Cytomegalovirus Infection - BMJ Best Practice

Cytomegalovirus
infection
Straight to the point of care
Last updated: Jun 22, 2023

Table of Contents
Overview 3
Summary 3
Definition 3
Theory 4
Epidemiology 4
Aetiology 4
Pathophysiology 4
Classification 4
Case history 5
Diagnosis 7
Approach 7
History and exam 13
Risk factors 15
Investigations 17
Differentials 21
Criteria 21
Management 24
Approach 24
Treatment algorithm overview 27
Treatment algorithm 29
Emerging 38
Primary prevention 38
Secondary prevention 39
Patient discussions 39
Follow up 41
Monitoring 41
Complications 42
Prognosis 43
Guidelines 44
Diagnostic guidelines 44
Treatment guidelines 44
Online resources 47
References 48
Images 57
Disclaimer 60
Cytomegalovirus infection Overview
Summary
Cytomegalovirus (CMV) infection is often asymptomatic or manifests as infectious mononucleosis-like
syndrome (fever, lymphadenopathy, and atypical lymphocytosis) in people with normal immune systems.
OVERVIEW
In immunocompromised people (patients with AIDS and transplant recipients), disease manifests with fever,
bone marrow suppression, and tissue-invasive disease such as pneumonitis, hepatitis, colitis, nephritis, and
retinitis.
In the fetus, CMV infection may lead to cytomegalic inclusion disease, characterised by severe neurological
abnormalities, intellectual disability, and hearing defects.
Tests for diagnosis include: serology, pp65 antigenaemia test, histopathology, and nucleic acid amplification
and detection systems, most commonly quantitative polymerase chain reaction-based assays.
In immunocompetent people, infection is usually self-limiting; therefore, treatment is usually not indicated.
In patients with compromised immune function, the treatment of choice is oral valganciclovir or intravenous
ganciclovir. Intravenous foscarnet and cidofovir are less preferred agents.
Definition
Cytomegalovirus (CMV) is a ubiquitous beta-herpes virus that infects the majority of humans. Primary
infection in individuals with normal immune function is usually asymptomatic. After primary infection, CMV
establishes a state of lifelong latency in various host cells, with periodic sub-clinical re-activations that are
controlled by a functioning immune system. When re-activation (or primary infection) occurs in patients
with severely compromised immune function (transplant patients or patients with AIDS and CD4 count
<50 cells/microlitre), uncontrolled CMV replication often ensues, which leads to the clinical manifestations
characterised by fever, bone marrow suppression, and tissue-invasive disease.[1] [2]
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Cytomegalovirus infection Theory
Epidemiology
CMV is a ubiquitous virus that infects people regardless of age, sex, race, or socioeconomic and
geographical backgrounds. CMV seroprevalence rate ranges from 25% to 100% depending on the
THEORY
population. Seroprevalence is generally higher in developing countries compared with countries in the
developed world, and is higher in urban compared with rural communities.[3] [11]
In the US, congenital infection with CMV results in 30,000 to 40,000 infected infants annually.[8] [9]
Prevalence at birth is estimated at 0.5% to 1.0%.[12] It is the most common congenital infectious cause of
sensorineural hearing loss and intellectual disability.[13]
Aetiology
CMV is a member of the herpes virus family.[14] It contains a genome of double-stranded linear DNA, an
icosahedral viral capsid, and a viral envelope protein that includes the highly immunogenic glycoprotein
B. The biological characteristic of all herpes viruses, including CMV, is the ability to establish latency after
primary infection. Such a biological characteristic allows for periodic viral re-activations during the life of the
human host.[14]
Routes of transmission include person-to-person spread (kissing, intimate contact, sexual intercourse),
vertical transmission (mother-to-child transmission resulting in congenital infection), blood transfusion, and
organ or haematopoietic stem cell transplantation.
Pathophysiology
CMV infects a variety of cells, including mononuclear leukocytes and endothelial cells. It has a replication
cycle of approximately 1 day in CMV-naive individuals, resulting in a viral progeny.
During infection, CMV antigens trigger the innate immune system to secrete various antiviral peptides,
including interferon. Some studies suggest that this is partly mediated by a toll-like receptor family of pattern
recognition molecules.[15] [16] Subsequently, the innate immune response orchestrates the development of
humoral and cell-mediated adaptive immunity, which eventually controls the viral infection, thereby leading to
a state of latency.[17] Factors that impair innate and adaptive immune responses predispose to uncontrolled
viral reactivation and replication, which lead to viral cytopathic effects and clinical illness.
Classification
CMV classification[3] [4] [5]
CMV is the fifth member of the human herpes virus family and is classified under the beta-herpesvirus group
together with human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7).
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jun 22, 2023.
Case history
Case history #1
THEORY
A 45-year-old CMV-seronegative (CMV R-) man presents with 1 week of fever, malaise, and diarrhoea.
Five months prior to this clinical illness, he received a kidney transplant from a CMV-seropositive (CMV
D+) donor. He has a history of long-standing diabetes mellitus that was complicated by end-stage
renal failure. He received valganciclovir prophylaxis for the first 3 months after kidney transplantation.
Laboratory examination shows leukopenia, thrombocytopenia, and elevated serum levels of creatinine,
alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Colonoscopic examination shows
severe hyperaemia and mucosal ulcerations involving the entire length of the colon.
Case history #2
A 35-year-old man with uncontrolled HIV infection and AIDS complains of a 2-week history of visual
floaters and blurring of vision involving both eyes. His HIV RNA load is >750,000 copies/mL and his
CD4 cell count is 2 cells/microlitre. Physical examination reveals a severely cachectic man with enlarged
cervical, axillary, and inguinal lymph nodes. Ophthalmological examination reveals creamy-coloured areas
with overlying retinal haemorrhages, consistent with a diagnosis of chorioretinitis.
Fundoscopy (left eye) showing area of CMV retinitis inferonasally involving the vascular
arcades and the optic disc, associated with vasculitis and flame haemorrhages
Adapted from BMJ Case Reports 2009, copyright © 2009 by the BMJ Publishing Group Ltd
5
Other presentations
In a healthy, immunocompetent patient with no significant medical history, CMV infection may present
with a mononucleosis-like syndrome that includes fever, body aches, and malaise. Enlarged cervical
THEORY
lymph nodes may be present. Laboratory examination reveals atypical lymphocytosis, normal renal
function, and mildly elevated hepatic aminotransferases. Clinical symptoms usually resolve within 1 week,
although severe end-organ disease has been described in some immunocompetent patients. In patients
with inflammatory bowel disease refractory to conventional treatment, CMV is implicated as a co-factor,
because the virus has been demonstrated in colon biopsies. Some patients have responded to treatment
with intravenous ganciclovir.[6] In critically ill people who require admission to the intensive care unit, such
as those with sepsis, asymptomatic CMV re-activation may occur and may be associated with higher all-
cause mortality.[7] Congenital CMV infection presenting in a newborn can result in microsomal, intra-
cranial calcification, hepatosplenomegaly, neurological abnormality (presenting as poor tone and motor
function), petechiae or purpura, and hearing loss.[8] [9] Intellectual disability and sensorineural deafness
are long-term complications.[10]
Cytomegalovirus infection Diagnosis
Approach
The clinical presentation of CMV infection depends on the immune status of the patient. Immunocompetent
individuals often do not manifest clinical symptoms. However, immunocompromised individuals have
fever, bone marrow suppression, and end-organ diseases. Full blood count, serum creatinine, and liver
function tests (LFTs) are recommended for all patients presenting with clinical features of CMV. Testing for
confirmation of CMV should be performed in each suspected case, and the method of testing depends on
immune status.
Laboratory evaluation of CMV

In immunocompetent patients, primary CMV infection is diagnosed using serology, demonstrating CMV-
specific IgM. A low avidity of CMV antibodies can confirm the diagnosis of recent CMV infection. Serology
in the transplant setting is useful to establish the risk for CMV disease, but not for the diagnosis of acute
CMV infection.
In the immunocompromised host, the diagnosis of CMV disease is confirmed by the demonstration or
detection of the virus in blood and tissue specimens.[28] Viral culture of blood, respiratory secretions,
vitreous fluid, cerebrospinal fluid, and tissue specimens may be used to demonstrate CMV. Conventional
tube culture takes several weeks before cytopathic effects can be demonstrated; hence, it is not useful in
real-time clinical care. The shell vial assay (another type of viral culture technique) produces results within
48 hours, but viral culture generally has modest sensitivity and has been replaced by molecular assays in
most settings.
Currently, the most rapid and sensitive molecular method for detecting CMV in these specimens is
the use of quantitative nucleic acid testing (NAT) that detects and quantifies viral nucleic acid. Many
physicians consider this as a diagnostic method of choice. The assay is rapid, and its quantitative
property allows for disease prognostication, and serves as a guide during treatment. However, results
from various NAT assays have not been directly compared. A WHO standard for CMV quantitation
has been developed and viral loads can now be reported in international units allowing for greater
standardisation, although some data suggest that significant ongoing variability between laboratories may
DIAGNOSIS
still exist.[29] [30]
In some centres, detecting pp65 antigen (antigenaemia assay) in peripheral blood leukocytes is a
rapid method for diagnosis. The requirement for leukocytes in this assay limits its utility in people with
leukopenia, such as haematopoietic stem cell transplant recipients, and those receiving cytotoxic
chemotherapeutic agents. In addition, it is semi-quantitative and difficult to standardise across centres.
Clinical presentation and investigation in people with normal

immune function
Presenting features:
• In healthy people CMV infection is usually asymptomatic.

• If symptomatic, the clinical manifestations of CMV infection may also resemble infectious
mononucleosis syndrome (fever, malaise, sore throat).
• A maculopapular rash after administration of antibiotics may present.
• Physical examination is often unremarkable except for the presence of lymphadenopathy.
Splenomegaly is occasionally present.
7
FBC:
• Atypical lymphocytosis, which may be the laboratory marker of viral infection such as CMV, in an
immunocompetent patient.
LFTs:
• Aminotransferases or alkaline phosphatase may be elevated.

Detection of CMV:
• Every patient with suspected CMV infection should be tested to confirm the presence of CMV.
While NAT and antigenaemia assays provide rapid diagnosis, CMV serology (CMV IgM) is the most
accessible test in the community setting and often sufficient for diagnosis in immunocompetent
individuals
Clinical presentation and investigation in solid organ and

haematopoietic stem cell transplant patients
• Fever in solid organ and haematopoietic stem cell transplant patients should be assessed as
a possible manifestation of CMV disease. This is especially relevant in solid organ transplant
recipients with certain risk factors such as being CMV-seronegative with a seropositive donor
(CMV D+/R-), acute rejection, receipt of intense immunosuppressive drugs, or sepsis.[25] It is also
relevant in the case of a CMV-seropositive allogeneic haematopoietic stem cell transplant recipient
at high risk because of severe T-cell depletion, or patients with graft-versus-host disease.[20] Many
patients may also present with significant malaise in the absence of fever.
• In a large proportion of these patients, CMV may affect the gastrointestinal tract, so that vomiting
(gastritis) and diarrhoea (colitis) can occur. Cough and dyspnoea (pneumonitis), jaundice and
abdominal pain (hepatitis), and other organ-specific manifestations are much less common in this
setting. Myocarditis, pancreatitis, nephritis, and encephalitis occur rarely. In contrast to patients with
DIAGNOSIS
AIDS, CMV retinitis is not commonly observed in transplant recipients.[31]

• Virtually any organ system may be affected by CMV.
FBC:
• Often shows anaemia, leukopenia, or thrombocytopenia.

