What is Cytomegalovirus Infection?
Cytomegalovirus infection (Human Cytomegalovirus Infection, CMV infection, cytomegaly, salivary gland viral disease, inclusive cytomegaly, inclusion disease) – an anthroponous opportunistic infection that usually occurs latently or easily. It is dangerous in various immunodeficiency conditions and pregnancy (due to the risk of intrauterine infection of the fetus).
As far back as 1882, a German pathologist X. Ribbert discovered peculiar giant cells with inclusions in the nucleus in the renal tubules of a stillborn child. Subsequently, they received the name of cytomegalic cells (Goodpascher E., Talbot F., 1921). Later, L. Smith and W. Rowe (1956) isolated a virus that causes a disease with the development of characteristic cytomegaly. It was called cytomegalovirus (CMV), and the disease itself was called cytomegalovirus infection.
Causes of Cytomegalovirus Infection
The causative agent of cytomegalovirus infection is the DNA genomic virus of the genus Cytomegalovirus (Cytomegalovirus hominis) of the subfamily Vetherpesvirinae of the family Herpesviridae. There are 3 known strains of the virus: Davis, AD-169 and Kerr. Slow reproduction of the virus in the cell is possible without damaging it. The virus is inactivated by heating and freezing, is well preserved at room temperature. At – 90 ° C, it remains for a long time, is relatively stable at pH 5.0–9.0 and rapidly degrades at pH 3.0.
The reservoir and source of infection is a person with an acute or latent form of the disease. The virus can be in various biological secrets: saliva, nasopharynx, tears, urine, bowel movements, seminal fluid, cervical secretions.
The transmission mechanisms are diverse, the transmission methods are airborne, contact (direct and indirect through household items) and transplacental. Possible infection through sexual contact, during transplantation of internal organs (kidney or heart) and blood transfusion of an infected donor. Intranatal infection of the child is observed much more often than transplacental. The most dangerous for the fetus infection of the mother in the first trimester of pregnancy. In such situations, the highest frequency of intrauterine developmental disorders.
The natural susceptibility of people is high, but latent infection is widespread. Clinical manifestations of infections attributable to opportunistic diseases are possible in conditions of primary or secondary immunodeficiency.
The main epidemiological signs of cytomegalovirus infection. The disease is registered everywhere, antiviral antibodies detected in 50-80% of adults testify to its widespread distribution. The variety of CMV infections and the polymorphism of the clinical picture determine the epidemiological and social significance of CMV infection. This disease plays an important role in transplantology, blood transfusion, perinatal pathology, can be the cause of prematurity, stillbirths, congenital defects of development. In adults, CMV infection is seen as a concomitant disease in various immunodeficiency states. Ongoing environmental pollution, the use of cytostatics and immunosuppressants contribute to an increase in the frequency of CMV infection. In recent years, its exacerbation in HIV-infected people has become especially relevant. In pregnant women with latent CMV infection, fetal damage does not always occur. The probability of intrauterine infection is significantly higher during the initial infection of a woman during pregnancy. No seasonal or occupational morbidity features have been identified.
Pathogenesis during Cytomegalovirus Infection
For various transmission routes, the mucous membranes of the upper respiratory tract, gastrointestinal tract or genitals can be the gates of infection. The virus enters the blood; short-term viremia quickly ends with the localization of the pathogen when introduced into white blood cells and mononuclear phagocytes, where it is replicated. Infected cells increase in size (cytomegaly), acquire a typical morphology with nuclear inclusions, which are accumulations of the virus. The formation of cytomegal cells is accompanied by interstitial lymphohistiocytic infiltration, the development of nodular infiltrates, calcifications and fibrosis in various organs, glandular structures in the brain.
The virus is able to persistently and latently persist in organs rich in lymphoid tissue, being protected from the effects of antibodies and interferon. At the same time, it can suppress cellular immunity by a direct effect on T-lymphocytes. In various immunodeficiency states (in early childhood, during pregnancy, the use of cytostatics and immunosuppressants, HIV infection) and, above all, with cellular immunity disorders, additionally aggravated by direct exposure to the virus, pathogen reactivation and hematogenous generalization with damage to almost all organs and systems are possible . In this case, the epitheliality of the virus is of great importance. It is especially pronounced in relation to the salivary gland epithelium, which, under the influence of the virus, turns into cytomegal cells.
Active CMV infection is considered as an indicator of defects in cellular immunity, it is included in the group of AIDS-associated conditions.
Symptoms of Cytomegalovirus Infection
International Classification of Diseases X Revision
International Statistical Classification of Diseases and Related Health Problems 10th Revision Version for 2006 does not classify cytomegalovirus infection as sexually transmitted infections and distinguishes between the following diseases associated with CMV.
