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Received: 2 February 2019    Accepted: 11 February 2019

DOI: 10.1111/ctr.13512

S P E C I A L I S S U E ‐T R A N S P L A N T I N F E C T I O U S D I S E A S E S

Cytomegalovirus in solid organ transplant recipients—

Guidelines of the American Society of Transplantation
Infectious Diseases Community of Practice

Raymund R. Razonable1 | Atul Humar2,3

1
Mayo Clinic, Rochester, Minnesota
2 Abstract
University Health Network, Toronto,
Ontario, Canada Cytomegalovirus (CMV) is one of the most common opportunistic infections that af‐
3
Transplant Institute, University of Toronto, fect the outcome of solid organ transplantation. This updated guideline from the
Toronto, Ontario, Canada
American Society of Transplantation Infectious Diseases Community of Practice pro‐
Correspondence vides evidence‐based and expert recommendations for screening, diagnosis, preven‐
Raymund R. Razonable, MD, Division of
Infectious Diseases, William J von Liebig
tion, and treatment of CMV in solid organ transplant recipients. CMV serology to
Center for Transplantation and Clinical detect immunoglobulin G remains as the standard method for pretransplant screen‐
Regeneration, Mayo Clinic, Rochester, MN.
Email: [email protected]
ing of donors and transplant candidates. Antiviral prophylaxis and preemptive ther‐
apy are the mainstays of CMV prevention. The lack of a widely applicable viral load
threshold for diagnosis and preemptive therapy is highlighted, as a result of variability
of CMV nucleic acid testing, even in the contemporary era when calibrators are
standardized. Valganciclovir and intravenous ganciclovir remain as drugs of choice
for CMV management. Strategies for managing drug‐resistant CMV infection are
presented. There is an increasing use of CMV‐specific cell‐mediated immune assays
to stratify the risk of CMV infection after solid organ transplantation, but their role in
optimizing CMV prevention and treatment efforts has yet to be demonstrated.
Specific issues related to pediatric transplant recipients are discussed.

KEYWORDS
cidofovir, cytomegalovirus, foscarnet, transplantation, valganciclovir

1  | E TI O LO G Y serves as reservoir for reactivation and transmission to susceptible

individuals, such as solid organ transplant (SOT) recipients.3
Cytomegalovirus (CMV) is a ubiquitous β‐herpesvirus that infects Cytomegalovirus is an important cause of morbidity and mortal‐
the majority of humans. In the Unites States, the overall CMV sero‐ ity after SOT.3 Accordingly, major efforts are exerted for CMV pre‐
prevalence rate is 50%, although this rate varies depending on age, vention, diagnosis, and treatment. This updated guideline from the
1,2
geography, and socioeconomic status. Outside the Unites States, American Society of Transplantation Infectious Diseases Community
the CMV seroprevalence rate has been reported between 30% and of Practice provides current evidence‐based and expert recommen‐
97%.1,2 Primary CMV infection may be asymptomatic or manifests dations for screening, diagnosis, prevention, and treatment of CMV
as a self‐limited febrile illness in immunocompetent individuals. in SOT recipients, with a section on specific issues that are unique to
After primary infection, CMV persists as a latent virus, which then pediatric transplant recipients.

Clinical Transplantation. 2019;e13512. clinicaltransplantation.com © 2019 John Wiley & Sons A/S.  |  1 of 23
https://doi.org/10.1111/ctr.13512 Published by John Wiley & Sons Ltd
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2  | E PI D E M I O LO G Y, C LI N I C A L deficiency in global (nonspecific) and/or CMV‐specific immunity. 27,28

M A N I FE S TATI O N S , A N D D E FI N ITI O N S In clinical practice, pretransplant CMV serology is the most com‐
monly recommended measure of CMV‐specific immunity. Based on
Without a prevention strategy, CMV infection and disease typically the results of CMV serology in transplant candidates and prospec‐
occurs during the first 3 months after SOT; this onset is delayed tive donors, the risk category of post‐transplant CMV disease is de‐
among patients receiving anti‐CMV prophylaxis (see “postprophy‐ fined. The risk of CMV disease is highest in CMV‐seronegative SOT
laxis” delayed‐onset CMV disease, discussed below).3‐9 recipient without preexisting CMV‐specific immunity who receives a
Consensus statements recommend the use of standardized latently infected organ from a CMV‐seropositive donor (D+/R−). 27‐30
definitions of CMV infection and disease in transplant recipients On the other hand, CMV‐seropositive (CMV R+) SOT recipients are
10,11
(Table 1). While these consensus definitions are intended to en‐ at a moderate risk of CMV infection and disease due to presence
sure uniformity of reporting in clinical research,10 the terminologies of preexisting CMV‐specific immunity.31 Among CMV R+ SOT re‐
should also facilitate communication between providers in the clini‐ cipients, the risk of CMV infection is higher when the donor is also
cal setting. The following definitions are recommended: CMV‐seropositive (D+/R+) when compared to CMV‐seronegative
donor (D−/R+), likely due to superinfection with donor‐transmitted
• CMV infection: presence of CMV replication in tissue, blood, or CMV. A CMV‐seronegative recipient who receives organ from CMV‐
other bodily fluids regardless of symptomatology (this term is seronegative donor (D−/R−) has the lowest risk of CMV disease.
different, and should be distinguished, from “latent CMV”). CMV Several assays are available to assess the presence of CMV‐specific
replication is detected by (a) nucleic acid testing (NAT), (b) anti‐ T cells, but their use during the pretransplant period to guide the
gen testing, and (c) viral culture. Depending on the method used, risk of post‐transplant CMV disease risk is very limited and remains
CMV replication in the blood can be termed as CMV DNAemia investigational.32
or RNAemia (NAT), CMV antigenemia (antigen testing), and CMV Drug‐induced immunosuppression, which depletes the quan‐
10
viremia (culture). tity (ie, severe lymphopenia) and paralyzes the function of T cells
• CMV disease: CMV infection that is accompanied by clinical signs (ie, lymphocyte anergy), increases the risk of CMV after SOT.33,34
and symptoms. CMV disease is categorized into (a) CMV syn‐ In particular, use of lymphocyte‐depleting agents (anti‐thymocyte
drome, which typically manifests as fever, malaise, atypical lym‐ globulins and alemtuzumab),35,36 or high doses of maintenance im‐
phocytosis, leukopenia or neutropenia, thrombocytopenia, and munosuppressive drugs, increases the risk of CMV.31,37 The use of
elevated hepatic transaminases, and (b) end‐organ CMV disease mTOR inhibitors (such as sirolimus and everolimus), in contrast, has
(eg, gastrointestinal disease, pneumonitis, hepatitis, nephritis, been associated with a lower risk of CMV.38‐40 Collectively, the net
myocarditis, pancreatitis, encephalitis, retinitis, others) (Table 1). functional defect of the combination of induction and maintenance
13
CMV has a predilection to invade the transplanted allograft ; immunosuppressive drugs influences the overall risk of CMV after
hence, CMV more commonly causes hepatitis in liver recipients, SOT.
nephritis in kidney recipients, or pneumonitis in lung recipients. Allograft rejection is a major risk factor for CMV, especially when
The consensus definitions for these CMV diseases were recently treated with lymphocyte‐depleting antibodies.41 The risk of CMV
published.10 disease also varies by transplant type; lung, 25,42,43 vascularized com‐
• Asymptomatic CMV infection: CMV replication without clinical posite allograft tissue,44‐46 and small intestinal47‐49 transplant recip‐
10
signs and symptoms of disease. ients are at highest risk among SOT populations.

CMV has several indirect effects resulting in part from its ability
3.1 | Specific recommendations for pretransplant
to modulate the immune system. CMV has been associated with in‐
assessment of CMV risk after transplant
creased risk of other infectious complications such as bacteremia,14,15
invasive fungal diseases,16 and Epstein‐Barr virus‐mediated post‐trans‐ • All organ donors and transplant candidates should be tested for
17
plant lymphoproliferative disorders. CMV infection is associated with baseline CMV immune status using CMV‐IgG serology prior to
acute rejection and chronic allograft injury, including chronic allograft transplantation (strong, high).
nephropathy (in kidney recipients),18‐21 bronchiolitis obliterans (in lung • The combined interpretation of CMV‐IgG serology in the
recipients),22 and coronary vasculopathy (in heart recipients).23,24 A organ donor and transplant recipient should be used to cat‐
significant association between CMV infection and a decrease in pa‐ egorize post‐transplant CMV risk and guide CMV prevention
tient survival is well described in many (but not all) studies.19,25,26 strategies (strong, high). CMV‐seronegative recipients who
receive an organ from CMV‐seropositive donor (D+/R−) are
at highest risk of CMV disease after transplantation (strong,
3  | R I S K FAC TO R S A N D S TR ATI FI C ATI O N high).
▪ Transplant candidates who are CMV‐seronegative during the
The major risk factor that predisposes to the development of initial pretransplant evaluation should have repeat CMV serol‐
CMV disease after SOT is a qualitative (functional) or quantitative ogy immediately prior to transplantation (strong, low).
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TA B L E 1   Consensus definitions of cytomegalovirus infection and disease

Proven or definite Probable

CMV syndrome Not defined Detection of CMV in the blood by viral isolation, rapid culture,
antigenemia, or QNAT
Plus, at least two of the following:
1. Fever ≥38°C for at least 2 d
2. New or increased malaise or fatigue
3. Leukopenia or neutropenia on 2 separate measurements
4. 5% atypical lymphocytes
5. Thrombocytopenia
6. Hepatic aminotransferases increase to two times ULN
(except non‐liver transplant recipients)
Gastrointestinal Presence of upper and/or lower GI symptoms plus Presence of upper and/or lower GI symptoms and CMV
CMV disease macroscopic mucosal lesions plus CMV documented in documented in tissue but without macroscopic mucosal
tissue by histopathology, virus isolation, rapid culture, lesions
immunohistochemistry, or DNA hybridization CMV documented in blood by NAT or antigenemia alone is not
techniques sufficient for diagnosis of CMV GI disease
CMV pneumonia Clinical symptoms and/or signs of pneumonia such as Clinical symptoms and/or signs of pneumonia such as new
new infiltrates on imaging, hypoxia, tachypnea, and/or infiltrates on imaging, hypoxia, tachypnea, and/or dyspnea
dyspnea combined with CMV documented in lung tissue combined with detection of CMV by viral isolation and rapid
by virus isolation, rapid culture, histopathology, culture of BALF, or quantitation of CMV DNA in BALF
immunohistochemistry, or DNA hybridization
techniques
CMV hepatitis Abnormal liver tests plus CMV documented in liver tissue Not defined
by histopathology, immunohistochemistry, virus
isolation, rapid culture, or DNA hybridization techniques
plus the absence of other documented cause of
hepatitis
CMV retinitis Typical ophthalmological signs as assessed by an Not defined
ophthalmologist experienced with the diagnosis of CMV
retinitis
If the presentation is atypical or an experienced
ophthalmologist is not available, the diagnosis should be
supported by CMV documented in vitreous fluid by NAT
CMV encephalitis CNS symptoms plus detection of CMV in CNS tissue by CNS symptoms plus detection of CMV in CSF without visible
virus isolation, rapid culture, immunohistochemical contamination of blood (“bloody tap”) plus abnormal imaging
analysis, in situ hybridization, or quantitative NAT results
Refractory CMV CMV DNAemia or antigenemia increases (ie, >1 log10 Viral load persistence (at the same level or higher than the
infection increase in CMV DNA levels in blood between peak viral peak viral load within 1 wk but <1 log10 increase in CMV
load within the first week and the peak viral load at 2 wk DNA titers) after at least 2 wk of appropriately dosed
or more) after at least 2 wk of appropriately dosed antiviral therapy
antiviral therapy
Refractory CMV Worsening in signs and symptoms or progression into Lack of improvement in clinical signs and symptoms after at
disease end‐organ disease after at least 2 wk of appropriately least 2 wk of appropriately dosed antiviral therapy
dosed antiviral therapy
Resistant CMV Presence of viral genetic alteration that confer reduced
susceptibility to one or more antiviral drugs

