Herpesvirus Infections in Immunocompromised Patients An Overview

Immunocompromising conditions Congenital immunodeficiencies e.g.. Di George, Wiskott-Aldrich syndrome. AIDS Haematological malignancies such as leukaemia. Organ transplant recipients Autoimmune diseases eg. SLE Iatrogenically immunosuppressed patients e.g. cancer patients receiving chemotherapy.

Herpesvirus Enveloped DNA viruses. Set up latent infection following primary infection. Reactivation are more likely to take place during periods of immunosuppression. Both primary infection and reactivation are likely to be more serious in immunocompromised patients.

Herpesvirus Particle HSV-2 virus particle. Note that all herpesviruses have identical morphology and cannot be distinguished from each other under electron microscopy. (Courtesy of Linda Stannard, University of Cape Town, S.A.)

Herpes Simplex Virus Normal individuals Primary HSV infection usually occurs in childhood, the majority of infections are asymptomatic or present with a gingivostomatitis. The virus becomes latent in the craniospinal ganglia. The virus may then be reactivated from time to time by various triggers such as stress, infection, sunlight, immunosuppression.

Herpes Simplex Virus Immunocompromised individuals Patients receiving cytotoxic therapy, organ graft recipients, and patients with AIDS are at risk of severe HSV disease. HSV disease are more frequent and severe in these patients. Severe local disease or disseminated infection may be seen. Acyclovir may be used to treat HSV infection, but resistance to acyclovir may emerge during long term therapy. Acyclovir is now routinely given as prophylaxis for those receiving organ graft transplant, and HSV has ceased to be a major problem in these patients.

Varicella-Zoster Virus Normal individuals Primary infection (chickenpox) is one of the classical rash diseases of childhood. Following primary infection, the virus remains latent in the cranial-spinal ganglia. Reactivation leading to the appearance of shingles occurs in 10-20% of infected individuals and usually occurs after the fourth decade of life. Usually, only one episode of reactivation occurs.

Immunocompromised individuals Primary infection Chickenpox is much more severe in children undergoing treatment for malignancies such as leukaemia and lymphoma. Life-threatening complications such as disseminated varicella, pneumonia, and encephalitis are much more likely to be seen. Reactivation Immunocompromised individuals are at risk of developing herpes zoster, herpes zoster may appear at an earlier age than usual in these individuals, furthermore, more than one episode may occur. Severe, disseminated disease may occur but fatality is rare.

Treatment and Prevention Acyclovir may be used for the treatment of severe varicella or zoster infections. A live attenuated vaccine has now been licensed in many countries. Its use is still controversial in immunocompromised individuals because it is a live vaccine. Recent data suggests that it is safe in children with leukaemia provided that they are in remission. VZIG can be used to prevent primary infection in susceptible individuals.

Cytomegalovirus Normal individuals Primary infection is usually asymptomatic, occasionally an infectious mononucleosis-like illness may be seen. Reactivations or re-infections are common throughout life and are usually asymptomatic.

Immunocompromised individuals Both primary and recurrent infection may lead to symptomatic disease. Primary CMV infection is usually more severe than recurrent infection, with the exception of bone marrow transplant recipients, where primary and recurrent infections are just as severe.

Clinical Manifestations Fever Pneumonitis Hepatitis Gastrointestinal manifestations eg. colitis Encephalopathy Retinitis Poor graft function Pneumonitis is the most severe manifestation, and carries a mortality rate of 85% in the absence of treatment.

AIDS Patients CMV disease is present in 7.4% to 30% of all AIDS patient. Sight-threatening retinitis, colitis, and encephalopathy are the most common manifestations of CMV disease in AIDS patients. Pneumonitis is extremely rare.

Solid organ transplant recipients e.g. renal, liver, heart Most common infection, leading cause of morbidity and mortality. Occurs 1 - 3 months following transplant. Primary infection more severe than recurrent infection. Patients may present with fever, pneumonitis, GI manifestations, hepatitis, and poor graft function. Does not appear to be associated with organ rejection.

Bone marrow transplant recipient The host immune system is ablated before the transplant and thus every aspect of the immune system is deficient. CMV is the leading infection and the greatest cause of transplant failure. Both primary and recurrent infection may cause severe disease, pneumonitis is seen in 15% of patients. At special risk are seropositive recipients of graft from seronegative donors, and seronegative recipients of graft from seropositive donors.

Laboratory Diagnosis (1) In general, the detection of CMV from blood specimens or bronchioalveolar lavage is more prognostic of clinical CMV disease than the detection of the virus from urine or saliva. 1. Virus isolation (a) Conventional cell culture - human embryo lung fibroblasts used, requires 1 to 3 weeks for characteristic CPE to appear, remains the gold standard for the diagnosis of CMV infection (b) Rapid culture methods - eg. DEAFF test - detects the expression of CMV early antigens within 24 to 48 hours of inoculation. Appears to be as sensitive and specific as conventional cell culture.

Cytopathic Effect of CMV (Courtesy of Linda Stannard, University of Cape Town, S.A.)

