disease with HIV and HCV infection. Patients were classified into four groups according to simultaneous HCV and/or HIV infection: group 1, HDV infection (20 cases); group 2, HDV and HCV infection (11 cases); group 3, HDV and HIV infection (12 cases), and group 4, HDV, HCV, and HIV infection (43 cases). All but 14 patients were asymptomatic at presentation. Liver histology showed chronic active hepatitis in 53 cases and cirrhosis in 19 cases. During followup, 52 patients remained asymptomatic, 34 developed hepatic dysfunction, 28 died, and 1 received a liver transplant. Among the 28 patients who died, 4 had HDV infection; 3 HDV and HCV infection; 3 HDV and HIV infection; and 18 HDV, HCV, and HIV infection. Death was due to liver failure in 16 (57%), AIDS in 10 (36%), and was unrelated to liver disease in 2 (8%) cases. There results demonstrate that chronic delta hepatitis is a severe disease, especially among drug users with HIV and HCV infection. The high morbidity and mortality of chronic delta hepatitis justifies the use of antiviral therapy to modify the natural course of the disease.

Early detection of nonresponse to interferon plus ribavirin combination treatment of chronic hepatitis C.

We have investigated the value of early hepatitis C virus (HCV) RNA decline (DeltaHCV RNA) to predict response to combination therapy in 66 chronic hepatitis C patients treated with IFN-alpha2b (3 MU thrice weekly) and ribavirin (800 mg daily) for 12 months [25 sustained responders (SR) and 41 nonresponders or relapsers (NR)]. Serum HCV RNA was retrospectively measured in samples obtained at baseline and 4, 8 and 12 weeks after treatment onset, using a commercially available quantitative RT-PCR assay. At 4 weeks, serum HCV RNA had decreased a mean of 2.6 +/- 0.8 logs among SR as compared with only 0.5 +/- 0.8 logs in NR (P < 0.001), and was already undetectable (< 600 IU/mL) in 12 (48%) of the SR but in none of the NR. At 8 weeks, HCV RNA was undetectable in 21 SR and in 2 NR and mean DeltaHCV RNA were 4.2 +/- 1.3 and 0.8 +/- 1.0 logs, respectively (P < 0.001). At week 12 all SR had undetectable HCV RNA as compared with only five NR (P < 0.001). Stepwise logistic regression analysis identified DeltaHCV RNA at 12 weeks as the strongest predictor of sustained response. Receiver operating characteristic (ROC) curves of DeltaHCV RNA for sustained response prediction identified sensitivity peaks with 100% negative predictive value corresponding to DeltaHCV RNA > 1 log at 4 weeks, > 2 logs at 8 weeks and > 3 logs at 12 weeks. Our results show that early changes in the HCV RNA level may reliably identify patients having no chance of a sustained virological response during the first 3 months of combination therapy, thus providing an excellent tool for optimizing antiviral treatment of chronic hepatitis C.

Paracentesis with intravenous infusion of albumin as compared with peritoneovenous shunting in cirrhosis with refractory ascites.

BACKGROUND: There is no satisfactory treatment for refractory ascites in patients with cirrhosis. Both peritoneovenous shunts and paracentesis have been used, but there is uncertainty about their relative merits. METHODS: We studied 89 patients with cirrhosis and refractory ascites who were randomly assigned to receive either repeated large-volume paracentesis plus intravenous albumin or a LeVeen peritoneovenous shunt. Patients in the paracentesis group in whom recurrent tense ascites developed during follow-up were treated with paracentesis, and those in the peritoneovenous-shunt group with diuretic agents or by the insertion of a new shunt if there was shunt obstruction. RESULTS: During the first hospitalization, ascites was removed in all 41 patients in the paracentesis group and in 44 of the 48 patients in the peritoneovenous-shunt group. The mean (+/- SD) duration of hospitalization in the two groups was 11 +/- 5 and 19 +/- 9 days, respectively (P less than 0.01). There were no significant differences in the number of patients who had complications or died. During follow-up, 37 patients in each group were hospitalized again. In the paracentesis group, the number of rehospitalizations for any reason (174 vs. 97 in the peritoneovenous-shunt group) or for ascites (125 vs. 38) was significantly higher, and the median time to a first readmission for any reason (1 +/- 1 vs. 2 +/- 2 months) or for ascites (2 +/- 2 vs. 8 +/- 17 months) was significantly shorter than in the peritoneovenous-shunt group. The total times in the hospital during follow-up, however, were similar in the two groups (48 +/- 49 and 44 +/- 39 days, respectively). Three patients had obstructions of their peritoneovenous shunts during their first hospitalizations, and 15 patients had a total of 20 obstructions during follow-up. Survival was similar in both groups. CONCLUSIONS: The LeVeen shunt and paracentesis are equally effective in relieving refractory ascites. The former may provide better long-term control of ascites, but shunt occlusion is common and survival is not improved.

Interferon-alpha in acute posttransfusion hepatitis C: a randomized, controlled trial.

