ETIOLOGY

 Cytomegalovirus (CMV) is a ubiquitous human viral pathogen. The first descriptive report of histologic changes characteristic of those now associated with CMV infection was originally published in 1904, when protozoan-like cells in the lungs, kidneys, and liver of a syphilitic fetus were seen. It was not until 1956 and 1957 that CMV was isolated in the laboratory. Actual isolation of the virus after transfusion, and observation of elevated antibody titers, occurred in 1966.

Human CMV is classified as a member of the herpes family of viruses (herpesviruses). All the herpesviruses are relatively large, enveloped DNA viruses that undergo a replicative cycle involving DNA expression and nucleocapsid assembly within the nucleus. The viral structure gains an envelope when the virus buds through the nuclear membrane, which in turn is altered to contain specific viral proteins.

Although the herpesviruses produce diverse clinical dis eases, they share the basic characteristic of being cell associated.

The requirements for cell association vary, but herpesviruses may spread from cell to cell, presumably via intercellular bridges and in the presence of antibody in the extracellular phase. CMV spreads to the lymphoid tissues and proceeds to circulate to systemic lymph nodes. The virus finally comes to rest in the epithelial cells of many tissues. This common characteristic may play a role in the ability of these viruses to produce sub clinical infections that can be reactivated under appropriate stimuli.

EPIDEMIOLOGY

 CMV infection is endemic worldwide, with most urban adults demonstrating evidence of infection; 50% to 80% of U.S. adults are infected with CMV by age 40 years. The prevalence of CMV seropositivity increases steadily with age. CMV is found in all geographic and socioeconomic groups, but in general it is more widespread in developing countries and areas of lower socioeconomic conditions.

CMV is a major health risk because a large proportion of women, particularly white women, entering their childbearing years lack antibody to CMV. Those at greatest risk of infection are fetuses and immunocompromised persons. CMV is the most common virus transmitted to the fetus. Approximately 1 in 150 children is born with congenital CMV infection, and about 8000 children each year suffer permanent disabilities caused by CMV.

Transmission

Transmission of CMV may be by the oral, respiratory, or venereal route. The virus has been isolated in urine, saliva, feces, breast milk, blood, cervical secretions, virus-infected grafts from a donor, semen, vaginal fluid, and respiratory droplets. It may also be transmitted by the transfusion of fresh blood. Transmission of CMV appears to require intimate contact with secretions or excretions. CMV can be transmitted from a pregnant woman to her fetus during pregnancy. Low-birth weight (LBW) neonates are also at high risk for CMV infection through transfusion of CMV-infected blood products.

Peripheral blood leukocytes and transplanted tissues have been strongly incriminated as sources of CMV. Transmission of CMV by transfusion of blood or blood components containing white blood cells (WBCs) has assumed increased importance in patients with severely impaired immunity who require supportive therapy. In the United States, CMV screening is required for all units of blood collected from donors. Preventive methods in these patients include effective donor screening, leukocyte-depleted or irradiated blood products, and immune globulin containing passively acquired CMV antibodies. The use of irradiated blood products has become more popular.

Once in a person’s body, CMV stays there for life. Most CMV infections are silent, causing no signs or symptoms. Individuals who are CMV-positive (infected with CMV in the past) usually do not have virus in urine or saliva, so the risk of acquiring a CMV infection from casual contact is negligible.

Women who are pregnant or planning a pregnancy should follow hygienic practices (e.g., careful handwashing) to avoid CMV infection. Because young children are more likely to have CMV in their urine or saliva than older children or adults, pregnant women who have or work with young children should be especially careful.

Health care professionals represent a group that has become increasingly concerned about the risks associated with expo sure to CMV. Nosocomial transmission from patients to health care workers has not been documented, but observance of good personal hygiene and handwashing offer the best measures for preventing transmission.

