Prevalence of cryoglobulinemia in chronic hepatitis C virus infection and response to treatment with interferon-alpha

A recombinant Schistosoma mansoni protein has been identified as a useful antigen for the detection of S. mansoni and Schistosoma haematobium antibodies. The purified recombinant protein, Sm22.3, was assayed using an enzyme-linked immunosorbent assay format against a battery of 491 well defined sera, including S. mansoni, S. haematobium, and Schistosoma japonicum infection sera, normal human sera, sera from 9 other parasitic infections, and sera from 2 additional infections. The sensitivity for detecting S. mansoni and S. haematobium infections with this single recombinant protein is 80.1%. The specificity is 94.8%. However, 15 of the 16 cross-reactive sera are malaria infection sera, and we have data suggesting that these malaria sera are actually recognizing an epitope on the vector-derived 6Xhistidine tag of recombinant Sm22.3. If this is the case, then, the actual specificity of the assay is 99.6%.     

Hepatitis GB virus C infection in Japanese hemophiliacs with persistent hepatitis C virus infection

We investigated the prevalence of infection of GBV-C, which has been cloned recently and is considered a parenterally transmissible virus. Ninety-one Japanese hemophiliacs who were persistently infected with HCV were evaluated. The presence of GBV-C RNA was measured by nested RT-PCR. We analyzed the prevalence and the association with subtypes of coinfected HCV. 20.9% of hemophiliacs were infected with GBV-C. The distribution of HCV subtypes of patients who are coinfected with GBV-C was similar to that of patients who are coinfected with HIV, and the prevalence of GBV-C infection of patients with HCV subtype la was significantly higher than that of patients without HCV subtype la. High prevalence of GBV-C infection was observed in Japanese hemophiliacs, and most were thought to be imported isolates from foreign origins, as well as HIV infection in these patients.     

Epidemiology of hepatitis C virus infection in Nepal

The impact of the Prehospital Trauma Life Support (PHTLS) programme, introduced in Trinidad and Tobago in 1992, was assessed by questionnaires completed by 26 medical personnel (MP); 71 ambulance personnel (AP); and 50 non ambulance paramedical personnel (NAP). Of the 23 MP, 45 AP and 38 NAP who were aware of the programme, 19 (82.6%) MP, 40 (88.9%) AP and 25 (65.8%) NAP were able to differentiate personnel that had taken the PHTLS programme based on their performance. 32 (71.1%) of the AP were PHTLS trained. 24 (53.3%) and 4 (9%) of the AP identified poor equipment and poor supervision, respectively, as reasons for difficulty in applying PHTLS principles. Improvements observed among those completing the PHTLS programme were: improved resuscitation techniques by 20 (86.9%) MP, 38 (84.4%) AP and 27 (71.1%) NAP; better vital signs recording by 8 (34.8%) MP, 27 (60%) AP and 8 (21.1%) NAP; improved immobilization by 23 (100%) MP, 40 (88.9%) AP and 33 (86.8%) NAP; better haemorrhage control by 22 (95.6%) MP, 40 (88.9%) AP and 24 (63.2%) NAP; appropriate splinting of fractures by 23 (100%) MP, 40 (88.9%) AP and 32 (84.2%) NAP; and increased utilization of oxygen by 15 (65.2%) MP, 31 (68.9%) AP and 21 (55.3%) NAP. 32 (71.1%) AP with PHTLS training indicated improvement in their ability to resuscitate and transport trauma victims, with 42 (93.3%) reporting improvement in overall prehospital care. Medical, paramedical and ambulance personnel all perceive a significant positive impact of PHTLS training on prehospital trauma care. Although improvements in supervision, documentation and equipment are still required, improved trauma resuscitative techniques after PHTLS training should improve trauma patient outcome in Trinidad and Tobago.     

Vertical transmission of hepatitis C virus infection

BACKGROUND: Cavernous carotid aneurysms are generally benign entities. Certain indications exist for their treatment, however, including transient ischemic events, subarachnoid hemorrhage or risk of subarachnoid hemorrhage, epistaxis or its risk, ophthalmoplegia, pain, and progressive visual loss. We feel certain angiographic features may indicate a greater likelihood that cavernous carotid aneurysms extend into the subarachnoid space, thus making their rupture a life-threatening event. METHODS: A case report of an intracavernous carotid aneurysm, which at surgery extended into the subarachnoid space, is described. RESULTS: In this particular case, deformation of the aneurysm (waisting) as seen at angiography was in retrospect an indication that the cavernous carotid aneurysm extended into the subarachnoid space, either through the dural ring or through the eroded dural roof of the cavernous sinus. This finding was verified at surgery when the lesion was explored and trapped. CONCLUSION: Angiographic waisting of a cavernous carotid aneurysm may indicate that the aneurysm extends into the subarachnoid space. Such extension means that rupture would be a life-threatening event. While deformation of the aneurysm may be secondary to compression against the optic nerve or anterior clinoid process with an intact layer of dura overlying the aneurysm, the neurosurgeon confronted with such findings should analyze such lesions carefully and consider surgical exploration.     

