HCMV (human cytomegalovirus)
Encyclopedia
Human cytomegalovirus is a species
of virus
that belongs to the viral family known as Herpesviridae
or herpesviruses. It is typically abbreviated as HCMV and is alternatively known as human herpesvirus-5 (HHV-5). Within Herpesviridae
, HCMV belongs to the Betaherpesvirinae
subfamily, which also includes cytomegalovirus
es from other mammal
s.
Although they may be found throughout the body, HCMV infections are frequently associated with the salivary gland
s. HCMV infection is typically unnoticed in healthy people, but can be life-threatening for the immunocompromised, such as HIV
-infected persons, organ transplant
recipients, or new born infants. After infection, HCMV has an ability to remain latent
within the body over long periods. Eventually, it may cause mucoepidermoid carcinoma
and possibly other malignancies.
HCMV is found throughout all geographic locations and socioeconomic groups, and infects between 50% and 80% of adults in the United States (40% worldwide) as indicated by the presence of antibodies in much of the general population. Seroprevalence
is age-dependent: 58.9% of individuals aged 6 and older are infected with CMV while 90.8% of individuals aged 80 and older are positive for HCMV. HCMV is also the virus
most frequently transmitted to a developing fetus. HCMV infection
is more widespread in developing countries and in communities with lower socioeconomic status and represents the most significant viral cause of birth defects in industrialized countries. CMV "seems to have a large impact on immune parameters in later life and may contribute to increased morbidity and eventual mortality."
Most healthy people who are infected by HCMV after birth have no symptoms. Some develop a syndrome
similar to infectious mononucleosis
or glandular fever, with prolonged fever
, and a mild hepatitis
. A sore throat is common. After infection, the virus remains latent in the body for the rest of the person's life. Overt disease rarely occurs unless immunity
is suppressed either by drugs, infection or old age. Initial HCMV infection, which often is asymptomatic
, is followed by a prolonged, inapparent infection during which the virus resides in T-cells without causing detectable damage or clinical illness.
Infectious CMV may be shed in the bodily fluids of any infected person, and can be found in urine
, saliva
, blood
, tears
, semen
, and breast milk
. The shedding of virus
can occur intermittently, without any detectable signs or symptoms.
CMV infection can be demonstrated microscopically by the detection of intranuclear inclusion bodies
. On H&E stain
ing, the inclusion bodies stain dark pink and are called "owl's eye" inclusion bodies.
HCMV infection is important to certain high-risk groups. Major areas of risk of infection include pre-natal or postnatal
infants and immunocompromised individuals, such as organ transplant
recipients, persons with leukemia
, or those infected with human immunodeficiency virus (HIV
). In HIV infected persons, HCMV is considered an AIDS
-defining infection, indicating that the T-cell count has dropped to low levels.
Lytically replicating
virus disrupts the cytoskeleton
, causing massive cell enlargement, which is the source of the virus' name.
A study published in 2009 links infection with CMV to high blood pressure in mice, and suggests that the result of CMV infection of blood vessel endothelial cells (EC) in humans is a major cause of atherosclerosis
. Researchers also found that when the cells were infected with CMV, they created renin
, a protein known to contribute to high blood pressure.
, urine
, or other bodily fluids. CMV can be transmitted sexually
and via breast milk
, and also occurs through receiving transplanted organs or blood transfusion
s. Although HCMV is not highly contagious, it has been shown to spread in households and among young children in day care centers.
, Rubella
, Cytomegalovirus and Herpes simplex
. Congenital HCMV infection occurs when the mother suffers a primary infection or reactivation during pregnancy.
Up to 5/1000 live births are infected. 5% develop multiple handicaps, and develop cytomegalic inclusion disease with nonspecific signs that resemble rubella. Another 5% later develop cerebral calcification (decreasing IQ levels dramatically and causing sensorineural deafness and psychomotor retardation).
Infection with CMV is a major cause of disease and death in immunocompromised patients, including organ transplant recipients, patients undergoing hemodialysis
, patients with cancer
, patients receiving immunosuppressive drugs, and HIV
-infected patients. Exposing immunosuppressed patients to outside sources of CMV should be minimized to avoid the risk of serious infection. Susceptible patients without CMV infection can be infected by receiving infected organs and blood products unless care is taken.