BALF, bronchoalveolar lavage fluid; CMV, cytomegalovirus; CNS, central nervous system; NAT, nucleic acid amplification test; QNAT, quantitative NAT;
ULN, upper limit of normal.
References (Ljungman et al and Chemaly et al).10,12

• A serologic assay that measures CMV‐IgG is recommended recipient is miscategorized as CMV D+/R+ instead of D+/R−),
(strong, high). and resulting in severe clinical consequences.
▪ Unless clinically indicated (ie, if primary CMV infection is • Recent blood transfusion or receipt of immunoglobulins and
suspected), CMV‐IgM is not routinely recommended due to other blood products should be considered in the interpretation
potential for false‐positivity (strong, low). CMV‐IgM false‐ of CMV serology, as they may cause false‐positive results due
positivity may lead to erroneous assignment of risk profile (eg, to passive transfer of CMV antibodies (strong, low). The clinical
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consequences for miscategorizing D+/R− as a D+/R+ due to false‐ reactivation in CMV R+ SOT recipients.57,58 Higher viral load values
positive results can be severe. in blood are also generally associated with end‐organ disease, while
• For organ donors and transplant candidates with borderline or lower values are seen with asymptomatic CMV infection, and inter‐
indeterminate CMV‐IgG serology results, the assignment of base‐ mediate‐range viral loads are seen with CMV syndrome, although
line serologic status should consider the “highest‐risk” scenario there is overlap in viral load values among categories.52,57‐59 A sig‐
for CMV prevention purposes (strong, low). nificant correlation between end‐organ CMV disease and CMV
▪ If a donor CMV‐IgG serology is borderline or indeterminate, it QNAT in blood has been observed during primary gastrointestinal
should be considered as positive (strong, low). CMV disease in CMV D+/R− SOT recipients. However, the sensitiv‐
▪ If the recipient CMV‐IgG is borderline or indeterminate, the ity of CMV QNAT in blood is lower among CMV R+ patients with
60,61
result should be considered in the context of donor serology, gastrointestinal CMV disease ; this suggests that CMV QNAT
as described below (strong, low). in blood may not be able to detect compartmentalized CMV cases
o If donor CMV serology is positive, the recipient with border‐ (such as CMV retinitis and some cases of gastrointestinal CMV dis‐
line or indeterminate CMV‐IgG will be considered CMV‐sero‐ ease without systemic dissemination).60,61 CMV QNAT has also been
negative (ie, CMV D+/R−) (strong, low). used to quantify viral load in other body fluids such as bronchoalve‐
o If donor CMV serology is negative, the recipient with border‐ olar fluid (BALF) and cerebrospinal fluid (CSF).43 Detection of CMV
line or indeterminate CMV‐IgG will be considered CMV‐sero‐ DNA in CSF suggests probable CNS disease.10 CMV QNAT in BALF
positive (strong, low). may serve as a less invasive method for diagnosis of probable CMV
• CMV‐specific T‐cell immune responses may be assessed in trans‐ pneumonia, particularly when risk of performing transbronchial bi‐
plant candidates prior to transplantation to determine baseline opsy is prohibitive.10,43 Higher viral load in BALF was correlated with
CMV immune status (weak, low), but the role of CMV‐specific T‐ biopsy‐proven CMV pneumonia when compared to asymptomatic
cell assay as a predictor of the risk of CMV after transplantation shedding, although BALF viral load values reported among different
remains under clinical investigation. studies are highly variable.10,43 Hence, further research is needed
to standardize bronchoscopy procedures and CMV QNAT values in
BALF.
4  | L A B O R ATO RY D I AG N OS I S The major drawback to CMV QNAT is the lack of widely applica‐
ble thresholds for various clinical indications. While the implemen‐
The laboratory methods for the detection of CMV after SOT are (a) tation of WHO International Standard for calibration has markedly
molecular assays, (b) antigenemia, (c) histopathology, and (d) culture. improved the degree of agreement in viral load values among var‐
Measures to detect immune response to CMV after SOT are serol‐ ious assays,51 there remains clinically significant variability in viral
ogy and CMV‐specific T‐cell assays (various platforms are available). load values reported for the same sample when it is tested by dif‐
ferent CMV QNAT assays.63 Accordingly, viral load results of one
assay cannot be directly extrapolated as equal to that of another
4.1 | Molecular assays
assay.63 Factors that account for viral load variability among WHO‐
Molecular tests that detect CMV DNA or RNA (collectively termed calibrated assays are differences in assay platform,63 clinical samples
NAT) are the preferred methods for detection of CMV replication (plasma or whole blood),57 gene target and amplicon size,63 and ex‐
in clinical specimens, thereby aiding in rapid diagnosis of CMV in‐ traction techniques, among others.64,65 Hence, for CMV surveillance
fection and disease, guiding the initiation and duration of antiviral and monitoring after SOT, one should rely on the use of only a single
50
therapy, and monitoring treatment responses. Detection of CMV CMV QNAT using a similar sample (eg, plasma only or whole blood
RNA is a highly specific indicator of CMV replication (although there only). Moreover, because viral load results vary among different as‐
is currently no commercial assay available), while CMV DNA may or says, it is strongly recommended that each transplant center work
may not always reflect CMV replication since a highly sensitive NAT with their clinical laboratories to define and validate relevant center‐
may simply amplify latent viral DNA (particularly in cell‐containing specific and assay‐specific viral load thresholds for various clinical
samples). For assays that detect and amplify DNA, a quantitative applications.59
NAT (QNAT) assay is preferred over qualitative assay. CMV QNAT
may differentiate CMV replication (associated with high viral load)
4.2 | Antigenemia
from latent virus (low‐level CMV DNAemia).50,51 The kinetics of viral
replication, as measured by the rate of increase in viral load, is an The use of pp65 antigenemia assay, a semiquantitative assay that de‐
equally important marker of CMV disease risk52‐54; the faster the rise tects pp65 antigen in CMV‐infected peripheral blood leukocytes, has
in CMV viral load, the higher the risk of CMV disease.53,54 significantly declined as it has been replaced in most centers by mo‐
Plasma and whole blood are used as clinical samples for detection lecular assays.50 Studies have shown that pp65 antigenemia is compa‐
of CMV DNA by QNAT; higher viral load values are detected in whole rable to CMV NAT in guiding preemptive therapy, in rapid and sensitive
blood compared to plasma.55‐57 Higher viral loads are also generally diagnosis of CMV disease, and in guiding treatment responses.66,67 The
observed during primary CMV disease in CMV D+/R− compared to main disadvantages of antigenemia are the need to process the clinical
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sample within few hours (due to short lifespan of neutrophils) and the CMV risk stratification and management after SOT.74,75 Nonspecific
lack of assay standardization across centers. Since the test relies on leu‐ measures such as absolute lymphocyte count, CD4+ T‐cell count,
kocytes, it has limited utility in SOT patients with leukopenia.50 and nonspecific (mitogen) T‐cell immune responses have been cor‐
related with the risk of CMV disease after SOT. 27,34,76 In addition,
several platforms are available to assess CMV‐specific T‐cell re‐
4.3 | Histopathology
sponses, including interferon‐gamma release assays (IGRA), 27,75 en‐
Histopathology remains as the gold standard for the definitive diag‐ zyme‐linked immunosorbent spot (ELISPOT) assays,77,78 intracellular
nosis of end‐organ CMV diseases (with the exception of CMV retini‐ cytokine staining (ICS) for interferon‐gamma (or other cytokines)
tis, where ophthalmologic examination by expert ophthalmologist is using flow cytometry,80,81 and major histocompatibility complex
sufficient; Table 1).10 An invasive procedure is required to obtain tis‐ (MHC)‐multimer‐based assays that directly stain peptide‐specific
sue samples for CMV diagnosis. Hence, its use has declined in recent T cells.34 Numerous studies, often single‐center and observational,
years due to the availability of less invasive tests to demonstrate have highlighted the potential role of immune assays in CMV risk
CMV replication in the blood60,61 or other bodily fluids such as CSF assessment. 27,34,75,83 In general, regardless of the assay that is used,
and BALF.43 Histopathology is strongly recommended when another the absence of adequate CMV‐specific CD4+ and/or CD8+ T‐cell
concomitant pathology (eg, acute allograft rejection) or copathogens immunity correlates with a higher risk of CMV disease, treatment
are suspected, especially when patients do not adequately respond failure, and CMV relapse.
to anti‐CMV treatment. Histopathology may be needed when CMV
disease is suspected but CMV QNAT in blood is negative, such as in
4.6.1 | Specific recommendations for laboratory
some cases of compartmentalized gastrointestinal CMV disease.60,61
diagnosis of CMV in SOT recipients
Repeat histopathology to document clearance of CMV infection
from the affected organ, such as gastrointestinal tract, is not neces‐ • CMV QNAT is the laboratory method of choice for rapid diagnosis
sary in most cases, unless there is severe tissue involvement at the of CMV infection in blood after SOT (strong, high). CMV QNAT is
time of initial diagnosis.61 the preferred laboratory method for CMV surveillance to guide
preemptive therapy (strong, high). See the Preemptive Therapy
section for specific details.
4.4 | Viral culture
▪ pp65 antigenemia is an alternative laboratory method for sur‐
While it is highly specific for the diagnosis of CMV infection, the use veillance and diagnosis of CMV infection after SOT (strong,
of viral culture has markedly declined due to poor sensitivity and high).
slow turnaround time, compared to the more sensitive and rapid mo‐ • CMV QNAT assays should be calibrated using the WHO
50
lecular tests. Viral culture of urine is of low clinical utility in adult International Reference Standard (strong, high).
CMV R+ SOT patients since urinary viral shedding is common (see its ▪ Studies should report CMV viral load in IU/ml using QNAT
use in pediatrics below).32,50,68 The clinical utility of viral culture for assays that have been calibrated to the WHO International
phenotypic antiviral drug resistance testing has been supplanted by Reference Standard (strong, high).
genotypic assays that provide a more rapid method of detecting mu‐ ▪ Even if viral loads are reported in IU/ml, the viral load values
tations that confer resistance to antiviral drugs (see the Refractory are not similar among CMV QNAT assays, and should not be
and Resistant CMV section below).69,70 interpreted interchangeably during clinical care (strong, high).
• Transplant centers are encouraged to derive specific viral load
thresholds depending on the CMV QNAT assay they use and the
4.5 | CMV serology
population at risk (strong, high).
Due to immunosuppression, SOT recipients have impaired ability to ▪ CMV QNAT for surveillance and diagnosis should be per‐
mount a robust antibody response.73 Accordingly, CMV seroconver‐ formed using the same assay (strong, high). In reporting viral
sion has a limited utility (and is not recommended) for the diagnosis of load values, the name of the CMV QNAT assay should be
CMV disease after SOT. CMV serology may be used after SOT to deter‐ specified (strong, high).
mine ongoing susceptibility among CMV‐seronegative SOT recipients, • Whole blood and plasma are the recommended clinical samples
although its predictive ability is only modest.73 In interpreting CMV for the detection of CMV replication by QNAT in the peripheral
serology results after SOT, one should consider potential false‐posi‐ blood (strong, high).
tive results from passively transferred antibodies among patients who ▪ CMV viral load is higher in whole blood than in plasma. CMV
received blood products (including IVIg) during or after transplantation. monitoring should only use one sample type (plasma only or
whole blood only) (strong, high).
▪ CMV QNAT in BAL fluid may be used for the diagnosis of
4.6 | Cellular immunity assays
probable CMV pneumonia, but the viral load threshold to sug‐
Immune monitoring to measure nonspecific and CMV‐specific T‐cell gest end‐organ lung disease vs asymptomatic shedding needs
quantity and/or function is emerging as a clinical tool to assist in to be defined (weak, low).
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▪ CMV QNAT of CSF may be used for the diagnosis of probable strategies for CMV disease prevention after SOT are (a) antiviral
central nervous system CMV disease (strong, high). prophylaxis and (b) preemptive therapy (Table 2). Antiviral prophy‐
▪ CMV QNAT of urine sample should not be used for diagnosis laxis entails the administration of an antiviral drug to all “at‐risk” pa‐
and surveillance in adult CMV R+ SOT recipients (strong, low). tients for a defined period of time after SOT. In contrast, preemptive
• The diagnosis of CMV syndrome should be supported by the therapy is the administration of antiviral drug only to asymptomatic
demonstration of CMV by QNAT in whole blood or plasma patients with evidence of early subclinical CMV replication, as meas‐
(strong, high). ured by CMV QNAT, with the aim of halting its progression to CMV
▪ CMV QNAT of whole blood or plasma may also be used as disease. While most transplant centers employ either one of these
a surrogate method for the diagnosis of probable end‐organ two major strategies for CMV prevention, others have used a hy‐
CMV disease, when the risk of performing invasive procedure brid approach wherein antiviral prophylaxis (of varying duration) is
such as biopsy is prohibitive (strong, moderate). followed by CMV surveillance and preemptive therapy during the
▪ A negative CMV QNAT in the blood does not completely period of CMV risk.84,85 Table 3 lists the antiviral drugs for preven‐
rule out the presence of end‐organ CMV disease, particularly tion and treatment.
among CMV R+ SOT recipients with gastrointestinal disease Antiviral prophylaxis and preemptive therapy have their specific
(strong, moderate). advantages and disadvantages (Table 2). There are only a limited
• The diagnosis of most end‐organ CMV diseases should be con‐ number of clinical trials that have directly compared preemptive
firmed by histopathology (strong, high). Histopathology with or therapy and antiviral prophylaxis. 20,21,86,87 These few small‐scale
without immunohistochemical staining remains as the standard studies, which were performed mainly in kidney recipients, demon‐
method for definitive diagnosis of most end‐organ CMV diseases strate that both strategies are similarly effective for CMV disease
(strong, high). prevention, even in CMV D+/R− patients. A recently concluded ran‐
▪ Patients suspected to have end‐organ CMV disease but with domized controlled clinical trial in 205 CMV D+/R− liver recipients
negative QNAT in blood or negative pp65 antigenemia should demonstrated that the incidence of CMV disease at one year was
have tissue biopsy and histopathology to confirm the clinical significantly lower among patients who were managed with CMV
suspicion of CMV disease (strong, moderate). DNA surveillance and preemptive therapy compared to antiviral pro‐
▪ Histopathology is not necessary for the diagnosis of CMV phylaxis for 3 months (9% vs 19%).88 Indirect outcomes, including the
retinitis. A detailed ophthalmologic examination by expert incidence of opportunistic infection, rejection, and all‐cause mortal‐
ophthalmologist is sufficient (strong, high). Only in atypical ity, were not significantly different between antiviral prophylaxis and
cases, the demonstration of CMV by NAT in vitreous fluid is preemptive therapy.88 The specific recommendations for CMV pre‐
suggested (strong, high). vention among SOT populations are summarized in Table 4.
• Viral culture of blood and urine has limited clinical utility for pre‐
diction, diagnosis, and management of CMV disease in adult SOT
5.1 | Antiviral prophylaxis
patients and is not recommended in routine practice (strong,
high). The antiviral drugs for CMV prophylaxis are valganciclovir and in‐
• CMV‐IgM and ‐IgG serology should not be used for the diagnosis travenous ganciclovir.5 Oral ganciclovir is no longer commercially
of CMV disease after SOT (strong, high). available.6 For kidney recipients, high‐dose valacyclovir is an alter‐
• Immunologic monitoring after SOT may be used to stratify the risk native.7 Letermovir, a novel viral terminase inhibitor, was recently
of CMV disease. approved for CMV prophylaxis after allogeneic hematopoietic stem
▪ Absolute lymphocyte count and CD4+/CD8+ T‐cell subsets cell transplantation,89 but this is not approved for use in SOT re‐
may be used to stratify the risk of CMV disease after SOT, cipients. A randomized controlled clinical trial comparing letermovir
but specific lymphocyte thresholds will need to be clinically and valganciclovir is ongoing for the prevention of CMV in CMV D+/
validated (weak, low). R− kidney recipients (ClinicalTrials.gov NCT03443869). In selected
▪ Hypogammaglobulinemia is associated with CMV disease, and patient populations (eg, heart and lung and intestinal transplant re‐
measurement of total immunoglobulin G levels may be used to cipients), immunoglobulin preparations are occasionally used as an
assess the risk (weak, low). adjunct in combination with antiviral drugs. Acyclovir should not be
▪ Measures of global (nonspecific) and CMV‐specific CD8+ and/ used for anti‐CMV prophylaxis.
or CD4+ T cells may be used to stratify the risk of CMV dis‐ The efficacy of ganciclovir, valganciclovir, and valacyclovir
ease after SOT (strong, moderate). prophylaxis was demonstrated in clinical trials. 5,6 In a randomized
clinical trial of 372 CMV D+/R− kidney, liver, pancreas, and heart
recipients, CMV disease rate was comparable between patients
5  | PR E V E NTI O N O F C M V D I S E A S E who received 3 months of oral ganciclovir vs valganciclovir pro‐
phylaxis (17.2% valganciclovir vs 18.4% ganciclovir at 12 months). 5
The approaches to CMV prevention in SOT recipients vary among In subgroup analysis, there was a higher incidence of end‐organ
different transplant populations and risk profiles. The two major CMV disease among liver recipients who received valganciclovir
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TA B L E 2   Characteristics of antiviral prophylaxis and preemptive therapy

