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Herpesvirus Infections in the Immunocompromised Patient
- Herpesviruses in the Immunocompromised
- HUMAN IMMUNODEFICIENCY VIRUS (HIV) AND HERPES SIMPLEX VIRUS (HSV) COINFECTION
- HUMAN HERPESVIRUS 6 (HHV-6) INFECTION
- HUMAN HERPESVIRUS 8 (HHV-8) INFECTION
- EPSTEIN-BARR VIRUS (EBV) INFECTION
- CYTOMEGALOVIRUS (CMV) INFECTION
Herpesviruses in the Immunocompromised
Patient Infections with the human herpesviruses are extremely common. Primary and recurrent infections with Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) are usually asymptomatic, with each virus eventually infecting more than 90% of Americans. In addition, by age 50 approximately 50% of healthy Americans have been infected with cytomegalovirus (CMV). Infection is, again, generally asymptomatic unless it occurred congenitally. Human herpesvirus 8 (HHV-8) infection is less common, affecting 0%-4% of healthy American adults (the prevalence is higher in men who have sex with men), and, similar to the above, primary and reactivated HHV-8 infection is generally asymptomatic in the immunocompetent population.
Most transplant recipients harbor several human herpesviruses, which is not surprising given their wide distribution. Infection with any of these herpesviruses can threaten the survival of both the patient and the graft. If the recipient is seronegative for CMV, EBV, HHV-6, or HHV-8, he or she is at risk of infection from donor organs. In addition, persons immunocompromised due to human immunodeficiency virus (HIV) infection or cancer can be strongly affected by herpesviruses. This section briefly describes CMV, EBV, HHV-6, and HHV-8 infections in immunocompromised patients, as well as herpes simplex virus (HSV) infection in persons with HIV infection.
The International Herpes Management Forum's journal, Herpes, available online at http://www.ihmf.org/journal/journal.asp, contains many detailed articles on all herpesvirus infections in the immunocompromised patient. Details also can be found in a number of issues of the American Herpes Foundation's The Herpes Monitor available at http://www.herpes-foundation.org/monitor.htm.
Human Immunodeficiency Virus (HIV) and Herpes Simplex Virus (HSV) Coinfection
Human Herpesvirus 6 (HHV-6) Infection
Human Herpesvirus 8 (HHV-8) Infection
Epstein-Barr Virus (EBV) Infection
Cytomegalovirus (CMV) Infection
HUMAN IMMUNODEFICIENCY VIRUS (HIV) AND HERPES SIMPLEX VIRUS (HSV) COINFECTION
HSV is the most common opportunistic infection in HIV-infected American adults, with 50% to 80% of HIV-seropositive males coinfected with HSV-2, and perhaps 90% or more coinfected with HSV-1. Coinfection with HSV-2 is also extremely common in HIV-infected pregnant women, with 75% found to have HSV-2 antibodies compared with 32% of those who are HIV seronegative. This coinfection increases the risk of HIV disease progression, decreases survival rates, and alters the natural history of HSV-2 through the complex interrelationship between the 2 viruses.
Effect of HIV on HSV Disease
Although genital herpes may be as unrecognizable in persons with early stage HIV infection as it is in HIV-seronegative individuals, outbreaks of HSV-2 infection are generally more severe, extensive, persistent, and invasive in those with more advanced HIV disease. First-episode genital herpes in this population can be characterized by extensive and progressive anogenital lesions and systemic symptoms, while reactivation of HSV infection can present as multiple necrotic lesions in atypical locations, particularly in the perirectal area. Symptoms can include large sloughing ulcers, rectal spasm with tenesmus, severe pain, obstipation, sacral paresthesias, and bacterial superinfection. Orolabial lesions can also progress to severe disease, such as oral stomatitis or esophagitis. Furthermore, individuals coinfected with HSV-2 and HIV are 3 to 7 times more likely to symptomatically and asymptomatically shed HSV-2 than those who are HIV seronegative. This increased likelihood of shedding puts HIV-infected persons at greater risk of unwittingly transmitting HSV, particularly when such shedding is asymptomatic.