Immunoglobulin M antibody response to hepatitis C virus core protein in patients with chronic hepatitis C

We retrospectively assessed the frequency and clinicopathologic and virologic significance of production of immunoglobulin M (IgM) antibody to hepatitis C virus (HCV) core protein in patients with chronic hepatitis C. Sera from 60 patients with chronic hepatitis C were tested for IgM anti-HCVcore (anti-HCc). Twenty of these patients received ribavirin plus interferon-alpha for 24 weeks, and were classified as sustained, transient, or nonresponders on the basis of alanine aminotransferase levels and the presence of HCV RNA at the end of treatment and 24 weeks later. IgM anti-HCc was detected in 21 patients. There was no correlation between the presence of IgM anti-HCc and clinical features such as sex, age, mode of transmission, serum levels of alanine aminotransferase, HCV genotype, serum HCV titer, or histologic findings. Among the patients who received ribavirin plus interferon-alpha, the mean IgM anti-HCc level before therapy was comparable between sustained (n = 10), transient (n = 8), and nonresponders (n = 2). A statistically significant decrease in IgM anti-HCc response during antiviral therapy was observed in the 18 responders who became negative for serum HCV RNA at the end of therapy. These data suggest that IgM anti-HCc is of limited clinical usefulness as a marker of chronic HCV infection. Serial testing for IgM anti-HCc may provide a marker of antiviral response.     

Limited humoral immunity in hepatitis C virus infection

BACKGROUND & AIMS: The extremely high rate of chronicity to hepatitis C virus (HVC) infection suggests an inefficient immune response. The humoral immune response to HCV was evaluated in 60 patients with chronic HCV infection and in 12 patients acutely infected with HCV. METHODS: A number of recombinant HCV antigens including the core, envelope 2 (E2), nonstructural (NS) 3, NS4, and NS5 proteins, and NS4a and E2-HVR-1 peptides were used in enzyme-linked immunoassays. RESULTS: Immunoglobulin (Ig) G antibody responses to these viral antigens, except for the HCV core, were highly restricted to the IgG1 isotype. The prevalence of antibodies of the IgG1 isotype specific for the HCV core, E2, E2-HVR1, NS3 (helicase domain), NS4, and NS5 antigens was 97%, 98%, 28%, 88%, 33%, and 68%, respectively. Antibodies of the IgG3 isotype specific for E2, E2-HVR-1, NS3, NS4, and NS5 were detected in a minority of serum samples. The IgG2 and IgG4 isotypes were rarely if ever detected. Furthermore, antibody responses to HCV viral antigens were of relatively low titer and, with the exception of anti-HCV core, were delayed in appearance until the chronic phase of infection. CONCLUSIONS: The IgG1 restriction, low titer, and delayed appearance of antibody responses elicited during HCV infection suggest that the immunogenicity of HCV proteins is limited in the context of natural infection. Inasmuch as recombinant HCV viral antigens perform as relatively normal immunogens in small animals, we suggest that the defective humoral immune responses during HCV infection may be attributable to an "immune avoidance" strategy.     

Non-Hodgkin's lymphoma and hepatitis C virus infection

The hepatitis C virus (HCV) is a recently described and important cause of acute and chronic liver disease. A hallmark of HCV is its propensity to become chronic, some patients with chronic HCV progressing to cirrhosis and hepatocellular carcinoma (HCC). HCV is also lymphotrophic and we report 2 patients with HCV cirrhosis who developed non-Hodgkins lymphoma (NHL). These cases raise the possibility that chronic HCV infection of lymphocytes plays an aetiological role in this malignancy. However screening of a further 63 consecutive patients over the age of 50 years with NHL for HCV antibody by second generation enzyme linked immunoassay (ELISA) failed to identify any patients with evidence of HCV infection. This suggests that HCV is an uncommon contributory factor for the development of non-Hodgkins lymphoma in the United Kingdom.     

Assisted reproduction and hepatitis C virus infection

Medically assisted procreation poses a difficult problem when one or both partners of couple are infected with HCV. Epidemiologic and fundamental works show a low risk of HCV sexual transmission and no pregnancy complications or fetal abnormalities have been reported. However, the outcome of HCV infected children is unknown. These contrasting findings suggest that medically assisted procreation using sperm of spouse needs to be cautious. Before medically assisted procreation, testing of couples for HCV antibodies must be done and interferon therapy is required for patients with histological chronic active hepatitis and for HCV positive mothers or infected couples. In the absence of specific legislation or consensual recommendations, detailed informations must be given to the couples in order to obtain an informed consent.     

