Cytomegalovirus in Primary Immunodeficiency

Download as pdf or txt
Download as pdf or txt
You are on page 1of 9

REVIEW

CURRENT
OPINION Cytomegalovirus in primary immunodeficiency
Jack Godsell a,, Samantha Chan a,b,c,, Charlotte Slade a,b, Vanessa Bryant a,b,
Jo Anne Douglass a,c, Joe Sasadeusz d, and Michelle K. Yong d,e,f

Purpose of review
Cytomegalovirus (CMV) infection and disease are well described in the setting of secondary
immunodeficiency. Less is known about CMV in the context of primary immunodeficiencies (PIDs), where
inborn errors in one or more arms of the immune system result in variable degrees of CMV susceptibility.
Recent findings
PID presents unique challenges in the diagnosis and management of CMV disease. The clinical
presentation of CMV in PID is often severe, accelerated by underlying immune dysregulation and iatrogenic
immunosuppression. Here we describe the clinical significance of CMV infection in PID, the key
components of immune defence against CMV and how these are affected in specific PIDs. CMV disease is
under-recognized as a complication of common variable immunodeficiency (CVID). High rates of CMV
end-organ disease, mortality, development of CMV resistance and prolonged antiviral use have been
observed in individuals with CVID.
Summary
We recommend that clinicians tailor their approach to the individual based on their underlying immune
deficit and maintain a high index of suspicion and low threshold for treatment. More research is required
to improve stratification of CMV risk in PID, develop new diagnostic tools and manage end-organ disease
in this cohort.
Keywords
common variable immunodeficiency, cytomegalovirus, primary immunodeficiency

INTRODUCTION reactivate even in the immunocompetent host,


Primary immunodeficiencies (PIDs) are potentially determining the significance of cytomegalovirus
lethal disorders caused by inborn errors in one or (CMV) infection within this setting is difficult. Fur-
more arms of the immune system. The prevalence of thermore, CMV disease (defined as the presence of
PID is poorly characterised, with estimates ranging tissue invasive CMV associated with a clinical syn-
from 5.6 per 100,000 to 1 per 1,200 people world- drome) is commonly encountered in states of sec-
wide [1,2]. All PIDs share the finding of absent, ondary immunodeficiency, for example, following
reduced, or dysfunctional immune cells, but the solid organ or haematopoietic stem cell trans-
phenotypic spectrum is broad. ‘PID’ encompasses plantation.
over 400 distinct disorders, with manifestations that Evidence for CMV screening, diagnosis, monitor-
may include allergy, autoimmunity, autoinflamma- ing and management in PID is scant. With the
&
tion and malignancy [3 ]. Due to the complex,
multisystem impact of immune dysregulation, a
Department of Clinical Immunology & Allergy, Royal Melbourne Hospital,
b
cross-speciality collaboration is often required to Immunology Division, Walter & Eliza Hall Institute of Medical Research,
c
manage the competing risks of recurrent infection Department of Medicine, University of Melbourne, dVictorian Infectious
Diseases Service, Royal Melbourne Hospital, Melbourne, eSir Peter
and relapses in noninfectious complications, which
MacCallum Department of Oncology, The University of Melbourne, Park-
typically require immunosuppressive therapies. ville and fNational Centre for Infections in Cancer, Peter MacCallum
One of most common presentations for initiating Cancer Centre, Melbourne, Victoria, Australia
PID work-up is a history of Severe, Prolonged, Correspondence to Jack Godsell, Royal Melbourne Hospital, 300 Grat-
Unusual or Recurrent – ’SPUR’ – infection. For tan St, Parkville, Melbourne, Victoria, Australia. Tel: +61493427000;
instance, in a child, persistent thrush, two or more e-mail: [email protected]

pneumonias in a year, or two or more months on Jack Godsell and Samantha Chan are co-first authors.
antibiotics should be considered ‘red flags’ [4]. Since Curr Opin Infect Dis 2021, 34:663–671
human herpesviruses establish latency and can DOI:10.1097/QCO.0000000000000797

0951-7375 Copyright ß 2021 Wolters Kluwer Health, Inc. All rights reserved. www.co-infectiousdiseases.com

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.