Effect of HSV on HIV
Disease Reactivation of HSV-2 accelerates the progression of HIV disease toward and beyond AIDS. Acute HSV infection has been shown to result in a significant increase in levels of HIV RNA. Reactivation of HSV in the prior year was reported to be significantly associated with the rapid onset of AIDS.
Diagnosis of HSV Infection in HIV-Seropositive Persons
HSV antibody status can be easily determined by type-specific serological testing, while the causative agent of ulcers can be confirmed by viral culture. Once HSV status is known, patients can be counseled about virus transmission and, if HSV seropositive, appropriately managed. For example, HIV-seropositive pregnant women may require cesarean section delivery if HSV reactivates at delivery, while HIV-seropositive individuals in HSV-discordant relationships may need to desist from oral sex and use condoms during sexual activities.
Treatment of HSV Infection in HIV-Seropositive Persons
Because of the complex molecular interaction between HIV and HSV, coinfected patients need to be managed far more aggressively than patients infected with HSV alone. By optimizing control of HIV disease with highly active antiretroviral therapy (HAART), the reactivation of HSV-2 will be reduced. In addition, antiherpes therapy may help to control HIV disease and reduce HIV transmission and acquisition. Although the antiherpes drugs, acyclovir, famciclovir, foscarnet, and valacyclovir, are effective in the HIV-infected patient, in coinfected patients they often work more slowly and higher doses may be required (eg, acyclovir 400 mg 3-5 times daily for 10 or more days for episodic therapy). Furthermore, HSV is likely to be more resistant to antiviral therapy in individuals coinfected with HIV, though the level of resistance remains fairly low. Nonetheless, aggressive antiherpes therapy will usually limit and resolve HSV disease in the HIV-infected individual, even when HSV manifestations are severe.
Additional Information can be found at:
http://www.medscape.com/pages/editorial/resourcecenters/public/herpes/rc-herpes3
Genital herpes resource center, section on HSV/HIV coinfection.
http://www.who.int/docstore/hiv/herpes_meeting/
Herpes Simplex Virus Type 2: Programmatic and Research Priorities in Developing Countries (report of a WHO/UNAIDS/LSHTM Workshop (London, February 14-16, 2001). World Health Organization.
http://www.findarticles.com/cf_dls/m0CYD/4_37/83530604/p1/article.jhtml
Jancin B. Genital herpes may raise HIV transmissibility. News; Feb 15, 2002.
HUMAN HERPESVIRUS 6 (HHV-6) INFECTION
HHV-6 in Transplantation
The pathogenic role of HHV-6 in transplant patients is not yet clear due to the high seroprevalence of HHV-6 in the general population (more than 90% of American adults). The virus is commonly reactivated in renal, liver, and bone marrow transplant (BMT) patients within the first several weeks following transplantation, though most recurrences are asymptomatic. Nonspecific fever is the most common symptom associated with reactivated HHV-6 infection in BMT recipients, and this may be accompanied by leukopenia and/or a rash resembling graft-versus-host disease. It also can result in bone marrow failure. In solid organ transplant recipients, symptomatic reactivated HHV-6 includes fever, bone marrow suppression, and pneumonitis, and may result in graft dysfunction or rejection and the development of opportunistic fungal infections. HHV-6 reactivation also may be a risk factor for CMV disease in this population, with coinfection more likely to lead to pneumonia, gastrointestinal disease, hepatitis, neutropenia, thrombocytopenia, and retinitis.
Some transplant centers routinely monitor for HHV-6 infection using specialized virological techniques (eg, culture, in situ hybridization, polymerase chain reaction [PCR], serology) on blood, saliva, peripheral blood mononuclear cells, and/or cerebrospinal fluid samples. This is despite the fact that optimal treatment for reactivated HHV-6 infection has not been established. Asymptomatic disease is generally not treated, while a combination of ganciclovir and foscarnet may be an effective treatment for symptomatic disease. Prophylaxis with ganciclovir or acyclovir may reduce the incidence of HHV-6 infection.