In patients with a depressed immune system, CMV-related disease may be much more aggressive.
Specific disease entities recognised in those people are
Patients without CMV infection who are given organ transplants from CMV-infected donors require prophylactic treatment with valganciclovir
(ideally) or ganciclovir
, and regular serological monitoring to detect a rising CMV titre; if treated early establishment of a potentially life-threatening infection can be prevented.
(PCR) testing for CMV are available as well, allowing physicians to monitor the viral load
of CMV-infected patients.
CMV pp65 antigenemia test is a immunofluorescence based assay which utilizes an indirect immunofluorescence technique for identifying the pp65 protein of cytomegalovirus in peripheral blood leukocytes. The CMV pp65 assay is widely used for monitoring CMV infections and its response to antiviral treatment in patients who are under immunosuppressive therapy and have had renal transplantation surgery as the antigenemia results are obtained about 5 days before the onset of symptomatic CMV disease. The advantage of this assay is the rapidity in providing results in a few hours and that the pp65 antigen determination represents a useful parameter for the physician to initiate antiviral therapy. The major disadvantage of the pp65 assay is that only limited number of samples can be processed per test batch.
CMV should be suspected if a patient has symptoms of infectious mononucleosis
but has negative test results for mononucleosis and Epstein-Barr virus
, or if they show signs of hepatitis, but has negative test results for hepatitis A
, B, and C
.
For best diagnostic results, laboratory tests for CMV antibody should be performed by using paired serum samples. One blood sample should be taken upon suspicion of CMV, and another one taken within 2 weeks. A virus culture can be performed at any time the patient is symptomatic. Laboratory testing for antibody to CMV can be performed to determine if a woman has already had CMV infection. However, routine testing of all pregnant women is costly and the need for testing should therefore be evaluated on a case-by-case basis.
) is the most commonly available serologic test for measuring antibody to CMV. The result can be used to determine if acute infection, prior infection, or passively acquired maternal antibody in an infant is present. Other tests include various fluorescence assays, indirect hemagglutination
, (PCR) and latex agglutination
.
An ELISA technique for CMV-specific IgM
is available, but may give false-positive results unless steps are taken to remove rheumatoid factor
or most of the IgG antibody
before the serum sample is tested. Because CMV-specific IgM may be produced in low levels in reactivated CMV infection, its presence is not always indicative of primary infection. Only virus recovered from a target organ, such as the lung, provides unequivocal evidence that the current illness is caused by acquired CMV infection. If serologic tests detect a positive or high titer of IgG, this result should not automatically be interpreted to mean that active CMV infection is present. However, if antibody tests of paired serum samples show a fourfold rise in IgG antibody and a significant level of IgM antibody, meaning equal to at least 30% of the IgG value, or virus is cultured from a urine or throat specimen, the findings indicate that an active CMV infection is present.
(donations not specified for a particular patient) in the U.S., the UK and many other countries. CMV-negative donations are then earmarked for transfusion to infants or immunocompromised patients. Some blood donation centers maintain lists of donors whose blood is CMV negative due to special demands.
Alone or in combination with an antiviral agent, it has been shown to:
Ganciclovir
(Cytovene) treatment is used for patients with depressed immunity who have either sight-related or life-threatening illnesses. Valganciclovir
(Valcyte) is an antiviral drug that is also effective and is given orally. The therapeutic effectiveness is frequently compromised by the emergence of drug-resistant virus isolates. A variety of amino acid changes in the UL97 protein kinase and the viral DNA polymerase have been reported to cause drug resistance. Foscarnet
or cidofovir are only given to patients with CMV resistant to ganciclovir, because foscarnet has notable nephrotoxicity, resulting in increased or decreased Ca2+ or P, and decreased Mg2+.
, pUL54. Ganciclovir
(GCV) acts as nucleoside analogue. Its antiviral activity requires phosphorylation by the HCMV protein kinase, pUL97. The second drug, Cidofovir
(CDV), is a nucleotide analogue, which is already phosphorylated and thus active. Finally, Foscarnet
(FOS) has a different mode of action. It directly inhibits polymerase function by blocking the pyrophosphate
binding site of pUL54.