Antimicrobial agents: viral

has been described as the first presentation of mono-


KEY POINTS genic immunodeficiency [11].
 Primary immunodeficiency, as a label, encompasses Host defence against CMV infection relies on
over 400 heterogeneous clinical syndromes, each with multiple facets of the innate and adaptive immune
unique predispositions to infections. systems [12]. Early viral replication is largely
addressed by Natural Killer (NK) cell cytoxicity, with
 Cytomegalovirus is an underrecognized cause of
type-1 interferons, interleukin (IL)-18 & IL-12
morbidity and mortality in primary immunodeficiency.
described as important early mediators [13–15].
 Clinicians must tailor their approach to CMV disease to Following primary infection, CMV, like other her-
the specific immune context of the PID in which it pesviridae, escapes the initial immune response to
has occurred. establish a latent reservoir in the host. This is accom-
plished through a range of mechanisms, including
expression of inhibitory proteins that abrogate the
host NK cell response, downregulation of major
notable exception of severe combined immunodefi-
histocompatibility complex (MHC) expression,
ciency (SCID), the published literature in this field
acceleration of premature T-cell death and modula-
comprises case reports or small series in specific sub-
tion of the host cytokine response [14,16–18].
diagnoses. Considering the significant heterogeneity
CD4þ and CD8þ T-cell responses are largely
of immune defects and CMV susceptibility across the
responsible for suppression of viral replication. T-
spectrum of PIDs, the development of a protocolized
cells specific to a range of viral epitopes are detect-
approach to CMV in all PIDs may not be feasible.
able within the first week of infection. In contrast to
In this article, we will review the epidemiology,
the natural history of other viral infections, a large
clinical presentation, and outcome of CMV infec-
population of CMV-specific CD8þ effector memory
tion, as well as discussing antiviral resistant or
T-cells persist post-initial infection and may con-
refractory CMV in some commonly encountered
tinue to expand over time, in a process known as
PIDs, and highlight the complexity of diagnosing
‘memory inflation’ [19]. This population of CMV
and managing CMV disease in the context of PID.
epitope-specific T-cells may account for up to 10–
20% of circulating blood lymphocytes in healthy
A PRIMER ON CYTOMEGALOVIRUS CMV-infected individuals [20]. The expanded CD8þ
INFECTION AND IMMUNITY effector memory pool may continue to expand well
CMV infection is common in the general adult into old age and lacks the features of T-cell exhaus-
population, with seroprevalence ranging from 40 tion expected in response to a persistent antigen
to 90% [5]. There are no large-scale studies of [21,22].
CMV seroprevalence in PID. Interpretation of seros- In parallel with the cellular immune response,
tatus in this cohort is complicated by inadequate CMV-specific IgM is usually detectable within
antibody responses to infection as a feature of the 2 weeks of acquisition and may persist for several
PID and the frequent use of Immunoglobulin months post-exposure. Low avidity CMV-specific
Replacement Therapy (IRT), consisting of regular IgG becomes detectable 2–3 weeks after acquisition.
infusions of purified Immunoglobulin G (IgG) col- However, it is unlikely that the humoral response to
lected from the pooled plasma of healthy blood CMV is important to early control of infection. In
donors and likely containing CMV IgG. mice rendered antibody deficient, there is no differ-
Primary CMV infection typically occurs in the ence in ability to achieve viral clearance [23]. Multi-
first decade of life [6]. In developed countries, there ple trials of CMV-specific immunoglobulin therapy
is a second peak of infection in middle age, due to to passively immunise individuals have failed to
lower childhood rates of CMV acquisition and demonstrate efficacy in the context of pregnancy,
delayed exposure [6]. The majority of primary lung transplant and renal transplant [24,25]. Simi-
CMV infection is asymptomatic, but a ‘mononucle- larly, there is no correlation between serum titers of
osis syndrome’ or ’symptomatic viraemia’ may CMV-specific IgG and protection from tissue repli-
occur, consisting of fever, myalgia and adenopathy. cation of CMV in the context of reactivation [26].
Severe primary CMV infection has been identified in Thus IRT is likely to be ineffective for treatment of
immunocompetent individuals [7–10]. Nonethe- CMV disease in PID.
less, consultation with a clinical immunologist to Latent CMV infection continues for the dura-
consider an underlying PID should be sought in tion of the host’s life. A reservoir is established
cases of adult onset severe CMV if risk factors such within undifferentiated cells of the myeloid lineage,
as iatrogenic immunosuppression or malnutrition including CD34þ myeloid progenitor cells and
are absent. Fatal primary CMV infection in an adult CD14þ monocytes. Given the broad tropism of

664 www.co-infectiousdiseases.com Volume 34  Number 6  December 2021

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.