Antiviral prophylaxis Preemptive therapy

Clinical efficacy Yes (based on large randomized controlled clinical trials) Yes (based on fewer and smaller trials), including D+/
R− kidney and liver recipients
Ease of application Easier to coordinate More difficult to coordinate
Viral load thresholds not defined; each program should
develop viral load thresholds for various clinical
indications
Delayed‐onset CMV Common in CMV D+/R− transplant recipients (post‐ Less common
disease prophylaxis delayed‐onset CMV disease)
Cost Higher drug costs Higher laboratory costs
Toxicity Greater drug toxicity (myelosuppression) Lesser drug toxicity with shorter courses of antiviral
therapy
Indirect effects (graft Positive impact (meta‐analyses and limited comparative Very limited data
loss, mortality, and trials)
opportunistic
infections)
Drug resistance Yes Yes

Risks and benefits may help guide the choice for CMV prevention after solid organ transplantation.

prophylaxis. 5 Hence, valganciclovir was not approved by US FDA The efficacy of prophylaxis with either CMV immunoglobulin or
for CMV prophylaxis after liver transplantation. The improved intravenous immune globulin in SOT recipients was suggested in a
bioavailability of valganciclovir and its lower pill burden make it few trials.96,97 A pooled analysis of previous studies suggests that
90
the preferred drug for CMV prophylaxis, even in liver recipients. the addition of immunoglobulin preparations to antiviral prophylaxis
The recommend dose of valganciclovir prophylaxis is 900 mg once may reduce severe CMV disease and mortality,98 but this finding has
8
daily (for patients with normal renal function). Because of the risk been debated.99
of leukopenia, some transplant centers use “mini‐dose” valganci‐
clovir prophylaxis (450 mg orally),91 but this has been shown to be
5.1.1 | Postprophylaxis delayed‐onset CMV disease
associated with the emergence of drug‐resistant CMV, especially
for CMV D+/R− patients.92 Despite extending antiviral prophylaxis to 6 months after kid‐
Because of postprophylaxis delayed‐onset CMV disease, which oc‐ ney transplantation or 12 months after lung transplantation, CMV
curs most commonly during the first 3‐6 months after completion of disease commonly occurs in CMV D+/R− SOT recipients during
antiviral prophylaxis in CMV D+/R− patients,5 a randomized clinical trial 3‐6 months after completion of antiviral prophylaxis. The term
was performed to assess the efficacy of extended (200 days) valganci‐ “postprophylaxis delayed‐onset CMV disease” has been suggested
8
clovir prophylaxis. In this study of 318 CMV D+/R− kidney recipients, to distinguish this entity from the truly late‐onset CMV diseases that
the incidence of CMV disease was reduced to 16.1% with 200 days occur many years after transplantation.4 In contrast to the truly late‐
8
compared to 36.8% with 100 days of valganciclovir prophylaxis. onset CMV disease, the risk factors for postprophylaxis delayed‐
Similar studies to assess the duration of prophylaxis in liver, heart, and onset CMV disease are predictably similar to the “traditional‐onset”
pancreas recipients have not been performed, although some trans‐ CMV, such as D+/R− status, allograft rejection, severe lymphopenia,
plant centers have extrapolated these kidney‐specific trial results in the and intense immunosuppression.4,34 Because postprophylaxis de‐
prevention of CMV disease in liver, heart, and pancreas recipients. layed‐onset CMV disease remains associated with poor long‐term
Among SOT populations, lung,25,42,43 intestinal,47,48 and vascular‐ outcome, there have been numerous efforts to develop strategies
44,45
ized composite tissue allograft recipients are at highest risk of for its prevention and treatment, as follows:
CMV infection and disease. There are no randomized clinical trials to
assess the optimal duration of antiviral prophylaxis in these patients. • Close clinical follow‐up with early treatment of CMV disease when
Among lung recipients, the rates of CMV infection and disease are high symptoms occur. SOT recipients (especially CMV D+/R−) should be
93
with <6 months of antiviral prophylaxis. The rates of CMV infection advised of the heightened risk of CMV disease within 3‐6 months
and disease were significantly reduced when antiviral prophylaxis is after discontinuation of antiviral prophylaxis and that they should
given for at least 6 months.94 In a multicenter randomized clinical trial, immediately seek medical assistance when signs and symptoms
CMV D+/R− and CMV D+/R+ lung recipients who received 12 months of CMV disease occur. Clinicians should have a low threshold for
of valganciclovir prophylaxis had significantly lower rates of CMV considering CMV disease as a diagnosis in SOT patients present‐
disease and infection (4% and 10%) compared to those who received ing with compatible signs and symptoms after cessation of antivi‐
3 months of valganciclovir prophylaxis (34% and 64%).42,95 ral prophylaxis.
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TA B L E 3   Antiviral drugs for