Two HCMV proteins are implicated in antiviral resistance against these three drugs: pUL97 and pUL54. Specific mutations in pUL97 can cause reduced phosphorylation activity of this viral protein kinase. Thus, fewer monophosphorylated – and thus active – GCV can be synthesized, leading to antiviral resistance against GCV. About 90% of all GCV resistances are caused by such mutations in UL97. Mutations in pUL54 may have different effects leading to antiviral drug resistance
: A. They can lead to decreased affinity to antiviral compounds. This resistance mechanism concerns GCV, CDV and FOS and may lead to multidrug resistance. B. Some mutations in pUL54 can increase the polymerase’s exonuclease
activity. This causes enhanced recognition of incorporated GCV and CDV. As a result, these dNTP analogues are excised more efficiently.
Major risk factors for HCMV drug resistance are the residual capacity of the host’s immune system to control viral replication and the overall amount and duration of viral replication.
HCMV antiviral drug resistance can be detected by phenotypic or by genotypic drug resistance testing. Phenotypic resistance testing involves cultivation of the virus in cell culture and testing its susceptibility using different antiviral drug concentrations in order to determine EC50
values. In contrast, genotypic resistance testing means the detection of resistance associated mutations in UL97 and UL54 by sequencing
. Genotypic resistance testing is becoming the method of choice because it is faster, but requires previous phenotypic characterisation of each newly found mutation. This can be performed via a web-based search tool that links a patient’s HCMV sequence to a database containing all published UL97 and UL54 mutations and corresponding antiviral drug susceptibility phenotypes.
Species
In biology, a species is one of the basic units of biological classification and a taxonomic rank. A species is often defined as a group of organisms capable of interbreeding and producing fertile offspring. While in many cases this definition is adequate, more precise or differing measures are...
of virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
that belongs to the viral family known as Herpesviridae
Herpesviridae
The Herpesviridae are a large family of DNA viruses that cause diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word herpein , referring to the latent, recurring infections typical of this group of viruses...
or herpesviruses. It is typically abbreviated as HCMV and is alternatively known as human herpesvirus-5 (HHV-5). Within Herpesviridae
Herpesviridae
The Herpesviridae are a large family of DNA viruses that cause diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word herpein , referring to the latent, recurring infections typical of this group of viruses...
, HCMV belongs to the Betaherpesvirinae
Betaherpesvirinae
Betaherpesvirinae is a subfamily of Herpesviridae distinguished by reproducing less quickly than other subfamilies of Herpesviridae.Betaherpesvirinae establish latency in leukocytes...
subfamily, which also includes cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
es from other mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s.
Although they may be found throughout the body, HCMV infections are frequently associated with the salivary gland
Salivary gland
The salivary glands in mammals are exocrine glands, glands with ducts, that produce saliva. They also secrete amylase, an enzyme that breaks down starch into maltose...
s. HCMV infection is typically unnoticed in healthy people, but can be life-threatening for the immunocompromised, such as HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
-infected persons, organ transplant
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
recipients, or new born infants. After infection, HCMV has an ability to remain latent
Virus latency
Virus latency is the ability of a pathogenic virus to lie dormant within a cell, denoted as the lysogenic part of the viral life cycle. A latent viral infection is a type of persistent viral infection which is distinguished from a chronic viral infection...
within the body over long periods. Eventually, it may cause mucoepidermoid carcinoma
Mucoepidermoid carcinoma
Mucoepidermoid carcinoma is the most common type of salivary gland malignancy in children. Mucoepidermoid carcinoma can also be found in other organs, as bronchi, lacrimal sac and thyroid.Mucicarmine staining is one stain used by pathologist for detection....
and possibly other malignancies.
