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Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C.

BACKGROUND Hepatitis A virus (HAV) infection rarely causes fulminant hepatic failure in people with no underlying liver disease. There are limited data on the course of this infection in patients with chronic hepatitis B and chronic hepatitis C. METHODS We prospectively followed, from June 1990 to July 1997, 595 adults with biochemical and histologic evidence of chronic hepatitis B (163 patients) or chronic hepatitis C (432 patients) who were seronegative for HAV antibodies. All were tested every four months for serum IgM and IgG antibodies to HAV. RESULTS Twenty-seven patients acquired HAV superinfection, 10 of whom had chronic hepatitis B and 17 of whom had chronic hepatitis C. One of the patients with chronic hepatitis B, who also had cirrhosis, had marked cholestasis (peak serum bilirubin level, 28 mg per deciliter [479 micromol per liter]); the other nine had uncomplicated courses of hepatitis A. Fulminant hepatic failure developed in seven of the patients with chronic hepatitis C, all but one of whom died. The other 10 patients with chronic hepatitis C had uncomplicated courses of hepatitis A. CONCLUSIONS Although most patients with chronic hepatitis B who acquired HAV infection had an uncomplicated course, patients with chronic hepatitis C had a substantial risk of fulminant hepatitis and death associated with HAV superinfection. Our data suggest that patients with chronic hepatitis C should be vaccinated against hepatitis A.

Identification of hepatitis A virus as a trigger for autoimmune chronic hepatitis type 1 in susceptible individuals

To identify factors contributing to the pathogenesis of autoimmune chronic active hepatitis (CAH) healthy relatives of 13 patients with the disorder were followed prospectively for 4 years. 58 relatives were monitored for various serological markers and for T-lymphocyte migration inhibitory activity every 2 months. 3 cases of subclinical acute hepatitis A occurred during the study. In 2 of the 3 subjects, before hepatitis A virus (HAV) infection, there was a defect in suppressor-inducer T lymphocytes specifically controlling immune responses to the asialoglycoprotein receptor, an antigen expressed on the hepatocyte surface. In these 2 subjects, specific helper T cells and antibodies to the asialoglycoprotein receptor persisted and increased after acute hepatitis A, and autoimmune CAH type 1 developed within 5 months. Thus, in susceptible individuals HAV is a trigger for autoimmune CAH.

Nosocomial Candidemia in Non-Neutropenic Patients at an Italian Tertiary Care Hospital

Abstract In a retrospective study conducted in an Italian tertiary care hospital, the incidence of nosocomial candidemia was evaluated together with causative pathogens, treatment, and risk factors for death. Over a 6-year period (1992–1997), a total of 189 episodes of candidemia occurred in 189 patients (mean age 58±19 years), accounting for an average incidence of 1.14 episodes per 10,000 patient-days per year. The most common reasons for hospitalization were solid neoplasia (21%), trauma (17%), abdominal diseases requiring surgery (13%), and cardiovascular diseases (13%). No patient was neutropenic within 3 weeks prior to the onset of candidemia. One hundred thirty patients were hospitalized in intensive care units, 47 patients in surgical wards, and 12 patients in medical wards. Candida albicans was the most frequently isolated pathogen, accounting for 54% of fungal isolates, followed by Candida parapsilosis (23%), Candida glabrata (7%), Candida tropicalis (5%), Candida pelliculosa (4%), Candida lusitaniae (1%), Candida humicula (1%), and other non-albicans Candida spp. (5%). Seventy-six (41%) patients received adequate antifungal therapy. Seventy-one (58%) of the 123 evaluable patients with central venous catheters underwent line removal; 51 of them had catheter-related candidemia. The 30-day crude mortality rate was 45%. Older age, hospitalization in an intensive care unit, a longer duration of candidemia, retention of central lines, and inadequate antifungal therapy were significantly associated with poor outcome. In the present study, nosocomial candidemia was a frequent and relatively underestimated illness. Adequate antifungal therapy and central line removal independently reduced the high mortality of the disease.

