on 03-Nov-2018 (Sat)

Cytomegalovirus (CMV), the fifth member of the human herpesvirus family, is one of the largest viruses known to cause clinical disease. It is a double-stranded DNA virus that belongs to the beta-herpesvirus subfamily

A survey in the United States reported an overall CMV seroprevalence rate of 50.4%. The prevalence increases with age; in children ages 1 to 5, it may be as low as 20.7%, but it approaches 100% in older adults in de- veloping countries ( 3, 4). CMV seroprevalence rate varies widely with (a) geographic location, with higher rates in developing countries; (b) age, with the rate in- creasing directly with older age; and (c) socioeconomic status, with highest seroprevalence in crowded and economically challenged populations.

CMV is acquired most commonly early in life, during childhood to early adulthood, through exposure to sa liva, tears, urine, stool, breast milk, semen, and other bodily secretions from infected individuals. The virus has been showntoretainviabilityforupto6hoursoncertain surfaces, and therefore, transmission via fomites is possi- ble ( 5). It can also be transmitted efficiently via organ and tissue transplantation and blood transfusions ( 6–9); leu- koreduction of blood products have markedly r educed the risk of transfusion-transmitted CMV infections ( 7, 9, 10)

In the immunocompetent healthy host, primary CMV infection is usually asymptomatic, although it may also present as a nonspecific febrile illness, or an infectious mononucleosis-like syndrome characterized by fever, lymphadenopathy, and lymphocytosis ( 11)

After a self- limited course, CMV establishes latency in a wide vari- ety of cells, including endothelial cells, epithelial cells, smooth-muscle cells, and fibroblasts, where the virus can multiply and may be carried by peripheral monocytes and circulating endothelial cells to reach distant sites of the body ( 12). The initial infection leads to production of CMV-specific IgM and, later, IgG antibody that persists for life ( 13).

The clinical presentation of CMV infection is highly influenced by the immune fitness of the host ( 14). Its reactivation in healthy immunocompetent hosts, which occurs intermittently throughout life, triggers immuno- logic memory that leads to effective control of viral rep- lication ( 15). On the other hand, the loss of CMV-specific CD4+ and CD8+ T-cells in the immunocompromised host, such as those with human immunodeficiency virus (HIV) infection, recipients of solid-organ transplant (SOT), or hematopoietic stem-cell transplant (HSCT), may permit uncontrolled viral replication, leading sub- sequently to clinical disease ( 16, 17)(Table 1).

SOT recipients can develop either primary or secondary (reactivation) CMV infection and disease. Primary in- fection occurs when a CMV-seronegative (R-) individual receives an allograft from a CMV-seropositive donor (D+) ( 23). CMV-seronegative recipients lack pre-existing CMV-specific humoral and cell-mediated immunity and,

in the presence of drug-induced immunosuppression, this results in the inability to control primary infection ( 8, 24). This CMV “donor positive-recipient negative” (D+/R-) mismatch constitutes the highest-risk scenario for CMV disease after SOT.

Secondary CMV disease may occur in CMV- seropositive (R+) SOT recipients, either as reactivation (of endogenous latent CMV in the recipient) or super- infection (with CMV transmitted by transplantation) ( 23). Allostimulation, allograft rejection, and intense pharmacologic immunosuppression, particularly with antithymocyte-immunoglobulin therapy, combine to provide an environment that permits CMV reactivation after SOT ( 25)

CMV infection after SOT can be classified as asymp- tomatic (subclinical), whereby viral replication is detected in the blood in a patient without clinical signs and symp- toms, or symptomatic CMV disease, which can be further categorized into CMV syndrome or tissue-invasive dis- ease. CMV syndrome is characterized by fever, malaise, and some degree of myelosuppression. CMV could also invade various organ systems leading to tissue-invasive CMV disease. The most common organ affected by CMV is the GI tract, accounting for over 70% of tissue-invasive CMV disease cases. CMV has a predilection to infect the transplanted allograft, where it may manifest as hepa- titis, pneumonitis, myocarditis, pancreatitis, or nephritis among liver, lung, heart, pancreas, and kidney recipients, respectively. Rarely, it can cause retinitis, meningoen- cephalitis, and polyradiculopathy after transplantation

CMV has numerous indirect effects after SOT, in- cluding an increased predisposition to develop other opportunistic infections, such as bacteremia, invasive fungal disease, and Epstein-Barr virus infection leading to posttransplant lymphoproliferative disease. CMV infection has also been associated with acute and chronic allograft injury, manifesting as allograft nephropathy, coronary vasculopathy, and bronchiolitis obliterans after kidney, heart, and lung transplantation, respec- tively

CMV infection during pregnancy can lead to intrauter- ine fetal infection and congenital CMV disease. Con- genital CMV infection occurs most commonly among infants born to mothers who developed primary CMV infection during pregnancy. In this situation, transmis- sion of infection has been described to occur in ap- proximately 40% of cases ( 35). The risk of transmission is highest if CMV infection occurs during the first half of pregnancy, although it may occur at any stage. Less commonly, transmission of CMV may occur among infants born to CMV-immune women, when the mother is superinfected with a different strain of CMV, since preconceptional immunity provides only partial protec- tion

Congenital CMV infection may manifest as clinical disease in only about 10% to 15% of cases.

