Cytomegalovirus (CMV)

A betaherpesvirus that targets epithelial cell lining respiratory and gastrointestinal tract for primary infection.

A double stranded DNA virus that typically remains latent in a host after acute infection.

Prevalent Herpesviridia family pathogen with 40-100% of population with positive serology.

Transmitted by body fluids.

The average age of primary infection and seroprevalence vary according to geographic location.

CMV rarely is a cause of severe disease in immunocompetent individuals.

CMV is among the most consequential infections affecting cellular organ transplant recipients.

Along with direct consequences of viral infection, the immunomodulatory effects of CMV predisposed to other complications, including graft loss, and increase rates of opportunistic infections.

In some countries, a primary infection occurs during childhood and seroprevalence is nearly 100% among teenagers, whereas in other countries primary infection can occur well into adulthood, even in the 5th-6 decade of life with seroprevalence reaching only 60-70% for the age of 60 years.

Primary infection may be asymptomatic, but is usually associated with a short mononucleosis-like syndrome.

Infection is lifelong.

Healthy individuals are generally able to maintain sufficient anti–CMV immunity to maintain continuous control of the latent virus.

Primary CMV infection children or adults with primary T-cell immunodeficiency can be severe and lead to manifestations such as pneumonitis, hepatitis, esophagitis, gastroenteritis, retinitis, and encephalitis.

In immunocompromised patients such as those with HIV, solid organ or hematopoietic transplants it can cause life-threatening, tissue invasive disease.

A major pathogen in recipients of solid organ transplant, particularly in CMV-sero negative patients with seropositive donors.

Such transplant patients have the highest risk for CMV-associated complications.

In children and adults with acquired T-cell immunodeficiencies such as HIV infection and immunodeficiency related to bone marrow or solid organ transportation, severe CMV disease can develop.

Rarely life-threatening CMV infection occurs in a previously healthy children or adults.

Establishes a latent infection for the life of the host, which can be periodically reactivated.

Most patients with infection are immunocompromised.

All patients with invasive CMV disease should undergo ophthalmoscopic examination to evaluate for concomitant CMV retinitis.

It can affect any portion of the gastrointestinal tract but typically involves the esophagus and colon which account for 15% and 57% of G.I. tract involvement in immunocompromise hosts, respectively.

The diagnosis of tissue invasive CMV infection requires histopathological confirmation and DNA polymerase chain reaction and blood antigen tests are inadequate.

Infection with drug resistant CMV develops in 5-14% of transplant recipients.

CMV disease results from CMV replication through reactivation or new infection in a seriously immunocompromised individual.

CMV viremia occurs and 50 to 60% of patients who undergo allogeneic hematopoietic stem cell transplant (HSCT) and may progress to CMV disease.

Causes significant morbidity and mortality in the immunocompromised groups of transplant recipients, developing fetuses, and HIV positive persons.

Human herpesvirus 5, a DNA virus.

Has a large genetic content contained in a capsid of 162 hexagonal capsomeres.

Encodes for UL86 the major capsid protein, and protein UL83 which allows antigen identification.

Encodes for UL18 and UL40 proteins that down regulate host immunity.

Macrophages and endothelial cells contain latent infection.

Latent virus maintained by CD33+ progenitor cells of dendritic and myeloid lines.

Differentiation to dendritic cells and macrophages that enter with inflammation can lead to viral reactivation and replication.

Tumor necrosis factor and interferon-gamma are inflammatory mediators that can help to trigger viral reactivation.

Infection causes induction of cytokines and modulates immune responses.

Primary CMV infection in pregnant women is made by protection of virus specific IgM and low IgG avidity.

Approximately 0.6% of newborns in the United States are congenitally infected with human cytomegalovirus virus.

Approximately 20% of infected newborns with CMV are symptomatic at birth or will have sequelae of sensorineural hearing loss, motor defects, and cognitive defects.

Congenital cytomegalovirus infection is a leading cause of brain damage and sensorineural hearing loss in children.

Congenital infection causes auditory, cognitive and neurologic impairment in children.

Congenital cytomegalovirus infection occurs in estimated 20-40,000 infants born each year in the U.S., but 90-95% of children have no clinical detectable abnormalities at birth and will not be identifiable by routine clinical examination.

Administration of hyperimmune globulin to pregnant women with primary CMV infection reduces rate of intrauterine transmission from 40% to 16%, and decreased risk of congenital disease decreased from 50% to 3% (Nigro G et al).

In a study of 123 pregnant women with primary CMV the administration of hyperimmunoglobulin in a randomized fashion did not significantly modify the course of disease during pregnancy.

Among pregnant women, administration of CMV hyper immune globulin starting before 24 weeks gestation did not result in the low incidence of a composite of congenital CMV infection pr perinatal death then placebo (Hughes BL).

Sensorineural hearing loss occurs in approximately 10-15% of infants with clinically unapparent congenital CMV infection and the majority of children with CMV related sensorineural hearing loss will have late onset disease with progressive losses.