HCMV is found throughout all geographic locations and socioeconomic groups, and infects between 50% and 80% of adults in the United States (40% worldwide) as indicated by the presence of antibodies in much of the general population. Seroprevalence
Seroprevalence
Seroprevalence is the number of persons in a population who test positive for a specific disease based on serology specimens; often presented as a percent of the total specimens tested or as a proportion per 100,000 persons tested...
is age-dependent: 58.9% of individuals aged 6 and older are infected with CMV while 90.8% of individuals aged 80 and older are positive for HCMV. HCMV is also the virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
most frequently transmitted to a developing fetus. HCMV infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
is more widespread in developing countries and in communities with lower socioeconomic status and represents the most significant viral cause of birth defects in industrialized countries. CMV "seems to have a large impact on immune parameters in later life and may contribute to increased morbidity and eventual mortality."
Pathogenesis
Syndrome
In medicine and psychology, a syndrome is the association of several clinically recognizable features, signs , symptoms , phenomena or characteristics that often occur together, so that the presence of one or more features alerts the physician to the possible presence of the others...
similar to infectious mononucleosis
Infectious mononucleosis
Infectious mononucleosis is an infectious, widespread viral...
or glandular fever, with prolonged fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, and a mild hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
. A sore throat is common. After infection, the virus remains latent in the body for the rest of the person's life. Overt disease rarely occurs unless immunity
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
is suppressed either by drugs, infection or old age. Initial HCMV infection, which often is asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
, is followed by a prolonged, inapparent infection during which the virus resides in T-cells without causing detectable damage or clinical illness.
Infectious CMV may be shed in the bodily fluids of any infected person, and can be found in urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
, blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, tears
Tears
Tears are secretions that clean and lubricate the eyes. Lacrimation or lachrymation is the production or shedding of tears....
, semen
Semen
Semen is an organic fluid, also known as seminal fluid, that may contain spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...
, and breast milk
Breast milk
Breast milk, more specifically human milk, is the milk produced by the breasts of a human female for her infant offspring...
. The shedding of virus
Viral shedding
Viral shedding refers to the successful reproduction, expulsion, and host-cell infection caused by virus progeny. Once replication has been completed and the host cell is exhausted of all resources in making viral progeny, the viruses may begin to leave the cell by several methods.The term is used...
can occur intermittently, without any detectable signs or symptoms.
Inclusion bodies
Inclusion bodies are nuclear or cytoplasmic aggregates of stainable substances, usually proteins. They typically represent sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins...
. On H&E stain
H&E stain
H&E stain, HE stain or hematoxylin and eosin stain is a popular staining method in histology. It is the most widely used stain in medical diagnosis; for example when a pathologist looks at a biopsy of a suspected cancer, the histological section is likely to be stained with H&E and termed H&E...
ing, the inclusion bodies stain dark pink and are called "owl's eye" inclusion bodies.
HCMV infection is important to certain high-risk groups. Major areas of risk of infection include pre-natal or postnatal
Postnatal
Postnatal is the period beginning immediately after the birth of a child and extending for about six weeks. Another term would be postpartum period, as it refers to the mother...
infants and immunocompromised individuals, such as organ transplant
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
recipients, persons with leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
, or those infected with human immunodeficiency virus (HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
). In HIV infected persons, HCMV is considered an AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
-defining infection, indicating that the T-cell count has dropped to low levels.
Lytically replicating
Lytic cycle
The lytic cycle is one of the two cycles of viral reproduction, the other being the lysogenic cycle. The lytic cycle is typically considered the main method of viral replication, since it results in the destruction of the infected cell...
virus disrupts the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
, causing massive cell enlargement, which is the source of the virus' name.
A study published in 2009 links infection with CMV to high blood pressure in mice, and suggests that the result of CMV infection of blood vessel endothelial cells (EC) in humans is a major cause of atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
. Researchers also found that when the cells were infected with CMV, they created renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
, a protein known to contribute to high blood pressure.
Transmission
The mode of HCMV transmission from person to person is entirely unknown but is presumed to occur through bodily fluids. Infection requires close, intimate contact with a person secreting the virus in their salivaSaliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
, urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, or other bodily fluids. CMV can be transmitted sexually
Sexually transmitted disease
Sexually transmitted disease , also known as a sexually transmitted infection or venereal disease , is an illness that has a significant probability of transmission between humans by means of human sexual behavior, including vaginal intercourse, oral sex, and anal sex...
and via breast milk
Breastfeeding
Breastfeeding is the feeding of an infant or young child with breast milk directly from female human breasts rather than from a baby bottle or other container. Babies have a sucking reflex that enables them to suck and swallow milk. It is recommended that mothers breastfeed for six months or...