LFT:
• CMV hepatitis may be manifested by elevated serum levels of alanine and aspartate
aminotransferases. Elevated alkaline phosphatase levels often indicate an accompanying
hepatobiliary system involvement.[28]
Detection of CMV:
• Quantitative NAT is preferred over pp65 antigenaemia and viral culture as it is more sensitive and
provides rapid results. CMV serology is not usually ordered in transplant patients for the diagnosis
of acute CMV disease.
Chest x-ray:
• This should be performed in any severely immunocompromised patient with pulmonary symptoms
suggestive of CMV disease. In the presence of CMV pneumonitis, this may demonstrate interstitial
infiltrates, although nodules may occasionally be observed. If the diagnosis of lung involvement
requires further radiological evaluation, a lung CT scan should be performed.
Chest CT scan of a lung transplant recipient with diffuse interstitial

and parenchymal changes as a result of primary CMV pneumonitis
From the collection of Dr Raymund Razonable; used with permission
Endoscopy and colonoscopy:
• These may be indicated in patients with signs of gastrointestinal involvement, and may demonstrate
mucosal hyperaemia and ulcerations typical of CMV disease. In clinical practice; however, a
presumptive diagnosis of gastrointestinal disease is made based on detection of viraemia,
accompanied with appropriate signs and symptoms.
DIAGNOSIS
Biopsy:
• Patients with clinical illness suggestive of tissue-invasive CMV disease may have tissue specimen
(liver, intestinal mucosa, lung) obtained by biopsy for the detection of CMV inclusion bodies.[32]
Often, symptoms may mimic acute allograft rejection, and the biopsy will help to differentiate the
clinical entities.
Clinical presentation and investigation in patients with AIDS

• In patients with AIDS, the most common clinical manifestation of CMV disease is retinitis.[2] Colitis
is the second most common manifestation.
• Involvement of other organ systems may be manifested by headache (encephalitis), weakness,
cough and dyspnoea (pneumonitis), vomiting (gastritis), diarrhoea, and other gastrointestinal
symptoms (colitis).[2] Virtually any organ system may be affected by CMV.[33]
• Fundoscopy: visual floaters are the most common complaint that leads to medical evaluation, and
in severe cases blindness occurs within months of diagnosis. Fundoscopic examination is important
9
to assess the retina in asymptomatic and symptomatic patients suspected to have CMV retinitis.
In the presence of CMV retinitis, fundoscopy will reveal areas of infarction, haemorrhage, peri-
vascular sheathing, and retinal opacification.
FBC:
• May show anaemia, leukopenia, or thrombocytopenia.

DIAGNOSIS
Detection of CMV:
• NAT and pp65 antigen detection as well as viral culture may be used to detect CMV in blood,
affected fluid, or tissue specimens.
CD4 count:
• Clinically, the patient has severe immunosuppression, as indicated by CD4 T-cell count of <50 cells/
microlitre.[2]
Chest x-ray:
• This should be performed in any immunocompromised patient with pulmonary symptoms

suggestive of CMV disease. May demonstrate interstitial infiltrates in the presence of CMV
pneumonitis.
Chest x-ray showing diffuse pulmonary infiltrates in an

immunocompromised patient with severe CMV pneumonitis
Biopsy:
• In patients with clinical illness suggestive of tissue-invasive CMV disease, biopsy of tissue
specimens (liver, intestinal mucosa, lung) is recommended.[2] CMV retinitis presents with classic
fundoscopic findings and biopsy is not required. However, in atypical cases, CMV NAT of the
vitreous fluid will confirm the diagnosis.
Clinical presentation and investigation in infants with congenital

CMV infection
Antenatal diagnosis:
• Congenital CMV infection should be suspected if there are symptomatic or asymptomatic maternal
DIAGNOSIS
seroconversion during pregnancy or if there are any abnormalities detected on antenatal ultrasound
that may suggest CMV infection.[13]
• The diagnosis of maternal primary CMV infection in pregnancy is usually based on positive
CMV-IgG in a pregnant woman who was previously seronegative, or on detection of specific
IgM antibody associated with low IgG avidity. In the absence of universal maternal screening,
serological testing for CMV is indicated for women with influenza-like illness during pregnancy,
following detection of sonographic findings suggestive of congenital CMV infection or if requested
by an asymptomatic mother. Similar clinical outcomes have been reported in newborns born to
mothers with primary infection versus those born to mothers with non-primary infections.[34] As
such, seronegative mothers at higher risk of exposure to CMV (e.g., healthcare and childcare
workers, mothers with a child attending daycare) may be offered serological monitoring during
pregnancy.[26]
• Antenatal ultrasound features suggestive of congenital CMV infection include: intra-uterine fetal
growth restriction, enlargement of the cerebral ventricles, intra-cranial calcification, microcephaly,
and increase or decrease in the volume of amniotic fluid. Enlargement of the liver, spleen, or heart
and hyperechogenicity of the bowel may also be seen.[13] Serial ultrasound examinations should
be performed every 2 to 4 weeks after a diagnosis of congenital CMV infection in order to detect
11
sonographic abnormalities, which may aid in determining the prognosis of the fetus, although the
absence of sonographic findings does not guarantee a normal outcome.[26]
• Amniocentesis or fetal blood sampling allow for testing of CMV starting from 21 weeks of
gestation.[26] Fetal blood specimens and amniotic fluid are tested for CMV using NAT. IgM antibody
measurement, pp65 antigenaemia, and viral culture are not commonly used.
• Important factors to consider in antenatal diagnosis are: confirmation of primary CMV infection in
the mother, attempting to establish the time at which the mother was infected, and to choose an
appropriate time at which to acquire fetal samples. There is an increased risk of false-negative
results if fetal sampling is performed too close to the initial start of infection in the mother,
usually before 21 weeks of gestation.[35] Mothers should be counselled about the risks of fetal
transmission, diagnostic procedures, and risks involved in fetal infection in order to make a decision
on further testing, and how to continue with pregnancy.[13]
Presenting features at birth:
• Around 85% to 90% of newborns with congenital CMV infection are asymptomatic at birth. The
remaining 15% to 20% may present with microcephaly, hepatosplenomegaly, petechiae or purpura,
or sensorineural hearing loss. Less frequently, clinical examination may reveal hypotonia or
abnormal head lag.[8] [9] From the 10% to 15% of newborns with symptoms at birth, 40% to
60% will develop permanent and long-term neurodevelopmental abnormalities and sensorineural
deafness.[13]
Tests at birth:
• FBC: may show thrombocytopenia

• LFTs: may be elevated.
Detection of CMV:
• CMV can be detected by molecular assays of saliva and/or urine drawn within the first 3 weeks of
life. Other diagnostic methods such as viral culture, pp65 antigen detection, and CMV serology
are not performed routinely given the increased sensitivity of molecular assays. CMV can also be
DIAGNOSIS
detected by molecular assays from central nervous system and blood samples.[8]
Brain ultrasound/MRI:
• All infants suspected with congenital CMV infection should have a cerebral ultrasound, with brain
MRI, to determine neurological involvement at baseline.
• Intra-cranial calcifications, microcephaly, cerebral ventricular enlargement, and abnormalities of the
white matter may be detected.[8]
Antenatal screening for CMV

Antenatal CMV screening is not routinely performed but is advised if the mother has mononucleosis-
like symptoms or there are fetal abnormalities on antenatal ultrasound. It can be offered to mothers who
request testing.[12]
History and exam

Key diagnostic factors
presence of risk factors (common)
• Risk factors include: transplant recipients who are CMV-seronegative with a seropositive
donor, transplant recipients who are CMV-seropositive, graft-versus-host disease, certain
immunosuppressive drugs, AIDS, organ or haematopoietic stem cell transplant, acute illness in
intensive care setting, and CMV infection in pregnancy (risk of congenital CMV disease in the
newborn).
malaise (common)
• New or significant increase in malaise/fatigue is often the first symptom in solid-organ transplant
(SOT)-related CMV disease, and may not initially be accompanied by fever.[1]
fever (common)
• Fever is a common clinical presentation of CMV disease in transplant recipients.[18]
diarrhoea (common)
• The most common organ-invasive symptom of CMV disease in transplant recipients.[18]
nausea and vomiting (common)

• A common gastrointestinal tissue-invasive symptom of CMV disease.[18]
visual floaters and blindness (common)

• CMV chorioretinitis is the most common organ-invasive disease caused by CMV in patients with AIDS.
[2] [31]
abnormalities on fundoscopy (common)

• A fundoscopic examination is indicated in AIDS patients with CD4 T-cell count of <50 cells/microlitre.
DIAGNOSIS
Transplant patients with visual complaints should be examined by fundoscopy to check for the
presence of CMV retinitis.[31]
• In the presence of CMV retinitis, fundoscopy will reveal areas of infarction, haemorrhage, peri-vascular
sheathing, and retinal opacification.
13
newborn: microcephaly (common)

• Microcephaly may be evident at antenatal ultrasound or at birth.
newborn: poor tone and motor function and abnormal head lag (common)
DIAGNOSIS
• Common neurological involvement in the newborn.[13]
newborn: hearing loss (common)

• One of the most common clinical manifestations of congenital CMV infection and may be suspected by
the inability of the newborn to respond to sound and verbal stimuli.[13]
Other diagnostic factors

newborn: hepatosplenomegaly (common)
• Hepatosplenomegaly may be evident at antenatal ultrasound or at birth.
newborn: petechiae or purpura (common)

• Severe thrombocytopenia in the newborn may lead to multiple purpura and petechial lesions.[13]
pain and weakness (uncommon)

• Pain and weakness may indicate the presence of CMV polyradiculopathy, especially in AIDS patients.
Risk factors
Strong
CMV D+/R- status (donor CMV seropositive, recipient seronegative) in solid
organ transplant recipients
• Transmission of CMV through the allograft to the immunologically-naive transplant recipient is
considered the most important risk factor for the development of CMV disease following solid organ
transplantation.
• Without antiviral prophylaxis, up to 75% of CMV-seronegative transplant recipients develop primary
CMV disease if they receive organ allografts from CMV-seropositive donors. The risk is highest
in CMV D+/R- lung transplant recipients and relatively lower in CMV D+/R- kidney transplant
recipients.[18]
CMV R+ (recipient seropositive) in transplant recipients

• The re-activation of latent CMV is particularly common in recipients after allogeneic haematopoietic
stem cell transplant, and in CMV-seropositive solid organ transplant recipients, particularly in patients
who receive lymphocyte-depleting antibodies and patients who previously developed acute allograft
rejection.[19]
• CMV-seropositivity in allogeneic stem cell transplant recipients is one of the strongest risk factors
for the development of CMV viraemia and disease after haematopoietic stem cell transplantation, in
particular in patients developing graft-versus-host disease.[20]
type of immunosuppressive drugs

• The overall net state of immunosuppression, which is partly due to the combined effects of
immunosuppressive drugs, is a major risk factor for CMV disease in transplant recipients. In contrast,
the impact of an individual immunosuppressive drug on the risk of CMV disease is variable.
• High doses of corticosteroids, mycophenolate mofetil, anti-thymocyte globulin, and alemtuzumab have
all been reported to significantly increase the risk of CMV disease in solid organ and haematopoietic
DIAGNOSIS
stem cell transplant recipients. These drugs impair the ability of patients to combat a re-activating
CMV, thereby leading to uncontrolled viral replication and clinical disease.
• Sirolimus and everolimus have been associated with lower risk of CMV disease.[21] [22] [23]
AIDS
• Patients with AIDS who have a CD4 T-cell count of <50 cells/microlitre are at highest risk of developing
CMV retinitis and other organ-invasive CMV diseases.[2]
• The use of antiretroviral therapy that is directed against HIV infection leads to immune reconstitution
(illustrated by the recovery of CD4+ T cells) and significantly reduces the risk of CMV disease.
inflammatory bowel disease

• In patients with Crohn's disease and ulcerative colitis, CMV is considered to be a cause of severe or
refractory colitis, and it is associated with an increased incidence of complications. Older age and use
of high doses of corticosteroids have been identified as risk factors for CMV colitis in patients with
inflammatory bowel disease.[24]
15
acute illness in intensive care set ting
• In critically ill patients (e.g., those with sepsis), reactivation of latent CMV can occur due to a pro-
inflammatory environment characterised by release of tumour necrosis factor-alpha in a condition
called cytokine storm.
• Even in critically ill patients with apparent normal immune function, CMV reactivation has been
observed during periods of bacterial sepsis.[25]
newborn in CMV infection during pregnancy

• The immunologically-naive fetus is at risk of congenital CMV disease and its complications, such as
hearing loss and neurological deficits. This can occur if the pregnant mother develops primary CMV
infection during pregnancy, but also in CMV-seropositive mothers.[12] [26]
DIAGNOSIS
Investigations
1st test to order
Test Result
FBC immunocompetent:
atypical lymphocytosis;
• FBC, serum creatinine, and liver function tests (LFTs) are
transplant or
recommended for all patients presenting with clinical features of
immunocompromised
CMV.
• Can be used at baseline and for monitoring while on treatment. Bone patients: anaemia,
leukopenia, or
marrow involvement with CMV leads to suppression of all cell lines.
Treatment with ganciclovir/valganciclovir can also cause bone marrow thrombocytopenia;
newborns:
suppression.
thrombocytopenia
serum creatinine normal; solid organ and

haematopoietic stem
cell transplant patients
with tissue-invasive CMV
CMV.
• Symptoms and signs of tissue-invasive CMV infection in solid organ infection: may be elevated.
or bone marrow recipients may mimic acute allograft rejection (rise in
serum creatinine and aminotransferases).
• Serum creatinine measurement is also recommended during
treatment with antiviral drugs.
serum aspartate aminotransferase (AST) and alanine both immunocompetent
aminotransferase (ALT) and immunocompromised
patients: elevated
CMV.
• Can also be elevated at initial presentation of a healthy person. Often
suggests tissue-invasive disease in immunocompromised patients.
serum alkaline phosphatase hepatobiliary system
involvement: elevated
DIAGNOSIS
CMV.
• Often one of the initial manifestations of CMV hepatitis and
cholangitis in immunocompromised patients, such as those with
AIDS.
serology CMV-IgM titre is
indicative of acute
• The test is done using ELISA. The utility of CMV-IgM is modest
infection; CMV-IgG titre
for the diagnosis of acute CMV disease in immunocompromised
suggests past infection;
patients.[32]
antibody avidity is low in
recent infection
pp65 antigenaemia number of pp65-positive