Cytomegalovirus in primary immunodeficiency Godsell et al.

CMV, it is likely that there are many other silos of (9) Bone marrow failure disorders, such as
latency [27,28]. Reactivation of latent CMV is asso- Fanconi anaemia.
ciated with any pathological process compromising (10) Phenocopies of PID, which may be associated
the T-cell compartment, as CMV control is largely with somatic mutations or auto-antibodies
&
maintained through the cytopathic effect of the [3 ].
expanded CMV-specific CD8þ T-cell population
[29]. The degree of insult to T-cell immunity needed The spectrum of PID encompasses over 400
to ‘permit’ CMV reactivation is surprisingly low, distinct clinical phenotypes, with an enormous
with reports of detectable replication in individuals breadth of clinical disease described. Reported cases
who are critically ill, postsurgery, with sepsis, and in of CMV disease are described across a wide variety of
other instances of physiological catecholamine PID phenotypes, from IFN-gamma deficiency [37] to
release [30–33]. Age-related decline in T-cell immu- hepatic veno-occlusive disease with immunodefi-
nity is another risk factor for CMV reactivation, ciency (VODI) [38].
however opportunistic infection with varicella or It is evident that the impact of CMV in discrete
tuberculosis are more common clinical manifesta- PIDs cannot be discussed in generalities. We will first
tions of T-cell senescence [9,34–36]. explore its presentation in theoretically ‘high-risk’
PIDs: entities where the phenotype is characterised
by viral infection (e.g. SCID, PI3K gain-of-function
CYTOMEGALOVIRUS ACROSS A syndrome). Secondly, we will present the literature
SPECTRUM OF ADULT PRIMARY on CMV in CVID: the most prevalent PID and the
IMMUNODEFICIENCIES condition in which CMV is most likely to be encoun-
PIDs have been broadly organised by the Interna- tered. Here we provide a practical approach to evalu-
tional Union of Immunological Societies expert ating the likelihood of CMV disease in PID and
committee into the following ten categories: recommend that clinicians adapt their approach
according to the patient’s degree of lymphocyte
(1) Combined immunodeficiencies, in which impairment (particularly in the T-cell compartment,
both cellular and humoral immunity are see Fig. 1) and burden of iatrogenic immunosuppres-
affected, e.g. SCID. sion.
(2) Combined immunodeficiencies with syn-
dromic features, for example, diseases of
DNA repair such as ataxia telangectasia. High-risk primary immunodeficiencies
(3) Predominantly antibody deficiencies, charac- CMV is a well-recognised cause of morbidity and
terised by defective B cell development and mortality in PIDs characterised by T- and NK-cell
hypogammaglobulinaemia, e.g. common var- impairment, such as X-linked/common gamma
iable immunodeficiency (CVID). chain deficiency SCID: a profound immunodefi-
(4) Diseases of immune dysregulation, such as ciency that typically presents within months of
haemophagocytic lymphohistiocytosis (HLH). birth and is rapidly fatal without definitive treat-
(5) Congenital defects of phagocyte number or ment such as haematopoietic stem cell transplant or
function, such as chronic granulomatous dis- gene therapy [39]. Avoidance of CMV acquisition in
ease or pulmonary alveolar proteinosis. the pretransplant period is imperative for these
(6) Defects in intrinsic and innate immunity, patients; infants with SCID must be screened for
which may result in predisposition to pyogenic CMV every 1–2 weeks [40], receive CMV negative,
bacterial infection, parasitic or fungal infec- irradiated blood products and avoid breastfeeding if
tions (e.g. chronic mucocutaneous candidiasis the mother is seropositive and the infant CMV PCR
due to STAT1 gain-of-function), mycobacterial negative [41,42]. If individuals with SCID survive to
disease (e.g. Mendelian susceptibility to myco- adulthood, CMV disease is also frequently encoun-
bacterial disease as a result of IFNGR1 defi- tered in the context of immunosuppression post-
ciency), and viral infections (e.g. due to transplant [43].
STAT1 or STAT2 deficiency). CMV disease is also an established concern in
(7) Autoinflammatory disorders, such as familial phosphatidylinositol-3-Kinase (PI3K) gain-of-func-
Mediterranean fever. tion syndrome, in which individuals have constitu-
(8) Complement deficiencies, which may mani- tive over-activation of the PI3K/Akt pathway
fest as recurrent pyogenic infections, dissemi- resulting in T-cell senescence and defects in B-cell
nated Neisserial infection, SLE-like syndrome, Ig class switching [44]. Up to 50% of patients with
atypical haemolytic uraemia syndrome or activated P13Kdelta syndrome are reported to have
recurrent angioedema. persistent or recurrent human herpesvirus infections,