Drug Treatmenta  Prophylaxis Comments on use and toxicity
cytomegalovirus prevention and
Valganciclovir 900 mgb  po 900 mgb  po Ease of administration treatment in solid organ transplant
twice daily once daily Leukopenia is major toxicity recipients
IV ganciclovir 5 mg/kg IV 5 mg/kg IV Intravenous access and its associated
every 12 h once daily complications
Leukopenia is major toxicity
Valacyclovir NOT 2 g po four For kidney transplant recipients only
recommended times daily NOT recommended for heart, liver,
pancreas, lung, intestinal, and
composite tissue transplant recipients
High pill burden
Neurotoxicity
NOT recommended for treatment of
CMV disease or asymptomatic
infection
Foscarnet 60 mg/kg IV NOT Second‐line alternative agent for
every 8 h (or recom‐ treatment
90 mg/kg mended Highly nephrotoxic
every 12 h) Used for UL97‐mutant ganciclovir‐re‐
sistant CMV infection or disease
NOT recommended for preemptive
therapy
Cidofovir 5 mg/kg once NOT Third‐line agent
weekly ×2, recom‐ Highly nephrotoxic
then every mended May be used for UL97‐mutant
2 wk ganciclovir‐resistant CMV infection
thereafter or disease
NOT recommended for preemptive
therapy

Intravenous or CMV‐specific immunoglobulin has been used by some centers as an adjunct to anti‐
viral prophylaxis, especially in heart, lung, and intestinal transplant recipients. The efficacy of this
approach is debated. The doses of the antiviral drugs are for adults and should be adjusted based on
renal function.
a
These treatment doses are also recommended for preemptive therapy of asymptomatic CMV repli‐
cation. Foscarnet, valacyclovir, oral ganciclovir, and cidofovir are not recommended for preemptive
therapy. Letermovir is not approved for prevention and treatment of CMV in solid organ transplant
recipients.
b
Pediatric valganciclovir Dose is mg = 7 × BSA × Creatinine clearance.

• Viral surveillance after completion of antiviral prophylaxis. Patients completed antiviral prophylaxis may be tested for nonspecific
who completed antiviral prophylaxis may be monitored using CMV and CMV‐specific immune recovery to assess their risk of post‐
QNAT periodically for a period of time.84 The optimal duration and prophylaxis delayed‐onset CMV disease. 27,104 CMV serology at
frequency of CMV monitoring are not defined. A few small‐scale the end of antiviral prophylaxis was not highly predictive of sub‐
100
studies indicate that less frequent monitoring (every 2 weeks) and sequent risk.73 In contrast, studies have suggested that lymph‐
101
for short‐term monitoring (up to 2 months only) were not clinically openia (absolute lymphocyte count, CD4+ T‐cell count)33,34 and
helpful in capturing postprophylaxis delayed‐onset CMV disease in lack of CMV‐specific (and nonspecific) T‐cell response27,34 are as‐
CMV D+/R− SOT recipients. However, one study reported no end‐ sociated with an increased risk of postprophylaxis delayed‐onset
organ CMV disease occurred when CMV surveillance was performed CMV disease. However, the immune cell thresholds for protection
once weekly for 3 months after completion of antiviral prophylaxis.102 among various measures are not yet fully defined.
• Further prolongation of antiviral prophylaxis. Some centers have
observed postprophylaxis delayed‐onset CMV disease in CMV
D+/R− lung recipients despite 12 months of antiviral prophylaxis
5.1.2 | CMV after use of lymphocyte‐depleting drug
and have extended the duration of prophylaxis beyond 12 months
for treatment of acute rejection
(sometimes anticipated as lifelong). 25,103 However, this was asso‐
ciated with significant myelotoxicity.103 The use of lymphocyte‐depleting therapy, such as anti‐thymocyte
• Immunologic monitoring at the end of antiviral prophylaxis, and globulin or alemtuzumab, for the treatment of acute cellular re‐
thereafter. Patients who are completing or who have recently jection significantly increases the risk for CMV disease.36,105,106
RAZONABLE ANd HUMAR |
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TA B L E 4   Recommendations for cytomegalovirus prevention in solid organ transplant recipients

Risk Recommendation/Options (see Table 3 for dose and text for special
Organ category pediatric issues) Level of evidence

Kidney D+/R− Antiviral prophylaxis Strong, high

Drugs: valganciclovir (preferred), intravenous ganciclovir, or
valacyclovir
Duration: 6 mo
Preemptive therapy (if logistic support is available) Strong, high
Weekly CMV QNAT (or pp65 antigenemia) for 12 wk after kidney
transplantation, and if a positive CMV threshold is reached, treat with
(a) valganciclovir 900 mgb p.o. BID (preferred), or (b) IV ganciclovir
5 mg/kg IV every 12 h until negative test
R+ Antiviral prophylaxis Strong, high
Drugs: valganciclovir (preferred), intravenous ganciclovir, or
valacyclovir
Duration: 3 mo
Preemptive therapy (if logistic support is available) Strong, high
Weekly CMV QNAT (or pp65 antigenemia) for 12 wk after kidney
transplantation, and if a positive CMV threshold is reached, treat with
(a) valganciclovir 900 mgb  po BID (preferred), or (b) IV ganciclovir
5 mg/kg IV every 12 h until negative test
Pancreas and D+/R− Antiviral prophylaxis is preferred Strong, high (3‐month prophylaxis)
kidney/ Drugs: valganciclovir (preferred) or intravenous ganciclovir Strong, moderate (6‐month
pancreas Duration: 3‐6 mo prophylaxis)
Preemptive therapy is an option (if logistic support is available) Strong, moderate
Weekly CMV QNAT (or pp65 antigenemia) for 12 wk after pancreas
alone or kidney‐pancreas transplantation, and if a positive CMV
threshold is reached, treat with (a) valganciclovir 900 mgb  po BID
(preferred), or (b) IV ganciclovir 5 mg/kg IV every 12 h until negative
test
R+ Antiviral prophylaxis Strong, moderate
Drugs: valganciclovir (preferred) or intravenous ganciclovir
Duration: 3 mo
Preemptive therapy (if logistic support is available). Strong, moderate
Weekly CMV QNAT (or pp65 antigenemia) for 12 wk after pancreas
alone or kidney‐pancreas transplantation, and if a positive CMV
threshold is reached, treat with (a) valganciclovir 900 mgb  po BID
(preferred), or (b) IV ganciclovir 5 mg/kg IV every 12 h until negative
test
Liver D+/R− Antiviral prophylaxis Strong, high (3‐month prophylaxis)
Drugs: valganciclovir (note FDA cautiona ) or intravenous ganciclovir Strong, moderate (6‐month
Duration: 3‐6 mo prophylaxis)
Preemptive therapy (if logistic support is available) Strong, high
Weekly CMV QNAT (or pp65 antigenemia) for 12 wk after liver
transplantation, and if a positive CMV threshold is reached, treat with
(a) valganciclovir 900 mgb  po BID (preferred), or (b) IV ganciclovir
5 mg/kg IV every 12 h until negative test
R+ Antiviral prophylaxis Strong, high
Drugs: valganciclovir (note FDA cautiona ) or intravenous ganciclovir
Duration: 3 mo
Preemptive therapy (if logistic support is available) Strong, high
Weekly CMV QNAT (or pp65 antigenemia) for 12 wk after liver
transplantation, and if a positive CMV threshold is reached, treat with
(a) valganciclovir 900 mgb  po BID (preferred), or (b) IV ganciclovir
5 mg/kg IV every 12 h until negative test

(Continues)
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10 of 23       RAZONABLE ANd HUMAR

TA B L E 4   (Continued)

Risk Recommendation/Options (see Table 3 for dose and text for special
Organ category pediatric issues) Level of evidence

Heart D+/R− Antiviral prophylaxis is preferred. Strong, high (3‐month prophylaxis)

Drugs: valganciclovir (preferred), or intravenous ganciclovir. Some Strong, moderate (6‐month
centers add adjunctive CMV immune globulin. prophylaxis)
Duration: 3‐6 mo Weak, low (immune globulin)
Preemptive therapy is an option (if logistic support is available), but not Weak, low
preferred.
Weekly CMV QNAT (or pp65 antigenemia) for 12 wk after heart
transplantation, and if a positive CMV threshold is reached, treat with
(a) valganciclovir 900 mgb  po BID (preferred), or (b) IV ganciclovir
5 mg/kg IV every 12 h until negative test
R+ Antiviral prophylaxis Strong, moderate
Drugs: valganciclovir (preferred) or intravenous ganciclovir. Some Weak, low (immune globulin)
centers add adjunctive CMV immune globulin.
Duration: 3 mo
Preemptive therapy Strong, moderate
Weekly CMV QNAT (or pp65 antigenemia) for 12 wk after heart
transplantation, and if a positive CMV threshold is reached, treat with
(a) valganciclovir 900 mgb po BID (preferred), or (b) IV ganciclovir
5 mg/kg IV every 12 h until negative test
Lung, D+/R− Antiviral prophylaxis Strong, high (12‐month prophylaxis)
heart‐lung Drugs: valganciclovir or intravenous ganciclovir Strong, low (6‐month prophylaxis)
Duration: at least 6‐12 mo. Weak, low (>12 mo prophylaxis)
Some centers prolong prophylaxis beyond 12 mo. Weak, low (immune globulin)
Some centers add CMV immune globulin.
R+ Antiviral prophylaxis Strong, moderate
Drugs: valganciclovir or intravenous ganciclovir
Duration: 6‐12 mo.
Intestinal D+/R−, R+ Antiviral prophylaxis Strong, low
Drugs: valganciclovir or intravenous ganciclovir
Duration: 3 mo for CMV R+; 6 mo for D+/R−.
Composite D+/R−, R+ Antiviral prophylaxis Strong, low
tissue Drugs: valganciclovir or intravenous ganciclovir
allograft Duration: 3 mo for CMV R+; 6 mo for D+/R−.