• Can be used in initial testing and subsequent disease monitoring, but cells/150,000 to 200,000
cells
has largely been replaced by nucleic acid testing. Slide method to
17
Test Result
demonstrate the presence and the number of leukocytes containing
CMV pp65 antigen. More sensitive than viral culture.
• Limited utility in patients with severe leukopenia, such as
haematopoietic stem cell transplant recipients.
• The quantitative and semi-quantitative property of this test may guide
therapeutic response.[32]
nucleic acid detection number of genomic
copies per volume of
• Used in initial testing and subsequent disease monitoring. Nucleic
specimen
acid testing (NAT) is the most sensitive method for the detection of
CMV in blood/plasma and tissue specimens.
• The clinical significance of the number of genomic copies depends
on the testing platform, the specimen used (plasma vs. whole blood)
and the patient population. In most cases, however, a positive test
suggests infection.
• The quantitative property of the test is used for predicting the risk
of disease, to guide pre-emptive therapy, to monitor response to
treatment, and to indicate the presence of drug-resistant virus.[32]
CD4 count severe
immunosuppression in
• Used initially to assess the risk of CMV disease in transplant
AIDS: <50 cells/microlitre
patients. Also used to guide when to discontinue treatment in AIDS
patients who have undergone immune reconstitution following use of
antiretroviral therapy.[2]
chest x-ray CMV pneumonitis:
• Chest x-ray should be performed in any immunocompromised patient presence of interstitial
infiltrates; nodules may
with pulmonary symptoms suggestive of CMV disease. It may be
occasionally be seen
used in subsequent monitoring for improvement.
DIAGNOSIS
Chest x-ray showing diffuse pulmonary infiltrates in an

immunocompromised patient with severe CMV pneumonitis
Other tests to consider
Test Result
chest CT scan diffuse interstitial and
parenchymal changes
• Chest CT scan will assist in demonstrating diffuse interstitial and
parenchymal changes as a result of CMV pneumonitis in a lung
transplant recipient.
Chest CT scan of a lung transplant recipient with diffuse interstitial

and parenchymal changes as a result of primary CMV pneumonitis
histopathology of biopsy demonstration of CMV-
specific cytoplasmic and
• In patients with clinical illness suggestive of tissue-invasive CMV
intra-nuclear inclusions
disease, biopsy of tissue specimens (liver, intestinal mucosa, lung) is
recommended.[32]
DIAGNOSIS
Active cytomegalovirus infection of lung in AIDS

Centers for Disease Control and Prevention: Dr Edwin P. Ewing, Jr
19
Test Result
upper gastrointestinal endoscopy and colonoscopy spectrum of endoscopic
• Upper gastrointestinal endoscopy and colonoscopy can be performed lesions is variable and
ranges from patchy
in patients with suspected CMV disease and gastrointestinal
erythema, exudates,
symptoms. This can be useful for confirming the diagnosis,
particularly in patients with negative blood nucleic acid tests for and micro-erosions to
diffusely oedematous
CMV. Repeat colonoscopy is suggested by some experts where
mucosa, to multiple
symptoms persist despite appropriate therapy, or in patients with
inflammatory bowel disease, to document clearance of disease prior mucosal erosions, to
deep ulcers and pseudo-
to discontinuation of treatment.
tumours
serial fetal ultrasound examinations (congenital CMV infection) features suggestive of

• Should be performed every 2-4 weeks after a diagnosis of congenital congenital CMV infection
include: intrauterine
CMV infection in order to detect sonographic abnormalities.
fetal growth restriction;
• May aid in determining the prognosis of the fetus, although the
absence of sonographic findings does not guarantee a normal enlargement of the
cerebral ventricles;
outcome.[26]
intracranial calcification;
microcephaly; increase
or decrease in the
volume of amniotic
fluid; enlargement of the
liver, spleen, or heart;
hyperechogenicity of the
bowel
amniocentesis or fetal blood sampling (congenital CMV documentation of CMV

infection) from amniotic fluid or
fetal blood specimen by at
• These antenatal investigations allow for testing for CMV.[26]
• Important factors to consider in antenatal diagnosis are: confirmation least two positive different
of primary CMV infection in the mother and subsequent determination assays
of the time at which the mother was infected, as well as the most
appropriate timing for viral detection (usually after 21 weeks of
gestational age). There is an increased risk of false-negative results if
DIAGNOSIS
fetal sampling is performed before 21 weeks of gestation or too close

to the initial start of infection in the mother.
• Mothers should be counselled about the risks of fetal transmission,
diagnostic procedures, and risks involved in fetal infection in order
to make a decision on further testing and how to continue with
pregnancy.[13]
• Fetal blood specimen and the amniotic fluid are tested for CMV using
nucleic acid testing. IgM antibody measurement, pp65 antigenaemia,
and viral culture are not commonly used.
brain ultrasound/brain MRI: newborns intra-cranial
calcifications;
• Brain ultrasounds and MRI are part of the systematic neonatal
screening of any newborn with congenital CMV infection. Audiological microcephaly; cerebral
ventricular enlargement
testing and an ophthalmologic examination are part of routine
neonatal screening. Developmental assessments beginning at the
first year of life are also part of screening.
Differentials
Condition Differentiating signs / Differentiating tests

symptoms
Infectious mononucleosis • The clinical presentation of • Heterophile test, EBV
infectious mononucleosis serology.
syndrome is most commonly
caused by Epstein-Barr
virus (EBV) infection, and is
clinically indistinguishable
from CMV.
HIV • Acute HIV seroconversion • HIV serology; HIV RNA level.

often manifests with a febrile
syndrome that may be
difficult to distinguish from
primary CMV disease.
• This syndrome may include
fever, chills, and generalised
lymphadenopathy.
Toxoplasmosis • In immunocompetent • IgA, IgM, IgG toxoplasma

patients, acute serology.
toxoplasmosis may present
as a mononucleosis-like
syndrome.
Other viral illness • Viral infections often • Virus-specific culture and

present as fever in nucleic acid testing.
immunocompromised
patients and thus may be
indistinguishable from CMV.
Criteria
DIAGNOSIS
Definitions of CMV infection and disease in transplant
recipients[36] [37]
• CMV infection:
• Defined as isolation of the CMV virus or detection of viral proteins or nucleic acid in any body
fluid or tissue specimen.
• Recurrent infection:
• Defined as new detection of CMV in a patient who has had previously documented infection and
who has not had virus detected on two consecutive tests usually a week apart.
• Reinfection:
• Defined as detection of a CMV strain that is distinct from the strain that was the cause of the
original infection. Note that strain typing is not done outside research.
21
• CMV syndrome:
• Denotes the presence of significant malaise and/or fever often accompanied by bone marrow
suppression. Other pathogens should be excluded.
• In solid organ transport recipients, CMV syndrome is defined by the presence of fever and/or
malaise, leukopenia, and thrombocytopaenia.
• CMV pneumonitis:
• Defined by the presence of signs and/or symptoms of pulmonary disease combined with the
detection of CMV in bronchoalveolar lavage fluid or lung tissue samples.
• CMV gastrointestinal disease:
• Defined by identification of clinical symptoms, findings of macroscopic mucosal lesions on

endoscopy, and demonstration of CMV (by culture, histopathology, immuno-histochemical
analysis, or in situ hybridisation) in a gastrointestinal tract biopsy specimen.
• CMV hepatitis:
• Defined by findings of elevated bilirubin and/or enzyme levels, absence of other documented
cause of hepatitis, and detection of CMV (by culture, histopathology, immuno-histochemical
analysis, or in situ hybridisation) in a liver biopsy specimen.
• Typical lesions must be confirmed by an ophthalmologist for the diagnosis of CMV retinitis.
Definitions of resistant and refractory CMV infection and disease in

transplant recipients[38]
The following definitions for refractory and resistant CMV infection and disease in transplant recipients are
proposed by the CMV Resistance Working Group of the CMV Drug Development Forum, for use in clinical
trials.[38]
DIAGNOSIS
• Refractory CMV infection
• Defined as CMV viraemia that increases after at least 2 weeks of appropriately-dosed antiviral
therapy.
• Probably refractory CMV infection
• Persistent viral load after at least 2 weeks of appropriately-dosed antiviral therapy.

• Refractory CMV end-organ disease
• Worsening signs and symptoms or progression into end-organ disease after at least 2 weeks of
appropriately-dosed antiviral therapy.
• Probable refractory CMV end-organ disease
• Lack of improvement in signs and symptoms after at least 2 weeks of appropriately-dosed

antiviral drugs.
• Antiviral drug resistance
• Viral genetic alteration that decreases susceptibility to one or more antiviral drugs.
DIAGNOSIS
23
Cytomegalovirus infection Management
Approach
In immunocompetent patients, CMV infection is usually self-limiting and antiviral treatment is not indicated.
The clinical manifestation of CMV infection in transplant patients is dependent on the overall immune status
of the host, so in severe clinical disease the intensity of immunosuppression should be reduced, if feasible.
In patients with AIDS, initiation of antiretroviral therapy (ART) should be considered for the treatment of
underlying HIV infection. There is a risk of immune reconstitution CMV uveitis among patients initiated on
ART.
Immunocompetent individuals
CMV infection and disease resolves without antiviral treatment in patients with a competent immune
system. In these people, the generation of CMV-specific immunity during the course of illness is sufficient
to resolve the clinical illness. Accordingly, antiviral treatment is not required.
Transplant recipients with CMV disease

The goal of therapy for CMV infection is rapid control of viral replication and clinical disease with the
use of oral valganciclovir or intravenous ganciclovir.[1][39] Oral valganciclovir has been shown to be
non-inferior to intravenous ganciclovir for the treatment of CMV disease in kidney, liver, and heart
transplant recipients.[40] Therefore, oral valganciclovir is preferred for the treatment of CMV disease
owing to a reduced risk of complications related to intravenous administration and hospital stay.[39]
However, intravenous ganciclovir may be preferred in severe and life-threatening CMV disease (i.e.,
pneumonitis, disease necessitating intensive care unit admission, severe gastrointestinal disease
with profuse diarrhoea, or when optimal drug exposure is essential or may be an issue).[39] In this
context, valganciclovir should be used as a step-down approach following initial therapy with intravenous
ganciclovir upon clinical improvement. Owing to the significant associated nephrotoxicity, foscarnet is a
second-line option for the treatment of CMV disease and should be reserved for patients intolerant to
valganciclovir or ganciclovir during the induction phase.[1] [39]
Routine use of immunoglobulins (unselected or CMV-hyper-immune globulins) is not currently

recommended as adjunct treatment.[39] In case of severe CMV disease, especially in lung transplant
and haematopoietic stem cell transplant patients with CMV pneumonitis, the adjunctive use of
immunoglobulins may be considered, although evidence for a clear benefit is lacking.[1] There are no
guidelines to define severity of disease; a judgement is made by the managing clinician.
Patients with AIDS and CMV disease, such as retinitis