B25.0 Cytomegalovirus disease
B25.0 Cytomegalovirus pneumonitis
B25.1 Cytomegalovirus hepatitis
B25.2 Cytomegalovirus pancreatitis
B25.8 Other diseases caused by cytomegalovirus
B25.9 Cytomegalovirus disease nonspecific
B27.1 Cytomegalovirus mononucleosis
P35.1 Congenital cytomegalovirus infection
Among the various variants of the course of CMV infection, subclinical forms and latent virus carriers predominate. Clinically expressed infection becomes in conditions of immunodeficiency. A single clinical classification of CMV infection has not been developed. In accordance with one of the classifications, congenital CMV infection in acute and chronic forms and acquired CMV infection in latent, acute mononucleosis or generalized forms are distinguished.
Congenital CMV infection.
In most cases, it does not clinically manifest in the early stages of a child’s life, however, in the later stages of its development, a variety of pathologies are revealed: deafness, chorioretinitis with optic atrophy, decreased intelligence, and speech impairment. However, in 10-15% of cases with congenital CMV infection, the so-called clear cytomegalovirus syndrome develops. Its manifestations depend on the timing of infection of the fetus during pregnancy.
Acute congenital CMV infection.
In early pregnancy, it leads to fetal death or the birth of a child with various malformations: microcephaly, micro- and macrogyria, lung hypoplasia, atresia of the esophagus, abnormalities in the structure of the kidneys, defects in the atrial and interventricular septa, narrowing of the pulmonary trunk and etc.
When the fetus is infected in the late stages of pregnancy, malformations do not form, however, from the first days of life, newborns show signs of a variety of diseases: hemorrhagic syndrome, hemolytic anemia, jaundice of various origins (due to congenital hepatitis, cirrhosis, biliary atresia). Various clinical manifestations are possible, indicating damage to various organs and systems: interstitial pneumonia, enteritis and colitis, polycystic pancreas, nephritis, meningoencephalitis, hydrocephalus.
Acute congenital CMV infection with the development of overt cytomegalovirus syndrome has a tendency to generalization, a severe course with the addition of secondary infections. Often, death is inevitable during the first weeks of a child’s life.
Chronic congenital CMV infection.
Microgyria, hydrocephalus, microcephaly, clouding of the lens and vitreous body are characteristic.
Acquired CMV infection.
In adults and older children, in most cases it proceeds latently in the form of asymptomatic carriage or a subclinical form with a chronic course.
The acute form of acquired CMV infection. Often it may not have clear clinical symptoms, sometimes it is similar in its main clinical manifestations to flu, infectious mononucleosis or viral hepatitis.
In adults with immunodeficiency states of varying severity (from physiological immunosuppression during pregnancy to HIV infection), as well as in children under 3 years of age, CMV reactivation manifests itself in the form of a generalized form with various organ and system lesions. The central nervous system, lungs, liver, kidneys, gastrointestinal tract, genitourinary system, etc. can be involved in the process. Most often diagnosed with hepatitis, interstitial pneumonia, enterocolitis, inflammatory processes in various parts of the genital organs (usually in women), encephalitis. With multiple organ lesions, the disease is distinguished by a severe course, it can take the features of sepsis. The outcome is often unfavorable.
Ulcers of the esophagus, stomach, intestines (thick and thin) may develop. Ulcers can lead to bleeding, with perforation peritonitis develops. Cytomegalovirus hepatitis often develops. In AIDS patients, cytomegalovirus infection often leads to the development of chronic encephalitis or to the appearance of subacute encephalopathy. Apathy builds up and in a few weeks or months passes into dementia. The cytomegaly virus can cause the development of retinitis, which leads to blindness of AIDS patients, as well as persons who underwent organ transplant surgery. On the retina appear areas of necrosis, which gradually expand.
Eye lesions must be differentiated from similar changes that are observed with toxoplasmosis, candidiasis and herpetic infection.
In addition to HIV-infected, cytomegalovirus infection is an important pathogenetic factor that complicates organ transplant operations. During transplantation of kidneys, heart, liver, cytomegalovirus causes fever, leukopenia, hepatitis, pneumonia, colitis, retinitis. Most often this occurs within 1-4 months after surgery. It should be noted that during primary infection the complication is more difficult than with activation of latent cytomegalovirus infection. The severity and clinical manifestations depend on the degree of immunosuppression and on the immunosuppressive drugs used.
Cytomegalovirus pneumonia develops in approximately 20% of patients; undergoing bone marrow transplant surgery. Mortality in this group of patients is 88%. The maximum risk of developing the disease is observed from the 5th to the 13th week after transplantation. More severe cytomegaly occurs in the elderly. In patients who have undergone kidney transplantation, a cytomegalovirus infection can cause transplant dysfunction.