Latent Infection

 Persistent infections characterized by periods of reactivation are frequently termed latent infections. CMV can persist in a latent state and active infections may develop under a variety of conditions (e.g., pregnancy; immunosuppression; after organ, bone, or stem cell transplantation). Of immunosuppressed patients, only seronegative patients appear to be at a significant risk of developing CMV infection. Patients at the highest risk of mortality from CMV infections are allograft transplant, seronegative patients who receive tissue from a seropositive donor. The great majority of infections in allograft recipients are transmitted by a donated organ or arise from the reactivation of the recipient’s latent virus.

True viral latency is defined by the presence of the genetic information in an unexpressed state in the host cell. An operational definition of latency can include the conditions of a dynamic relationship between the virus and host, along with evidence of latency and reactivation of a latent infection. As with any herpesvirus, CMV reactivation is possible at any time, but rarely manifests in immunocompetent individuals.

Congenital Infection

 Primary and recurrent maternal CMV infection can be trans mitted in utero. Congenital CMV infection is the most common intrauterine infection, affecting 0.4% to 2.3% of all live births in the United States. The presence of maternal antibody to CMV before conception provides substantial protection against damaging, congenital CMV infection in the newborn.

Primary maternal infection during pregnancy, occurring in 1% to 3% of U.S. women, is associated with more severe sequelae of congenital CMV infection. Infected infants can become severely ill and premature infants may die. Most newborns infected with CMV survive, but they may be mentally impaired or may develop other health problems. Approximately 10% of congenitally infected infants have symptoms at birth and, of the 90% who are asymptomatic, 10% to 15% will develop symptoms over months or even years.

SIGNS AND SYMPTOMS

 Acquired Infection Acquired CMV infection is usually asymptomatic and can persist in the host as a chronic or latent infection. The incubation period is believed to be 3 to 12 weeks.

In most patients, CMV infection is asymptomatic. Occasionally, a self-limited, heterophile-negative, mononucleosis like syndrome results. CMV hepatitis can also develop.

Symptoms include a sore throat and fever, swollen glands, chills, profound malaise, and myalgia. Lymphadenopathy and splenomegaly may be observed. Infections occurring in healthy immunocompetent individuals usually result in seroconversion. Virus may be excreted in the urine during primary and recur rent CMV infections; it can persist sporadically for months or years. Persons experiencing acquired infection, reinfection with the same or different strains of CMV, or reactivation of a latent infection can excrete the virus in titers as high as 106 infective units/mL in the urine or saliva for weeks or months.

Normal adults and children usually experience CMV infection without serious complications. Infrequent complications of CMV infection in previously healthy individuals, however, include interstitial pneumonitis, hepatitis, Guillain-Barré syn drome, meningoencephalitis, myocarditis, thrombocytopenia, and hemolytic anemia.

CMV infection can be life-threatening in immunosuppressed patients. Infections in these patients may result in disseminated multisystem involvement, including pneumonitis, hepatitis, gastrointestinal (GI) ulceration, arthralgias, meningoencephalitis, and retinitis. Retinitis and encephalitis are common manifestations of disseminated CMV. Ulcerative damage of tissues (e.g., esophagus) is another demonstration of the cytopathic effects of CMV. Interstitial pneumonitis, frequently associated with CMV infection, is a major cause of death after allogeneic bone marrow transplantation. In premature infants, acquired CMV infection can result in atypical lymphocytosis, hepatosplenomegaly, pneumonia, or death.

Transfusion-acquired CMV infections may cause not only mononucleosis-like syndrome, but also hepatitis and increased rejection of transplanted organs. The following three types of CMV infections are possible in blood transfusion recipients:

1. Primary infection occurs when a previously unexposed (seronegative) recipient is transfused with blood from an actively or latently infected donor. This type of infection is accompanied by the presence of virus in the blood and urine, an immediate antibody response, and eventual seroconversion. Patients with primary infections may be symptomatic, but the great majority are asymptomatic.

2. Reactivated infection can occur when a seropositive recipient is transfused with blood from a CMV antibody–positive or –negative donor. Donor leukocytes are thought to trigger an allograft reaction, which in turn reactivates the recipient’s latent infection. These infections may be accompanied by significant increases in CMV-specific antibody. Some reactivated infections exhibit viral shedding as their only manifestation. Reactivated infections are largely asymptomatic.