In patients with AIDS, blindness caused by CMV chorioretinitis is often irreversible, and treatment is
aimed at arresting disease progression. Forms of ganciclovir are the usual first choice for CMV infection
or disease. Treatment should be individualised and should ideally involve an ophthalmologist experienced
with management of CMV retinitis.[2]
For patients with immediate sight-threatening CMV retinitis, intravenous ganciclovir or oral valganciclovir
with or without intravitreal ganciclovir or foscarnet is the preferred initial therapy.[2] Alternative therapies
MANAGEMENT
include intravitreal ganciclovir or foscarnet in combination with intravenous foscarnet or cidofovir (with
probenecid and saline hydration therapy before and after cidofovir therapy).[2] Initial therapy should be
followed by chronic maintenance therapy. For small peripheral lesions that are not sight-threatening, oral
valganciclovir alone may be adequate.[2]
It is important that systemic therapy be administered when intravitreal ganciclovir is given, to prevent
progression to contralateral retinitis and other extraocular CMV disease. Although effective, cidofovir and
foscarnet are less-preferred choices because of associated toxicities.[2]
For gastrointestinal disease, intravenous ganciclovir for 21-42 days is recommended (or until signs and
symptoms have resolved) and intravenous foscarnet is an alternative. Oral valganciclovir is the first line
option when symptoms are not severe enough to interfere with oral absorption. Maintenance therapy is
usually not needed for CMV oesophagitis or colitis, but should be considered following relapses.[2]
For pneumonitis, intravenous ganciclovir or foscarnet is used, although few data are available regarding
therapy impact outcomes and the optimal duration of therapy has not been established.[2] Intravenous
ganciclovir and foscarnet are used in combination to stabilise neurological disease and maximise
response.[2] Maintenance therapy should be continued for life unless there is evidence of immune
recovery.
Patients should also be promptly initiated on ART to control the HIV infection and promote immune
reconstitution. In some patients with a recovering immune system, an immune reconstitution syndrome
may occur, characterised by worsening of the inflammation due to CMV retinitis.[41]
Resistant CMV
Resistant CMV should be suspected in the presence of persistent or recurrent CMV viraemia and
prolonged exposure to antivirals, and it should be tested with genotypic resistance analysis.[39] Treatment
of resistant CMV is complex; in the absence of data from controlled trials to determine the best approach,
treatment should be done in conjunction with a specialist. Depending on the gene mutation, resistant
CMV infection may be treated with foscarnet or cidofovir, or with investigational anti-CMV drugs.[1] [39]
Maribavir is an option for post-transplant CMV infection that does not respond to available antiviral
treatment. In the US, maribavir is approved for treating adults and children (12 years of age and older
and weighing at least 35 kg), and in Europe it is approved for adults only. In the phase 3 SOLSTICE
trial, maribavir demonstrated superior viral clearance compared with investigator-assigned therapy
(valganciclovir/ganciclovir, foscarnet, cidofovir, or foscarnet plus valganciclovir/ganciclovir) in transplant
recipients with refractory/resistant CMV infection (55.7% achieving CMV clearance at 8 weeks compared
with 23.9%).[42]
UL97-mutant CMV confers resistance to ganciclovir, and antiviral treatment in these patients is
with intravenous foscarnet, and less commonly cidofovir. Occasionally, higher than normal doses of
intravenous ganciclovir may also be an option. UL54-mutant CMV, which has mutation in CMV DNA
polymerase, may confer cross-resistance among ganciclovir, foscarnet, and cidofovir (depending on the
exact site of the mutation), and the treatment of these patients may be more limited.
Reduction in immunosuppression should accompany the antiviral therapy, as this will allow immune
reconstitution and immune control of virus infection. Use of newer, experimental antiviral agents, such as
letermovir, may be considered if available, although studies are ongoing. Letermovir is currently approved
for prevention of CMV infection in hematopoietic stem cell transplant recipients, but not for therapy of
MANAGEMENT
established CMV disease because of its low genetic barrier. See Emerging treatments .
Congenital CMV
Neonates with moderate-to-severe, symptomatic congenital CMV disease are commonly treated with oral
valganciclovir in the first month of life for a duration of 6 months.[43] [44] Intravenous ganciclovir is an
25
alternative option for severe, symptomatic congenital infection, but is seldom used.[45] [46] Valganciclovir
and ganciclovir have been shown to prevent progression in hearing loss in symptomatic congenital CMV
infection.[44] [45] [46] One placebo-controlled trial demonstrated no improvement in the short term, but
significant, although modest, improvement in neurodevelopment and hearing in the long term with a 6-
month valganciclovir regimen when compared with placebo.[44] Neutropenia is a frequent adverse event
of ganciclovir.[45] [46]
To date, there is no sufficient evidence for recommending treatment of neonates with asymptomatic or
mild congenital CMV. Several studies aiming to establish whether there is a benefit to treating neonates
with isolated sensorineural loss or in treating newborns beyond the first month of life are ongoing.[43]
MANAGEMENT
Treatment algorithm overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute ( summary )
acquired self-limited illness:
immunocompetent
1st reassurance
infection in transplant recipient: no

known drug resistance
with pneumonitis, 1st intravenous ganciclovir

severe GI disease, or ICU
admission
adjunct immunoglobulins
adjunct step down to oral valganciclovir
2nd intravenous foscarnet
without pneumonitis, 1st oral valganciclovir

admission
2nd intravenous ganciclovir
3rd intravenous foscarnet
infection in patient with AIDS: no

with retinitis (immediate 1st initial antiviral therapy

sight-threatening lesions)
plus antiviral maintenance therapy
with retinitis (non-sight- 1st antiviral therapy

threatening lesions)
with GI disease 1st antiviral therapy
with pneumonitis 1st antiviral therapy
with neurological disease 1st antiviral therapy
infection: known drug resistance

MANAGEMENT
1st foscarnet, cidofovir, high-dose ganciclovir,

or maribavir
congenital infection
27
Acute ( summary )
1st oral valganciclovir or intravenous
ganciclovir
MANAGEMENT
Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute
acquired self-limited illness:
immunocompetent
1st reassurance
» Antiviral treatment of CMV infection and

disease in immunocompetent individuals is not
generally recommended because the disease is
self-limited.
infection in transplant recipient: no
with pneumonitis, 1st intravenous ganciclovir

Primary options
admission
» ganciclovir: 5 mg/kg intravenously every 12
hours for at least 2-4 weeks and until clinical
resolution and CMV is no longer detected in
the blood
» There are no guidelines to define severity of

disease; a judgement is made by the managing
clinician.
» Intravenous ganciclovir is the first-line antiviral

treatment of severe CMV disease, including
severe colitis and pneumonitis, and for patients
who require admission to the intensive care unit
(ICU).
Treatment recommended for SOME patients in
selected patient group
Primary options
» normal immunoglobulin human: consult

specialist for guidance on dose
OR
» cytomegalovirus immunoglobulin (human):

consult specialist for guidance on dose
MANAGEMENT
» Immunoglobulins (unselected or CMV-

hyperimmune globulins) may be used as adjunct
treatment of severe CMV disease, especially in
lung transplant and haematopoietic stem cell
transplant patients with CMV pneumonitis.[47]
[39]
29
Acute
adjunct step down to oral valganciclovir
Primary options
» valganciclovir: 900 mg orally twice daily for

at least 2-4 weeks and until clinical resolution
and CMV is no longer detected in the blood
» Valganciclovir can be used as a rapid step-

down approach following initial therapy with
intravenous ganciclovir in patients with severe
disease.[1]
2nd intravenous foscarnet
Primary options
» foscarnet: 90 mg/kg intravenously every

12 hours; or 60 mg/kg intravenously every 8
blood and tissue specimens
» Foscarnet is a less-preferred choice of therapy

because of its associated nephrotoxicity.[1]

clinician.
Primary options
» normal immunoglobulin human: consult

specialist for guidance on dose
OR
» cytomegalovirus immunoglobulin (human):

consult specialist for guidance on dose
» Immunoglobulins (unselected or CMV-

hyperimmune globulins) may be used as adjunct
treatment of severe CMV disease, especially in
lung transplant and haematopoietic stem cell
transplant patients with CMV pneumonitis.[47]
[39]
MANAGEMENT
without pneumonitis, 1st oral valganciclovir

Primary options
admission
at least 2-4 weeks and until clinical resolution
Acute
and CMV is no longer detected in the blood
and tissue specimens
» In those patients without severe diarrhoea

or problems with absorption, pneumonitis, or
need for ICU admission, oral valganciclovir is
considered first-line treatment.[40] There are
no guidelines to define severity of disease; a
judgement is made by the managing clinician.
2nd intravenous ganciclovir
Primary options

the blood or tissue specimens
» Ganciclovir is a less-preferred choice of

therapy because of the route of administration.[1]

clinician.
3rd intravenous foscarnet
Primary options
» foscarnet: 90 mg/kg intravenously every

12 hours, or 60 mg/kg intravenously every 8
blood and tissue specimens
» Foscarnet is a less-preferred choice of therapy

because of associated nephrotoxicity.[1]

clinician.
infection in patient with AIDS: no
with retinitis (immediate 1st initial antiviral therapy

sight-threatening lesions)
Primary options
» ganciclovir: 2 mg intravitreally weekly until

lesion inactivity achieved
-or-
» foscarnet: 2.4 mg intravitreally weekly until
MANAGEMENT

--AND--
hours for 14-21 days
-or-
31
Acute
14-21 days
OR

OR

14-21 days
Secondary options

-or-
--AND--
» foscarnet: 60 mg/kg intravenously every 8
hours, or 90 mg/kg intravenously every 12
OR

-or-
--AND--
» cidofovir: 5 mg/kg intravenously once
weekly for 2 weeks
--AND--
» probenecid: 2 g orally 3 hours before
cidofovir dose, followed by 1 g given 2 hours
and 8 hours after the dose
» Intravenous ganciclovir or oral valganciclovir

with or without intravitreal ganciclovir or
foscarnet is the preferred initial therapy for
patients with immediate sight-threatening
lesions. Alternative options include intravitreal
ganciclovir or foscarnet in combination with
intravenous foscarnet or cidofovir (with
probenecid and saline hydration therapy before
and after cidofovir therapy).[2]
MANAGEMENT
» An ophthalmologist familiar with CMV retinitis

should ideally be involved in management.[2]
plus antiviral maintenance therapy
Acute
Treatment recommended for ALL patients in
Primary options
» valganciclovir: 900 mg orally once daily
Secondary options
» ganciclovir: 5 mg/kg intravenously once

daily
OR
» foscarnet: 90-120 mg/kg intravenously once

daily
OR
» cidofovir: 5 mg/kg intravenously every 2

weeks
-and-
» probenecid: 2 g orally 3 hours before
cidofovir dose, followed by 1 g given 2 hours
and 8 hours after the dose
» Initial therapy should be followed by chronic

maintenance therapy.
» Maintenance therapy can be safely

discontinued in patients with inactive disease
and sustained CD4+ count (>100 cells/
microlitre for ≥3 to 6 months); consultation with
ophthalmologist is recommended. Regular
eye examinations should be performed every
3 months in patients who have discontinued
maintenance therapy, for early detection of
relapse, or immune recovery uveitis.[2]
» Early relapse is most often caused by the

limited intraocular penetration of systemically
administered drugs.[48]
» If patients relapse while receiving maintenance

therapy, reinduction with the same drug followed
by reinstitution of maintenance therapy is
recommended. Changing to an alternative drug
at the time of first relapse should be considered
if drug resistance is suspected or if side effects
or toxicities interfere with optimal courses of the
initial agent.
MANAGEMENT
with retinitis (non-sight- 1st antiviral therapy

threatening lesions)
Primary options

14-21 days, followed by 900 mg once daily
33
Acute
» For small peripheral lesions, oral valganciclovir
alone may be adequate.[2]
» Systemic antiviral therapy is administered for