The above recommendations do not represent an exclusive course of action. Several factors influence the precise nature and duration of antiviral
prophylaxis or preemptive therapy.Antiviral prophylaxis should be started within 10 d after transplantation (strong, high). Oral ganciclovir is no longer
commercially available. Preemptive therapy is NOT recommended for lung and heart‐lung recipients (strong, low). Preemptive therapy is less preferred
for intestinal and composite tissue allograft transplantation (weak, low).
a
The US FDA has cautioned against valganciclovir prophylaxis in liver recipients due to high rate of tissue‐invasive disease compared to oral ganciclovir.
However, many experts still recommend its use as prophylaxis in liver recipients (strong, moderate). CMV D−/R− SOT recipients do not require anti‐
CMV prophylaxis, but if they are HSV1‐ or HSV2‐seropositive, they should receive anti‐HSV prophylaxis during the early period after transplantation
(strong, high; see separate HSV guidelines). If blood transfusion is required, CMV D−/R− patients should receive CMV‐seronegative or leuko‐reduced
blood products (strong, high).
b
Pediatric valganciclovir Dose is mg = 7 × BSA × Creatinine clearance.

Administration of intravenous ganciclovir prophylaxis was associ‐ ▪ The antiviral drugs that can be used for prophylaxis are listed
ated with lower incidence of CMV disease in kidney recipients re‐ in Table 3.
ceiving anti‐lymphocyte antibodies.105,106 ▪ Specific recommendations for various organ recipients are listed
in Table 4.
• Valganciclovir is the preferred drug for antiviral prophylaxis in
5.1.3 | Specific recommendations for antiviral
adults (level of evidence varies depending on transplant type; see
prophylaxis
Table 4). Alternative drug options for antiviral prophylaxis are intra‐
• Antiviral prophylaxis may be given to any “at‐risk” SOT recipient to venous ganciclovir (which entails the need for vascular access) and,
prevent CMV infection and disease after transplantation (strong, for kidney recipients only, high‐dose valacyclovir (2 g PO qid) (level
high). of evidence varies depending on transplant type; see Table 4).
RAZONABLE ANd HUMAR |
      11 of 23

▪ Despite US FDA caution, valganciclovir is the recommended ▪ CMV serology at the end of antiviral prophylaxis has limited
drug for CMV prophylaxis in liver recipients (strong, high). role in assessing the risk of postprophylaxis delayed‐onset
▪ The use of low‐dose (“mini‐dose”) valganciclovir is not recom‐ CMV disease and is not routinely recommended (weak, low).
mended, particularly in CMV D+/R− SOT recipients (strong, • Antiviral prophylaxis with valganciclovir or intravenous ganciclo‐
high). vir should be given to patients receiving lymphocyte‐depleting
▪ Unselected IVIg and CMV‐Ig may be used, but only as an ad‐ anti‐lymphocyte antibodies for the treatment of rejection (strong,
junct to antiviral therapy in lung, heart, and intestinal trans‐ high).
plant recipients (weak, low). ▪ The optimal duration of antiviral prophylaxis after treatment
• Antiviral prophylaxis should generally be started within the first of rejection with lymphocyte‐depleting drug is not known, but
10 days after transplantation (strong, high). has been given for 1‐3 months (weak, moderate).
• The duration of antiviral prophylaxis varies depending on the
CMV donor and recipient serologies and the transplant types
5.2 | Preemptive therapy
(level of evidence varies depending on serologies and transplant
type; see Table 4). An algorithm for CMV surveillance and preemptive therapy is de‐
▪ CMV D+/R−: Antiviral prophylaxis for 6 months is recom‐ picted in Figure 1. Most studies have performed CMV surveillance
mended for CMV D+/R− kidney recipients (strong, high), at least once weekly after SOT to guide initiation of preemptive
3 months to 6 months for CMV D+/R− heart, liver, and therapy.
pancreas recipients (level of evidence varies; see Table 4), CMV QNAT is the most common method for CMV surveillance
6‐12 months for CMV D+/R− lung recipients (strong, moder‐ to guide the initiation of preemptive therapy, although other centers
ate to high), and 6 months for CMV D+/R− intestinal and com‐ may be using pp65 antigenemia. As discussed above (Laboratory
posite tissue allograft recipients (weak, low). Diagnosis section), there is no widely applicable viral load threshold
▪ CMV R+: Antiviral prophylaxis for 3 months is recommended to guide preemptive therapy.50,59 Hence, site‐specific and assay‐spe‐
for CMV R+ kidney, heart, liver, and pancreas recipients cific viral load threshold values for initiation of preemptive therapy
(strong, high), 6‐12 months for CMV R+ lung recipients (strong, should be locally validated. It is likely that such viral load thresholds
moderate to high), and 3‐6 months for CMV R+ intestinal and may be specific for various risk groups (eg, lower viral load threshold
composite tissue allograft transplant recipients (weak, low). for CMV D+/R− compared to R+ patients) and patient populations
▪ The use of CMV‐specific T‐cell immune measures to guide the (lung vs kidney recipients) and be immunosuppression‐dependent
duration of antiviral prophylaxis has been suggested, but this (lymphocyte‐depleting vs nondepleting regimens). In the absence
remains investigational (weak, low). of absolute viral load threshold to guide preemptive therapy, others
• CMV‐specific prophylaxis is not recommended for CMV D−/R− have suggested viral kinetics as another approach to predicting the
SOT recipients (strong, high). risk of CMV disease and the need for preemptive therapy,54,107,108
▪ HSV1‐ or HSV2‐seropositive CMV D−/R− SOT recipients although this requires more frequent viral load monitoring. There is a
should receive antiviral prophylaxis for prevention of her‐ concern that the rapid viral kinetics in CMV D+/R− SOT patients may
pes simplex infection (eg, acyclovir, valacyclovir, famciclovir) lead to failure to detect CMV replication early despite weekly CMV
(strong, high). Please refer to the HSV guidelines. surveillance, and this may result in CMV disease.53 Those studies
▪ If blood transfusion is indicated, CMV D−/R− should receive were conducted at a time when CMV QNAT results are not avail‐
CMV‐negative blood or leuko‐depleted blood products able same day or in real time.109,110 In the contemporary era when
(strong, high). results of CMV QNAT are available on the same day of testing, this
• For the prevention of postprophylaxis delayed‐onset CMV concern may no longer be valid. Indeed, data from recent studies
disease: conducted in kidney and liver recipients have shown that preemp‐
▪ CMV QNAT at least once weekly for 3 months may be consid‐ tive therapy was effective in preventing CMV disease, even in CMV
ered for surveillance to detect CMV replication after comple‐ D+/R− patients. 21 The results of a recent randomized controlled clin‐
tion of antiviral prophylaxis (strong, low). Detection of CMV ical trial reported a lower incidence of CMV disease among CMV
DNA above a predefined threshold should be preemptively D+/R− liver recipients who had CMV surveillance and preemptive
treated with valganciclovir or intravenous ganciclovir. therapy when compared to antiviral prophylaxis (ClinicalTrials.gov
▪ Transplant recipients should be counseled of the risk of post‐ NCT01552369).88
prophylaxis delayed‐onset CMV disease upon discontinuation Once CMV QNAT or pp65 reaches the predefined viral load
of antiviral prophylaxis (strong, low). Close clinical follow‐up is threshold, treatment with oral valganciclovir (900 mg twice daily)
highly recommended (strong, low). or intravenous ganciclovir (5 mg/kg twice daily) should be initi‐
▪ Measures of lymphopenia (weak, low) and impairment in global ated.107,111 In a clinical trial, viral decay kinetics was similar between
(nonspecific) and CMV‐specific T‐cell responses (strong, mod‐ valganciclovir and intravenous ganciclovir for preemptive treat‐
erate) at the end of antiviral prophylaxis may be used to assess ment of asymptomatic CMV reactivation.111 Since preemptive ther‐
the risk of postprophylaxis delayed‐onset CMV disease. apy should treat low‐level asymptomatic CMV replication, experts
 |
12 of 23       RAZONABLE ANd HUMAR