Persons With HIV Infection
HHV-6 frequently reactivates in persons with HIV infection, sometimes leading to pneumonitis, encephalitis, and retinal disorders. As with HIV, HHV-6 infects T cells, and primary HHV-6 infection may accelerate HIV disease. There seems to be little consensus on the treatment of HHV-6 infection in persons coinfected with HIV, though foscarnet, cidofovir, ganciclovir, and adefovir may be active against HHV-6 in this population.
Cancer
Because HHV-6 was originally isolated from tissues of patients with lymphoproliferative disease, HHV-6 has been considered an etiologic agent or cofactor for several malignancies, including lymphoma. The virus has been detected in tissues from patients with non-Hodgkin's lymphoma, Hodgkin's disease, Rosai-Dorfman disease, and other lymphoproliferative conditions. However, a causative role has yet to been determined.
Additional Information can be found at:
http://www.medscape.com/viewarticle/416732
Fantry LE, et al. HHV-6 infection in patients with HIV-1 infection and disease. The AIDS Reader. 1999;9:198-203, 221.
http://organtx.org/dc/hhv6.htm
Articles on HHV-6 from the Organ Transplant Association.
http://www.cdc.gov/ncidod/eid/vol5no3/pdf/campadelli.pdf
Campadelli-Fiume G, et al. Human herpesvirus 6: an emerging pathogen. Emerg Infect Dis. 1999;5:353-367.
HUMAN HERPESVIRUS 8 (HHV-8) INFECTION
HHV-8 is an oncogenic virus causing Kaposi's sarcoma (KS) and primary effusion lymphoma, mainly in immunosuppressed individuals. Disease caused by HHV-8 infection is more common than disease due to HHV-6 infection in patients with AIDS, while the converse is true for transplant recipients.
Kaposi's Sarcoma
KS is the most common manifestation of HHV-8 in adults with HIV infection, with approximately 15% to 20% of American patients with AIDS having the disease (particularly homosexual and bisexual males). KS is also the major complication from HHV-8 infection in tissue transplant patients, representing about 6% of all cancers in transplant recipients. Between 14% and 28% of kidney transplant patients with a reactivation of HHV-8 may develop KS, equating to between 0.2% and 5% of all renal transplant recipients. Furthermore, HHV-8 can be transmitted by donor tissue to HHV-8 seronegative renal transplant patients, and up to 14% of these recipients subsequently develop KS. The disease can be very aggressive in transplant recipients, with a mortality rate of 34% within 3 years of diagnosis.
KS is characterized by elliptic lesions that follow skin tension lines and may be symmetrically distributed. The lesions (generally papules of various colors ranging from millimeters to centimeters in size) tend to be concentrated on the lower extremities, genitalia, and face. Patients with AIDS may first present with oral manifestations of disease, though the disease can eventually involve the lymph nodes and the gastrointestinal and/or pulmonary systems. In transplant recipients, KS is generally cutaneous, though it also may affect the allografted and other organs. Management of KS generally involves palliative and cosmetic therapy. Limited KS is also treated with radiotherapy; intralesional chemotherapy with interferon-alpha, vinblastine, or tumor necrosis factor-a; and surgical excision.
Lymphoproliferative Disorders
HHV-8 has been strongly associated with 2 lymphoproliferative disorders, primary effusion lymphoma and multicentric Castleman's disease (MCD), particularly in patients coinfected with HIV. The former is an uncommon, rapidly progressive fatal disease that occurs predominantly in men with AIDS. It presents in the absence of tissue-based disease, involves distension of the relevant body cavity (abdomen, pericardium, pleura), and may be present concurrently with KS. Treatment is usually palliative as patients are often too sick to tolerate chemotherapy. MCD is a relatively rare, possibly fatal, lymphoproliferative disorder of B cells in patients with AIDS. Symptoms include angiofollicular hyperplasia associated with fever, lymphadenopathy, splenomegaly, and perhaps upper respiratory tract symptoms and peripheral edema. It is also sometimes reported in conjunction with KS. The disease is currently treated with low-dose chemotherapy.
