**9. Hepatitis C Virus (HCV)**

mixture of cells (R-Mix) has become commercially available [109]. Rapid antigen detection using several different techniques is available for Influenza, RSV, and Adenovirus. Direct fluorescent antibody (DFA) testing of primary patient specimens has documented sensitivity that approached PCR [110]. Nucleic acid amplification assay appears to be the most sensitive diagnostic tool available, and most allow for simultaneous detection of a broad range of

Treatment depends on the etiological agent. Reduction of immune suppression, if possible, is recommended for all the transplanted recipients. For infections caused by RSV, combination therapy with aerosolized ribavirin and intravenous immunoglobulins appears to have the greatest benefit in reducing mortality [103, 112]. PIV and hMPV infections are treated with oral, aerosolized, or intravenous ribavirin in a combination with intravenous immunoglobu‐ lins [113]. Adenovirus infections are treated with cidofovir, vidarabin, and gancyclovir. Lymphocyte reconstitution plays a crucial role in the clearance of Adenovirus [114]. Treatment of Rhinovirus infections is done with pleconaril and 3C-protease inhibitors, but there is insufficient experience with them and this limits their application. Topical interferon might be efficacious in moderating viral shedding and symptoms [115, 116]. Prevention of Influenza depends on aider vaccination with Influenza vaccine [117] or antiviral therapy. Vaccination is not suitable for bone marrow transplant patients 6–12 months after the transplantation. Patients with severe Influenza should be treated with both M2 inhibitors (rimantadin and

Acute infection with HBV can result in fulminant hepatic failure, whereas chronic HBV infection can lead to end-stage liver disease, including cirrhosis and hepatocellular carcinoma. Understanding of the natural history and basic biology of HBV has increased greatly in recent years. HBV infection is by far the most common chronic viral infection affecting the liver [119]. Reactivation of HBV replication in patients undergoing immunosuppressive therapy is well recognized and is a frequently reported complication of considerable clinical importance [120, 121]. HBV reactivation following immunosuppression is defined by an abrupt rise in HBV replication followed by laboratory signs of hepatocellular injury in "silent" HBV-infected individuals (HBsAg carriers). Reactivation can also occur at a lower rate in patients with "occult" HBV infections. The clinical presentation of reactivation is variable, ranging from an asymptomatic course to severe hepatitis, liver failure, and death. It is most frequently observed in patients with lymphoma treated with rituximab and corticosteroids, as well as in patients undergoing stem cell and bone marrow transplantation. Others risk groups include patients with solid tumors, subjects infected with HIV, organ transplant recipients, and those with autoimmune diseases [122, 123]. It is believed that about 12% of patients with malignancy have chronic HBV infection. In transplanted patients, infection can also reactivate after immuno‐ suppressive therapy. For these reasons, high-risk individuals should be identified and screened. Recommendation for screening for all three serologies, including HBcAb, HBsAg, and HBsAb in those planned for immunosuppression is available [124]. Despite advances in

respiratory pathogens from a simple sample [111].

114 Immunopathology and Immunomodulation

**8. Hepatitis B Virus (HBV)**

amantadin) and neuraminidase inhibitors (relenza and tamiflu [118].

Infections with HCV can result in both acute and chronic hepatitis. Acute HCV typically leads to chronic infection in about 80% of cases. This condition leads to both extrahepatic and hepatic disorders, mainly chronic liver inflammation, cirrhosis and liver cancer [127, 128]. Chronic HCV infection is usually slowly progressive. Approximately 20% to 30% of chronic-infected individuals develop cirrhosis over a 20–30-year period of time. HCV-associated cirrhosis is the most common indication for orthotopic liver transplantation among adults. It is well docu‐ mented, that recurrence of HCV and reinfection of the graft following liver transplantation more frequently occurs. The observations indicate that up to 40% of the patients experience recurrent hepatitis and cirrhosis 5 years later [129]. This progression depends on the age of the donor (below 40 years old), the gravity of the immunosuppression, viral status of the patient before transplantation and a month after it. Prevention and treatment of HCV reinfection and reactivation after liver transplantation remains an unsolved major clinical challenge. HCVpositive patients have poorer long-term outcomes after liver transplantation in comparison with patients with other underlying liver diseases. While treatment with pegilated interferon alpha and ribavirin can cure up to one-third of HCV-positive transplanted patients, there are many promising drugs in clinical and preclinical development targeting either the virion or essential host factors. New strategies to prevent HCV reinfection include neutralizing anti‐ bodies or drugs targeting cellular HCV entry factors. Unfortunately, it will take at least several years until most of these drugs will reach routine clinical practice.