3. Reinfection can occur by a CMV strain in the donor’s blood that differs from the strain that originally infected the recipient. A significant antibody response is observed and viral shedding occurs. Although it is difficult to differentiate a reactivated infection if the patient and donor are CMV antibody–positive before transfusion, reinfections can be documented if isolates can be obtained from the donor and recipient.

Congenital Infection

 About 1 in 750 children in the United States is born with or develops permanent problems due to congenital CMV infection. In the United States, more than 5000 children/year suffer permanent problems caused by CMV infection.

The classic congenital CMV syndrome is manifested by a high incidence of neurologic symptoms, as well as neuromuscular disorders, jaundice, hepatomegaly, and splenomegaly (Fig. 1). Petechia is the most common clinical sign, seen in about 50% of CMV-infected infants.

Fig1. Four-month-old child with symptomatic congenital  cytomegalovirus (CMV) infection manifesting severe failure to thrive,  hepatitis with hepatosplenomegaly, bilateral inguinal hernia, and  micropenis. (From Katz SL, Gershon AA, Wilfert CM, Krugman S, editors: Infectious diseases of children, ed 9, St Louis, 1992, Mosby.)

Congenitally infected newborns, especially those who acquire CMV during a maternal primary infection, are more prone to develop severe cytomegalic inclusion disease (CID). T he severe form of CID may be fatal or can cause permanent neurologic sequelae, such as intracranial calcifications (Fig. 2), mental retardation, deafness, vision defects, microcephaly, and motor dysfunction. Psychomotor impairment is seen in 51% to 75% of survivors. Hearing loss is observed in 21% to 50% and visual impairment in 20% of patients. Infants without symptoms at birth may develop hearing impairment and neurologic impairment later.

Fig2. Brain of infant with congenital CMV infection. Note  extensive periventricular necrosis and calcification. (From Katz SL, Gershon AA, Wilfert CM, Krugman S, editors: Infectious diseases of children, ed 9, St Louis, 1992, Mosby.)

IMMUNOLOGIC MANIFESTATIONS

Immune System Alterations

 CMV infection is known to alter the immune system and to produce overt manifestations of infection. Infection interferes with immune responsiveness in normal and immunocompromised individuals. This diminished responsiveness results in a decreased proliferative response to the CMV antigen, which per sists for several months. In patients with CMV mononucleosis like syndrome, alterations of T lymphocyte subsets result, producing an increase in the absolute number of CD8+ lymphocytes and a decrease in CD4+ lymphocytes. These subset abnormalities persist for months.

Questions have been raised regarding CMV as a potentially oncogenic virus because viral antigens and nucleic acids have been found in human malignancies, including adenocarcinoma of the colon, carcinoma of the cervix, cancer of the prostate, and Kaposi’s sarcoma. CMV does have transforming properties in vitro. Although considerable circumstantial evidence exists linking CMV to human malignancies, especially Kaposi’s sarcoma, a direct cause and effect relationship has not been established.

Serologic Markers

In cells infected by CMV, several antigens appear at varying times after infection. Before replication of viral DNA takes place, immediate-early antigens and early antigens are present in the nuclei of infected cells. Immediate-early antigens appear within 1 hour of cellular infection and early antigens are present within 24 hours. At about 72 hours after infection, or the end of the viral replication cycle, late antigens are demonstrable in the nucleus and cytoplasm of infected cells.

The immune antibody response to these various antigens differs in incidence and significance. The presence of antibodies against immediate-early and early antigens is associated with active infection, either primary or reactivated. New CMV infections can be identified by testing for immunoglobulin G (IgG) antibodies on blood samples taken at different times. If the first sample is negative and the second sample is positive, the patient became infected with CMV between the two blood samples.

A newer method, called IgG avidity testing, which measures antibody maturity, has been shown to detect recent primary CMV infection reliably. This test is available on a limited basis in the United States.