0951-7375 Copyright ß 2021 Wolters Kluwer Health, Inc. All rights reserved. www.co-infectiousdiseases.com 665

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.


Antimicrobial agents: viral

FIGURE 1. ’Heatmap’ of CMV disease in PID. APDS, activated phosphatidylinositol-3-Kinase deficiency; C, complement
factor; CVID, common variable immunodeficiency; GATA2, GATA binding protein 2; HLH,
haemophagocyticlymphohistiocytosis; LOCID, late-onset combined immunodeficiency; MSMD, Medelian susceptibility to
mycobacterial diseases; NK, natural killer cell; SAD, specific antibody deficiency; SCID, severe combined immunodeficiency;
WHIM, Warts, hypogammaglobulinaemia, immunodeficiency & Myelocathexis; XLA, X-linked agammaglobulinaemia; Created
with Biorender.com.

including CMV viraemia or lymphadenitis. Despite cloud the diagnosis of PID and increase susceptibil-
this, CMV pneumonia, colitis or retinitis have not ity to opportunistic infections such as CMV.
been reported in this context [45]. There are 27 published case reports or series detail-
PIDs characterised by predisposition to severe ing 34 total patients presenting with CMV-related
viral infections and in particular Epstein–Barr Virus complications in the CVID population (see Table 1)
(EBV) should also raise a red flag for CMV suscepti- [48–71]. These reports describe a wide spectrum of
bility; for example, STAT1 deficiency, XMEN (XL clinical disease including: CMV enterocolitis (25/34,
magnesium, EBV and neoplasia) disease secondary 73.5%), CMV pneumonitis (6/34, 17,6%), CMV reti-
to MAGT1 mutation, RAS Guanyl Releasing Protein 1 nitis (3/34, 8.8%), symptomatic viraemia (2/34, 5.8%),
(RASGRP1) deficiency and particular HLH genotypes CMV myelitis (1/34, 2.9%) and asymptomatic virae-
(e.g. XLP1 associated or CD27 deficient HLH) [46]. mia (1/34, 2.9%). Diagnosis of end-organ CMV disease
in 91% (31/34) of cases and the high all-cause mortal-
ity evident in this cohort (8/34, 24%) indicate late
Cytomegalovirus in common variable presentation and severity of illness. Two cases of mul-
immunodeficiency tiple drug resistant CMV disease occurred in adoles-
The diagnostic criteria for CVID include recurrent cent PIDs, developing both UL54 and UL97
sinopulmonary infection, reduced serum IgG, IgA mutations. Both cases were fatal despite extensive
and/or IgM, impaired vaccine responses and exclu- drug therapy – viral resistance was attributed to the
&&
sion of secondary causes such as myeloma or pro- necessity for prolonged treatment [72 ]. The most
tein-wasting. Most (>70%) of individuals with CVID common site of CMV disease was the gastrointestinal
also have features of chronic immune dysregulation, system, followed by the lungs; parallel to what is
such as autoimmunity, malignancy or autoinflam- observed in the postallogeneic haematopoetic stem
mation [47]. The noninfectious manifestations of cell transplant (HSCT) setting [73].
CVID frequently precede the diagnosis of immuno- Peak blood CMV viral loads were generally very
deficiency and are treated with broad immunosup- high in patients with CMV organ disease, however,
pression, for example, systemic steroids, B cell some cases of CMV enteritis and CMV pneumonitis
depletion or antimetabolites. Such interventions were associated with relatively low CMV viral loads

666 www.co-infectiousdiseases.com Volume 34  Number 6  December 2021

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.