The relationship between HCV infection and immunosuppression is complex. The complexity is further complicated by the intrinsic tendency of HCV infection in itself to lead to disorders of the immune system. After HCV discovery, it was shown that HCV is also a lymphotropic virus, and as a consequence of lymphatic infection, several lymphoproliferative disorders have been associated. Although HCV-related hepatocytolysis is classically interpreted as secondary to attack by cytotoxic T-lymphocytes against infected cells, the liver disease is usually exacer‐ bated and more rapidly evolutive in immunosuppressed patients [130, 131]. Liver disease secondary to chronic HCV infection is an important cause of morbidity and mortality in dialysis patients and kidney transplant recipients. Eradication of infection before transplan‐ tation seems to reduce the risk for HCV-associated renal dysfunction after transplantation, and may reduce risk of HCV disease progression. For dialysis patients, ribavirtin is generally contraindicated and alternatives are needed to enhance antiviral effects of interferon. New therapies with taribavirin may offer specific advantage in this patient group [132, 133]. In individuals with defects in cell-mediated immunity, predominantly CD4Th1, occurring in HIV infection and in patients requiring multi-drug immunosuppression following solid organ transplantation, chronic liver disease caused by HCV progresses more rapidly than in immunocompetent individuals. The rate of progress seems to correlate with the degree of immunosuppression. The prolonged suppressive therapy aggravates liver function [134]. Liver-related mortality is higher in those patients who are co-infected with HCV and HIV. All immunosuppressed and HIV infected patients should be screened for HCV infection using sensitive immunoassay licensed for detection of antibodies to HCV. For laboratory tests, ELISA is most widely used from the serological methods. HCV seropositive patients should be tested for HCV RNA using a sensitive quantitative assay to confirm the presence of active infection by RT PCR. Patients with positive HCV-RNA test should be genotyped and should be evaluated for HCV therapy [134, 135]. Liver disease in an immunosuppressed patient is typically severe with unusual progression to cirrhosis. However, accurate screening and specialized advice is recommended as soon as possible in HCV-positive patients.

For the last few years, there has been great progress in the production and application of drugs for prophylaxis and treatment of latent and chronic viral infections in immunosuppressed and transplanted patients. Various schemes for drug usage have been developed and have been permanently completed. Immunosuppressed patients very often are affected with nosocomial infections in hospitals, and with infections in the society. For this reason, accurate screening and prompt and precise diagnosis can be performed to prevent exacerbation of diseases and provide appropriate treatment.

#### **Author details**

Liliya Ivanova\* , Denitza Tsaneva, Zhivka Stoykova and Tcvetelina Kostadinova

\*Address all correspondence to: liivanova@abv.bg

Medical University "Prof. d-r Paraskev Stoyanov" – Varna, Department of Microbiology and Virology, St. Marina University Hospital – Varna, Bulgaria

#### **References**

[1] Cohen LI. Epstein-Barr virus infection. N Engl J Med. 2000;343(7):481-492.

[2] Ivanova L. Herpesvirus infections in human population in Northeastern Bulgaria. Scr Sci Med (ISSN 0582-3250). 2007;39(2):1-6.

secondary to chronic HCV infection is an important cause of morbidity and mortality in dialysis patients and kidney transplant recipients. Eradication of infection before transplan‐ tation seems to reduce the risk for HCV-associated renal dysfunction after transplantation, and may reduce risk of HCV disease progression. For dialysis patients, ribavirtin is generally contraindicated and alternatives are needed to enhance antiviral effects of interferon. New therapies with taribavirin may offer specific advantage in this patient group [132, 133]. In individuals with defects in cell-mediated immunity, predominantly CD4Th1, occurring in HIV infection and in patients requiring multi-drug immunosuppression following solid organ transplantation, chronic liver disease caused by HCV progresses more rapidly than in immunocompetent individuals. The rate of progress seems to correlate with the degree of immunosuppression. The prolonged suppressive therapy aggravates liver function [134]. Liver-related mortality is higher in those patients who are co-infected with HCV and HIV. All immunosuppressed and HIV infected patients should be screened for HCV infection using sensitive immunoassay licensed for detection of antibodies to HCV. For laboratory tests, ELISA is most widely used from the serological methods. HCV seropositive patients should be tested for HCV RNA using a sensitive quantitative assay to confirm the presence of active infection by RT PCR. Patients with positive HCV-RNA test should be genotyped and should be evaluated for HCV therapy [134, 135]. Liver disease in an immunosuppressed patient is typically severe with unusual progression to cirrhosis. However, accurate screening and

specialized advice is recommended as soon as possible in HCV-positive patients.

provide appropriate treatment.

116 Immunopathology and Immunomodulation

\*Address all correspondence to: liivanova@abv.bg

and Virology, St. Marina University Hospital – Varna, Bulgaria

**Author details**

Liliya Ivanova\*

**References**

For the last few years, there has been great progress in the production and application of drugs for prophylaxis and treatment of latent and chronic viral infections in immunosuppressed and transplanted patients. Various schemes for drug usage have been developed and have been permanently completed. Immunosuppressed patients very often are affected with nosocomial infections in hospitals, and with infections in the society. For this reason, accurate screening and prompt and precise diagnosis can be performed to prevent exacerbation of diseases and

, Denitza Tsaneva, Zhivka Stoykova and Tcvetelina Kostadinova

Medical University "Prof. d-r Paraskev Stoyanov" – Varna, Department of Microbiology

[1] Cohen LI. Epstein-Barr virus infection. N Engl J Med. 2000;343(7):481-492.


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