Antibody to early antigen undergoes a relatively rapid decline after recovery but can persist for up to 250 days and may identify patients with recent, as well as active, infection. The presence of antibody to early antigen is strongly associated with viral shedding. Antibodies to late antigens persist in high titer long after the recovery from an active infection.

The incidence of viral exposure and subsequent antibody formation (seropositivity) varies greatly, depending on the socioeconomic status and living conditions of the population surveyed. The prevalence of CMV antibody varies with age and geographic location but ranges from 40% to 100%.

The characteristic antibody responses associated with infection are as follows:

• Primary infection, demonstrated by a transient virus specific IgM antibody response and eventual seroconversion to produce immunoglobulin G (IgG) antibodies to the virus.

• Reactivation of latent infection in seropositive (IgG) individuals, which may be accompanied by significant increases in IgG antibodies to the virus, but elicits no detectable IgM response.

• Reinfection by a strain of CMV different from the original infecting strain. A significant IgG antibody response is demonstrated. It is not known whether an IgM response occurs.

There is no vaccine currently available for preventing con genital CMV disease (present at birth). A few CMV vaccines are being tested in humans, including live attenuated (weakened) virus vaccines and vaccines that contain only pieces of the virus.

In CMV infection, hematologic examination of the blood usually reveals a characteristic leukocytosis. A slight lymphocytosis with more than 20% variant lymphocytes is common. CMV infection is possible in the following situations:

• The patient has mononucleosis-like symptoms but exhibits a negative EBV test result.

• The patient manifests hepatitis symptoms but does not demonstrate any positive results when tested for common hepatitis viruses.

In affected infants, the most common laboratory abnormality is a low platelet count (thrombocytopenia). Clinical chemistry assays may demonstrate abnormal liver function. Presence of infection is also demonstrated by inclusion bodies in leukocytes in urine sediment.

LABORATORY EVALUATION

 In immunocompromised patients, CMV serology is not recommended. The preferred method for diagnosis is culture of virus and/or polymerase chain reaction (PCR). A variety of methods can be used for screening purposes (Table 1).

A fourfold rise in IgG antibody titer suggests, but does not prove, recent CMV infection. The presence of IgG antibody in infants complicates the interpretation of serologic results during the first 6 months of life because the antibody may be maternal in origin.

Table1. Laboratory Diagnosis of Cytomegalovirus Infection*

اخر الاخبار

اخبار العتبة العباسية المقدسة

المجمع العلمي يجري اختباره الشهري لطلبة الحفظ في المثنى

قسم الصناعات: اعتماد أعلى معايير الجودة في التنجيد والتأثيث لدعم البنية الخدمية في العتبة المقدسة

قسم الشؤون الفكريّة يصدر الجزء الخامس من سلسلة دراسات في المنهج

جامعة الكفيل تنظّم دورة عن أساسيات الدفاع المدني لملاكاتها

المزيد

الآخبار الصحية

العنب.. فاكهة صغيرة بمفعول "خارق" للقلب والدماغ

دراسة تحدد "الحلقة المفقودة".. تسبب ارتفاع ضغط الدم

هذه الأطعمة تحمي دماغك من الشيخوخة وتزيد حدة الذكاء

خبراء يحذرون من مخاطر "الدهون المخفية" على القلب

المزيد

الآخبار التكنلوجية

الأرصاد الجوية تلجأ إلى الذكاء الاصطناعي.. لأي غرض؟

في منزلك.. "تعديل بسيط" يخفض ضغط الدم بشكل طبيعي

"ميزة جديدة" من إنستغرام تنافس تيك توك.. طال انتظارها

غوغل في مأزق.. بيانات 2.5 مليار مستخدم بقبضة القراصنة

المزيد

مواضيع ذات صلة

General Characteristics of Hepatitis

Hepatitis D Virus (Delta Agent)

Hepadnaviridae

Poxviridae

West Nile Virus

Epstein-Barr Virus

Herpes simplex virus, types 1 and 2

Herpesviridae: Structure and Replication

Adenoviridae

Human Cowpox

Human Monkeypox

Smallpox virus