Manifestations of cytomegalovirus infection in pregnant women. In pregnant women, CMVI has various clinical forms. In acute infections, damage to the liver, lungs, and brain may develop. As a rule, patients complain of general malaise, headache, fatigue, mucous discharge from the nose, whitish-blue discharge from the genitals, an increase and tenderness of the submandibular salivary glands. Some characteristic symptoms manifest themselves in the complex: pronounced uterine body hypertonicity resistant to the therapy, vaginitis, colpitis, hypertrophy, cysts and premature placental aging, polyhydramnios. Against this background, fetal weight often exceeds gestational age, and there is also an intimate attachment of the chorionic placental tissue, premature detachment of the normally located placenta, childbirth loss, which reaches 1% of the woman’s body weight, a clinic of the latent postpartum endometritis with further development of menstrual irregularities.
Most often, cytomegalovirus infection occurs as a latent infection with periodic exacerbations. When making a diagnosis, the results of a laboratory examination are crucial. An auxiliary role is played by the presence of a burdened obstetric history, the threat of termination of a previous pregnancy, premature birth, the birth of sick children, with malformations. In women with chronic CMVI, pseudo-erosion of the cervix, endometritis, ovarian dysfunction, extragenital diseases (hepatitis, chronic cholecystitis, pancreatitis, urolithiasis, chronic sinusitis, pneumonia, chronic diseases of the submandibular and parotid glands) are more often observed.
Any manifestations of CMV infection are considered indicative of HIV infection. In this case, it is necessary to examine the patient for antibodies to HIV.
Complications of cytomegalovirus infection
Complications are diverse and depend on the clinical options for the course of the disease: interstitial or segmental pneumonia, pleurisy, myocarditis, arthritis, encephalitis, Guillain-Barré syndrome, but they are relatively rare. After the acute phase, asthenization, sometimes vegetative-vascular disorders, persists for many weeks.
Diagnosis of Cytomegalovirus Infection
Differential diagnosis of CMV infection is rather difficult due to the absence or variety of clinical manifestations.
For the diagnosis of CMV infection, it is necessary to use 2-3 laboratory tests at the same time. Examine saliva, washings obtained with bronchopulmonary lavage, urine, cerebrospinal fluid, blood, breast milk, sectional material, biopsy specimens. Due to the thermolability of the virus, the research material must be delivered to the laboratory no later than four hours from the moment of collection.
The examination is carried out by virological, cytological, serological methods. Identification of specifically altered CMC cells is the most affordable method, but its information content is 50-70%. The most reliable detection in the material of the virus itself or its DNA. The gold standard is still the virological method. It is the most reliable, but it takes a considerable amount of time to complete it; therefore, the retrospective nature of the diagnosis does not allow for adequate therapy and prevention.
For diagnosis, it is not necessary to isolate the virus itself; it is enough to isolate its antigen. For this, the immunofluorescence reaction (RIF), enzyme immunoassay (ELISA), DNA-CMV hybridization, polymerase chain reaction (PCR) are widely used.
The PCR method, due to its high sensitivity, even detects a segment of CMV DNA and is considered very progressive. Its most important advantage is the ability to diagnose the early stages of the process, latent and persistent infections, but it has two significant drawbacks. Firstly, the low prognostic value associated with the fact that PCR reveals the DNA of the virus even in a latent state. Secondly, this method is not specific enough.
In recent years, the most widely used method of ELISA, which allows the detection of CMV antigen and specific antibodies of classes G and M. Detection of IgG is of secondary importance. It should be carried out simultaneously with the detection of IgM, especially for the diagnosis of primary infection. With a single detection of IgG, analysis of their avidity level (ability to retain antigen) can help in differentiating between active and persistent infections.
It must be borne in mind that specific antibodies may not be detected in individuals with reduced immunity, with protein starvation, etc. The determination of IgG must be carried out in paired sera with an interval of at least 10 days.
A relapsing form of CMVI is diagnosed with re-isolation of the virus in seropositive individuals.
The diagnosis of intrauterine CMVI is established during the first three weeks of life. The presence of IgM in a newborn up to two weeks of life indicates intrauterine infection, after – about acquired.
The affinity and avidity of antibodies
The importance of diagnosing a primary cytomegalovirus infection in pregnant women has led to a study of the properties of antibodies produced by the body in response to infection.
Two main properties of antibodies were established:
- Affinity – the degree of specific affinity of an antibody to an antigen of a pathogen
- Avidity – the degree of binding of the antibody molecule to the antigen molecule
A close relationship was established between them, the higher the affinity, the stronger the antibody binds to the antigen (higher avidity). The degrees of affinity and avidity make it possible to determine the age of class G antibodies and use it to judge the duration of infection and the course of the infection process (latent course, relapse). The primary phase of infection is judged by the presence of virus-specific IgM antibodies, the duration of which in the body is several weeks to months. An increase in IgG occurs within a few weeks. Initially, low affinity antibodies are formed, which are formed when the virus multiplies actively in the body and lasts up to 1.5 months. from the onset of the disease. Further, the body produces high affinity IgG antibodies that persist for a long time. High affinity antibodies remain in the body for a long time, providing immunity from infection.