recommend oral valganciclovir as preferable compared to intrave‐ treated with anti‐lymphocyte antibody (weak, low) or high‐
nous ganciclovir for logistic issues. dose steroids (weak, low).
The duration of preemptive antiviral therapy should be guided • The laboratory test recommended for CMV monitoring to guide
by viral load monitoring. Generally, preemptive antiviral therapy preemptive therapy is CMV QNAT (preferred) or a pp65 antigen‐
is continued until virologic clearance (ie, the virus is no longer de‐ emia assay (strong, high).
tectable by CMV QNAT or has reached levels below a predefined ▪ The recommended monitoring frequency is at least once
viral load threshold). 50 Two consecutive negative weekly CMV weekly and the duration is at least 12 weeks after transplan‐
QNAT was previously suggested (in studies that used less sen‐ tation (strong, high). The duration of CMV QNAT monitoring
sitive CMV QNAT assays), but a single negative test may suffice may be extended longer for patients considered at highly
if using a highly sensitive QNAT. 55,112 One study reported that immune suppressed status, or CMV‐specific T cell‐deficient
CMV QNAT positivity persisted for about a week longer when (strong, low).
monitored by a more sensitive assay,112 or using a more sensitive ▪ There is no widely applicable viral load threshold for initiation
specimen. 55 of preemptive therapy, and this value should be assay‐specific,
The strategy of allowing subclinical CMV replication before center‐specific, and risk‐specific (strong, moderate). Future
preemptive treatment is started may allow for immune priming and studies are needed to define clinically relevant viral load
generation of CMV‐specific T cells; this could account for the low thresholds in IU/ml for the initiation of preemptive therapy.
incidence of delayed‐onset CMV disease (in contrast to antiviral However, these thresholds will likely remain assay‐specific
prophylaxis). Hence, in addition to viral load, CMV immune moni‐ and risk profile‐dependent.
toring has been proposed to guide the need for, and the duration • The recommended antiviral drugs for preemptive therapy are
of, antiviral therapy.75 The presence of functional CMV‐specific T‐ valganciclovir (900 mg twice daily) and intravenous ganciclo‐
cell immunity at the onset of asymptomatic low‐level CMV viremia vir (5 mg/kg every 12 hours), adjusted based on renal function
may indicate potential for spontaneous resolution, without the need (strong, high).
for antiviral therapy.113 On the other hand, the lack of functional • The duration of preemptive antiviral therapy should be individual‐
CMV‐specific T cells at the time of virologic clearance may indicate a ized (strong, high).
heightened risk of CMV relapse.75 The failure to develop functional ▪ CMV QNAT (or pp65 antigenemia) should be performed once
CMV‐specific T cells during CMV replication suggests a highly sup‐ weekly to monitor response to preemptive treatment (strong,
pressed immune system, and the potential need to reduce pharma‐ high).
cologic immunosuppression. ▪ Antiviral therapy should be continued until CMV DNAemia or
antigenemia is no longer detectable or has declined to levels
below a predefined threshold (strong, high). When using less
5.2.1 | Specific recommendations for
sensitive assays, CMV QNAT should be undetectable or below
preemptive therapy
a predefined threshold for at least 2 consecutive weeks in the
• Preemptive therapy may be used for effective prevention of CMV blood prior to stopping antiviral treatment (strong, moderate).
disease in SOT recipients (strong, moderate to high). The duration may be reduced to a single negative result when
▪ Preemptive therapy is clinically useful for the prevention of using a highly sensitive CMV QNAT assay (weak, moderate).
CMV disease in CMV R+ kidney, liver, pancreas, and heart re‐ ▪ There are data supporting the potential role of CMV‐specific
cipients (strong, high). T‐cell immune monitoring to guide the need and the duration
▪ Preemptive therapy is effective for the prevention of CMV of preemptive antiviral therapy (weak, low). However, further
disease in CMV D+/R− liver and kidney patients, as long as research is needed before this can be adapted widely in clini‐
personnel and logistics of close surveillance and follow‐up (ie, cal practice.
CMV QNAT results are available on the same day of testing) • HSV1‐ or HSV2‐seropositive SOT recipients who are undergo‐
are available (strong, high). If these are not available, antiviral ing CMV surveillance, and not actively receiving valganciclovir
prophylaxis is preferred for D+/R− liver and kidney recipients or intravenous ganciclovir, should receive herpes simplex virus‐
(strong, high). targeted antiviral prophylaxis with acyclovir, valacyclovir, or
▪ Preemptive therapy is not recommended for prevention of famciclovir (strong, high). Refer to the HSV guidance for specific
CMV disease in CMV D+/R− and R+ lung (strong, high) and recommendations.
it is less preferred for CMV D+/R− heart recipients (weak,
low). Antiviral prophylaxis is preferred over preemptive ther‐
apy for lung and heart recipients (strong, moderate to high). 6 | TR E ATM E NT O F C M V D I S E A S E
Preemptive therapy is less preferred after intestinal and com‐
posite tissue allograft transplantation (weak, low). The first‐line antiviral drugs for treatment of CMV disease are intra‐
▪ Preemptive therapy may be considered as alternative ap‐ venous ganciclovir and oral valganciclovir (Table 3).114 Foscarnet and
proach to CMV prevention in patients with acute rejection cidofovir are regarded as second‐line agents due to the high risk of
RAZONABLE ANd HUMAR |
      13 of 23

Validate appropriate threshold for

site-specific assay (CMV QNAT [preferred] or Ag)

Select appropriate population (risk profile) to

employ preemptive therapy

Test patients at least once weekly at weeks 1-12

post-transplant; longer duration for highly
immunocompromised hosts

Assay positive at threshold No positive assay or threshold not reached.

(assay and risk profile-dependent) Stop testing at week 12

Start oral valganciclovir (preferred) or IV ganciclovir at

treatment dose

Treat until “negative” threshold achieved

Resume weekly monitoring until week 12 or the

duration of highly-compromised status

F I G U R E 1   Suggested algorithm for preemptive therapy. CMV monitoring may be extended beyond the first 12 wk after transplantation
in patients who remain severely immunocompromised, as assessed by the clinician. A clinically relevant “negative” threshold should be
defined for every CMV quantitative nucleic acid test, depending on its lowest limit of detection and quantitation. This algorithm may be
followed for solid organ transplant recipients who receive lymphocyte‐depleting anti‐lymphocyte antibodies, when CMV surveillance and
preemptive therapy is chosen as the CMV prevention strategy

nephrotoxicity.115 Letermovir has been used off‐label in few cases assess virologic response. CMV relapse is higher among patients with
of SOT recipients with CMV disease, but the drug is not approved detectable CMV viral load at the end of antiviral therapy.118,119,121
116,117
for treatment indication. Because durable control of CMV in‐ Patients with CMV disease should receive full therapeutic dose of
fection relies on a functional immune system, cautious reduction in antiviral therapy until CMV DNAemia or antigenemia has declined
immunosuppression should be considered in SOT patients with CMV to undetectable levels or below a predefined viral load threshold.
disease, especially if the disease is moderate to severe. Accordingly, the duration of antiviral treatment is dependent on the
The efficacy of intravenous ganciclovir for treatment of CMV sensitivity of the assay being used. Theoretically, use of a highly sen‐
disease has been demonstrated in numerous trials.114,118,119 Routine sitive assay may lead to longer treatment duration when compared
measurement of serum ganciclovir levels during ganciclovir treat‐ to less sensitive assays.55 However, one study demonstrated that
ment has not been significantly associated with improved clinical the overall duration of treatment was not significantly different be‐
response.120 Because valganciclovir achieves blood levels that are tween cases monitored by an older less sensitive vs a newer more
comparable to intravenous ganciclovir, it has been used for treat‐ sensitive CMV QNAT.112 The use of CMV‐specific T‐cell immune
ment of mild‐to‐moderate CMV disease. In a randomized clinical monitoring may further guide the duration of antiviral therapy.75
trial that compared 3 weeks of oral valganciclovir to intravenous However, further research in this area is encouraged before this is
ganciclovir for treatment of CMV disease in 321 SOT recipients with widely implemented in clinical practice.
mild‐to‐moderate CMV disease, both drugs had similar efficacy.114 Recurrence of CMV viremia occurs in up to 35% of high‐risk SOT
Notably, many patients remained viremic at day 21 (end of induction recipients with CMV infection and disease.118,119 In an attempt to
treatment), suggesting that longer courses of antiviral therapy are reduce CMV recurrence, some programs provide secondary val‐
needed.114 ganciclovir prophylaxis for 1‐3 months after clinical and virologic
Indeed, the duration of antiviral therapy should be individual‐ response.61,122,123 However, the efficacy of this approach is not
ized based on resolution of clinical symptoms and virologic clear‐ proven. In observational studies, the incidence of CMV relapse was
ance.114,118,119,121 Generally, SOT recipients with CMV disease should not significantly different between patients who did and did not
be monitored once weekly using CMV QNAT or pp65 antigenemia to receive secondary prophylaxis.61,122,123 The risk of CMV relapse
 |
14 of 23       RAZONABLE ANd HUMAR

after treatment of CMV disease may be predicted by persistent threshold or to undetectable level prior to stopping antiviral
118,119,124 33,34
viral load or deficiency in the quantity (lymphopenia) treatment of CMV disease (strong, high). When using less sen‐
and function of T cells.75 Lack of CMV‐specific T‐cell response at sitive assays, CMV QNAT should be undetectable or below the
the time of virologic clearance was associated with higher rate of predefined threshold for at least two consecutive weeks in the
CMV relapse.75 However, the optimal approach to preventing CMV blood prior to stopping antiviral treatment (strong, moderate).
relapse is not defined, but may involve strategies to allow for CMV‐ The duration may be reduced to a single negative result when
specific T‐cell immune reconstitution. using a highly sensitive CMV QNAT assay (weak, moderate).
• Complete blood count (with differential) and serum creatinine
should be monitored once weekly to assess for potential drug
6.1 | Specific recommendations for treatment of
toxicity (strong, high).
CMV disease
▪ Antiviral drug dosing should not be adjusted down due to leu‐
• CMV disease should be treated with intravenous ganciclovir kopenia or pancytopenia (strong, high).
(5 mg/kg every 12 hours) or oral valganciclovir (900 mg twice ▪ Antiviral drug dosing should be adjusted based on renal func‐
daily), adjusted based on renal function (strong, high). tion (strong, high).
▪ Intravenous ganciclovir is the recommended initial treatment • Serum ganciclovir level monitoring (therapeutic drug monitoring)
for severe or life‐threatening CMV disease (strong, high), those is not recommended for routine clinical use (strong, moderate).
with very high viral load (strong, moderate), and those with • After completion of full‐dose antiviral treatment, secondary pro‐
questionable gastrointestinal absorption (strong, moderate). phylaxis intended to prevent CMV relapse is not recommended as
▪ Oral valganciclovir and intravenous ganciclovir are equally a routine practice for all patients (strong, moderate), but may be
effective initial therapy for mild‐to‐moderate CMV disease considered in subsets of high‐risk patients (weak, low).
(strong, high). ▪ Patients should have clinical and virologic follow‐up after dis‐
▪ Because of the risk of nephrotoxicity, foscarnet and cidofovir continuation of antiviral treatment to assess the risk of CMV
are considered second‐line alternative drugs for SOT recipi‐ relapse (strong, moderate).
ents unable to tolerate valganciclovir or intravenous ganciclo‐ ▪ Lymphopenia may be used to assess the risk of CMV relapse
vir (strong, moderate). (weak, low).
▪ Until clinical trials demonstrate its efficacy and safety in the ▪ CMV‐specific (and nonspecific) T‐cell immune monitoring may
SOT population, letermovir is not recommended for treatment be used to determine a patient's risk of CMV relapse (weak,
of CMV disease after SOT (strong, low). low).
• Antiviral treatment of CMV disease should be continued until the ▪ The approach to preventing CMV relapse in high‐risk T cell‐
following criteria are met (strong, high): deficient patients is not known, but approaches such as
▪ Resolution of clinical symptoms, AND secondary prophylaxis (weak, low) and further reduction in
▪ Virologic clearance below a threshold negative value (test immunosuppression to allow for T‐cell immune reconstitution,
specific; see text) based on laboratory monitoring with CMV if feasible (weak, low), are suggested.
QNAT or pp65 antigenemia once a week, AND • If feasible, cautious reduction in immunosuppression should be
▪ Minimum 2 weeks of antiviral treatment considered in SOT patients presenting with CMV disease, espe‐
• Transplant recipients with CMV disease treated initially with in‐ cially if moderate to severe (strong, moderate).
travenous ganciclovir may be switched to oral valganciclovir once ▪ Reduction in immunosuppression may not be feasible in pa‐
there is adequate clinical and virologic control, based on the clini‐ tients with recent rejection or at heightened risk of rejection
cal assessment of the treating provider (strong, high). episodes.
• Acyclovir, valacyclovir, and oral ganciclovir (no longer commer‐ ▪ Reduction in immunosuppression should be strongly considered
cially available in the United States) should NOT be used for treat‐ in SOT patients with severe lymphopenia and those with defi‐
ing CMV disease (strong, high). cient nonspecific or CMV‐specific T‐cell function (weak, low).
• The addition of IVIg or CMV‐Ig to antiviral treatment of CMV dis‐
ease may be considered for patients with life‐threatening disease,
CMV pneumonitis and possibly other severe forms of disease, 7 | R E FR AC TO RY A N D R E S I S TA NT C M V
drug‐resistant virus, and those with hypogammaglobulinemia
(weak, low). A one‐log decline in CMV viral load is the anticipated outcome after
• CMV QNAT (or pp65 antigenemia) should be performed once at least 2 weeks of appropriately dosed antiviral therapy. CMV in‐
weekly to assess virologic response to treatment (strong, high). fection is considered refractory if CMV DNAemia, or antigenemia
▪ Only one type of CMV QNAT assay and one sample type increases after at least 2 weeks of appropriately dosed antiviral ther‐
(plasma or whole blood) should be used to assess virologic re‐ apy (ie, >1 log10 increase between baseline value and viral load at
sponse over the course of CMV disease (strong, high). 2 weeks or more).12 It is defined as probable refractory CMV infec‐
▪ CMV QNAT should decline to a level below a predefined tion if the viral load persists (at the same level or increases <1 log10
RAZONABLE ANd HUMAR |
      15 of 23