Table 1. Reported cases of CMV disease in CVID
PEAK CMV
AGE/ INFLAMMATORY PHARMACOLOGIC CD4:CD8 VIRAL LOAD CMV CMV
AUTHOR/YEAR GENDER INFECTIONSa DISEASEa IMMUNOSUPPRESSION RATIO LYMPHOPENIA (COPIES/ML) MANIFESTATIONSc TREATMENT OUTCOME

Aghamohammadi 12M þ þ  0.14 Y NA CMV Retinitis, G Treatment Success


et al., 2012 [48] Macrophage
activation
syndrome
Agrawal et al., 2019 39M þ þ  0.98 N 9561 IU CMV Enteritis V Treatment Success
[49]
Aird et al., 2019 [50] 13F þ þ  1.34 N NA CMV Pneumonitis G, CMVIg Fatal

Bonetti et al., 2011 45M NA   N/A N/A N/A CMV Enteritis Not Described Unclear
[51]
Buckner et al., 1993 57M NA þ þ NA NA N/A CMV Enteritis G Recurrent Disease
[52]
Cabot et al., 1995 58M þ þ  0.13 N NA Symptomatic Not Described Treatment Success
[53] Viraemia
Chua et al., 2007 [54] 59F þ  þ NA NA N/A CMV Enteritis G, V Recurrent Disease
Ciccocioppo et al. – 29M þ þ  1.23 Y 100 CMV Enteritis G, CMVTCs Treatment Success
Case A, 2014 [55]
Ciccocioppo et al. – 46M þ   0.71 Y 1400 CMV Enteritis G, CMVTCs Treatment Success
Case B, 2014 [55]
Costantino et al., 2014 44M þ þ  NA NA N/A CMV Enteritis G, V Treatment Success
[56]
Elordui et al., 2018 37F NA þ  NA NA 2895 CMV Enteritis G, V Treatment Success
[57]
Ishikawa et al., 2002 26M NA þ þ NA NA NA CMV Retinitis G, V Treatment Success
[58]

0951-7375 Copyright ß 2021 Wolters Kluwer Health, Inc. All rights reserved.
Kathi et al., 2018 [59] 27M NA þ þ NA NA 30,900 CMV Enteritis G, V, F, CMVIg Treatment Success
Case 1,
Kim et al. – && 16M NA þ þ NA NA 124,202 CMV Enteritis, G, V, F, CMVIg Resistant Virus
2019 [72 ] CMV UL54/UL97, Fatal
Pneumonitis
Case 2,
Kim et al. – && 18M  þ  NA NA 2,322,273 CMV Enteritis G, V, F Resistant Virus
2019 [72 ] UL54/UL97, Fatal
Koźlik et al., 2018 69F þ   NA NA NA CMV Enteritis G Recurrent Disease
[60]
Kralickova et al. – 51F þ   1.17 N NA CMV Pneumonitis G Treatment Success
Case 1, 2014 [74]
Kralickova et al. – 56F þ þ þ 0.83 N 1000 CMV Pneumonitis G, V Treatment Success
Case 2, 2014 [74]
Kralickova et al. – 46M þ  þ 1.00 Y 420 CMV Enteritis G Treatment Success
Case 3, 2014 [74]
Kuntz et al., 2011 [61] 37F NA þ  NA NA 62 Asymptomatic Nil Unclear
Viraemia
Magalhães-Costa 69F NA þ þ NA NA NA CMV Enteritis G Treatment Success
et al., 2016 [62]

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.


Medlicott et al., 2006 47F þ þ þ NA NA NA CMV Enteritis G Treatment Success
[63]
Nasa et al., 2019 [64] 52M NA   NA NA NA CMV Enteritis G Treatment Success

www.co-infectiousdiseases.com
Raeiszadeh et al., 58M NA   NA NA NA CMV Enteritis G Recurrent Disease
2006 [65]
Sewell et al., 1998 65M þ þ þ NA NA NA CMV Pneumonitis G Treatment Success
[66]
Cytomegalovirus in primary immunodeficiency Godsell et al.