Epstein-Barr virus as a trigger for autoimmune hepatitis in susceptible individuals

During follow-up of healthy relatives of 13 patients with autoimmune hepatitis, seven cases of infectious mononucleosis due to Epstein-Barr virus (EBV) occurred. In two of these seven, before EBV infection, there was a defect in suppressor-inducer T lymphocytes specifically controlling immune responses to the asialoglycoprotein receptor, an antigen expressed on the hepatocyte surface. In these two, antibodies to this autoantigen persisted and increased after infectious mononucleosis, and autoimmune hepatitis developed within 4 months. In susceptible individuals, EBV is a trigger for autoimmune hepatitis.

Fulminant hepatitis on withdrawal of chemotherapy in carriers of hepatitis C virus.

BACKGROUND Fulminant hepatitis on withdrawal of chemotherapy has been described in chronic hepatitis B virus infection, but not in hepatitis C virus (HCV) infection. The relation between HCV and immune response to this virus, and disease severity, has not been examined. We present two patients with HCV who developed fulminant liver failure after chemotherapy was stopped. PATIENTS AND FINDINGS Two patients with chronic HCV infection and malignant lymphoma received chemotherapy (cyclophosphamide, adriamycin, vincristine, bleomycin, etoposide, and prednisolone in patient 1; doxorubicin, bleomycin, vinblastine, and dacarbazine in patient 2), on withdrawal of which both developed fulminant hepatitis. Alanine aminotransferase (ALT) concentrations were greatly raised (6030 and 3870 IU/L in patients 1 and 2, respectively), and serum HCV-RNA was low in both patients when severe disease developed (10(2) genome equivalents per mL). Patient 1 died, and necropsy showed massive liver necrosis. INTERPRETATION The findings suggest an immune-mediated mechanism for hepatocyte damage in HCV infection. Careful monitoring of ALT concentrations is necessary in such patients during and after chemotherapy.

Infections and solid organ transplant rejection: a cause-and-effect relationship?

Although evidence is far from being conclusive, several studies have suggested that infections could trigger rejection in different transplant settings. In this review we examine the evidence linking cytomegalovirus (CMV), adenovirus, enterovirus, parvovirus, and herpes simplex virus infections to the vasculopathy leading to cardiac allograft rejection, the association between CMV and chronic kidney, lung, and liver graft rejection, and the association of human herpesvirus 6 reactivation with CMV-related disease in kidney and liver transplant recipients. We also review the numerous antiviral prophylactic or pre-emptive treatments in use to control CMV infection, and suggest that they do not limit immune reactions leading to graft rejection or lower the risk of developing post-transplantation atherosclerosis in allograft recipients. Finally, we emphasise the need for prospective, international studies to clarify the role of infections in transplant rejection, to look at virus-to-virus interactions, and to establish specific therapeutic strategies. Such strategies must not rely exclusively on expensive antiviral agents but also on vaccination or other, innovative approaches, such as the use of agents able to inhibit the activity of natural killer cells, which might have an important role in acute allograft rejection.

Infections and thalassaemia

Infections are major complications and constitute the second most common cause of mortality and a main cause of morbidity in patients with thalassaemia, a group of genetic disorders of haemoglobin synthesis characterised by a disturbance of globin chain production. Thalassaemias are among the most common genetic disorders in the world. Predisposing factors for infections in thalassaemic patients include severe anaemia, iron overload, splenectomy, and a range of immune abnormalities. Major causative organisms of bacterial infections in thalassaemic patients are Klebsiella spp in Asia and Yersinia enterocolitica in western countries. Transfusion-associated viral infections (especially hepatitis C) can lead to liver cirrhosis and hepatocellular carcinoma. A unique and challenging infection detected in Asian patients is pythiosis, caused by a fungus-like organism, the mortality rate of which is very high. Because the prognosis for thalassaemia has much improved, with many patients surviving to the fifth decade of life in developed countries, it is mandatory to reduce mortality by recognising and presumptively treating infections in these patients as quickly as possible.