Congenital CMV disease has manifested as petechial rash, jaundice with hepatosplenomegaly, neurologic abnormalities such as microcephaly and lethargy, chorioretinitis and optic- nerve atrophy, and prematurity and low birth weight ( 37). About 10% to 15% of infants with congenital CMV disease may manifest solely with sensorineural hearing loss

In immunocompromised individuals, particularly transplant recipients, the most important clinical use of CMV serology is in the assessment of risk and suscep- tibility after transplantation. Specifically, CMV serology is useful in assessing prior CMV exposure during the pretransplant evaluation of transplant candidates (and their donors) in order to determine the risk of either pri- mary or reactivation CMV infection after transplantation.

NAT has emerged as the preferred method for the rapid diagnosis of CMV in immunocompromised hosts. In principle, the NAT assays are based on the detection and/or amplification of CMV nucleic acids in clinical samples. However, CMV persists in latent form in many nucleated cells; therefore, NAT has the risk of detect- ing inactive nonreplicating CMV. Generally, molecu- lar methods have higher sensitivity than nonmolecular methods. Among them, CMV PCR is the most widely used methodology. The basic principle of the CMV PCR is to generate a large number of target CMV gene-se- quence copies that can be easily detected.

In the field of transplantation, CMV serology is performed on blood samples from the prospective organ donor and recipient to determine the risk of primary infection or reactivation of disease. The knowledge of these risks influences the type of preventive efforts for each patient population. Specifically, a CMV D+/R- mismatch SOT recipient has the highest risk of primary CMV disease, and therefore may benefit from antiviral prophylaxis or aggressive CMV surveillance and pre- emptive therapy. Some centers have also used serology to determine ongoing risk of primary CMV disease after transplantation since seroconversion would suggest pro- tection from subsequent CMV disease

Serial surveillance for CMV replication, with the use of antigenemia or NAT, is a common practice during the early period after transplantation. This diagnostic approach is an integral component in the strategy of preemptive therapy against CMV disease

CMV disease in SOT patients can be classified as an asymptomatic infection, whereby viral replication is detected in the absence of symptoms; or symptomatic CMV disease, which can be further classified into CMV syndrome or tissue-invasive CMV disease ( 23). CMV syndrome is characterized by fever, malaise, myelosup- pression, and CMV DNA detected in blood.

CMV can be found in up to 50% of lung-transplant recipients without clinical or histopathologic findings of CMV pneumonia (termed CMV shedding)

It is noteworthy to em- phasize, however, that there are some cases of tissue- invasive CMV diseases without accompanying viremia, hence the importance of performing biopsy as clinically indicated

There are two approaches for CMV prevention after SOT—universal prophylaxis and preemptive therapy. Universal prophylaxis consists of the administration of antivirals for varying duration, from as short as 3 months to as long as >12 months, for the prevention of CMV disease in patients at high risk ( 26). The main drawback with antiviral prophylaxis is the high inci- dence of late-onset CMV disease after discontinuation of prophylaxis and CMV D+/R- SOT recipients

In the preemptive approach, serial monitoring of CMV replication, either by QNAT or pp65 antigenemia, is performed and thereafter, patients are treated with antiviral drugs once a predetermined threshold of viral replication is reached.The aim of this approach is to detect early viral replication and treat prior to progression to more severe disease.

Current-practice guidelines rec- ommend continuation of antiviral therapy until viral replication is undetectable on at least two weekly NAT measurements

Primary CMV infection in the mother can be diagnosed by documenting positive serology in a woman previ- ously known to be seronegative. CMV-specific IgM can be detected in women with primary infection; however, they may persist for 6 to 9 months after infection ( 38, 170). IgG-avidity assays can be utilized to distinguish primary from reactivation infections. A combination of CMV-IgM with IgG-avidity assays increases sensitivity for detecting a mother who could potentially transmit CMV to her offspring ( 171). The use of QNAT or pp65 antigenemia for diagnosis of primary maternal CMV infection is limited, since less than 50% of pregnant women have detectable viral replication

The diagnosis of congenital infection is often dem- onstrated by the presence of CMV or viral antigens in urine or saliva within the first two weeks of life