Additional Information can be found at:
http://www.nlm.nih.gov/medlineplus/kaposissarcoma.html
National Institutes of Health health topic on Kaposi's sarcoma.
http://depts.washington.edu/herpes/
Information on HHV-8 from the University of Washington.
http://cmr.asm.org/cgi/content/full/15/3/439
Ablashi DV, et al. Spectrum of Kaposi's sarcoma-associated herpesvirus, or human herpesvirus 8, diseases. Clin Microbiol Rev. 2002;15:439-464.
EPSTEIN-BARR VIRUS (EBV) INFECTION
EBV infection can be life threatening in immunocompromised individuals. The virus is oncogenic, and the failure of cellular immune constraints on EBV-infected B cells often results in lymphoproliferative disorders, particularly in patients with congenital or acquired immunodeficiency (eg, infants and children with severe combined immunodeficiency or patients with AIDS) or in immunosuppressed transplant recipients. EBV is also implicated in the development of other tumors. Between 40% and 60% of tumors from otherwise healthy American patients with Hodgkin's lymphoma contain EBV DNA. The virus may also be associated with nasopharyngeal carcinoma, nasal T-cell lymphomas, and cutaneous T-cell lymphomas.
Lymphoproliferative Disease in AIDS or Transplant Patients
Between 1% and 10% of solid organ and bone marrow transplant recipients develop EBV-associated proliferative disease. Mortality in such patients can reach 50% to 80%. Furthermore, approximately one third of B-cell lymphomas-particularly Hodgkin's, Burkitt's, and central nervous system lymphomas, and leiomyosarcomas (cancers of smooth muscle cells)-in patients with AIDS contain EBV DNA. In all cases of lymphoproliferative disease, tumors may grow quickly or slowly, and may be localized or disseminated. Patients can present with infectious mononucleosis and/or with lymphoproliferation involving one or more organs or systems (including lymph nodes, liver, lung, kidney, bone marrow, central nervous system, and small intestine). The disease is diagnosed histologically and through the presence of EBV DNA, EBV RNA, or protein in excisional biopsy tissue or in cerebrospinal fluid. It is usually managed in transplant recipients by significantly decreasing the dose of immunosuppressive therapy. If the reduction in immunosuppressive therapy fails or if the patient has AIDS, radiation or cytotoxic chemotherapy of tumors can be effective, as can the monoclonal antibody, rituximab. Surgery may be useful for anatomically limited disease, tumor debulking, or the management of local complications.
Oral Hairy Leukoplakia
Nonmalignant oral leukoplakia is also a relatively common EBV-associated disease in HIV-positive individuals and sometimes in patients with other immunodeficiences. Oral hairy leukoplakia is characterized by slightly raised, white, corrugated (or "hairy") lesions of the tongue and oral mucosa. Except for the presence of lesions, patients generally report no pain or other symptoms. Confirmation of disease can be obtained by identifying EBV in cell scrapings or in a biopsy specimen. Treatment is usually unnecessary, though the disease does respond well to antiviral therapy such as oral acyclovir (400 - 800 mg 5 times daily) or ganciclovir. However, lesions frequently reoccur after therapy is discontinued.
X-Linked Lymphoproliferative Disease
X-linked lymphoproliferative disease is a rare and generally fatal inherited congenital immunodeficiency disorder of young boys who develop fulminant mononucleosis after primary EBV infection. B and T cells infiltrate organs and displace bone marrow elements, resulting in hemorrhage or severe infection. More than two thirds of children die of the disease within weeks of infection. Those who survive experience aplastic anemia, hypo- or hypergammaglobulinemia, opportunistic infections, or lymphomas. All males with X-linked lymphoproliferative disease die by 40 years of age.