To distinguish between primary and latent infections, the avidity of class G antibodies is determined. If low avidity IgG is detected in the blood, this indicates a primary infection. Detection of high avidity antibodies G indicates a latent or transmitted infection. If highly avid antibodies G and IgM are present in the body, then reactivation of latent infection or re-entry of the virus into the body can be assumed. speaks of a secondary immune response in the event of a pathogen entering the body or exacerbation (reactivation).
In quantitative terms, determine the so-called avidity index.
An avidity index of up to 30% indicates the presence of low-avidity antibodies and, accordingly, a primary infection, 30-40% indicates a late stage of a primary infection or a recent infection, an index of over 40% indicates a long-standing infection.
Treatment of Cytomegalovirus Infection
Treatment of cytomegalovirus infection presents certain difficulties, since interferon and many antiviral agents (acyclovir, vidarabine, virazole) have been found to be ineffective, and in some cases their use causes paradoxical reactions. Ganciclovir slows down the development of cytomegalovirus retinitis, but has little effect on damage to the lungs, brain, and digestive tract. The drug foscarnet has certain prospects. Perhaps the use of anticytomegalovirus hyperimmune human immunoglobulin. For the treatment of women with a burdened obstetric history, it is proposed to prescribe immunomodulators (levamisole, T-activin).
Mononucleosis-like forms of infection do not require specific treatment.
For the treatment of severe forms of CMVI in immunocompromised individuals and intrauterine CMVI in infants, ganciclovir is used. It connects to the virus propagation cycle and interrupts it. After the cancellation of ganciclovir, relapses are possible. The drug has a number of side effects in the form of neutropenia, thrombocytopenia, liver and kidney damage, therefore, children are prescribed it for health reasons. Treatment is carried out under the supervision of a blood test every two days.
The appointment of interferons is considered effective.
At the present stage, it is important to combine antiviral drugs with interferons, which contributes to the elimination of CMV (a combination of acyclovir with a-interferon), and also potentiates the antiviral effect, reduces the toxicity of the drugs (ganciclovir with interferon inducers, its combination with amixin is most successful). At the same time, funds are prescribed for the correction of immune dysfunction.
Specific anticytomegalovirus immunoglobulin is administered intramuscularly in 3 ml daily for 10 days. It contains 60% specific for CMV antibodies.
Nonspecific immunoglobulins for intravenous administration (Sandoglobulin) are prescribed for the prevention of CMVI in immunocompromised individuals. Their effectiveness is lower than that of specific immunoglobulins.
Effective for the prevention of CMVI in seronegative recipients is the use of immunoglobulins in combination with acyclovir or valaciclovir.
They use vaginally 0.25% bonaphthonic, oxolinic, riodoxoleic, 0.5% tebrofenic, florenalic, 1% interferonic, 3-5% acyclic ointments 3-5 times a day for 12-15 days (ointments must be changed every 10-14 days).
For the treatment of the oral cavity, the same preparations are used in the form of solutions, as well as 0.5% etonium, 1: 5000 furatsilin, 1-5% aminocaproic acid; with fungal complications – 1% iodinol and 0.25% riodoxole ointment.
With retinitis, damage to the central nervous system, pneumonia in immunocompromised individuals, ganciclovir or foscarnet is most effective, the course of treatment is 14-21 days.
Cytomegalovirus Infection Prevention
Specific prevention is not developed. When transfusion of blood should be used, the blood of healthy donors, not containing antibodies to CMV, also applies to transplantation of internal organs. The use of prophylactic specific hyperimmune immunoglobulin in risk groups (to recipients of bone marrow, heart, kidneys and liver; to patients receiving cytostatic drugs, to pregnant women) has been shown. In the prevention of congenital infection, the prevention of contact between pregnant women and patients, strict adherence to the anti-epidemic regime in obstetric institutions is of great importance. Children born to mothers with CMV infection and not showing signs of infection cannot be breastfed. In the case of the birth of a child with CMV infection, repeated pregnancy can be recommended no earlier than 2 years later.
Prevention measures for CMV infection in pregnant women
No measures can completely eliminate the risk of infection, but compliance with these rules will reduce the likelihood of CMV infection.
- Wash your hands thoroughly with soap for 15-20 minutes, especially after changing diapers (diapers) in infants.
- Never kiss children under 5 years old on the lips.
- Allocate separate dishes and cutlery for yourself and small children.
- If you work in kindergartens (nurseries, kindergartens) during pregnancy, take a vacation or sharply limit contact with children.