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Cytomegalovirus (from the Greek p , "cell", and , "large") is a herpes viral
genus of the Herpesviruses group: in humans it is commonly known as HCMV or
(HHV-5). CMV belongs to the ¦
subfamily
of
, which also includes Roseolovirus. Other herpesviruses fall into the
subfamilies of
(including HSV 1 and 2 and varicella) or
(including Epstein-Barr virus). All herpesviruses share a
characteristic ability to remain latent within the body over long periods.
HCMV infections are frequently associated with salivary glands, though they may be
found throughout the body. HCMV infection can also be life threatening for patients
who are immunocompromised ( patients with HIV, organ transplant recipients, or
neonates). Other CMV viruses are found in several mammal species, but species
isolated from animals differ from HCMV in terms of genomic structure, and have not
been reported to cause human disease.
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."
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M t healthy people who are i ected by HCM after birth have no symptoms. Some
of them develop an infectious mononucleosis/glandular fever-li e syndrome, 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
HCM 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.
Micrograph of CMV placentitis. One cell on the image (centre) has the characteristic
large nucleus with peri-nuclear clearing. Two cells (centre-left) have the characteristic
(cytoplasmic) viral inclusion bodies (small pink globules). H&E stain.
Cytomegalovirus Retinitis
CMV retinitis is the most common retinal infection in patients with HIV disease, occurring in
15-40% of patients with advanced HIV disease.(20,36-39) It is bilateral in 30-50% of
patients,(40) although that rate may be lower in the setting of treatment, as the disease often
presents unilaterally and the administration of anti-CMV medication almost always prevents
the onset of retinitis in the fellow eye.(36) It is uncommon to find CMV retinitis in HIV-
infected patients with a CD4 count >40 cells/µL, and a CD4 count >50-100 cells/µL in an
individual with retinitis should prompt a reconsideration of the diagnosis of CMV retinal
infection.
CMV is a DNA virus classified in the herpes group of viruses. Serologic studies indicate a
past CMV infection in approximately 50% of the adult population in urban areas of the
United States and Europe (41) and close to 100% in the male homosexual population. CMV
disease affecting the eye, however, tends to occur only in developing fetuses and in
immunocompromised patients. CMV infection of the retina leads to viral invasion of retinal
cells with resultant retinal necrosis. Clinically, lesions appear within the retina as multiple
granular white dots with varying amounts of hemorrhage (Figure 2). Although they can be
confused with cotton-wool spots (which may be present in the same eye), CMV lesions differ
by their tendency to enlarge and coalesce over time. As areas of retinitis enlarge, they appear
to follow the vascular arcades, resulting in an arcuate or triangular zone of infection. Areas of
active infection also may appear to be linear, seemingly following the retinal vessels or nerve
fiber layer into the periphery. Frosted branch angiitis may be seen in conjunction with CMV
retinitis (Figure 3). After several weeks, atrophic tissue that has lost the capacity to support
viral replication replaces actively infected regions of retinal tissue.(42,43) The underlying
retinal pigment epithelium demonstrates pigment loss and migration, resulting in increased
visualization of the underlying choroidal vasculature.
Other findings associated with CMV retinitis include perivasculitis, vascular attenuation, and
vessel closure,(20,44) as well as vitritis, anterior uveitis, and papillitis.(45-47)
Although CMV retinitis usually responds to initial therapy, the prompt recognition of
recurrent CMV retinitis is of particular importance. The presentation of recurrence may be so
subtle that active disease may remain undetected for extended periods of time. Early
recurrences appear as subtle white or gray zones of retinitis with little, if any, accompanying
retinal hemorrhage. Recurrence usually begins at the margins of previously active infection
and tends to "smolder" rather than actively progress. Nevertheless, it will continue to spread,
slowly but inexorably, if the treatment regimen is not altered. The reintroduction of induction
doses of medication for a period of 2-3 weeks often will inhibit progression of these recurrent
lesions. Retinitis progression may recur, however, eventually necessitating alternative
treatments. Patients with recurrent infection that is quite "active" in appearance and
accompanied by the presence of significant retinal whitening and hemorrhage while they are
on appropriate levels of maintenance therapy have an especially poor prognosis for
preservation of sight, even with the use of increased doses of medication.