over baseline viral load) after at least 2 weeks of appropriately dosed foscarnet is the first‐line drug for the treatment of UL97‐mutant
12
antiviral therapy. Nonresolution or lack of improvement in the ganciclovir‐resistant CMV.115,127,136 There are only a few observa‐
clinical symptoms after two weeks of appropriately dosed antiviral tional studies of foscarnet and cidofovir use in SOT recipients, but
therapy is suggestive of refractory CMV disease (Table 1). Potential they support its efficacy.136,137 The major problem with foscarnet
reasons for refractory CMV infection are (a) an over‐immunosup‐ and cidofovir is nephrotoxicity, which is worrisome for transplant
pressed status, including absence or deficiency in CMV‐specific patients who are already be receiving potentially nephrotoxic
T‐cell immunity,125,126 (b) subtherapeutic antiviral drug concentra‐ drugs.136,137 Ocular complications (eg, uveitis) have been reported
127 128,129
tions, or (c) resistance to ganciclovir or other antiviral drugs. with cidofovir.140
The incidence of ganciclovir‐resistant CMV infection after Since ganciclovir, foscarnet, and cidofovir act by competitively
128,131,132
SOT is 0%‐3%. Risk factors for drug resistance are pro‐ inhibitingUL54‐encoded CMV DNA polymerase, mutations in UL54
longed subtherapeutic dose of antiviral drugs (eg, mini‐dosing), D+/ gene may confer mono‐ or cross‐resistance to any of these drugs
R− serostatus, intense immunosuppression, and lung transplanta‐ depending on the site of the mutation. A ganciclovir‐resistant CMV
tion.126,127,133,134 Drug resistance should be suspected in patients with UL54 mutation is more likely to be cross‐resistant to cidofovir;
with refractory CMV infection or disease and possess any of these hence, foscarnet is the empiric choice for treatment of ganciclovir‐
aforementioned risk factors. resistant CMV infection. However, definitive antiviral drug choice
When drug‐resistant CMV infection is suspected, genotypic re‐ should be guided by the results of the genotypic assays.128 Because
sistance testing should be obtained to detect specific mutations in of the complexity in the management of drug‐resistant CMV disease,
UL97 and UL54 genes. CMV UL97 is the gene that encodes for a viral referral to transplant infectious diseases experts for guidance is
kinase that catalyzes the initial mono‐phosphorylation and activa‐ highly recommended. An algorithm for evaluation and management
tion of ganciclovir. Subsequent phosphorylation by human cellular of ganciclovir‐refractory or ganciclovir‐resistant CMV infection or
enzymes leads to the active ganciclovir‐triphosphate (a nucleoside disease is presented in Figure 2.
analogue), which serves as a competitive substrate for incorporation Adjunctive intravenous immunoglobulin infusion has been
into the elongating CMV DNA chain, a process that is catalyzed by given anecdotally to supplement the management of resistant
CMV DNA polymerase (an enzyme encoded by CMV UL54 gene). CMV infection.99,127,134,136,141,142 Several investigational and off‐
Genotypic assays, which are preferred over culture‐based pheno‐ label drugs have also been used for the treating resistant CMV
typic assays, are performed on viral sequences that are directly am‐ disease. Letermovir, which is approved as CMV prophylaxis in al‐
plified from blood (whole blood, plasma, or leukocytes), body fluids logeneic hematopoietic stem cell transplant recipients, 89 has been
(urine, CSF, BALF, vitreous fluid), or tissue specimens. The degree used anecdotally for treatment of a lung recipient with CMV dis‐
of resistance to ganciclovir conferred by CMV UL97 genetic mu‐ ease that was resistant to ganciclovir, foscarnet, and cidofovir.117
tants depends on the site of mutation, which could confer either a Since its approval for clinical use, there have been reports related
low‐level or high‐level resistance.71,128,130 The most common UL97 to the off‐label use of letermovir for management of ganciclovir‐
genetic mutations that confer high‐level ganciclovir resistance are resistant CMV. The off‐label use of letermovir for treatment of
M460V/I, H520Q, C592G, A594V, L595S, and C603W.69 Less com‐ ganciclovir‐resistant CMV in SOT was complicated by emergence
monly observed causes of ganciclovir resistance are mutations in of UL56‐mutant letermovir‐resistant virus.116 Maribavir has been
128
UL54 (which encode CMV DNA polymerase). Since foscarnet and used in a case series of transplant patients with refractory and
cidofovir also act to inhibit UL54‐encoded CMV DNA polymerase, resistant CMV,143,144 and in a phase 2 study conducted in 120
mutations in UL54 gene may confer cross‐resistance to ganciclo‐ transplant patients (ClinicalTrials.gov NCT01611974).144 Maribavir
vir, foscarnet, and cidofovir.69 While letermovir is not yet approved is currently undergoing phase 3 clinical trials for the treatment of
clinically for use after SOT, genetic mutations have already been resistant and refractory CMV (ClinicalTrials.gov NCT02931539).
reported.116 Based on experimental models and early clinical ex‐ The clinical development of brincidofovir, an oral formulation of
perience, letermovir resistance correlates with genetic mutations cidofovir, is on hold due to its failure to prevent CMV infection
in UL56 and less commonly UL51 and UL89, which encode for viral in a phase 3 clinical trial in allogeneic hematopoietic stem cell
terminase complex.69,135 transplant recipients (ClinicalTrials.gov NCT01769170).145,146
The options for the treatment of refractory and resistant CMV Leflunomide and artesunate have been used off‐label for treat‐
are limited. Because an over‐immunosuppressed status may account ment of a few cases of drug‐resistant CMV disease, but their role
for the occurrence of refractory and resistant CMV, it is highly rec‐ is controversial.147,148 Finally, sirolimus and mTOR inhibitors have
ommended, as a first‐line strategy, to cautiously reduce the degree been associated with a lower risk of CMV disease and may be a
of immunosuppression. However, the specific approach to reducing useful adjunct in the immunosuppressive management of SOT re‐
immunosuppression is not defined or standardized. cipients with resistant CMV disease.40,149,150
There are no controlled clinical trials to guide the optimal choice Adoptive transfer of CMV‐specific T cells, derived from au‐
for antiviral treatment of resistant CMV infection. Generally, ganci‐ tologous and allogeneic (organ donor or third party donors)
clovir‐resistant CMV isolates withUL97‐only mutations remain sus‐ sources, has been used in experimental settings for the treatment
ceptible to foscarnet and cidofovir. Based on observational studies, of resistant and refractory CMV after transplantation, especially
 |
16 of 23       RAZONABLE ANd HUMAR

allogeneic hematopoietic stem cell transplantation.153,154 Only to adults, but there are unique characteristics in children that war‐
sporadic reports have suggested its clinical utility in SOT recipi‐ rant emphasis.
ents.157,158 In a pilot trial, adoptive transfer of in vitro‐expanded First, there are considerably fewer studies to support recom‐
autologous CMV‐specific T cells was effective in 11 of 13 SOT mendations for CMV prevention and treatment in pediatric SOT
patients with recurrent or ganciclovir‐resistant CMV infection, as populations. Hence, most recommendations for CMV prevention
indicated by improvement in symptoms, clearance or reduction in and treatment in children are extrapolated from studies conducted
CMV DNAemia, or cessation in use of antiviral drugs.159 in adult SOT recipients.
Second, the estimate of the burden of CMV disease in pedi‐
atric SOT recipients is based on limited number of pediatric co‐
7.1 | Specific recommendations for ganciclovir‐
hort studies.160 These cohort studies suggest that there are more
resistant CMV
CMV‐seronegative pediatric SOT patients (compared to adults), and
• Patients who develop refractory CMV infection or disease after therefore, a relatively larger cohort are at increased risk of primary
prolonged antiviral drug exposures and those failing to respond and potentially severe CMV disease. Even if the CMV‐seronegative
after at least two weeks of appropriately dosed antiviral treat‐ pediatric SOT recipient receives an organ from CMV‐seronegative
ment should be suspected of having drug‐resistant virus (strong, donor (CMV D−/R−), there is risk of acquiring de novo CMV infec‐
moderate). tion as a result of exposures in the community, such as day care
• Genotypic assays to detect UL97 mutation should be performed facilities.
among patients suspected to have resistance to ganciclovir, and Third, transplacental transfer of maternal CMV‐IgG antibodies
UL54 mutation analysis should be performed among patients sus‐ makes for a difficult interpretation of CMV serology in pediatric
pected to have resistance to ganciclovir, foscarnet, and cidofovir, SOT patients less than 18 months of age. In this context, detec‐
and this is preferred over phenotypic resistance testing (strong, tion of CMV shedding in urine or saliva by CMV QNAT or culture
moderate to high). may be used to confirm CMV infection status in infants and chil‐
▪ Genotypic assay to detect mutations in UL56 and less com‐ dren less than 18 months of age. 32 Even if viral shedding in the
monly in UL51/UL89 should be performed when resistance to urine and saliva is intermittent, studies have shown that this test
letermovir is suspected (strong, low). is clinically useful to determine baseline CMV infection status in
• Cautious reduction in immunosuppression is recommended for infants and young children.68 Detection of CMV‐specific T cells is
patients with refractory or resistant CMV infection and disease another measure that could indicate baseline CMV status in chil‐
(strong, moderate). dren awaiting organ transplantation, when interpretation of CMV
▪ A switch to sirolimus‐containing regimen may be an option serology is confounded by transplacental transfer of maternal IgG
due to the reportedly lower risk of CMV disease in patients antibodies. 32
receiving mTOR inhibitors (weak, moderate).
• Options for empiric treatment of suspected resistant CMV dis‐
8.1 | Pretransplant screening in children
ease include high‐dose intravenous ganciclovir (up to 10 mg/kg q
12 hours, renally adjusted) or foscarnet (weak, low to moderate). In pediatric SOT candidates <18 months of age who may have pas‐
Definitive antiviral treatment should be guided by results of geno‐ sively acquired maternal CMV IgG antibody, CMV QNAT or culture
typic testing (strong, moderate to high). of urine specimen may be performed to determine baseline CMV
▪ Other therapeutic options are cidofovir (weak, low), partici‐ status (strong, moderate).
pation clinical trials (eg, maribavir treatment of refractory and
resistant CMV) (strong, low), and off‐label letermovir (weak, • If urine CMV QNAT or culture is positive, the transplant candidate
very low). is considered CMV‐infected (strong, high).
• CMV immunoglobulin or IVIg may be used as an adjunct to an‐ • If urine CMV QNAT or culture is negative, the assignment of CMV
tiviral drugs in transplant recipients with resistant CMV disease status should be based on the highest‐risk level for the purposes
(weak, low). of CMV prevention, and will take into account the CMV status of
• If available, adoptive transfer of CMV‐specific T cells may be con‐ the donor (strong, moderate). For donors <18 months age, if the
sidered for the treatment of refractory and resistant CMV (weak, CMV serology is positive, the donor should be assumed as truly
low), but this will need to be investigated further in controlled seropositive (strong, moderate).
clinical trials.