3-6 months until antiretroviral therapy-induced
immune recovery.[2]
with GI disease 1st antiviral therapy
Primary options
» valganciclovir: 900 mg orally twice daily
OR

hours, may switch to oral valganciclovir once
patient can tolerate oral therapy
Secondary options

hours
» For gastrointestinal disease (e.g., oesophagitis

or colitis), oral valganciclovir, intravenous
ganciclovir or foscarnet for 21 to 42 days is
recommended (or until signs and symptoms
have resolved).
» Valganciclovir is the first-line treatment if

symptoms are not severe enough to interfere
with oral absorption.
» Maintenance therapy is usually not needed

for CMV oesophagitis or colitis, but should be
considered following relapses.[2]
with pneumonitis 1st antiviral therapy
Primary options

hours
OR

hours
» For pneumonitis, intravenous ganciclovir

or foscarnet is used, although few data are
MANAGEMENT
available regarding therapy impact outcomes.
» The optimal duration of therapy has not been

established.[2]
with neurological disease 1st antiviral therapy
Acute
Primary options

hours
-and-
hours
» Combination regimen is used to stabilise

disease and maximise response.
» The optimal duration of therapy has not been

established.[2] Maintenance therapy should be
continued for life unless there is evidence of
immune recovery.
infection: known drug resistance
1st foscarnet, cidofovir, high-dose ganciclovir,

or maribavir
Primary options
» foscarnet: consult specialist for guidance on

dose
OR
» cidofovir: consult specialist for guidance on

dose
Secondary options
» ganciclovir: consult specialist for guidance

on dose
Tertiary options
» maribavir: consult specialist for guidance on

dose
» Resistant CMV should be suspected

in the presence of persistent or recurrent
CMV viraemia and prolonged exposure to
antivirals and tested with genotypic resistance
analysis.[39]
» Treatment of these patients is complex and

should be done in conjunction with a specialist.
Depending on the gene mutation, resistant
CMV infection may be treated with foscarnet
or cidofovir, or with investigational anti-CMV
MANAGEMENT
drugs.[1] [39]
» Maribavir is an option for post-transplant CMV

infection that does not respond to available
antiviral treatment. In the US, maribavir is
approved for treating adults and children
35
Acute
(12 years of age and older and weighing at
least 35 kg), and in Europe it is approved for
adults only. In the phase 3 SOLSTICE trial,
maribavir demonstrated superior viral clearance
compared with investigator-assigned therapy
(valganciclovir/ganciclovir, foscarnet, cidofovir,
or foscarnet plus valganciclovir/ganciclovir) in
transplant recipients with refractory/resistant
CMV infection (55.7% achieving CMV clearance
at 8 weeks compared with 23.9%).[42]
» UL97-mutant CMV confers resistance to

ganciclovir, and antiviral treatment in these
patients is with intravenous foscarnet, and less
commonly cidofovir. Higher than normal doses
of intravenous ganciclovir may also be an option.
UL54-mutant CMV, which has mutation in CMV
DNA polymerase, may confer cross-resistance
among ganciclovir, foscarnet, and cidofovir, and
the treatment of these patients is very limited. A
specialist should be consulted.
» Reduction in immunosuppression should

accompany the antiviral therapy, as this will allow
immune reconstitution and immune control of
virus infection. Treatment should be determined
and administered in a consultant setting.
» Investigational drugs may be considered in

consultation with a specialist.
congenital infection
1st oral valganciclovir or intravenous

ganciclovir
Primary options
» valganciclovir: consult specialist for

guidance on dosing
Secondary options
» ganciclovir: consult specialist for guidance

on dosing
» Oral valganciclovir is recommended for the

treatment of symptomatic newborns infected
with CMV.[43] [44] Intravenous ganciclovir
is recommended as an alternative option for
severe, symptomatic congenital infection.[45]
[46]
MANAGEMENT
» Valganciclovir and ganciclovir have been

shown to prevent progression in hearing
loss.[44] [45] [46] Therapy should be
administered for 6 months, starting within
the first month after birth.[43] [44] Prolonged
treatment with valganciclovir results in
Acute
modest long-term improvement of long-term
outcomes.[44] Neutropenia is a frequent adverse
event of ganciclovir.[45] [46]
» To date, there is no sufficient evidence for

recommending treatment of neonates with
asymptomatic or mild congenital CMV. Several
studies aiming to establish whether there is
a benefit to treating neonates with isolated
sensorineural loss or in treating newborns
beyond the first month of life are ongoing.[43]
MANAGEMENT
37
Emerging
Brincidofovir (CMX001)
In a placebo-controlled, dose-escalating study, brincidofovir (an orally administered nucleotide analogue)
significantly reduced the incidence of CMV events in patients who had undergone allogeneic haematopoietic-
cell transplantation.[49] Diarrhoea was a dose-limiting adverse effect. A phase 3 trial failed to demonstrate
superiority compared with placebo in the prevention of CMV infection in haematopoietic stem cell transplant
recipients.[50]
Letermovir
Letermovir, an oral anti-CMV compound that targets the viral terminase complex, is approved in Europe
and the US for the prevention of CMV infection in haematopoietic stem cell transplant recipients. In one
placebo-controlled, dose-finding study in haematopoietic-cell transplant patients, letermovir was effective
in reducing the incidence of CMV infection; the highest dose in the study was well tolerated and had the
greatest efficacy.[51] In another randomised controlled trial in haematopoietic stem cell transplant recipients,
letermovir administered for 14 weeks showed a reduced incidence of CMV infection at week 24 post-
transplant, as compared with placebo (37% vs. 61%, respectively; P <0.001).[52] Letermovir is also being
investigated in solid organ transplant recipients. Letermovir significantly decreased CMV-DNA copy number
from baseline in one small, open-label, proof of concept study.[53] In one randomised, double-masked
trial comparing letermovir with valganciclovir in CMV-seronegative adults who received an organ from a
CMV-seropositive kidney transplant donor, letermovir was non-inferior to valganciclovir for the prevention
of CMV disease for 52 weeks after transplant (10.4% vs. 11.8%) and had a lower rate of leukopenia or
neutropenia.[54]
CMV vaccines
Several candidate vaccines, including live attenuated, recombinant/chimeric viral vectors, recombinant
subunits, or gene based, are in pre-clinical and early-phase clinical development.[39] Phase II studies have
reported reduction in CMV infection in pregnant women and transplant recipients who received the CMV
glycoprotein B vaccine containing the MF59 adjuvant; a bivalent DNA vaccine reduced the occurrence
and recurrence of CMV viraemia in CMV-seropositive, allogeneic haematopoeitic stem cell transplant
recipients.[55] [56] [57] However, in a phase II trial of CMV seronegative kidney transplant recipients
receiving a kidney from a CMV seropositive donor, the bivalent DNA vaccine did not prevent episodes of
CMV viraemia needing antivirals when compared with placebo.[58] A chimeric vaccine has been shown to
reduce CMV viraemia in patients undergoing haematopoietic stem cell transplantation in a phase I study.[59]
Adoptive T-cell therapies

The critical role of adaptive immunity in the control of CMV infection has led to few clinical trials of infusing
CMV-specific CD8+ T cells in patients with refractory and resistant CMV diseases.[60]
Immune monitoring
Monitoring of CMV-specific CD4+ and CD8+ T-cell responses may be a promising way of refining prevention
and treatment strategies.[61] [62] For example, patients with strong cell-mediated immune responses could
have antivirals safely discontinued at an earlier stage. Interventional studies are ongoing.
Primary prevention
MANAGEMENT
Prevention of primary CMV infection in pregnant women is encouraged through good hand hygiene methods.
[CDC: CMV and congenital CMV infection] (http://www.cdc.gov/cmv/index.html)
Vaccination is still in the investigational stage for the prevention of CMV disease. CMV-seronegative
transplant recipients who need blood transfusion should receive blood from CMV-seronegative donors.
This is not logistically possible in all instances due to the scarcity of CMV-seronegative blood donors. If not
available, use of leuko-reduced irradiated blood products is recommended. This reduces the incidence of
CMV transmission to about 1%.[27]
In patients with HIV infection, use of antiretroviral therapy to keep the CD4+ cell count to above 100 cells/
microlitre is the recommended approach to prevent CMV end-organ disease.[2]
Secondary prevention
Antiviral prophylaxis:
This method entails the administration of antiviral drugs, such as valganciclovir, or oral or intravenous
ganciclovir, to all patients at risk of CMV disease. Typically, this would include all donor CMV-seropositive,
recipient seronegative (CMV D+/R-) solid organ transplant recipients, CMV recipient seropositive (CMV R+)
lung transplant recipients, and all transplant patients receiving lymphocyte-depleting agents for the treatment
of rejection. Studies have demonstrated that antiviral prophylaxis reduces not only the incidence of CMV
disease but also all-cause mortality after organ transplantation.[69] [70] [71] [72] [73] [74] It has also been
used in CMV-seropositive AIDS patients with CD4 T-cell count of <50 cells/microlitre.[75] [76] Although
antiviral prophylaxis (e.g., ganciclovir) may be used in HIV patients with CD4 count <50 cells/microlitre,
antiretroviral therapy (ART) is generally the preferred management option in order to improve CD4 count.[2]
Pill burden and additional medication side effects are important considerations when considering adding
further prophylactic therapy in these patients.
Letermovir has been adopted as the drug of choice for antiviral prophylaxis in haematopoietic stem cell
transplant recipients at high risk for CMV replication, such as mismatched or unrelated donors, cord blood
transplantation, or presence of graft-versus-host disease.[52]
Prevention of congenital infection by treating pregnant women with CMV infection is an area of ongoing
investigation. One prospective, randomised, controlled trial found that valaciclovir reduced vertical
transmission of CMV compared with placebo when given to pregnant women with primary CMV infection,
particularly for CMV acquired in the first trimester; however, more studies are needed to determine the
effect of timing and duration of treatment.[77] One study evaluating efficacy of hyperimmunoglobulin
given to pregnant women with primary CMV infection found it did not significantly decrease the rate
of vertical transmission compared with placebo.[78] Another randomised controlled trial evaluating
hyperimmunoglobulin for preventing congenital CMV infection was stopped early for futility.[79]
Pre-emptive therapy:
This method entails the administration of antiviral drugs, often valganciclovir or intravenous ganciclovir, only
to people with laboratory markers of asymptomatic viral replication. A major component of this strategy
is a highly predictive and sensitive method for detection of CMV in the blood, such as nucleic acid testing
(NAT) or an antigenaemia assay.[71] [72] [80] The duration of antiviral drug administration in these patients
is guided by the results of CMV surveillance with NAT or antigenaemia. Generally, it is administered until
2 weeks after negative CMV NAT or antigenaemia assay. Pre-emptive therapy appears to be effective at
preventing CMV disease compared with placebo or standard care, but there are limited studies to determine
its effect relative to that of prophylaxis in solid organ transplant recipients.[81] While both antiviral prophylaxis
and pre-emptive therapy are recommended for prevention of CMV in solid organ transplant recipients, one
study comparing the two approaches in donor CMV seropositive, recipient seronegative (D+/R-) CMV liver
transplant recipients found that pre-emptive therapy resulted in a lower incidence of CMV disease over 12
months; more studies are needed.[82]
Patient discussions
MANAGEMENT
All pregnant women should be instructed to wash their hands regularly and thoroughly.
Transplant recipients and AIDS patients should be instructed to visit their doctor urgently if symptoms of
fever, visual impairment or floaters, vomiting, diarrhoea, cough, dyspnoea, headache, or weakness occur.
Online resources from recommended websites may be helpful. [NHS Choices: CMV] (http://www.nhs.uk/
39
conditions/cytomegalovirus/pages/introduction.aspx) [CDC: CMV and congenital CMV infection] (http://
www.cdc.gov/cmv/index.html)
MANAGEMENT
Cytomegalovirus infection Follow up
Monitoring
Monitoring
FOLLOW UP
Patients with CMV disease should have regular monitoring with CMV quantitative nucleic acid testing
(NAT), usually once weekly, to document the clearance of CMV from the blood and to guide the duration
of treatment. Regular CMV monitoring is generally not clinically indicated during routine antiviral
prophylaxis in solid organ transplant recipients or for AIDS patients (see below for consideration of AIDS
patients with CD4 T-cell count of <50 cells/microlitre). Monitoring is commonly used as part of a pre-
emptive strategy in solid organ transplant recipients or allogeneic haematopoietic stem cell transplant
recipients who are not receiving antiviral prophylaxis. Monitoring is also occasionally used in solid organ
transplant recipients after completion of a course of prophylaxis (hybrid strategy).
Patients with detectable CMV in their blood or with clinical signs consistent with active or persistent CMV
disease should be continued on antiviral therapy.
• CMV NAT in transplant recipients and AIDS patients: solid organ and allogeneic haematopoietic
stem cell transplant recipients are monitored at least once weekly with CMV NAT for the detection
of asymptomatic CMV replication, so that pre-emptive antiviral therapy can be administered to
prevent the progression into clinical disease. AIDS patients with CD4 T-cell count of <50 cells/
microlitre are monitored regularly with CMV NAT of the blood to determine the need to initiate
antiviral therapy for the prevention of CMV retinitis and organ-invasive disease.[68]
• CMV serology in prospective transplant recipients and their donors: CMV serology is performed in
all prospective transplant recipients and their donors in order to determine the risk of CMV disease
after transplantation.[68]
Patients on long-term maintenance treatment should be monitored for potential side effects of the
medications, including bone marrow suppression, renal toxicity, or electrolyte disturbance.
Patients with CMV retinitis require close monitoring by an experienced ophthalmologist and the primary
clinician. Dilated indirect ophthalmoscopy should be performed at the time of diagnosis of CMV retinitis,
after completion of induction therapy, 1 month after the initiation of therapy, and monthly thereafter while
the patient is on anti-CMV treatment. Monthly fundus photographs, using a standardised photographic
technique that documents the appearance of the retina, provide the optimum method for following patients
and detecting early relapse.
41
Complications
Complications Timeframe Likelihood