DEAFF test for CMV (Virology Laboratory, Yale-New Haven Hospital)

Laboratory Diagnosis (2) 1. CMV antigenaemia test - widely used in many European countries. CMV antigens at the surface of polymorphonuclear leukocytes are detected by immunoperoxidase or immunofluorescence techniques. A result can be obtained within 4 to 6 hours but the technique is very tricky. 2. Polymerase chain reaction - becoming the method of choice in a few laboratories, had been reported to carry a higher prognostic value for CMV disease than the DEAFF test. Potential problems with sensitivity. 3. Serology - not reliable in general but occasionally, rises in IgG titre and the presence of IgM may be seen.

CMV pp65 antigenaemia test (Virology Laboratory, New-Yale Haven Hospital)

Management (1) Ganciclovir - is the drug of choice. However, it is associated with neutropenia and thrombocytopenia. Forscarnet - can be used as the 2nd line drug. Again it is very toxic and is associated with renal toxicity. Cifofovir (HPMCC) - approved for the treatment of CMV retinitis. It is also associated with renal toxicity. Fomivirsen - intravitreal fomivirsen is approved for the treatment of CMV retinitis. CMV hyperimmune globulin - found to be effective against CMV pneumonitis.

Management (2) Transplant Recipients - once clinical disease is established, the patient should be treated vigorously with antiviral agents. Ganciclovir is the drug of choice. CMV hyperimmune globulin had been found to be useful in the treatment of CMV retinitis. AIDS patient with retinitis - vigorous antiviral therapy should be given. Both systemic and local (intravitreal implants) may be used.

Prevention Pre-transplant donor-recipient matching - shown to be effective in reducing CMV disease but will be very difficult to implement in Hong Kong because of the high seropositive rate. Prophylaxis - prophylaxis with acyclovir/ganciclovir for all transplant recipients and CMV immunoglobulin for seronegative recipients of graft from seropositive donors should be considered. Vaccination - an experimental live attenuated vaccine known as the Towne strain is available but there is great reluctance to give it to immunocompromised individuals. Subunit vaccines are being developed.

Post-transplant surveillance Weekly surveillance blood, urine or saliva cultures are now routinely carried out for bone marrow transplant recipients and other organ transplant recipients if clinically indicated. Bronchioalveolar lavages are performed routinely at 1 month post-transplant in some centres. In general, a positive result from urine or saliva warrants extra vigilance and relaxation of immunosuppression should be considered. A positive result from the blood or BAL warrants the commencement of antiviral therapy with ganciclovir.

Epstein-Barr Virus After primary infection, EBV maintains a steady low grade latent infection in the body. During periods of immunosuppression, the virus may reactivate to cause clinical disease. In a few cases, lymphoproliferative lesions and lymphoma may develop. These lesions tend to be extranodal and in unusual sites such as the GI tract or the CNS. Three groups of immunocompromised patients are particularly susceptible to severe EBV associated diseases: X-linked lymphoproliferative syndrome, transplant recipients, and AIDS.

Risk Groups Ducan X-linked lymphoproliferative syndrome - this condition occurs exclusively in males who had inherited a defective gene in the X-chromosome . This condition accounts for half of the fatal cases of IM. Transplant Recipients - solid organ tranplant recipients encountering primary EBV infection in the post transplant period may develop Post Transplant Lymphoproliferative Disorder. Transplant recipients are also prone to develop lymphoproliferative disorders and lymphomas several years after the transplant. AIDS - EBV is associated to varying degrees with certain types of non-Hodgekin’s lymphoma in AIDS patients. These include primary lymphoma of the brain, Burkitt’s lymphoma, and immunoblastomas.

Post Transplant Lymphoproliferative Disorder PTLD is thought to be a lymphoproliferation of EBV infected B-cells arising in the setting of over immunosuppression. The patients at risk are those who encounter EBV as a primary infection during the post-transplant course. The proliferation may be seen anywhere lymphoid tissue presides, although in lung transplant recipients, presentation in the allograft is relatively common. Histopathological manifestation appears as nodular sheets of atypical lymphoid cell which are not dissimilar to Non-Hodgkins lymphomas. Some cases are similar to lymphomatoid granulomatosis or T-cell rich B-cell lymphomas with a large subset of reactive T-cells. Reduction in immunosuppression often results in regression of PTLD.

HHV-6 and HHV-7 Like other herpesviruses, HHV-6 and HHV-7 become latent following primary infection and are reactivated from time to time, especially during periods of immunosuppression. HHV-6 infection is firmly associated with roseala infantum. It had also been associated with neurological manifestations such as febrile convulsions, meningitis, and encephalitis. It had also been associated with a variety of symptoms in transplant recipients such as fever, graft vs host disease, liver and CNS manifestations. However such associations are very difficult to prove since CMV is almost always concomitantly reactivated. Likewise the role of HHV-6 reactivation in HIV infection remains unclear. HHV-7 is not associated conclusively with any human disease.

Human Herpes Virus 8 Now appears to be firmly associated with Kaposi’s sarcoma as well as some lesser known malignancies such as Castleman’s disease and primary effusion lymphomas. HHV-8 DNA is found in almost 100% of cases of Kaposi’s sarcoma. Most patients with KS have antibodies against HHV-8. The seroprevalence of HHV-8 is low among the general population but is high in groups of individuals susceptible to KS, such as homosexuals. Unlike other herpesviruses, HHV-8 does not have a ubiquitous distribution.