Reactivation of replication of hepatitis B and C viruses after immunosuppressive therapy: an unresolved issue

The liver is susceptible to the toxic effects of many cytotoxic or immunosuppressive treatments. However, in carriers of hepatitis B virus (HBV) and, less frequently, of hepatitis C virus, liver damage due to reactivation of viral replication can occur after withdrawal of immunosuppressive drugs. These reactivations, which are associated with fulminant forms of hepatitis in up to 25% of cases, are observed both in symptom-free chronic carriers of hepatitis B surface antigen and in patients who have chronic hepatitis B or C and concurrent haematological tumours or solid neoplasms or who have received transplants. HBV-related complications may cause delays or modifications of therapy, and the chance of cure is reduced. In this review, we analyse clinical, biochemical, and serological issues in reactivation of viral replication and examine the role of immune reactions in the pathogenesis and the possible toxicity of immunosuppressive drugs. We emphasise the importance of identifying predictive markers of a clinically relevant reactivation, review difficulties in drug prevention and treatment, indicate studies that are needed to address the key clinical issues, and give practical recommendations to practising physicians and oncologists.

Infections in patients with cancer undergoing chemotherapy: aetiology, prevention, and treatment.

Patients with cancer who are undergoing chemotherapy are highly susceptible, especially if neutropenic, to almost any type of bacterial or fungal infection. These infections cause substantial morbidity and mortality. Prophylactic use of antibiotics should be avoided, however, since this practice is associated with a risk of emergence of resistant bacteria and it does not lower the risk of death. However, chemoprophylaxis has a role for candidal fungal infections. Because infection in a neutropenic host can be rapidly fatal if not treated, the empirical administration of broad-spectrum intravenous antibiotics is generally indicated for these patients, and the local frequencies, susceptibility, and resistance patterns of various pathogens must be taken into account. Once therapy has been initiated, changes in antibiotic regimens during the first 5 days are useless unless the patients clinical condition deteriorates substantially. The treatment of invasive fungal infections is particularly difficult. Many unsolved questions remain, and studies are proposed here that may shed light on these issues.

ANTIGEN SPECIFIC SUPPRESSOR CELL FUNCTION IN AUTOIMMUNE CHRONIC ACTIVE HEPATITIS

An indirect migration inhibition assay has been used to show that lymphocytes from 26 of 29 patients with autoimmune chronic active hepatitis (CAH) generated T lymphocyte migration inhibitory factors (T-LIF) in the presence of liver specific protein (LSP), compared with only 1 of 21 patients with HBsAg-positive chronic liver disease and none of 19 controls. Generation of T-LIF activity in response to LSP was not observed in any of 5 patients with autoimmune thyroid disease although their T lymphocytes did generate T-LIF activity in the presence of thyroid membrane antigens. T lymphocytes from 1 patient with autoimmune liver and thyroid disease generated T-LIF activity in the presence of both LSP and thyroid membrane antigens. The generation of T-LIF activity by T cells from autoimmune CAH patients was suppressed when these cells were co-cultured in a 9:1 ratio with T cells from normal subjects and patients with HBsAg-positive chronic liver disease, but was unaffected if co-cultured with T cells from other patients with autoimmune CAH. T cells from patients with autoimmune CAH did, however, suppress the generation of T-LIF activity by T lymphocytes from patients with autoimmune thyroid disease when these cells were cultured with thyroid membrane antigens. After pretreatment with cimetidine or mitomycin-C for 30 min, T cells from normal subjects lost their ability to inhibit the generation of T-LIF activity to T lymphocytes from autoimmune CAH patients. These results are consistent with the hypothesis that there exists a defect in the specific suppressor T cell population controlling the immune response to LSP in autoimmune CAH which is unaffected by disease activity and treatment and which may be of fundamental importance in the pathogenesis of the disease.