FOLLOW UP
ganciclovir- and valganciclovir-induced bone marrow short term high

suppression
The most common side effect of intravenous ganciclovir or valganciclovir therapy is bone marrow
suppression, most commonly with leukopenia and thrombocytopenia.[66] Reducing ganciclovir dose has
been used to manage this complication, although this may lead to resistant virus. Use of granulocyte
colony-stimulating factor (G-CSF) has been suggested as potential treatment.[67]
cidofovir- and foscarnet-induced renal toxicity short term high
The most dreaded complication of cidofovir and foscarnet therapy is renal failure.[1] This can be managed
by adequate fluid infusions, and with the use of cidofovir, probenecid is given to prevent renal toxicity.[2]
foscarnet-induced electrolyte disturbances short term high
Disturbance in electrolytes, particularly with calcium, magnesium, and phosphorus, is common during
treatment with foscarnet.[2] Routine monitoring for these electrolyte deficiencies and supplementation of
deficient electrolytes is recommended.
immune recovery uveitis short term low
When the immune system recovers, as a result of antiretroviral therapy in treatment of AIDS, there may
be a paradoxical worsening of CMV-induced inflammation in the eye.[41] This has been treated by some
specialists with the use of corticosteroids.[2]
congenital CMV infection resulting in intellectual variable high

disability, sensorineural deafness, visual impairment,
and developmental abnormalities
Congenital CMV infection is the leading cause of sensorineural deafness, intellectual disability, and visual
impairment.[13] Neurological sequelae include spasticity, hemiparesis, seizures, and developmental
delay.[8] [9]
blindness variable medium
Invasion of CMV in the retina causes permanent damage, so that even if the virus infection is controlled,
the destruction of the retina is not reversible. Hence, early diagnosis of CMV retinitis is key to the
prevention of permanent blindness.[31]
indirect CMV effects variable medium
CMV disease is associated with increased risk of other opportunistic infections. In the long term, it has
been associated with acute and chronic allograft rejection and overall mortality.[64] [65]
Prognosis
FOLLOW UP
The outcome of treatment for CMV disease is good, in general, with the possible exception of CMV
retinitis, which could lead to irreversible blindness, both in transplant patients and in patients with AIDS.[31]
[63] In donor CMV-seropositive, recipient seronegative (CMV D+/R-) solid organ transplant recipients and
haematopoietic stem cell transplant recipients with graft-versus-host disease recurrence of CMV replication
is common, and repeated courses of antiviral therapy may be needed. In solid organ transplant recipients,
some experts administer secondary prophylaxis in patients at high risk for recurrence (CMV D+/R-).
There is increasing appreciation of the long-term deleterious outcomes of CMV infection and disease in
transplant recipients, such as increased risk of chronic allograft failure (including accelerated vasculopathy
after heart transplantation, obliterative bronchiolitis after lung transplantation, and tubulointerstitial fibrosis
after kidney transplantation).
The most common long-term clinical outcome of congenital CMV disease is hearing loss.
43
Cytomegalovirus infection Guidelines
Diagnostic guidelines
United Kingdom
Antenatal care (ht tps://www.nice.org.uk/guidance/ng201)

Published by: National Institute for Health and Care Excellence Last published: 2021
Cytomegalovirus serological testing in potential allogeneic haematopoietic

stem cell transplant recipients: a British Society for Haematology Good
Practice Paper (ht tps://b-s-h.org.uk/guidelines/guidelines)
Published by: British Society for Haematology Last published: 2021
Europe
Guidelines on the diagnosis and management of pericardial diseases (ht tps://

GUIDELINES
www.escardio.org/Guidelines/Clinical-Practice-Guidelines)
Published by: European Society of Cardiology Last published: 2015
International
The third international consensus guidelines on the management

of cytomegalovirus in solid-organ transplantation (ht tps://
journals.lww.com/transplantjournal/Abstract/2018/06000/
The_Third_International_Consensus_Guidelines_on.13.aspx)
Published by: Transplantation Society Last published: 2018
North America
Cytomegalovirus in solid organ transplant recipients (ht tps://www.myast.org/

education/guidelines-and-opinions)
Published by: American Society of Transplantation Last published: 2019
Treatment guidelines
United Kingdom
Congenital cytomegalovirus infection: update on treatment (ht tps://

www.rcog.org.uk/en/guidelines-research-services/guidelines)
Published by: Royal College of Obstetricians and Gynaecologists (UK) Last published: 2017
Europe
Guidelines for the management of cytomegalovirus infection in patients

with haematological malignancies and after stem cell transplantation from
the 2017 European Conference on Infections in Leukaemia (ECIL 7) (ht tps://
pubmed.ncbi.nlm.nih.gov/31153807)
Published by: European Conference on Infections in Leukaemia (ECIL Last published: 2019
7)
Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8)

infections in patients with hematological malignancies and after SCT
(ht tps://www.leukemia-net.org/content/treat_research/supportive_care/
standards_sop_and_recommendations/index_eng.html)
Published by: European Conference on Infections in Leukemia Last published: 2008
2008 prevention of opportunistic infections in HIV-infected adolescents and
GUIDELINES
adults guidelines: recommendations of GESIDA/National AIDS Plan AIDS
Study Group (GESIDA) and National AIDS Plan (ht tps://www.elsevier.es/es-
revista-enfermedades-infecciosas-microbiologia-clinica-28-sumario-vol-26-
num-7-S0213005X08X72040)
Published by: AIDS Study Group of the Spanish Society of Infectious Last published: 2008
Diseases; National AIDS Plan Committee
International
The third international consensus guidelines on the management

of cytomegalovirus in solid-organ transplantation (ht tps://
journals.lww.com/transplantjournal/Abstract/2018/06000/
The_Third_International_Consensus_Guidelines_on.13.aspx)
Published by: Transplantation Society Last published: 2018
Congenital cytomegalovirus infection in pregnancy and the neonate:

consensus recommendations for prevention, diagnosis and therapy (ht tps://
www.sciencedirect.com/science/article/pii/S1473309917301433)
Published by: International Congenital Cytomegalovirus Last published: 2017
Recommendations Group
45
North America
Guidelines for the prevention and treatment of opportunistic infections in

adults and adolescents with HIV (ht tps://clinicalinfo.hiv.gov/en/guidelines)
Published by: Centers for Disease Control and Prevention; National Last published: 2021
Institutes of Health; HIV Medicine Association of the Infectious Diseases
Society of America
Cytomegalovirus in solid organ transplantation recipients (ht tps://

www.myast.org/education/guidelines-and-opinions)
Published by: American Society of Transplantation Last published: 2019
GUIDELINES
Cytomegalovirus infection Online resources
Online resources
1. CDC: CMV and congenital CMV infection (http://www.cdc.gov/cmv/index.html) (external link)
2. NHS Choices: CMV (http://www.nhs.uk/conditions/cytomegalovirus/pages/introduction.aspx) (external

link)
ONLINE RESOURCES
47
Cytomegalovirus infection References
Key articles
• Humar A, Michaels M; AST ID Working Group on Infectious Disease Monitoring. American
REFERENCES
Society of Transplantation recommendations for screening, monitoring and reporting of infectious

complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant.
2006 Feb;6(2):262-74. Full text (http://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2005.01207.x/
full) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16426310?tool=bestpractice.bmj.com)
• Kotton CN, Kumar D, Caliendo AM, et al; The Transplantation Society International CMV Consensus
Group. The third international consensus guidelines on the management of cytomegalovirus in solid-
organ transplantation. Transplantation. 2018 Jun;102(6):900-31. Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/29596116?tool=bestpractice.bmj.com)
• Asberg A, Humar A, Rollag H, et al. Oral valganciclovir is noninferior to intravenous ganciclovir

for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J
Transplant. 2007 Sep;7(9):2106-13. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17640310?
tool=bestpractice.bmj.com)
• Rawlinson WD, Boppana SB, Fowler KB, et al. Congenital cytomegalovirus infection in pregnancy
and the neonate: consensus recommendations for prevention, diagnosis, and therapy. Lancet
Infect Dis. 2017 Jun;17(6):e177-e188. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/28291720?
• Kimberlin DW, Jester PM, Sánchez PJ, et al; National Institute of Allergy and Infectious Diseases
Collaborative Antiviral Study Group. Valganciclovir for symptomatic congenital cytomegalovirus
disease. N Engl J Med. 2015 Mar 5;372(10):933-43. Full text (http://www.ncbi.nlm.nih.gov/
pmc/articles/PMC4401811) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/25738669?
• Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in
hematopoietic-cell transplantation. N Engl J Med. 2017 Dec 21;377(25):2433-44. Full text
(https://www.nejm.org/doi/10.1056/NEJMoa1706640) Abstract (http://www.ncbi.nlm.nih.gov/
• Preiksaitis JK, Brennan DC, Fishman J, et al. Canadian society of transplantation consensus
workshop on cytomegalovirus management in solid organ transplantation final report. Am J Transplant.
References
1. Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients - Guidelines
of the American Society of Transplantation Infectious Diseases Community of Practice. Clin
Transplant. 2019 Sep;33(9):e13512. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/30817026?
2. HIV.gov, US National Institutes of Health. Guidelines for the prevention and treatment of opportunistic
infections in adults and adolescents with HIV. Jul 2021 [internet publication]. Full text (https://
clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/cytomegalovirus-
REFERENCES
disease?view=full)
3. Razonable RR, Paya CV. Beta-herpesviruses in transplantation. Rev Med Microbiol. 2002;13:163-76.
4. Razonable RR, Rivero A, Brown RA, et al. Detection of simultaneous beta-herpesvirus infection in
clinical syndromes due to defined cytomegalovirus infection. Clin Transplant. 2003 Apr;17(2):114-20.
Abstract (http://www.ncbi.nlm.nih.gov/pubmed/12709076?tool=bestpractice.bmj.com)
5. Hayward GS, Ambinder R, Ciufo D, et al. Structural organization of human herpesvirus DNA
molecules. J Invest Dermatol. 1984 Jul;83(1 suppl):29s-41s. Abstract (http://www.ncbi.nlm.nih.gov/
6. Ayre K, Warren BF, Jeffery K, et al. The role of CMV in steroid-resistant ulcerative colitis: a
systematic review. J Crohns Colitis. 2009 Sep;3(3):141-8. Abstract (http://www.ncbi.nlm.nih.gov/
7. Limaye AP, Kirby KA, Rubenfeld GD, et al. Cytomegalovirus reactivation in critically ill
immunocompetent patients. JAMA. 2008 Jul 23;300(4):413-22. Full text (http://jama.ama-
assn.org/content/300/4/413.long) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18647984?
8. Michaels MG, Greenberg DP, Sabo DL, et al. Treatment of children with congenital cytomegalovirus
infection with ganciclovir. Pediatric Infect Dis J. 2003 Jun;22(6):504-9. Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/12799506?tool=bestpractice.bmj.com)
9. Lagasse N, Dhooge I, Govaert P, et al. Congenital CMV infections and hearing loss.
Acta Otorhinolaryngology Belg. 2000;54(4):431-6. Abstract (http://www.ncbi.nlm.nih.gov/
10. Revello M. Pathogenesis and prenatal diagnosis of congenital cytomegalovirus infection. J

Clin Virol. 2004 Feb;29(2):71-83. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/14747024?
11. Fowler K, Mucha J, Neumann M, et al. A systematic literature review of the global seroprevalence of
cytomegalovirus: possible implications for treatment, screening, and vaccine development. BMC Public
Health. 2022 Sep 1;22(1):1659. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9435408)
12. Kenneson A, Cannon MJ. Review and meta-analysis of congenital cytomegalovirus (CMV) infection.
Rev Med Virol. 2007 Jul-Aug;17(4):253-76. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17579921?
13. Revello M. Pathogenesis and prenatal diagnosis of congenital cytomegalovirus infection. J