With the introduction of effective ART, the incidence of CMV retinitis has been noted to
decrease by about 75%.(48) However, the incidence of OI, especially new or recurrent CMV
retinitis, remains high during the first few months of ART, consistent with the delay in
immune recovery following initiation of ART.(49) Prior to the availability of effective ART,
the median time to progression of treated CMV was 3-9 months, and the lack of CMV
progression in patients on ART is most likely due to improved CMV-specific immunity.(50)
In patients with a history of CMV disease who subsequently receive ART, immune
reconstitution may result in inflammatory retinal lesions, vitritis, or uveitis. (See chapter
Immune Reconstitution.)
Chorioretinitis
Chorioretinitis most commonly occurs in patients with CD4 lymphocyte counts <50 cells/µL
and accounts for 80% to 90% of CMV disease in patients with AIDS.(12) Common
presenting symptoms include decreased visual acuity, the perception of floaters, or visual
field loss. Ophthalmologic screening of patients with a CD4 lymphocyte count <50 cells/µL
can detect asymptomatic retinitis. It is unclear, however, whether routine screening results in
a different clinical outcome, and screening practices for retinitis vary within different health
care settings.
Ophthalmologic examination of patients with CMV retinitis typically reveals large creamy to
yellowish-white granular areas with perivascular exudates and hemorrhages. These lesions
may occur at either the periphery or center of the fundus. If left untreated, lesions generally
progress within 2 to 3 weeks and can result in blindness. Retinitis often begins unilaterally,
but progression to bilateral disease is common. Systemic CMV disease involving other
viscera may also be present.
Patients with confirmed CMV chorioretinitis should begin treatment promptly. A variety of
systemically administered agents as well as local, intravitreal therapies have demonstrated
efficacy in delaying time to progression of retinitis. The choice of initial treatment should be
based on several factors, including the patient's antiretroviral history (treatment naive vs
failing therapy) and clinical status (especially underlying myelosuppression or renal
impairment), location of lesion (sight threatening or not), concomitant medication (with
potentially overlapping toxicity), and patient preference (especially regarding placement of
an indwelling intravenous catheter). Before the availability of ART, CMV retinitis regularly
progressed once therapy was discontinued, so maintenance treatment was considered
necessary; and even with maintenance therapy, reactivation of retinitis and/or development of
new lesions would commonly occur. However, if ART is successful in restoring CD4 counts
to at least 100 cells/µL (although to 150-200 cells/µL is better), it is possible to stop
maintenance therapy. This should not be attempted until a patient's CD4 count has remained
above the levels mentioned for at least 3 months because the lymphocyte response requires
time to reach full effectiveness. If maintenance therapy is discontinued, patients should be
followed carefully for clinical or laboratory evidence of drug failure. Other factors to
consider when deciding to discontinue maintenance therapy include patient adherence to
ART medications, location of the retinal lesion, and the patient's vision in the unaffected eye.
Cmv of retina
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Most people are exposed to CMV at birth or as children. The virus remains dormant in
their bodies for their lifetime
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Yes. It is important to test frequently for CMV while your immune system is sup-
pressed from the transplant and
immunosuppressive medication. You are at risk for having active CMV while your
immune system is suppressed.
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A CMV positive test will give a number, which tells the amount of virus found in your
blood. The number (amount of virus), will help your doctor decide if you should take
an antiviral medication to kill the virus.
If your doctor decides not to put you on antiviral medication, he or she will recheck a
blood sample in a few days.
If your doctor decides to put you on an antiviral medication, you will receive this
medication every day until your blood test for CMV comes back with a lower number
than the previous test or is negative.