8.2 | Prevention and treatment of CMV in children

8 | PE D I ATR I C I S S U E S
The recommendations for antiviral prophylaxis and preemptive
The basic principles in prevention and management of CMV infec‐ therapy in adult recipients are generally applicable to pediatric SOT
tion and disease in the pediatric SOT population are generally similar recipients, with the following qualifying statements:
RAZONABLE ANd HUMAR |
      17 of 23

Increase or unchanged viral load, or non-

resolution of clinical symptoms after at least 2
weeks of appropriately dosed intravenous
ganciclovir or valganciclovir

Assess for risk factors.

Reduce immunosuppression, if feasible.
Send for UL54 and UL97 resistance testing.
Assess severity of CMV infection.

Severe CMV disease Non-severe CMV disease

Empiric Therapy:
Empiric Therapy:
Increase intravenous Ganciclovir dose up to 10
Switch to Foscarnet (full dose)
mg/kg q12h, or Switch to Foscarnet (full dose)

Definitive Antiviral Therapy is based

F I G U R E 2   Algorithm for evaluation on genotypic resistance testing and
and management of refractory and clinical response. Adjunctive,
resistant cytomegalovirus infection and unproven, investigational therapy
may be required.
disease

• Antiviral prophylaxis, preemptive therapy, and hybrid approach and for treatment of more severe forms of CMV disease (weak,
are effective for prevention of CMV disease in pediatric SOT pa‐ low).
tients (strong, moderate). • Intravenous ganciclovir treatment of CMV disease in pediatric
• Intravenous ganciclovir and oral valganciclovir are recommended SOT recipients may be transitioned to oral valganciclovir in clin‐
for CMV prophylaxis, preemptive treatment of asymptomatic in‐ ically stable patients with declining and well‐controlled viremia
fection, and treatment of established CMV disease. Dosing of val‐ and resolved or resolving clinical symptoms (strong, low).
ganciclovir in children should be based on body surface area and
renal function (strong, moderate).
• There is no single standard recommendation for the optimal du‐
ration of antiviral prophylaxis. The duration of intravenous ganci‐ 9 | FU T U R E R E S E A RC H D I R EC TI O N S
clovir prophylaxis varies from a minimum of 14 days to 3 months.
Other centers prolong antiviral prophylaxis to 6 months after There are a number of areas that are being actively explored in basic,
transplantation (weak, moderate). translational and clinical research fields related to CMV disease di‐
• The risk of postprophylaxis delayed‐onset CMV disease is highest agnosis, prevention, and treatment. Despite widespread adaption
during the first 3 months after cessation of antiviral prophylaxis, of the WHO International Reference Standard for calibration, there
and pediatric SOT patients should undergo CMV QNAT surveil‐ remains clinically significant variability in viral load values. Hence,
lance during this at‐risk period (strong, moderate). the search continues to define widely applicable viral load thresh‐
• For pediatric patients undergoing the strategy of preemptive olds that should guide risk stratification, preemptive therapy, and
therapy, CMV QNAT is recommended once weekly for at least therapeutic assessments. Clinical and commercial laboratories are
12 weeks (strong, high). encouraged not only to calibrate CMV QNAT assays based on the
• Oral valganciclovir is recommended for treatment of asymptom‐ recently available WHO International Reference Standard, but also
atic CMV DNAemia (strong, low). to work further to standardize the other steps in CMV QNAT. In
• Treatment of mild‐to‐moderate CMV disease is with intravenous the meantime, transplant providers should develop center‐specific/
ganciclovir (strong, moderate) or oral valganciclovir (strong, low). assay‐specific and patient population‐specific viral load thresholds
• Intravenous ganciclovir is recommended as first‐line therapy for for different CMV QNAT clinical applications.
severe CMV disease (strong, moderate). Numerous in‐house (laboratory‐developed) and commercial as‐
• CMV‐Ig or intravenous Ig is generally not recommended (weak, says for the assessment of CMV‐specific T‐cell immunity are avail‐
low) but may be considered in combination with intravenous able to predict the risk of CMV disease in adults.82,113,161 However,
ganciclovir for the treatment of CMV disease in young infants studies to assess the validity and utility of CMV immune assays in
 |
18 of 23       RAZONABLE ANd HUMAR

pediatric SOT recipients will need to be completed. In addition, in‐ 3. Meesing A, Razonable RR. New developments in the manage‐
terventional studies to assess the potential clinical uses of CMV‐ ment of cytomegalovirus infection after transplantation. Drugs.
2018;78(11):1085‐1103.
specific T‐cell assays beyond merely risk stratification are needed.
4. Razonable RR, Blumberg EA. It's not too late: a proposal to stan‐
In particular, the utility of these assays in determining duration of dardize the terminology of "late‐onset" cytomegalovirus infection
antiviral prophylaxis, the need for preemptive treatment, and guide and disease in solid organ transplant recipients. Transpl Infect Dis.
the duration of treating CMV disease, and assess the risk of relapse 2015;17(6):779‐784.
5. Paya C, Humar A, Dominguez E, et al. Efficacy and safety of val‐
after treatment.
ganciclovir vs. oral ganciclovir for prevention of cytomegalovi‐
There are novel preventive and therapeutic options in the hori‐ rus disease in solid organ transplant recipients. Am J Transplant.
zon. Several CMV vaccine candidates are being tested, although 2004;4(4):611‐620.
results of recent clinical trials performed in CMV D+/R− kidney 6. Gane E, Saliba F, Valdecasas GJ, et al. Randomised trial of efficacy
and safety of oral ganciclovir in the prevention of cytomegalo‐
recipients have been disappointing.162,163 Several novel antivi‐
virus disease in liver‐transplant recipients. The Oral Ganciclovir
ral drugs are in various stages of clinical development, including International Transplantation Study Group [corrected]. Lancet.
letermovir, maribavir, and brincidofovir. While letermovir has re‐ 1997;350(9093):1729‐1733.
cently been approved for CMV prophylaxis in allogeneic hemato‐ 7. Lowance D, Neumayer HH, Legendre CM, et al. Valacyclovir
for the prevention of cytomegalovirus disease after renal
poietic stem cell transplant recipients, it remains investigational
transplantation. International Valacyclovir Cytomegalovirus
in SOT recipients. Letermovir is currently being compared with
Prophylaxis Transplantation Study Group. New Eng J Med.
valganciclovir in a randomized controlled trial involving CMV D+/ 1999;340(19):1462‐1470.
R− kidney transplant recipients. The role of letermovir for treat‐ 8. Humar A, Lebranchu Y, Vincenti F, et al. The efficacy and
ment of CMV disease is not known. Maribavir, on the other hand, safety of 200 days valganciclovir cytomegalovirus prophy‐
laxis in high‐risk kidney transplant recipients. Am J Transplant.
is undergoing clinical trials for the treatment of refractory and
2010;10(5):1228‐1237.
resistant CMV infection. The clinical fate of brincidofovir, which 9. Humar A, Limaye AP, Blumberg EA, et al. Extended valganciclovir
had disappointing results in the recently concluded prophylaxis prophylaxis in D+/R‐ kidney transplant recipients is associated with
trial in allogeneic hematopoietic stem cell transplant recipients, long‐term reduction in cytomegalovirus disease: two‐year results
of the IMPACT study. Transplantation. 2010;90(12):1427‐1431.
is not known. Finally, studies should advance the potential for
10. Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of cytomega‐
adoptive transfer of CMV‐specific T cells as immunotherapy in lovirus infection and disease in transplant patients for use in clini‐
SOT recipients with refractory, recurrent, and resistant CMV cal trials. Clin Infect Dis. 2017;64(1):87‐91.
infection.117,143,164 11. Humar A, Michaels M. American Society of Transplantation rec‐
ommendations for screening, monitoring and reporting of infec‐
tious complications in immunosuppression trials in recipients of
AC K N OW L E D G E M E N T organ transplantation. Am J Transplant. 2006;6(2):262‐274.
12. Chemaly RF, Chou S, Einsele H, et al. Definitions of resistant and
This manuscript was modified from the Cytomegalovirus in Solid refractory cytomegalovirus infection and disease in transplant re‐
cipients for use in clinical trials. Clin Infect Dis. 2018.
Organ Transplantation Guideline included in the 3rd Edition of
13. Razonable R. Direct and indirect effects of cytomegalovirus: can
the American Society of Transplantation Infectious Diseases we prevent them? Enferm Infecc Microbiol Clin. 2010;28(1):1‐5.
Guidelines written by Raymund R. Razonable and Atul Humar, 14. Munoz‐Price LS, Slifkin M, Ruthazer R, et al. The clinical im‐
published in the American Journal of Transplantation 20013;13 pact of ganciclovir prophylaxis on the occurrence of bacte‐
remia in orthotopic liver transplant recipients. Clin Infect Dis.
(Suppl 4): 93‐106, and endorsed by the American Society of
2004;39(9):1293‐1299.
Transplantation.
15. Snydman DR. The case for cytomegalovirus prophylaxis in solid
organ transplantation. Rev Med Virol. 2006;16(5):289‐295.
16. George MJ, Snydman DR, Werner BG, et al. The independent role
C O N FL I C T O F I N T E R E S T of cytomegalovirus as a risk factor for invasive fungal disease in
orthotopic liver transplant recipients. Boston Center for Liver
RRR received research grant (funds given to the institution) from
Transplantation CMVIG‐Study. Group. Cytogam, MedImmune,
Roche and Shire and serves on data and safety monitoring board Inc., Gaithersburg, Maryland. Am J Med. 1997;103(2):106‐113.
for Novartis. AH received research support from Roche, Qiagen, 17. Walker RC, Marshall WF, Strickler JG, et al. Pretransplantation as‐
Astellas, and Merck; serves as a consultant to Astellas and Qiagen; sessment of the risk of lymphoproliferative disorder. Clin Infect Dis.
1995;20(5):1346‐1353.
and received speaker honorarium from Merck, Astellas, and Shire.
18. Helantera I, Lautenschlager I, Koskinen P. The risk of cytomeg‐
alovirus recurrence after kidney transplantation. Transpl Int.
2011;24(12):1170‐1178.
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