Additional Information can be found at:
http://www-ermm.cbcu.cam.ac.uk/01003842h.htm
Murray PG, et al. Epstein-Barr virus infection: basis of malignancy and potential for therapy. Exp Rev Mol Med. November 15, 2001.
http://www.bloodjournal.org/cgi/reprint/2002-01-0210v1.pdf
Porcu P, et al. Successful treatment of post-transplant lymphoproliferative disorder (PTLD) following renal allografting is associated with sustained CD8+ T-cell restoration. Blood. 2002.
http://www.emedicine.com/ped/topic2851.htm
Posttransplant lymphoproliferative disease. Updated April 9, 2002.
http://www.a-s-t.org/library/pdf/tr229901517p.pdf
Paya CV, et al. Epstein-Barr virus-induced posttransplant lymphoproliferative disorders. ASTS/ASTP EBV-PTLD Task Force and The Mayo Clinic Organized International Consensus Development Meeting. Transplantation. 1999;68:1517-1525.
http://www.cdc.gov/ncidod/diseases/ebv.htm
(One-page description of EBV disease by the Centers of Disease Control and Prevention)
CYTOMEGALOVIRUS (CMV) INFECTION
Approximately 40% to 90% of American adults have antibodies to CMV, with infection generally occurring in the perinatal period and during early childhood. Although primary infection is generally asymptomatic in healthy persons, it can cause serious illness in patients who are immunocompromised.
Solid Organ and Bone Marrow Transplant Recipients
Reactivated or primary CMV is the most common and well-studied opportunistic infection in transplant patients. CMV activity generally appears 4 to 6 weeks after transplantation and varies from a relatively benign manifestation to extensive involvement of the liver, lungs, and gastrointestinal tract, resulting in graft loss and/or death. Symptoms may include high fever, disseminated infection, pneumonitis, fatigue, anorexia, arthralgias or myalgias, leukopenia, thrombocytopenia, atypical lymphocytosis, gastrointestinal ulcerations, increased frequency of bacterial and fungal infections, or documented invasive CMV disease into organs. Retinitis is uncommon in transplant recipients.
The incidence of clinically apparent infection ranges from 20% to 60%, though these rates are steadily declining as serology is routinely used to identify those at risk. At-risk patients are managed with prophylactic and preemptive therapy such as ganciclovir or valganciclovir. However, such preventive strategies may result in late-onset CMV disease, which can occur once prophylactic therapy has been discontinued. In some cases, this can involve infection with ganciclovir-resistant mutant viruses. In those cases, foscarnet or cidofovir should be used.
Persons With HIV Infection
CMV infection used to be common in persons with HIV infection, with retinitis the most common manifestation of disease. CMV retinitis was associated with an increased risk of death and was characterized by relapsing disease resulting in progressive visual loss. With the introduction of highly active antiretroviral therapy (HAART), morbidity and mortality has decreased significantly. Not only is CMV retinitis far less common, but when it does occur, patient survival is greatly increased. Those patients at highest risk of developing CMV retinitis after HAART may be identified by the presence of CMV viremia at pre-HAART screening. These high-risk patients should be considered for preemptive therapy with ganciclovir or valganciclovir prior to starting HAART.
Additional Information can be found at:
http://www.cdc.gov/ncidod/diseases/cmv.htm
General description of the virus and its diagnosis and treatment by the Centers for Disease Control and Prevention.
http://www.medscape.com/viewarticle/466156
Pescovitz, MD. Prevention and treatment of cytomegalovirus disease in solid organ transplant recipients: the clinical and economic impact of evolving strategies. American Health Sys Pharm. 2003;60:S3-S4. Posted 01/09/2004.
http://www.medscape.com/viewprogram/2255
Drew WL, et al. New Perspectives on CMV and Other Viruses in the Immunocompromised Patient. University of Minnesota CME program.
http://www.medscape.com/viewprogram/2162
Rubin RH, et al. New Therapeutic Options in CMV Infection. Dannemiller Memorial Educational Foundation CME program.
http://www.medscape.com/viewprogram/663
Dunn JP, et al. Treatment of Cytomegalovirus (CMV) Retinitis in the Era of Highly Active Antiretroviral Therapy. Medical Education Collaborative CME Program.
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American Herpes Foundation - Hackensack, New Jersey
Telephone (201) 342-4441 | Fax (201) 342-7555