Depending on your transplant and blood test results, your medication will be either in
tablet or in I.V. (intravenous) form. If you need I.V. medication, you may need to be
admitted to the hospital for 1 to 2 weeks.
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Yes. If your donor is positive for CMV, he or she can transmit this infection to you
through the donated stem cells. Knowing if your donor is a CMV carrier helps your
doctor to predict your risk for active CMV infection.
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Simple hand washing with soap and water removes the virus from the hands. We
recommend frequent hand washing.
If you have other questions about CMV, please feel free to ask your doctor or nurse.
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Transmission of HCMV occurs from person to person through bodily fluids. Infection
requires close, intimate contact with a person excreting the virus in their saliva, urine,
or other bodily fluids. CMV can be sexually transmitted and can also be transmitted
via breast milk, transplanted organs, and rarely from blood transfusions.
Although HCMV is not highly contagious, it has been shown to spread in households
and among young children in day care centers.[1] Transmission of the virus is often
preventable because it is most often transmitted through infected bodily fluids that
come in contact with hands and then are absorbed through the nose or mouth of a
susceptible person. Therefore, care should be taken when handling children and items
like diapers. Simple hand washing with soap and water is effective in removing the
virus from the hands.
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Main article: Cytomegalovirus vaccine
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Main article: Congenital cytomegalovirus infection
HCMV is one of the TORCH infections that lead to congenital abnormalities. These
are: toxoplasmosis, rubella, herpes simplex, and cytomegalovirus. Congenital HCMV
infection occurs when the mother suffers a primary infection (or reactivation) during
pregnancy.
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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.
In patients with a depressed immune system, CMV-related disease may be much more
aggressive.
Patients without CMV infection who are given organ transplants from CMV-infected
donors should be given prophylactic treatment with valganciclovir (ideally) or
ganciclovir and require regular serological monitoring to detect a rising CMV titre,
which should be treated early to prevent a potentially life-threatening infection
becoming established.
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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 reaction (PCR) testing for CMV are available as well,
allowing physicians to monitor the viral load of CMV-infected patients.
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.
*
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The enzyme-linked immunosorbent assay (or ELISA) 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.
*
&+
&&
Although the risks discussed above are generally low, CMV assays are part of the
standard screening for non-directed blood donation (donations not specified for a
particular patient) in the U.S. 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. [13]
*
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? 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.[14]
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 bad nephrotoxicity,
resulting in increased or decreased Ca2+ or P, and decreased Mg2+.
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This section
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CMV is one of the herpes viruses. First infection takes place in youth and the majority
of adults harbour the virus in a latent stage. In HIV patients with severe
immunodepression, reactivation of CMV may cause gastrointestinal disease,
pneumonitis, encephalitis and retinitis. CMV retinitis will affect up to 30% of AIDS
patients in the industrialised world. In developing countries the prevalence seems to
be much lower, somewhere between 5 and 10%. The reason for this difference is that
CMV retinitis is an infection that mainly affects patients with profound immune
depression (CD4 count less than 50/cu.mm). This stage of profound immune
depression will be shorter for the average patient in developing countries which is
partly due to the absence of advanced and expensive medical care. In other words,
AIDS patients in developing countries will often die from other diseases (e.g., malaria,
cryptococcal meningitis) before they develop CMV retinitis.
These pictures shows several typical aspects of cytomegalovirus (CMV) retinitis, the
most common opportunistic eye infection. The pictures below show CMV retinitis in
the same eye before (left) and after treatment (right). The classical appearance of
CMV retinitis is that of a haemorrhagic retinal necrosis - sometimes described as
ketchup (tomato sauce) on cottage cheese at the posterior pole with extension of the
lesions along the vascular arcade and sheathing of the vessels. The white edge at the
border of the lesion represents the active infection which will progress at a rate of
about one disc diameter per week if untreated. The necrotic area left behind the
advancing white border shows a thinned and irregularly pigmented atrophic retina.