Predictors of long-term response to high-dose interferon therapy in type II cryoglobulinemia associated with hepatitis C virus infection

We have prospectively studied patients with type II cryoglobulinemia since 1985 to assess the efficacy of treatment with interferon-alpha at cumulative doses ranging from 234 to 849 MU. In the present study we retrospectively evaluated in this cohort parameters associated with complete response to therapy in 31 consecutive patients with type II cryoglobulinemia associated with hepatitis C virus (HCV) infection. Prevalence of complete response of cryoglobulinemia (disappearance of symptoms and signs of vasculitis and decrease of cryocrit below 10% of the initial value) was 62%, with a median response duration of 33 months and a range of 3 to 100 months. Three patients were putatively cured, as they remained in complete remission for more than 5 years off therapy. Eighteen patients (58%) had liver disease evidenced by histopathology and/or raised transaminase levels. Prevalence of normalization of transaminase levels was 100%, with a median response duration of 36 months. Relapse of hypertransaminasemia occurred in 100% and 8% of patients receiving less than or greater than 621 MU, respectively. By logistic regression analysis, the only pretherapy parameter that associated significantly (P = .0393) with complete response of cryoglobulinemia was the solitary anti-C22 (HCV core) antibody pattern, which was observed in 29% of patients. Association with older age and low cryocrit approached statistical significance (P = . 06), while no significant correlations were found with serum IgM levels, duration of disease, HCV genotype, NS5a gene mutations, liver histology, HLA-DR phenotype, or WA cross-idiotype. Complete responses were also associated, on univariate statistical analysis, with low pretherapy HCV viremia. Responses were accompanied by decrease of viremia, of anti-HCV antibody levels and cryocrit. The usefulness of a high dose regimen is underscored by the higher rates of sustained responses of cryoglobulinemia and transaminase levels compared with previous studies.     

T- and B-cell responses to different hepatitis C virus antigens in patients with chronic hepatitis C infection and in healthy anti-hepatitis C virus--positive blood donors without viremia

As the host's immune response may determine the course of hepatitis C virus (HCV) infection, we studied the humoral and cellular immune responses to HCV-related antigens in subjects with different outcomes of HCV infection. Lymphoproliferative responses and circulating antibodies to a panel of HCV core- and E1-related 25-mer peptides were examined in 10 healthy anti-HCV-seropositive blood donors (group A) and in 29 patients with chronic hepatitis C (group B). In addition, cellular recognition of recombinant HCV proteins (core, NS3, NS4A, NS5A, NS5B) were investigated. In group A, stronger T-cell responses were detected against both HCV proteins (core, P = .03; NS4, P = .005; NS5B, P = .03) and peptides. Proliferation was induced by the same peptides in each group, defining at least five distinctive epitopes within core (amino acids [aa] of 20-44, aa 39-63, aa 79-103, aa 118-152 and aa 148-172) and three regions within E1(aa 198-252, aa 308-372, and aa 368-392). Subjects with strong T-cell responses had low or no detectable levels of peptide-specific antibodies, and vice versa. In particular, T-cell responses were more common in group A; B-cell responses were more common in group B. From our data, we conclude that a benign course of HCV infection may be the consequence of the effective activation of T-helper lymphocytes.     

Cellular immunity to hepatitis C virus core protein and the response to interferon in patients with chronic hepatitis C

To investigate the involvement of T-cell response against hepatitis C virus (HCV) antigens in viral clearance after interferon therapy, we measured interleukin-2 (IL-2) production by peripheral mononuclear cells in response to HCV core in patients with chronic hepatitis C. In a cohort of 43 patients, we investigated the frequency of circulating core-specific T-helper (Th) cell precursors by the limiting-dilution assay, and in a second cohort of 60 patients, we analyzed the response to specific core epitopes using 52 synthetic 15-mer overlapping peptides. We observed that the frequency of core-specific Th cell precursors was significantly higher in patients with sustained biochemical and virological response (SR) after interferon (IFN) therapy (median, 1/55,736) than in untreated patients (1/274,023) or that in patients who remained viremic after completion of the treatment-nonresponders (NR) plus transient responders (TR) (1/1,909,972). Patients who failed to respond to IFN (NR) and those who relapsed after IFN discontinuation (TR) had a similarly low number of precursors. The number of core peptides recognized by SR, TR, NR, UT, and healthy controls was 8.2 +/- 1.5, 6.5 +/- 1.2, 2.0 +/- 0.5, 2.7 +/- 0.9, and 0.3 +/- 0.2, respectively. In SR, the intensity of the proliferative response to core peptides as estimated by the summation of stimulation indexes (sigmaSI) was significantly higher than in NR and than in UT, but not different from that of TR. Our results indicate that both expansion of HCV-specific Th cell precursors and Th cell recognition of multiple core epitopes seem to be important in the elimination of HCV after IFN therapy.     