Clin Virol. 2004 Feb;29(2):71-83. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/14747024?
49
14. Razonable RR, Paya CV. Beta-herpesviruses in transplantation. Rev Med Microbiol. 2002;13:163-76.
15. Kijpittayarit S, Eid AJ, Brown RA, et al. Relationship between Toll-like receptor 2 polymorphism and
REFERENCES
cytomegalovirus disease after liver transplantation. Clin Infect Dis. 2007 May 15;44(10):1315-20.
16. Compton T, Kurt-Jones EA, Boehme KW, et al. Human cytomegalovirus activates inflammatory
cytokine responses via CD4 and Toll-like receptor 2. J Virol. 2003 Apr;77(8):4588-96. Full text
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC152130) Abstract (http://www.ncbi.nlm.nih.gov/
17. Einsele H, Kapp M, Grigoleit GU. CMV-specific T cell therapy. Blood Cells Mol Dis. 2008 Jan-
Feb;40(1):71-5. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17851094?tool=bestpractice.bmj.com)
18. Eid AJ, Razonable RR. Cytomegalovirus in solid organ transplantation: advances lead to challenges
and opportunities. Curr Opin Organ Transplant. 2007;12:610-17.
19. Razonable RR, Rivero A, Rodriguez A, et al. Allograft rejection predicts the occurrence of late-
onset cytomegalovirus (CMV) disease among CMV-mismatched solid organ transplant patients
receiving prophylaxis with oral ganciclovir. J Infect Dis. 2001 Dec 1;184(11):1461-4. Abstract (http://
20. Boeckh M, Nichols WG. The impact of cytomegalovirus serostatus of donor and recipient before
hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy.
Blood. 2004 Mar 15;103(6):2003-8. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/14644993?
21. Tedesco-Silva H, Felipe C, Ferreira A, et al. Reduced incidence of cytomegalovirus infection in kidney
transplant recipients receiving everolimus and reduced tacrolimus doses. Am J Transplant. 2015
Oct;15(10):2655-64. Full text (http://onlinelibrary.wiley.com/doi/10.1111/ajt.13327/full) Abstract (http://
22. Tedesco-Silva H, Pascual J, Viklicky O, et al. Safety of everolimus with reduced calcineurin
inhibitor exposure in de novo kidney transplants: an analysis from the randomized TRANSFORM
study. Transplantation. 2019 Sep;103(9):1953-63. Full text (https://www.doi.org/10.1097/
TP.0000000000002626) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/30801548?
23. Kaminski H, Kamar N, Thaunat O, et al. Incidence of cytomegalovirus infection in seropositive

kidney transplant recipients treated with everolimus: a randomized, open-label, multicenter phase
4 trial. Am J Transplant. 2022 May;22(5):1430-41. Full text (https://www.amjtransplant.org/article/
S1600-6135(22)08213-2/fulltext) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/34990047?
24. Weng MT, Tung CC, Lee YS, et al. Cytomegalovirus colitis in hospitalized inflammatory bowel disease
patients in Taiwan: a referral center study. BMC Gastroenterol. 2017 Feb 13;17(1):28. Full text
(https://bmcgastroenterol.biomedcentral.com/articles/10.1186/s12876-017-0586-9) Abstract (http://
25. Razonable RR. Epidemiology of cytomegalovirus disease in solid organ and hematopoietic stem cell
transplant recipients. Am J Health Syst Pharm. 2005 Apr 15;62(8 suppl 1):S7-13. Abstract (http://
REFERENCES
26. Boucoiran I, Yudin M, Poliquin V, et al. Guideline No. 420: Cytomegalovirus infection in pregnancy.
J Obstet Gynaecol Can. 2021 Jul;43(7):893-908. Abstract (http://www.ncbi.nlm.nih.gov/
27. Nichols WG, Price TH, Gooley T, et al. Transfusion-transmitted cytomegalovirus infection after
receipt of leukoreduced blood products. Blood. 2003 May 15;101(10):4195-200. Full text (http://
bloodjournal.hematologylibrary.org/content/101/10/4195.long) Abstract (http://www.ncbi.nlm.nih.gov/
28. Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant
recipients. Clin Infect Dis. 2002 Apr 15;34(8):1094-7. Full text (http://cid.oxfordjournals.org/
content/34/8/1094.long) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/11914998?
29. Razonable RR, Åsberg A, Rollag H, et al. Virologic suppression measured by a cytomegalovirus
(CMV) DNA test calibrated to the World Health Organization international standard is predictive
of CMV disease resolution in transplant recipients. Clin Infect Dis. 2013 Jun;56(11):1546-53. Full
text (http://cid.oxfordjournals.org/content/56/11/1546.long) Abstract (http://www.ncbi.nlm.nih.gov/
30. Preiksaitis JK, Hayden RT, Tong Y, et al. Are we there yet? Impact of the first International Standard
for cytomegalovirus DNA on the harmonization of results reported on plasma samples. Clin
Infect Dis. 2016 Sep 1;63(5):583-9. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/27307504?
31. Eid AJ, Bakri SJ, Kijpittayarit S, et al. Clinical features and outcomes of cytomegalovirus retinitis
after transplantation. Transpl Infect Dis. 2008 Feb;10(1):13-8. Abstract (http://www.ncbi.nlm.nih.gov/
32. Razonable RR, Paya CV, Smith TF. Role of the laboratory in the diagnosis and management of
cytomegalovirus infection in hematopoietic and solid organ transplant recipients. J Clin Microbiol. 2002
Mar;40(3):746-52. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC120290) Abstract (http://
33. Wohl DA, Kendall MA, Andersen J, et al; A5030 Study Team. Low rate of CMV end-organ disease
in HIV-infected patients despite low CD4+ cell counts and CMV viremia: results of ACTG protocol
A5030. HIV Clin Trials. 2009 May-Jun;10(3):143-52. Full text (http://www.ncbi.nlm.nih.gov/pmc/
articles/PMC2754189/?tool=pubmed) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/19632953?
34. Boppana SB, Rivera LB, Fowler KB, et al. Intrauterine transmission of cytomegalovirus to infants
of women with preconceptional immunity. N Engl J Med. 2001 May 3;344(18):1366-71. Full text
(https://www.nejm.org/doi/10.1056/NEJM200105033441804) Abstract (http://www.ncbi.nlm.nih.gov/
51
35. Donner C, Liesnard C, Brancart F, et al. Accuracy of amniotic fluid testing before 21 weeks' gestation
in prenatal diagnosis of congenital cytomegalovirus infection. Prenat Diagn. 1994 Nov;14(11):1055-9.
REFERENCES
36. Humar A, Michaels M; AST ID Working Group on Infectious Disease Monitoring. American
Society of Transplantation recommendations for screening, monitoring and reporting of infectious
complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant.
37. Ljungman P, Boeckh M, Hirsch HH, et al; Disease Definitions Working Group of the Cytomegalovirus
Drug Development Forum. Definitions of cytomegalovirus infection and disease in transplant patients
for use in clinical trials. Clin Infect Dis. 2017 Jan 1;64(1):87-91. Abstract (http://www.ncbi.nlm.nih.gov/
38. Chemaly RF, Chou S, Einsele H, et al. Definitions of resistant and refractory cytomegalovirus
infection and disease in transplant recipients for use in clinical trials. Clin Infect Dis. 2019 Apr
8;68(8):1420-26. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348585) Abstract (http://
39. Kotton CN, Kumar D, Caliendo AM, et al; The Transplantation Society International CMV Consensus
Group. The third international consensus guidelines on the management of cytomegalovirus in solid-
organ transplantation. Transplantation. 2018 Jun;102(6):900-31. Abstract (http://www.ncbi.nlm.nih.gov/
40. Asberg A, Humar A, Rollag H, et al. Oral valganciclovir is noninferior to intravenous ganciclovir
for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J
Transplant. 2007 Sep;7(9):2106-13. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17640310?
41. Muller M, Wandel S, Colebunders R, et al; IeDEA Southern and Central Africa. Immune reconstitution
inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review
and meta-analysis. Lancet Infect Dis. 2010 Apr;10(4):251-61. Abstract (http://www.ncbi.nlm.nih.gov/
42. Avery RK, Alain S, Alexander BD, et al. Maribavir for refractory cytomegalovirus infections with or
without resistance post-transplant: results from a phase 3 randomized clinical trial. Clin Infect Dis.
2022 Sep 10;75(4):690-701. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9464078)
43. Rawlinson WD, Boppana SB, Fowler KB, et al. Congenital cytomegalovirus infection in pregnancy
and the neonate: consensus recommendations for prevention, diagnosis, and therapy. Lancet
Infect Dis. 2017 Jun;17(6):e177-e188. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/28291720?
44. Kimberlin DW, Jester PM, Sánchez PJ, et al; National Institute of Allergy and Infectious Diseases
Collaborative Antiviral Study Group. Valganciclovir for symptomatic congenital cytomegalovirus
disease. N Engl J Med. 2015 Mar 5;372(10):933-43. Full text (http://www.ncbi.nlm.nih.gov/
pmc/articles/PMC4401811) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/25738669?
REFERENCES
45. Kimberlin DW, Lin CY, Sanchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic
congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled
trial. J Pediatr. 2003 Jul;143(1):16-25. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/12915819?
46. Oliver SE, Cloud GA, Sánchez PJ, et al; National Institute of Allergy, Infectious Diseases Collaborative
Antiviral Study Group. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic
congenital cytomegalovirus infections involving the central nervous system. J Clin Virol. 2009 Dec;(46
suppl 4):S22-6. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/19766534?tool=bestpractice.bmj.com)
47. Bonaros N, Mayer B, Schachner T, et al. CMV-hyperimmune globulin for preventing cytomegalovirus
infection and disease in solid organ transplant recipients: a meta-analysis. Clin Transplant. 2008 Jan-
Feb;22(1):89-97. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18217909?tool=bestpractice.bmj.com)
48. Kuppermann BD, Quiceno JI, Flores-Aguilar M, et al. Intravitreal ganciclovir concentration after
intravenous administration in AIDS patients with cytomegalovirus retinitis: implications for therapy.
J Infect Dis. 1993 Dec;168(6):1506-9. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/8245536?
49. Marty FM, Winston DJ, Rowley SD, et al. CMX001 to prevent cytomegalovirus disease in
hematopoietic-cell transplantation. N Engl J Med. 2013 Sep 26;369(13):1227-36. Abstract (http://
50. Marty FM, Winston DJ, Chemaly RF, et al. A randomized, double-blind, placebo-controlled
phase 3 trial of oral brincidofovir for cytomegalovirus prophylaxis in allogeneic hematopoietic
cell transplantation. Biol Blood Marrow Transplant. 2019 Feb;25(2):369-81. Full text (https://
www.ncbi.nlm.nih.gov/pmc/articles/PMC8196624) Abstract (http://www.ncbi.nlm.nih.gov/
51. Chemaly RF, Ullmann AJ, Stoelben S, et al; AIC246 Study Team. Letermovir for cytomegalovirus
prophylaxis in hematopoietic-cell transplantation. N Engl J Med. 2014 May 8;370(19):1781-9. Abstract
(http://www.ncbi.nlm.nih.gov/pubmed/24806159?tool=bestpractice.bmj.com)
52. Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in
hematopoietic-cell transplantation. N Engl J Med. 2017 Dec 21;377(25):2433-44. Full text
(https://www.nejm.org/doi/10.1056/NEJMoa1706640) Abstract (http://www.ncbi.nlm.nih.gov/
53. Stoelben S, Arns W, Renders L, et al. Preemptive treatment of cytomegalovirus infection in

kidney transplant recipients with letermovir: results of a Phase 2a study. Transpl Int. 2014
Jan;27(1):77-86. Full text (http://onlinelibrary.wiley.com/doi/10.1111/tri.12225/full) Abstract (http://
54. Limaye AP, Budde K, Humar A, et al. Letermovir vs valganciclovir for prophylaxis of cytomegalovirus in
high-risk kidney transplant recipients: a randomized clinical trial. JAMA. 2023 Jun 6;e239106. Full text
53
(https://jamanetwork.com/journals/jama/fullarticle/2805945) Abstract (http://www.ncbi.nlm.nih.gov/
REFERENCES
55. Pass RF, Zhang C, Evans A, et al. Vaccine prevention of maternal cytomegalovirus infection.
N Engl J Med. 2009 Mar 19;360(12):1191-9. Full text (http://www.nejm.org/doi/full/10.1056/
NEJMoa0804749#t=article) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/19297572?
56. Griffiths PD, Stanton A, McCarrell E, et al. Cytomegalovirus glycoprotein-B vaccine with MF59
adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet. 2011 Apr
9;377(9773):1256-63. Full text (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075549) Abstract
57. Kharfan-Dabaja MA, Boeckh M, Wilck MB, et al. A novel therapeutic cytomegalovirus DNA vaccine
in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled,
phase 2 trial. Lancet Infect Dis. 2012 Apr;12(4):290-9. Abstract (http://www.ncbi.nlm.nih.gov/
58. Vincenti F, Budde K, Merville P, et al. A randomized, phase 2 study of ASP0113, a DNA-based
vaccine, for the prevention of CMV in CMV-seronegative kidney transplant recipients receiving a
kidney from a CMV-seropositive donor. Am J Transplant. 2018 Dec;18(12):2945-54. Full text (https://
www.amjtransplant.org/article/S1600-6135(22)09806-9/fulltext) Abstract (http://www.ncbi.nlm.nih.gov/
59. Nakamura R, La Rosa C, Longmate J, et al. Viraemia, immunogenicity, and survival outcomes
of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in
allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. Lancet Haematol. 2016
Feb;3(2):e87-98. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926626) Abstract (http://
60. Scheinberg P, Melenhorst JJ, Brenchley JM, et al. The transfer of adaptive immunity to
cytomegalovirus (CMV) during hematopoietic stem cell transplantation is dependent on the specificity
and phenotype of CMV-specific T cells in the donor. Blood. 2009 Dec 3;114(24):5071-80. Abstract
61. Snyder LD, Chan C, Kwon D, et al. Polyfunctional T-cell signatures to predict protection from
cytomegalovirus after lung transplantation. Am J Respir Crit Care Med. 2016 Jan 1;193(1):78-85.
62. Manuel O, Husain S, Kumar D, et al. Assessment of cytomegalovirus-specific cell-mediated

immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant
recipients: a multicenter cohort study. Clin Infect Dis. 2013 Mar;56(6):817-24. Full text
(http://cid.oxfordjournals.org/content/56/6/817.long) Abstract (http://www.ncbi.nlm.nih.gov/
63. Chen S, Pawelec G, Trompet S, et al. Associations of cytomegalovirus infection with all-cause
and cardiovascular mortality in multiple observational cohort studies of older adults. J Infect Dis.
2021 Feb 3;223(2):238-46. Full text (https://www.doi.org/10.1093/infdis/jiaa480) Abstract (http://
REFERENCES
64. Manuel O, Kralidis G, Mueller NJ, et al; Swiss Transplant Cohort Study. Impact of antiviral preventive
strategies on the incidence and outcomes of cytomegalovirus disease in solid organ transplant
recipients. Am J Transplant. 2013 Sep;13(9):2402-10. Full text (https://onlinelibrary.wiley.com/
doi/full/10.1111/ajt.12388) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/23914796?
65. Martin-Gandul C, Mueller NJ, Pascual M, et al. The impact of infection on chronic allograft dysfunction
and allograft survival after solid organ transplantation. Am J Transplant. 2015 Dec;15(12):3024-40 Full
text (https://onlinelibrary.wiley.com/doi/full/10.1111/ajt.13486) Abstract (http://www.ncbi.nlm.nih.gov/
66. American Society of Transplantation, American Society of Transplant Surgeons. Cytomegalovirus.

Am J Transplant. 2004;4(suppl 10):51-8. Full text (http://onlinelibrary.wiley.com/doi/10.1111/
j.1600-6135.2004.00727.x/full)
67. Preiksaitis JK, Brennan DC, Fishman J, et al. Canadian society of transplantation consensus
workshop on cytomegalovirus management in solid organ transplantation final report. Am J Transplant.
68. Razonable RR, Paya CV, Smith TF. Role of the laboratory in the diagnosis and management of
cytomegalovirus infection in hematopoietic and solid organ transplant recipients. J Clin Microbiol. 2002
Mar;40(3):746-52. Full text (http://jcm.asm.org/cgi/content/full/40/3/746?view=long&pmid=11880387)
69. Humar A, Lebranchu Y, Vincenti F, et al. The efficacy and safety of 200 days valganciclovir
cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant.
2010 May;10(5):1228-37. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/20353469?
70. Hodson EM, Jones CA, Webster AC, et al. Antiviral medications to prevent cytomegalovirus
disease and early death in recipients of solid organ transplants: a systematic review of randomized
clinical trials. Lancet. 2005 Jun 18-24;365(9477):2105-15. Abstract (http://www.ncbi.nlm.nih.gov/
71. Kalil AC, Levitsky J, Lyden E, et al. Meta-analysis: the efficacy of strategies to prevent organ disease
by cytomegalovirus in solid organ transplant recipients. Ann Intern Med. 2005 Dec 20;143(12):870-80.
72. Small LN, Lau J, Snydman DR. Preventing post-organ transplant cytomegalovirus disease
with ganciclovir: a meta-analysis comparing prophylactic and preemptive therapies. Clin Infect
Dis. 2006 Oct 1;43(7):869-80. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16941368?
55
73. Paya C, Humar A, Dominguez E, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for
prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2004
Apr;4(4):611-20. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/15023154?tool=bestpractice.bmj.com)
REFERENCES
74. Hodson EM, Ladhani M, Webster AC, et al. Antiviral medications for preventing cytomegalovirus
disease in solid organ transplant recipients. Cochrane Database Syst Rev. 2013;(2):CD003774.
Full text (http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003774.pub4/full) Abstract (http://
75. Spector SA, McKinley GF, Lalezari JP, et al. Oral ganciclovir for the prevention of cytomegalovirus
disease in persons with AIDS. N Engl J Med. 1996 Jun 6;334(23):1491-7. Full text (http://
www.nejm.org/doi/full/10.1056/NEJM199606063342302#t=article) Abstract (http://
76. Brosgart CL, Louis TA, Hillman DW, et al. A randomized, placebo-controlled trial of the safety and
efficacy of oral ganciclovir for prophylaxis of cytomegalovirus disease in HIV-infected individuals. Terry
Beirn Community Programs for Clinical Research on AIDS. AIDS. 1998 Feb 12;12(3):269-77. Abstract
77. Shahar-Nissan K, Pardo J, Peled O, et al. Valaciclovir to prevent vertical transmission of

cytomegalovirus after maternal primary infection during pregnancy: a randomised, double-
blind, placebo-controlled trial. Lancet. 2020 Sep 12;396(10253):779-85. Abstract (http://
78. Revello MG, Lazzarotto T, Guerra B, et al; CHIP Study Group. A randomized trial of hyperimmune
globulin to prevent congenital cytomegalovirus. N Engl J Med. 2014 Apr 3;370(14):1316-26.
Full text (http://www.nejm.org/doi/full/10.1056/NEJMoa1310214#t=article) Abstract (http://
79. Hughes BL, Clifton RG, Rouse DJ, et al; Eunice Kennedy Shriver National Institute of Child Health
and Human Development Maternal–Fetal Medicine Units Network. A trial of hyperimmune globulin
to prevent congenital cytomegalovirus infection. N Engl J Med. 2021 Jul 29;385(5):436-44. Abstract
80. Strippoli GF, Hodson EM, Jones C, et al. Preemptive treatment of cytomegalovirus viremia to
prevent cytomegalovirus disease in solid organ transplant recipients. Transplantation. 2006 Jan
27;81(2):139-45. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/16436954?tool=bestpractice.bmj.com)
81. Owers DS, Webster AC, Strippoli GF, et al. Pre-emptive treatment for cytomegalovirus viraemia to
prevent cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev.
2013;(2):CD005133. Full text (http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005133.pub3/
82. Singh N, Winston DJ, Razonable RR, et al. Effect of preemptive therapy vs antiviral prophylaxis
on cytomegalovirus disease in seronegative liver transplant recipients with seropositive
donors: a randomized clinical trial. JAMA. 2020 Apr 14;323(14):1378-87. Full text (https://
www.doi.org/10.1001/jama.2020.3138) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/32286644?
Cytomegalovirus infection Images
Images
IMAGES
Figure 1: Fundoscopy (left eye) showing area of CMV retinitis inferonasally involving the vascular arcades
and the optic disc, associated with vasculitis and flame haemorrhages
57
IMAGES Cytomegalovirus infection Images
Figure 2: Chest CT scan of a lung transplant recipient with diffuse interstitial and parenchymal changes as a
result of primary CMV pneumonitis
Figure 3: Chest x-ray showing diffuse pulmonary infiltrates in an immunocompromised patient with severe
CMV pneumonitis
Cytomegalovirus infection Images
IMAGES
Figure 4: Active cytomegalovirus infection of lung in AIDS
Centers for Disease Control and Prevention: Dr Edwin P. Ewing, Jr
59
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61
Contributors:
// Authors:
Mat teo Mombelli, MD

Infectious Disease Service and Transplantation Center
University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland
DISCLOSURES: MM declares that he has no competing interests.
Oriol Manuel, MD
Infectious Disease Service and Transplantation Center
University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland
DISCLOSURES: OM has been reimbursed by MSD, Takeda, and Biotest for Advisory Boards and Lectures
regarding CMV in organ transplantation.
// Acknowledgements:
Dr Matteo Mombelli and Dr Oriol Manuel would like to thank Dr Sandra Asner from the University Hospital
of Lausanne, Switzerland for her careful review of congenital CMV in this topic. They would also like to
gratefully acknowledge Dr Raymund R. Razonable and Dr Atul Humar, the previous contributors to this
topic.
DISCLOSURES: RRR is an author of a number of references cited in this topic. AH has done consultancy
work for Astellas, Chimerix, and Roche.
// Peer Reviewers:
Gregory H. Taylor, MD
Assistant Professor
Department of Family Medicine, University of Maryland School of Medicine, MD
DISCLOSURES: GHT declares that he has no competing interests.
Simon Barton, MD, FRCOG, FRCPEd, FRCP

Clinical Director
HIV and Sexual Health, Chelsea and Westminster Hospital, London, UK
DISCLOSURES: SB has been funded by GlaxoSmithKline and Gilead for speaking at scientific meetings.

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Cytomegalovirus

Straight to the point of care

Last updated: Jun 22, 2023

Laboratory evaluation of CMV

Clinical presentation and investigation in people with normal

• In healthy people CMV infection is usually asymptomatic.

• Aminotransferases or alkaline phosphatase may be elevated.

Clinical presentation and investigation in solid organ and

AIDS, CMV retinitis is not commonly observed in transplant recipients.[31]

• Often shows anaemia, leukopenia, or thrombocytopenia.

Chest CT scan of a lung transplant recipient with diffuse interstitial

Endoscopy and colonoscopy:

Clinical presentation and investigation in patients with AIDS

• May show anaemia, leukopenia, or thrombocytopenia.

• This should be performed in any immunocompromised patient with pulmonary symptoms

Chest x-ray showing diffuse pulmonary infiltrates in an

Clinical presentation and investigation in infants with congenital

• FBC: may show thrombocytopenia

Antenatal screening for CMV

History and exam

nausea and vomiting (common)

visual floaters and blindness (common)

abnormalities on fundoscopy (common)

newborn: microcephaly (common)

• Common neurological involvement in the newborn.[13]

newborn: hearing loss (common)

Other diagnostic factors

newborn: petechiae or purpura (common)

pain and weakness (uncommon)

CMV R+ (recipient seropositive) in transplant recipients

type of immunosuppressive drugs

inflammatory bowel disease

newborn in CMV infection during pregnancy

serum creatinine normal; solid organ and

pp65 antigenaemia number of pp65-positive

Chest x-ray showing diffuse pulmonary infiltrates in an

Other tests to consider

Chest CT scan of a lung transplant recipient with diffuse interstitial

Active cytomegalovirus infection of lung in AIDS

serial fetal ultrasound examinations (congenital CMV infection) features suggestive of

amniocentesis or fetal blood sampling (congenital CMV documentation of CMV

fetal sampling is performed before 21 weeks of gestation or too close

Condition Differentiating signs / Differentiating tests

HIV • Acute HIV seroconversion • HIV serology; HIV RNA level.

Toxoplasmosis • In immunocompetent • IgA, IgM, IgG toxoplasma

Other viral illness • Viral infections often • Virus-specific culture and

• Defined by identification of clinical symptoms, findings of macroscopic mucosal lesions on

Definitions of resistant and refractory CMV infection and disease in

• Refractory CMV infection

• Persistent viral load after at least 2 weeks of appropriately-dosed antiviral therapy.

• Lack of improvement in signs and symptoms after at least 2 weeks of appropriately-dosed

Transplant recipients with CMV disease

Routine use of immunoglobulins (unselected or CMV-hyper-immune globulins) is not currently

Patients with AIDS and CMV disease, such as retinitis

Treatment algorithm overview

infection in transplant recipient: no

with pneumonitis, 1st intravenous ganciclovir

adjunct step down to oral valganciclovir

2nd intravenous foscarnet

without pneumonitis, 1st oral valganciclovir

2nd intravenous ganciclovir

3rd intravenous foscarnet

infection in patient with AIDS: no