Infection of the perifoveal or peripapillary (around the optic nerve) area is associated
27
with early visual loss. Sometimes small islands of CMV infection are seen near to the
advancing border of a more massive lesion. The peripheral lesions may have a more
granular appearance with less haemorrhages (dry, granular form of CMV). The
disease
is bilateral in about 50% of patients. Once established, CMV retinitis is relentlessly
progressive and the whole retina is destroyed within six months if no treatment is
provided. Retinal detachment is a late complication of CMV retinitis and is estimated
to occur in about 20 to 30% of eyes with CMV infection.
Two drugs which are available for the treatment of CMV retinitis are ganciclovir and
foscarnet. Both drugs are virostatic which means that they should be continued
indefinitely in AIDS patients. The profile of toxicity is different: ganciclovir
suppresses
the bone marrow causing neutropenia while foscarnet is nephrotoxic. Foscarnet has
anti-HIV properties which would explain the prolongation of life seen in AIDS
patients
treated with this compound as opposed to ganciclovir. Unfortunately, the more
common side effects of foscarnet make ganciclovir a more convenient drug for most
patients. It should be emphasised that these drugs are very expensive and that their
administration pre-supposes careful monitoring of renal function (foscarnet) and
neutrophil counts (ganciclovir). These two factors mean that they cannot be used
routinely in most developing countries. (An alternative drug to ganciclovir and
foscarnet is cidofavir which does have the advantage of once weekly treatment).
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5 mg/kg IV twice daily for 2 to 3 weeks 5 mg/kg IV once every day or
6 mg/kg IV once daily for five
days a week
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60 mg/kg IV three times daily for 2 to
3 weeks
90 to 120 mg/kg IV once daily
After initiation of treatment there is usually a 2 to 3 week period before there is
clinical evidence of regression of the lesions. Oral ganciclovir may be given once the
disease is 'controlled'. Even on maintenance therapy, however, nearly all patients will
show evidence of reactivation of CMV retinitis with a median time of reactivation of 3
months.
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Three other eye diseases may have clinical similarities to CMV retinitis.
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Cotton-wool spots, especially when accompanied by small haemorrhages, may
simulate incipient CMV retinitis.
The photographs show cotton-wool spots above and an example of CMV retinitis
below.
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in AIDS patients is less common than CMV retinitis and
accounts probably for only 1 to 3% of retinal infections. The two infections can be
confused in AIDS patients because of similar clinical features. The exact diagnosis is
critical, if one intends to treat the patient, because toxoplasmosis requires different
medical treatment (sulfadiazine, pyrimethamine) to CMV retinitis. The photographs
show retinitis of toxoplasmosis above and an example of CMV retinitis below.
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[is a necrotising herpetic retinopathy due to herpes
zoster (or herpes simplex). It is the second most common infection of the eye in AIDS
patients, although it is still relatively uncommon in comparison to CMV retinitis.
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Microbiology (4th ed ) McGraw Hill pp 556; 566ʹ9
ISBN 0838585299
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540-3896-3
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0 pdf Retrieved 2009-2-04
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[www3 interscience wiley com/cgi-
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(August 2000) [cp bm com/cgi/content/full/53/8/62
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PMID 9436702 PMC 267369
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Med (2): 9ʹ9 doi:0 056/NEJMoa0804749
PMID 9297572
0 * Meinhard Classen; Guido N J Tytgat; M D Ph D ;
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Retrieved 26 June 200
* Gredmark-Russ S, Dzabic M, Rahbar A, Wanhainen A,
Brck M, Larsson E, Michel JB, Sderberg-Nauclér C (2009)
"Active cytomegalovirus infection in aortic smooth muscle cells
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2009 Apr;87(4):347-56 Gpub 2008 Dec 16 ºá (4): 347ʹ56
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2 * Yonemitsu Y, Nakagawa K, Tanaka S, Mori R, Sugimachi
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4 * [www cytogam com/pdfs/Cytogam%20PI pdf Cytogam
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