Routine physical examination and newborn hearing screening will miss many cases of the development of sensorineural hearing loss from congenital CMV infection.

Virus isolation from saliva or urine specimens in tissue culture is the standard method to identify infants with congenital CMV infection.

Infection is usually inapparent remaining latent until the host’s immune system becomes compromised.

Contracted form close personal contact with persons excreting the virus in body fluids.

Can present as a typical mononucleosis syndrome with atypical lymphocytes, lymphocytosis and monocytosis.

Rarely manifestations of acute illness may be severe and associated with organ dysfunction and death.

Level of IgG antibodies increase at least four-fold during the acute infection as is the best test to determine the cause of an acute mononucleosis like infection.

Most common cause of viral intrauterine infection, affecting 0.5-2.5% of all live births in different parts of the world.

The rate of congenital infection resulting from primary maternal infection is about 30%, ranging from 15-50%.

Prenatal diagnosis of infection is possible but no treatment presently exists.

10% of congenitally infected infants have congenital CMV syndrome, whereas 90% are asymptomatic at birth.

10-15% of asymptomatic neonates may eventually develop neurologic defects.

Seropositivity rate is 50-60% for women of middle class background and 70-80% for those from lower socioeconomic sectors.

The risk of seroconversion during pregnancy averages 2-2.5%.

Treatment of pregnant women with CMV-specific hyperimmune globulin may be effective in the treatment and prevention of congenital CMV infection.

Transmission rate of CMV to the fetus in women who have a primary infection occurred in 56% of patients in the control group and in 16% in a group receiving hyperimmune globulin.

The highest rate of congenital infection and sequelae occur in infected infants whose mothers had a primary infection during pregnancy.

Isolation of the virus from the amniotic fluid is the most reliable index of congenital infection.

An acute infection may make laboratory tests false positive and include rheumatoid factor, cryoglobulinemia, positive ANA, anti-smooth muscle antibodies and positive Coombs’ test.

Infection amplifies preexisting levels of immunosuppression with the greatest effects on T-cell mediated immunity.

Infection in immunocompromised patients often confused with EBV infection with CMV infection occurring in individuals older than 30 years of age and the peak incidence of EBV occurs between 15 and 20 years of age.

Fever usually lasts much longer with CMV infection compared to EBV infection.

Sore throat common in CMV and EBV infections but pharyngeal exudates and lymphadenopathy less common in CMV.

Associated with adverse outcome in patients undergoing liver transplantation.

CMV colitis is common among patients with inflammatory bowel disease, particularly those with glucocorticoid treatment.

CMV colitis may occur with C. Difficile infection in immunocompetent patients.

Infection one of the leading causes of morbidity and mortality after hematopoietic stem cell transplantation.

Infection in transplant recipients occurs by reactivation of a latent infection or from a newly acquired infection from donor tissue, organs or blood as a source of the virus.

In solid organ transplant recipients CMV infections characterized by fever, with or without end organ damage.

In solid organ transplant recipients CMV infections are transmitted from the organ donor rather than it being a reactivation of a latent infection.

In solid organ transplant recipients CMV infection risk is highest in CMV seronegative recipients of an organ from a CMV seropositive donor, but seropositive recipients are at increased risk for infection if the donor is also seropositive.

Antiviral prophylaxis with valganciclovir, for 3-6 months, is the most widely used prevention strategy in the setting of transplant patient in seonegative patients

Prior infection is a strong independent risk factor for restenosis after angioplasty procedures.

Treatment for CMV infection or disease is usually been intravenous ganciclovir or its oral prodrug valganciclovir or, alternatively intravenous foscarnet or cifofovir.

The above agents are associated with myelosuppression, and renal toxicity that complicate their use in patients with allogeneic hematopoietic cell transplants.

Available anti-CMV ages are effective but limited by the toxic effects, including myelosuppression, nephrotoxicity, and electrolyte iimbalances.

Lettemovir (Prevymis) is an anti-CMV agent that is highly potent and targets the viral terminate subunit pUL56, a component of the terminate complex involved in viral DNA cleavage and packaging.

Letermovir as compared with placebo is effective in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic cell transplants (Chemaly RF et al).

Maribavir has efficacy similar to valgangiclovir for clearing CMV viremia among recipients of hematopoietic or solid organ transplants.

Strategies for the prevention of CMV after solid organ transplant include universal prophylaxis involving administering antivirals to either all or a  subset of high-risk patients based on the type of organ transplant and serologic status for typically 3 to 12 months, and preemptive therapy consists of periodic monitoring and initiation of antiviral therapy on CMV DNA detection above a pre-defined threshold.

For either of the above approaches, IV gangliciclovir its oral prodrug valgangliclovir are the first line antivirals for prevention and treatment of CMV infection.

Letermovir is not inferior to vanganciclovir for prophylaxis in solid organ transplant in seronegative CMV patients.

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