To assess the efficacy of interferon-alpha in acute hepatitis C, 28 patients with acute posttransfusion hepatitis were randomized to receive 3 million units of recombinant interferon-alpha three times weekly for 12 wk or no treatment. Biochemical, histological and serological parameters were monitored during 1 yr of follow-up. Serum ALT levels were normal at the end of therapy in 73% of treated patients and only in 38% of control patients (p = 0.06); these differences disappeared at 6 and 12 mo of follow-up. Anti-hepatitis C virus seroconversion occurred later and at a lower rate in the group of patients who received interferon-alpha. Treated patients had a trend toward less severe hepatic lesions with lower histological activity as compared with the control group, but no statistical differences were observed. No severe side effects of interferon-alpha were detected during the study. In summary, a 3-mo course of interferon-alpha in acute hepatitis C is safe and might have some effect in diminishing disease activity only during the treatment period; however, and probably because of a small sample size, no benefit of interferon-alpha in the long-term outcome of this disease was demonstrated.

Efficacy of screening donors for antibodies to the hepatitis C virus to prevent transfusion-associated hepatitis: final report of a prospective trial.

Routine screening of blood donors for anti-hepatitis C virus (HCV) has been implemented in most developed countries. However, the independent efficacy of such screening has not been established in a controlled, prospective study. We tracked 478 patients transfused with anti-HCV-negative blood by first-generation enzyme-linked immunoassay (EIA) between July 1989 and May 1990 and compared the incidence of transfusion-associated hepatitis and HCV infections with that found among 280 patients transfused with blood unscreened for anti-HCV during the immediately preceding year. Of the 280 patients who had received transfusions before donors were screened for anti-HCV, 27 (9.6%) developed posttransfusion hepatitis and 1 additional patient seroconverted to anti-HCV without evidence of hepatitis, for a risk of posttransfusion HCV infection of 10.7% (28 of 262 recipients seronegative for anti-HCV before transfusion). Of the 478 patients transfused after July 1989 with blood screened for anti-HCV, only 9 (1.9%) developed posttransfusion hepatitis for a risk reduction of 80%. Seven of the 9 residual cases of hepatitis were caused by HCV (7 of 456 recipients seronegative before transfusion or 1.5%) for a risk reduction of transfusion-associated HCV infection of 86%. In retrospect, an anti-HCV positive donor was detected by second-generation immunoassay in 4 (57%) of the 7 HCV cases from the study cohort and in 19 of the 23 (83%) cases from whom all donor samples were available for testing in the historical cohort. No additional infectious donors were detected by third-generation immunoassay or serum HCV-RNA by polymerase chain reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatitis C virus antibodies among risk groups in Spain.

The frequency of hepatitis C virus (HCV) infection in Spain was assessed by means of a recombinant-based immunoassay for serum anti-HCV antibodies. 836 serum samples were tested from 676 patients selected according to their risk of blood-borne viral infections and presence of liver disease. Among patients at high risk of infection (with or without liver disease) anti-HCV antibodies were found in 85% of prospectively followed patients with post-transfusion non-A, non-B hepatitis, 62% of patients with chronic hepatitis or cirrhosis and a history of blood transfusion, 70% of haemophiliacs receiving replacement therapy, 70% of intravenous drug abusers, and 20% of haemodialysis patients. Only 8% of homosexual men infected with human immunodeficiency virus and 6% of female contacts of drug abusers were positive. Among patients with liver disease and no history of parenteral exposure to blood, anti-HCV antibodies were detected in 38% with cryptogenic, alcoholic, or primary biliary cirrhosis and in 44% with chronic active hepatitis. Among healthy subjects without risk factors for hepatitis the overall prevalence of anti-HCV was 1.2%.

Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection.

BACKGROUND: For many people infected with the hepatitis C virus (HCV), the route of exposure, risk of transmission, and severity of associated liver disease are unknown. We studied these variables in people who donated blood voluntarily. METHODS: Blood donors who tested positive for HCV antibodies on enzyme immunoassay were classified according to whether the results of a confirmatory second-generation recombinant immunoblot assay (RIBA) for HCV were positive, negative, or indeterminate. The evaluations also included an assessment of risk factors, a physical examination, serial determinations of alanine aminotransferase levels and HCV serologic assays, a polymerase-chain-reaction assay for HCV RNA, testing of sexual contacts and family members, and liver biopsies in some participants who were HCV-positive by RIBA. RESULTS: A total of 481 donors were studied, among whom 248 were positive for HCV by RIBA, 102 had indeterminate results, and 131 were HCV-negative. In a logistic-regression analysis, significant risk factors for HCV infection among the HCV-positive participants were a history of blood transfusion in 66 (27 percent; P < 0.001 for the comparison with RIBA-negative donors), intranasal cocaine use in 169 (68 percent, P < 0.001), intravenous drug use in 103 (42 percent, P = 0.001), sexual promiscuity in 132 (53 percent, P = 0.002), and ear piercing among men (P < 0.05). Nine of 85 sexual partners of HCV-positive donors were anti-HCV-positive; 8 had used intravenous drugs or received transfusions. HCV RNA was found in 213 HCV-positive donors (86 percent), 3 who had indeterminate results by RIBA (2 of these 3 tested positive with a more specific, third-generation RIBA), and none who were HCV-negative. Of the HCV-positive donors, 69 percent had biochemical evidence of chronic liver disease; among 77 donors positive for HCV by RIBA who underwent liver biopsy, 5 had severe chronic hepatitis or cirrhosis, 66 had mild-to-moderate chronic hepatitis, and 6 had no evidence of hepatitis. CONCLUSIONS: Among volunteer blood donors, prior blood transfusion, intranasal cocaine use, intravenous drug use, sexual promiscuity, and ear piercing in men are risk factors for HCV infection. The high frequency of intravenous drug use was unexpected, because these donors had denied such use when questioned directly at the time of their blood donations.