, and also occurs through receiving transplanted organs or blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
s. Although HCMV is not highly contagious, it has been shown to spread in households and among young children in day care centers.
Vaccine
A phase 2 study of a CMV-vaccine published in 2009 indicated an efficacy of 50% - the protection provided was limited, and a number of subjects contracted CMV infection despite vaccination. In one case also congenital CMV was encountered.CMV diseases
CMV infections are most significant in the perinatal period and in immunocompromised patients.Pregnancy and congenital infection
HCMV is one of the TORCH infections that lead to congenital abnormalities. These are: ToxoplasmosisToxoplasmosis
Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii. The parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid family. Animals are infected by eating infected meat, by ingestion of feces of a cat that has itself...
, Rubella
Rubella
Rubella, commonly known as German measles, is a disease caused by the rubella virus. The name "rubella" is derived from the Latin, meaning little red. Rubella is also known as German measles because the disease was first described by German physicians in the mid-eighteenth century. This disease is...
, Cytomegalovirus and Herpes simplex
Herpes simplex
Herpes simplex is a viral disease caused by both Herpes simplex virus type 1 and type 2 . Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever...
. Congenital HCMV infection occurs when the mother suffers a primary infection or reactivation during pregnancy.
Up to 5/1000 live births are infected. 5% develop multiple handicaps, and develop cytomegalic inclusion disease with nonspecific signs that resemble rubella. Another 5% later develop cerebral calcification (decreasing IQ levels dramatically and causing sensorineural deafness and psychomotor retardation).
Immunocompromised adults
Primary CMV infection in patients with weakened immune systems can lead to serious disease. However, a more common problem is reactivation of the latent virus.Infection with CMV is a major cause of disease and death in immunocompromised patients, including organ transplant recipients, patients undergoing hemodialysis
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
, patients with cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, patients receiving immunosuppressive drugs, and HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
-infected patients. Exposing immunosuppressed patients to outside sources of CMV should be minimized to avoid the risk of serious infection. Susceptible patients without CMV infection can be infected by receiving infected organs and blood products unless care is taken.
In patients with a depressed immune system, CMV-related disease may be much more aggressive.
Specific disease entities recognised in those people are
- CMV hepatitis, which may cause fulminant liver failureLiver failureAcute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
- cytomegalovirus retinitisCytomegalovirus retinitisCytomegalovirus retinitis, also known as CMV retinitis, is an inflammation of the eye's retina that can lead to blindness.-Presentation:...
(inflammation of the retinaRetinaThe vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
, characterised by a "pizza pie appearance" on ophthalmoscopyOphthalmoscopyOphthalmoscopy is a test that allows a health professional to see inside the fundus of the eye and other structures using an ophthalmoscope . It is done as part of an eye examination and may be done as part of a routine physical examination...
) - cytomegalovirus colitisCytomegalovirus colitisCytomegalovirus colitis, also known as CMV colitis, is an inflammation of the colon.-Diagnosis:The diagnosis of CMV colitis is based on serology, CMV antigen testing and colonscopy with biopsy.-Treatment:The usual treatment is antiretrovirals...
(inflammation of the large bowelColon (anatomy)The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
) - CMV pneumonitisPneumonitisPneumonitis or pulmonitis is a general term that refers to inflammation of lung tissue.Pneumonia is pneumonitis combined with consolidation and exudation...
- CMV esophagitisEsophagitisEsophagitis is inflammation of the esophagus. It may be acute or chronic. The acute esophagitis can be catarrhal or phlegmonous, whereas the chronic esophagitis may be hypertrophic or atrophic.-Infectious:...
- polyradiculopathy, transverse myelitis, and subacute encephalitis
Patients without CMV infection who are given organ transplants from CMV-infected donors require prophylactic treatment with valganciclovir
Valganciclovir
Valganciclovir hydrochloride is an antiviral medication used to treat cytomegalovirus infections. As the L-valyl ester of ganciclovir, it is actually a prodrug for ganciclovir...
