• Cytomegalovirus
• CMV Infections in the Neonate
• Human Herpesvirus Type 6 (HHV-6)
• Human Herpesvirus Type 7 (HHV-7)

Gamma-Herpesviruses

• Epstein–Barr Virus (EBV)
• Human Herpesvirus Type 8 (HHV-8)

Other Approaches to CMV Management

Pathogenesis of CMV Infections in Transplant Recipients

CMV is an important viral pathogen in transplant recipients and is a major cause of graft rejection, end-organ diseases and death:

• Symptomatic CMV infection occurs in 25% of patients following liver transplantation

• The most common organ-specific manifestations are CMV hepatitis and gastrointestinal disease

• Evidence from epidemiological studies shows that CMV has an immunosuppressive effect and increases the risk for secondary bacterial and fungal infections. The mechanisms for this effect include complex interactions between CMV and the host

• Clinical manifestations vary considerably, depending on the context of infection (i.e. type of transplant and type of immunosuppression).

Management of CMV Infections in Transplant Patients

Preventing Infection

There are a number of ways of preventing CMV infection, including:

The benefits achieved by preventing CMV disease may extend to other areas in the general health of the transplant recipient, such as graft rejection.   The polymerase chain reaction and antigenaemia help to decide when to trigger pre-emptive therapy. Prospective studies using the length of hospital stay as the primary parameter of morbidity have indicated that:

Treating Established CMV Disease in Transplant Recipients

For more information, see the monographs:

	Cytomegalovirus and Human Herpesvirus Type 6 Infections in the Immunocompromised (non-HIV) Host
	Herpesvirus Infections in the Immunocompromised Host with HIV

In solid organ transplant recipients, ganciclovir is indicated:

• Immunoglobulin could be combined with antiviral therapy in donor- positive/recipient-negative patients

• Some experts would add immunoglobulin to the treatment of severely ill patients. Such a combination can be useful in cases of interstitial pneumonia, but appears to be ineffective in gastrointestinal diseases

• Combination therapy with antivirals such as ganciclovir and foscarnet may be effective, but further studies are needed

• Bone marrow transplant recipients with CMV pneumonitis diagnosed by bronchoalveolar lavage should be treated with ganciclovir plus CMV immunoglobulin. There are no recommendations on whether polyspecific or hyperimmune immunoglobulin should be used

• By analogy with individual with AIDS, cidofovir should be considered for the treatment of CMV retinitis, although cases are rare in the transplant population.

• CMV infection is the most common congenital infection in the USA (neonatal infection is present in 1% of all live births), i.e. the infection is acquired in utero

• Approximately 10% of congenitally infected infants have signs of neurological and systemic infection at delivery

• CMV is also the most common microbial cause of birth handicap in the developed world. Manifestations of infection in the central nervous system (CNS) are often profound, and CMV infection is the second most identifiable cause of mental retardation in the USA

Skull film congenitally infected infant, showing periventricular calcifications	Head computed tomography scan of congenitally infected infant, showing cerebral calcifications

• Infants with CMV disease present with abnormal tone, microcephaly, lethargy and chorioretinitis. Hearing loss can develop in 15% of infected infants who are symptom-free at birth

• Severe sequelae, such as growth retardation, mental retardation, blindness, deafness, seizures, hepatosplenomegaly and death occur in between 3000 and 4000 infected infants per year in the USA

• Long-term disabilities may include seizures, deafness, blindness, and developmental delay

• The pathogenesis of CMV within neonatal CNS is not understood. It is presumed that CMV enters the CNS through the bloodstream. CMV is rarely cultured from the cerebrospinal fund (CSF) of congenitally infected infants

• The efficacy of antiviral therapy for CMV infection is unconfirmed, but a controlled trial showed that ganciclovir was well tolerated. The preferred dose is now being tested against no treatment, to determine if efficacy outweighs expected toxicity

• Maternal immunity to CMV has a protective effect. After primary infection, the rate of transmission from mother to fetus is around 40%; this rate falls to approximately 2% in women infected prior to conception

• Vaccination against CMV disease is a primary focus of research

• The live-attenuated Towne vaccine has demonstrated protective efficacy against severe disease in renal transplant recipients, but infection is not prevented. Other vaccines are in clinical development.

For more information, see the monographs:

	The Increasing Importance of Cytomegalovirus, Epstein-Barr Virus and The Human Herpesvirus Types 6, 7 and 8
	Cytomegalovirus and Human Herpesvirus Type 6 Infections in the Immunocompromised (non-HIV) Host

General Points

HHV-6 is widespread in the population and is the aetiological agent in the development of a usually mild childhood illness, exanthem subitum (roseola infantum).

• HHV-6 also is an important cause of undifferentiated febrile disease in children and has been implicated in some cases of hepatitis, meningoencephalitis, lymphadenopathy and mononucleosis. It is unclear whether these diseases are due to primary infection with HHV-6 or to reactivation

• HHV-6 has been linked with the pathogenesis of multiple sclerosis

• In the immunocompromised patient, reactivation appears to be associated with the degree of immunosuppression, as a higher frequency of HHV-6 viraemia is observed after bone marrow transplant compared with renal transplantation

• Several reports have described an association between HHV-6 infection and neurological disease in people with AIDS

• HHV-6 may have a role in increasing HIV replication in vitro. However, it is unclear whether HHV-6 has a pathogenic role in individuals with AIDS or if it facilitates the development or progression of AIDS

• There have been few trials on the efficacy of antiviral agents for HHV-6. Ganciclovir (most potent), foscarnet and aciclovir have been investigated in vitro. A study of bone marrow transplant recipients showed that aciclovir-treated patients had lower levels of HHV-6 DNA than patients who did not receive aciclovir. However no recommendations can yet be made on how HHV-6 infections should be treated

• Prophylactic antiviral therapy in transplant recipients may reduce hospitalization and acute rejection caused by HHV-6-related disease, and more studies are indicated

• In liver transplantation patients, infection with HHV-6 is associated with increased hospitalization

• Biopsy proven graft rejection can occur with HHV-6 infection.

For more information, see the monograph:

The Increasing Importance of Cytomegalovirus, Epstein-Barr Virus and The Human Herpesvirus Types 6, 7 and 8

HHV-7 is widespread in the population, although disease appears uncommon.

• A recent study reported a causal role in exanthem subitum (roseola infantum) and another reported an association with pytiriasis rosea

• A marked reciprocal interference between HHV-7 and HIV has been observed, as both viruses use the same CD4 receptor to infect T lymphocytes

• Studies are needed to investigate whether HHV-7 influences the natural history of HIV infection in vivo, as has been suggested for HHV-6

• As yet there are no set guidelines for management of patients with HHV-7-related infections.

   

   

Treatment of EBV-Associated Lymphoproliferative Diseases