High rate of infectivity and liver disease in blood donors with antibodies to hepatitis C virus.

OBJECTIVE: To determine the epidemiologic, clinical, serologic, and histologic importance of antibodies to hepatitis C virus (anti-HCV) in blood donors. DESIGN: Cross-sectional identification and prospective evaluation of seropositive donors; retrospective assessment of infectivity; and nested case-control study for risk factors. SETTING: Liver unit of a referral-based university hospital. SUBJECTS: Of 30,231 consecutive donors, 368 (1.2%) were found to be anti-HCV-reactive by enzyme-linked immunosorbent assay (ELISA). Two hundred and fifty-four of these 368 donors were evaluated for risk factors by comparison with 284 age- and sex-matched controls. Eighty-six spouses of seropositive donors were also evaluated. MEASUREMENTS AND MAIN RESULTS: Twenty-four percent of the seropositive donors had a history of percutaneous exposure to blood. This rate increased to 45% when only those donors confirmed to be anti-HCV positive by a second-generation recombinant immunoblot assay (RIBA-2) were considered. A family history of liver disease (odds ratio, 2.8; 95% Cl, 1.6 to 4.8), previous blood transfusion (odds ratio, 6.1; 95% Cl, 3 to 12.5), and a history of tattooing or intravenous drug abuse (odds ratio, 8.4; 95% Cl, 2.3 to 31) were associated with anti-HCV seropositivity. An elevated alanine aminotransferase (ALT) level was found in 58% of the seropositive donors. Of the 150 donors tested, 104 (69%; Cl, 62% to 77%) were confirmed by RIBA-2 to be anti-HCV positive. Of the 105 donors who had a biopsy, 16% had normal histologic findings, 11% had minimal changes, 21% had chronic persistent hepatitis, 45% had chronic active hepatitis, and 7% had active cirrhosis. All 77 donors with RIBA-2-confirmed seropositivity had histologic abnormalities. Of 43 donors evaluated in an infectivity study, 82% were implicated in previous HCV transmission. Only 2.3% of the spouses were anti-HCV positive. The ELISA, RIBA-2, and ALT results correlated with infectivity and abnormal histologic findings. CONCLUSIONS: In our geographic area, almost 70% of donors who are anti-HCV positive by ELISA are confirmed to be positive by RIBA-2; most of these donors appear to be chronic carriers of HCV and have substantial liver disease.

Evaluation of antibodies to hepatitis C virus in a study of transfusion-associated hepatitis.

BACKGROUND: The hepatitis C virus (HCV) is now known to be the chief cause of transfusion-associated non-A, non-B hepatitis, but the prevalence of HCV among blood donors and the frequency of transmission by blood transfusion are unknown. METHODS: To assess the sensitivity and specificity of a test for antibody to HCV, we tested serum samples from participants in a large study of transfusion-associated hepatitis. Samples were obtained prospectively from consecutive adults undergoing open-heart surgery in Spain, but were tested retrospectively, after the antibody enzyme immunoassay for anti-HCV became available. RESULTS: Of 280 transfusion recipients given a total of 1109 units of blood, 27 (9.6 percent) had transfusion-associated non-A, non-B hepatitis (mean follow-up, 52 weeks) and 24 of the 27 seroconverted to anti-HCV-positive, whereas only 2 (0.8 percent) of the remaining transfusion recipients seroconverted. Among the 1044 donor specimens available for testing, 16 (1.5 percent) had anti-HCV antibody. Only 1 additional seropositive donor was found when 44 implicated donors who had been seronegative were retested 9 to 12 months later. Of the 16 recipients of anti-HCV-positive blood, 14 (88 percent) had transfusion-associated hepatitis and seroconverted to anti-HCV-positive. The remaining two recipients had neither hepatitis nor anti-HCV antibody. Among 25 patients with non-A, non-B hepatitis for whom all transfused blood was tested, 14 had received blood positive for anti-HCV. CONCLUSIONS: About 90 percent of blood donors with antibody to HCV have infectious virus in their blood. The screening of blood donors for anti-HCV antibody should prevent about half the cases of transfusion-associated hepatitis, but the donors with infectious virus who are anti-HCV-negative may remain seronegative for prolonged periods.