(ideally) or ganciclovir
Ganciclovir
Ganciclovir INN is an antiviral medication used to treat or prevent cytomegalovirus infections.Ganciclovir sodium is marketed under the trade names Cytovene and Cymevene . Ganciclovir for ocular use is marketed under the trade name Vitrasert...
, and regular serological monitoring to detect a rising CMV titre; if treated early establishment of a potentially life-threatening infection can be prevented.
Immunocompetent adults
CMV infections can still be of clinical significance in adult immunocompetent populations:- CMV mononucleosisMononucleosisMononucleosis , is a disease most commonly caused by the Epstein-Barr virus . The EBV virus affects the lymphocytes- white blood cells that battle infections by attacking antibodies. Mononucleosis can also be caused by Cytomegalovirus , a herpes virus most commonly found in body fluids...
(some sources reserve "mononucleosis" for EBV only) - Post-transfusion CMV – similar to CMV mononucleosis
- A 2009 study suggests that CMV infection may be linked to the development of arterial hypertension. Mice fed a high cholesterolCholesterolCholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
diet showed significantly more vascular damage and hypertension when they had been infected with CMV. CMV infection stimulated cytokineCytokineCytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s – IL6Interleukin 6Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
, TNFTumor necrosis factorsTumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...
, and MCP1CCL2For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.Chemokine ligand 2 also known as monocyte chemotactic protein-1 or small inducible cytokine A2 is a protein that in humans is encoded by the CCL2 gene. CCL2 is a small cytokine belonging to the CC...
– in the infected mice, indicating that the infection led to an inflammatory response in vessels and other tissues. Further, reninReninRenin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
and angiotensin II release were increased in these animals as additional factors to lead to hypertension. In humans CMV infection has been demonstrated in the aortic smooth muscle cells from patients with abdominal aortic aneurysmAortic aneurysmAn aortic aneurysm is a general term for any swelling of the aorta to greater than 1.5 times normal, usually representing an underlying weakness in the wall of the aorta at that location...
s suggesting that CMV infection contributes to vascular disease.
Diagnosis
Most infections with CMV are not diagnosed because the virus usually produces few, if any, symptoms and tends to reactivate intermittently without symptoms. However, persons who have been infected with CMV develop antibodies to the virus, and these antibodies persist in the body for the lifetime of that individual. A number of laboratory tests that detect these antibodies to CMV have been developed to determine if infection has occurred and are widely available from commercial laboratories. In addition, the virus can be cultured from specimens obtained from urine, throat swabs, bronchial lavages and tissue samples to detect active infection. Both qualitative and quantitative polymerase chain reactionPolymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
(PCR) testing for CMV are available as well, allowing physicians to monitor the viral load
Viral load
Viral load is a measure of the severity of a viral infection, and can be calculated by estimating the amount of virus in an involved body fluid. For example, it can be given in RNA copies per milliliter of blood plasma...
of CMV-infected patients.
CMV pp65 antigenemia test is a immunofluorescence based assay which utilizes an indirect immunofluorescence technique for identifying the pp65 protein of cytomegalovirus in peripheral blood leukocytes. The CMV pp65 assay is widely used for monitoring CMV infections and its response to antiviral treatment in patients who are under immunosuppressive therapy and have had renal transplantation surgery as the antigenemia results are obtained about 5 days before the onset of symptomatic CMV disease. The advantage of this assay is the rapidity in providing results in a few hours and that the pp65 antigen determination represents a useful parameter for the physician to initiate antiviral therapy. The major disadvantage of the pp65 assay is that only limited number of samples can be processed per test batch.
CMV should be suspected if a patient has symptoms of infectious mononucleosis
Infectious mononucleosis
Infectious mononucleosis is an infectious, widespread viral...
but has negative test results for mononucleosis and Epstein-Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
, or if they show signs of hepatitis, but has negative test results for hepatitis A
Hepatitis A
Hepatitis A is an acute infectious disease of the liver caused by the hepatitis A virus , an RNA virus, usually spread the fecal-oral route; transmitted person-to-person by ingestion of contaminated food or water or through direct contact with an infectious person...