Antibody-negative chronic hepatitis C virus infection in immunocompetent children

Two new pyrrolidine alkaloids, broussonetines G and H, were isolated from the branches of Broussonetia kazinoki SIEB. (Moraceae). Broussonetines G and H were formulated as 2 beta-hydroxymethyl-3 alpha, 4 beta-dihydroxy-5 alpha-(1-hydroxy- 6:10;10:13-diepoxytridecyl)-pyrrolidine (1) and 2 beta-hydroxymethyl-3 alpha, 4 beta-dihydroxy-5 alpha-(1-hydroxy- 5:9;9:13-diepoxytridecyl)-pyrrolidine (2), respectively, by spectroscopic methods. 1 and 2 inhibited beta-glucosidase, beta-galactosidase and beta-mannosidase.     

Central nervous system involvement in hepatitis C virus infection

Few well-documented cases of central nervous system involvement in patients with hepatitis C virus infection have been reported. We describe three patients (two men and one woman) with cerebral involvement (ischemia and/or hemorrhage). Hepatitis C virus infection was confirmed in all patients by polymerase chain reaction detection of hepatitis C virus RNA. These three cases document the occurrence of central nervous system involvement in patients with hepatitis C virus infection and mixed cryoglobulinemia. Cerebral involvement may be the initial manifestation of hepatitis C virus infection.     

B-lymphoproliferative disorders in patients with hepatitis C virus infection

Blastomycosis is an endemic systemic fungal infection that usually involves the lungs and superficial skin. Although head and neck involvement has been reported in the literature, no previous cases of neck mass resulting from direct extension of a pulmonary lesion have been published. We encountered an immunocompetent 31-year-old woman with a rapidly enlarging subcutaneous neck mass and a chronic upper lung infiltrate. Imaging studies showed contiguity between both lesions. Blastomyces dermatitidis was recovered from the sputum, and typical yeast was observed in fungal stains of needle aspirate from the neck mass. The patient responded favorably to a 6-month course of itraconazole. Blastomycosis should be considered in patients with subcutaneous neck masses in areas where this disease is endemic.     

The natural course of hepatitis B and hepatitis C virus infection

Chronic hepatitis B and hepatitis C virus infections maintain a significant risk for the development of liver cirrhosis and hepatocellular carcinoma and cause a considerable morbidity in the population. Among patients with chronic HBV infection and histologically confirmed hepatitis the annual incidence of liver cirrhosis is 2%. The risk for hepatocellular carcinoma in chronic HBsAg carriers is elevated about 40-230 fold. 20-30% of patients with chronic HCV infection will develop cirrhosis over 20-30 years. Hepatocellular carcinoma evolves yearly in about 3% of patients with chronic HCV infection and cirrhosis, whereas HCV-carriers without cirrhosis usually do not develop hepatocellular carcinoma. The high incidence of serious sequelae warrants a regular surveillance of chronic virus carriers.     

Glomerulonephritis in autopsy cases with hepatitis C virus infection

1. The inducible isoform of nitric oxide synthase (iNOS) is expressed in human and experimental cardiac allografts and is localized to infiltrating macrophages, cardiac myocytes, endothelial cells and smooth muscle cells. A recent clinical report proposes a causal link between myocardial expression of iNOS and ventricular contractile dysfunction, a potentially graft- and life-threatening post-transplant complication. 2. Coronary blood flow is elevated in human graft recipients with biopsy proven cellular rejection, indicating that vasodilation accompanies graft rejection. In Lewis-to-F-344 coronary resistance vessels, which show intimal expression of iNOS, pressure-induced myogenic tone is significantly inhibited. Selective iNOS inhibition partially reverses the inhibition of myogenic tone, confirming that iNOS produces vasoactive nitric oxide (NO) and may mediate the rejection-induced vasodilation seen clinically. 3. Endothelial dysfunction, identified as loss of endothelium-dependent dilation, has tremendous prognostic significance in vascular diseases of multiple aetiologies. In transplantation, endothelial dysfunction predicts early cardiac allograft vasculopathy and poor clinical outcome. Lewis-to-F-344 coronary vessels develop endothelial dysfunction at 1 week post-transplantation, but this is preceded by a transient state of endothelial cell hyperfunction, with enhanced endothelial production of NO. 4. The normal interaction between endothelial and smooth muscle cells in coronary resistance vessels is critical for the regulation of coronary blood flow and the maintenance of fluid homeostasis. With allospecific expression of iNOS, the inhibition of vascular tone predicts greatly enhanced intravascular pressure in precapillary arterioles and capillaries; this would be expected to cause a net movement of fluid from the intravascular compartment into the myocardial interstitium, resulting in ventricular oedema, non-compliance and poor contractile performance.