, B, and C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
.
For best diagnostic results, laboratory tests for CMV antibody should be performed by using paired serum samples. One blood sample should be taken upon suspicion of CMV, and another one taken within 2 weeks. A virus culture can be performed at any time the patient is symptomatic. Laboratory testing for antibody to CMV can be performed to determine if a woman has already had CMV infection. However, routine testing of all pregnant women is costly and the need for testing should therefore be evaluated on a case-by-case basis.
Serologic testing
The enzyme-linked immunosorbent assay (or ELISAELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...
) is the most commonly available serologic test for measuring antibody to CMV. The result can be used to determine if acute infection, prior infection, or passively acquired maternal antibody in an infant is present. Other tests include various fluorescence assays, indirect hemagglutination
Hemagglutination
Hemagglutination, or haemagglutination, is a specific form of agglutination that involves red blood cells . It has two common uses in the laboratory: blood typing and the quantification of virus dilutions.-Blood Typing:...
, (PCR) and latex agglutination
Latex fixation test
A latex fixation test is an agglutination technique used to detect antibodies, such as those produced in response to the rubella virus or the rheumatoid factor...
.
An ELISA technique for CMV-specific IgM
IGM
IGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
is available, but may give false-positive results unless steps are taken to remove rheumatoid factor
Rheumatoid factor
Rheumatoid factor is an autoantibody most relevant in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG. RF and IgG join to form immune complexes that contribute to the disease process...
or most of the IgG antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
before the serum sample is tested. Because CMV-specific IgM may be produced in low levels in reactivated CMV infection, its presence is not always indicative of primary infection. Only virus recovered from a target organ, such as the lung, provides unequivocal evidence that the current illness is caused by acquired CMV infection. If serologic tests detect a positive or high titer of IgG, this result should not automatically be interpreted to mean that active CMV infection is present. However, if antibody tests of paired serum samples show a fourfold rise in IgG antibody and a significant level of IgM antibody, meaning equal to at least 30% of the IgG value, or virus is cultured from a urine or throat specimen, the findings indicate that an active CMV infection is present.
Relevance to blood donors
Although the risks discussed above are generally low, CMV assays are part of the standard screening for non-directed blood donationBlood donation
A blood donation occurs when a person voluntarily has blood drawn and used for transfusions or made into medications by a process called fractionation....
(donations not specified for a particular patient) in the U.S., the UK and many other countries. CMV-negative donations are then earmarked for transfusion to infants or immunocompromised patients. Some blood donation centers maintain lists of donors whose blood is CMV negative due to special demands.
Treatment
Cytomegalovirus Immune Globulin Intravenous (Human) (CMV-IGIV) is an immunoglobulin G (IgG) containing a standardized amount of antibody to Cytomegalovirus (CMV). It may be used for the prophylaxis of cytomegalovirus disease associated with transplantation of kidney, lung, liver, pancreas, and heart.Alone or in combination with an antiviral agent, it has been shown to:
- Reduce the risk of CMV-related disease and death in some of the highest-risk transplant patients
- Provide a measurable long-term survival benefit
- Produce minimal treatment-related side effects and adverse events.
Ganciclovir
Ganciclovir
Ganciclovir INN is an antiviral medication used to treat or prevent cytomegalovirus infections.Ganciclovir sodium is marketed under the trade names Cytovene and Cymevene . Ganciclovir for ocular use is marketed under the trade name Vitrasert...
(Cytovene) treatment is used for patients with depressed immunity who have either sight-related or life-threatening illnesses. Valganciclovir
Valganciclovir
Valganciclovir hydrochloride is an antiviral medication used to treat cytomegalovirus infections. As the L-valyl ester of ganciclovir, it is actually a prodrug for ganciclovir...
(Valcyte) is an antiviral drug that is also effective and is given orally. The therapeutic effectiveness is frequently compromised by the emergence of drug-resistant virus isolates. A variety of amino acid changes in the UL97 protein kinase and the viral DNA polymerase have been reported to cause drug resistance. Foscarnet
Foscarnet
Foscarnet is the conjugate base of the chemical compound with the formula HO2CPO3H2.-Uses:This phosphonic acid derivative is an antiviral medication used to treat herpes viruses, including drug resistant cytomegalovirus and herpes simplex viruses types 1 and 2...
or cidofovir are only given to patients with CMV resistant to ganciclovir, because foscarnet has notable nephrotoxicity, resulting in increased or decreased Ca2+ or P, and decreased Mg2+.
Drug resistance
All three currently licensed anti-HCMV drugs target the viral DNA polymeraseDNA polymerase
A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand....
, pUL54. Ganciclovir
Ganciclovir
Ganciclovir INN is an antiviral medication used to treat or prevent cytomegalovirus infections.Ganciclovir sodium is marketed under the trade names Cytovene and Cymevene . Ganciclovir for ocular use is marketed under the trade name Vitrasert...
(GCV) acts as nucleoside analogue. Its antiviral activity requires phosphorylation by the HCMV protein kinase, pUL97. The second drug, Cidofovir
Cidofovir
Cidofovir is an injectable antiviral medication for the treatment of cytomegalovirus retinitis in patients with AIDS. It suppresses CMV replication by selective inhibition of viral DNA polymerase and therefore prevention of viral replication and transcription...
(CDV), is a nucleotide analogue, which is already phosphorylated and thus active. Finally, Foscarnet
Foscarnet
Foscarnet is the conjugate base of the chemical compound with the formula HO2CPO3H2.-Uses:This phosphonic acid derivative is an antiviral medication used to treat herpes viruses, including drug resistant cytomegalovirus and herpes simplex viruses types 1 and 2...
(FOS) has a different mode of action. It directly inhibits polymerase function by blocking the pyrophosphate
Pyrophosphate
In chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. Any salt or ester containing two phosphate groups is called a diphosphate. As a food additive, diphosphates are known as E450.- Chemistry :...
binding site of pUL54.
Two HCMV proteins are implicated in antiviral resistance against these three drugs: pUL97 and pUL54. Specific mutations in pUL97 can cause reduced phosphorylation activity of this viral protein kinase. Thus, fewer monophosphorylated – and thus active – GCV can be synthesized, leading to antiviral resistance against GCV. About 90% of all GCV resistances are caused by such mutations in UL97. Mutations in pUL54 may have different effects leading to antiviral drug resistance
Drug resistance
Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
: A. They can lead to decreased affinity to antiviral compounds. This resistance mechanism concerns GCV, CDV and FOS and may lead to multidrug resistance. B. Some mutations in pUL54 can increase the polymerase’s exonuclease
Exonuclease
Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3’ or the 5’ end occurs. Its close relative is the endonuclease, which cleaves phosphodiester bonds in the middle ...
activity. This causes enhanced recognition of incorporated GCV and CDV. As a result, these dNTP analogues are excised more efficiently.
Major risk factors for HCMV drug resistance are the residual capacity of the host’s immune system to control viral replication and the overall amount and duration of viral replication.
HCMV antiviral drug resistance can be detected by phenotypic or by genotypic drug resistance testing. Phenotypic resistance testing involves cultivation of the virus in cell culture and testing its susceptibility using different antiviral drug concentrations in order to determine EC50
EC50
The term half maximal effective concentration refers to the concentration of a drug, antibody or toxicant which induces a response halfway between the baseline and maximum after some specified exposure time...
values. In contrast, genotypic resistance testing means the detection of resistance associated mutations in UL97 and UL54 by sequencing
Sequencing
In genetics and biochemistry, sequencing means to determine the primary structure of an unbranched biopolymer...
. Genotypic resistance testing is becoming the method of choice because it is faster, but requires previous phenotypic characterisation of each newly found mutation. This can be performed via a web-based search tool that links a patient’s HCMV sequence to a database containing all published UL97 and UL54 mutations and corresponding antiviral drug susceptibility phenotypes.
External links
- Cytomegalovirus (CMV) US Centers for Disease Control and PreventionCenters for Disease Control and PreventionThe Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
(CDC). May 22, 2009 - Cytomegalovirus (CMV) Clinical DNA Information Resource (CDIR)
- National Institute of Standards and Technology (NIST)
- HCMV drug resistance mutations tool