667
Stack et al., 2004 [67] 66F þ   NA Unclear NA CMV Enteritis G Fatal
Antimicrobial agents: viral

Inflammatory disease defined as the presence of autoimmune cytopaenia, enteropathy, lymphadenopathy/splenomegaly, lymphoproliferative disease, interstitial lung disease or seronegative spondlyoarthritis attributable
(<1500 cp/ml) [74]. The occurrence of CMV disease

Treatment Success

Treatment Success

Treatment Success
Post HSCT, Fatal

Post HSCT, Fatal

Post HSCT, Fatal


with low or absent CMV viral loads is also observed
in the posttransplant setting [75]. This adds further
OUTCOME

Post HSCT
difficulty to the diagnosis of CMV disease using viral

Fatal
load results in PID patients. Clinicians must be alert
to the possibility of disease in the presence of low
level or even absent viraemia. The high rates of
Not Described

Not Described

Not Described

Not Described

Not Described
TREATMENT

inflammatory disease reported within this cohort


G, CMVIg

of CVID patients with CMV disease (24/34, 77%)


CMV

were not more frequent than the rates of inflamma-


G

G
tory/autoimmune manifestations described in
MANIFESTATIONSc

other large CVID cohorts [47,76–78].

CMV Retinitis
CMV Myelitis, Studies into the overall prevalence of CMV
CMV Enteritis

CMV Enteritis
CMV Enteritis

CMV Enteritis

CMV Enteritis

CMV Enteritis

CMV Enteritis
infection in CVID suggest that it accounts for a
relatively low burden relative to all causes of infec-
CMV

tion, with visceral CMV disease reported in just 3


patients in a cohort of 252 CVID patients [79].
(COPIES/ML)
VIRAL LOAD

However, such findings might under-represent


PEAK CMV

G, ganciclovir; CMV TCs, adoptive CMV-specific T lymphocyte therapy; CMVIg, CMV-specific immunoglobulin; F, Foscarnet; V, valganciclovir. the significant burden of CMV disease in CVID
and its potential lethality, as screening is not cur-
NA

NA
NA

NA

NA

NA

NA

NA

rently routine practice.


LYMPHOPENIA

PITFALLS OF CYTOMEGALOVIRUS
DIAGNOSIS
NA

NA

NA
Yes

Yes
No

No

No

CMV serology is typically the first-line investiga-


CD4:CD8

tion to stratify an individual’s risk of CMV reacti-


RATIO

vation and disease. It is inherently unreliable in


NA

NA
NA

NA

NA

NA

NA

NA

most PIDs, with high rates of both ‘false-positives’


secondary to IRT, and ‘false-negatives’ due to
IMMUNOSUPPRESSION

impaired antibody production/failed seroconver-


PHARMACOLOGIC

sion. Consequently, clinicians are more reliant on


molecular testing (CMV PCR) and histology. Rou-
tine monitoring and diagnosis of CMV infection
through viral load testing is costly, difficult to
interpret and not currently recommended. The



þ

clinical significance of asymptomatic CMV virae-


INFLAMMATORY

mia and fluctuations in viral levels are poorly


defined. Novel assays of CMV immune compe-
DISEASEa

tence, such as CMV-specific interferon gamma


release and CMV-specific T-cell immunity panels
þ

þ


are being assessed in the posttransplant setting


a

[80–84], but their utility in PID cohorts is not


INFECTIONS

Recurrent Sinopulmonary/gastrointestinal Infections.

yet established. Further studies are required to


evaluate whether tests of CMV immunity can
NA

HSCT, haematopoetic stem cell transplant.

improve identification of PID patients at the high-


þ

þ
þ

est risk of CMV complications and overcome the


GENDER

impact of deficient antibody production on


AGE/

40M

11M

54M
22F
22a
a

18a
a
12

22

traditional diagnostics.
Table 1 (Continued)

Witte et al., 2000 [70]


Ünal et al., 2015 [69]
Wehr et al. – Case 6,

Wehr et al. – Case

Wehr et al. – Case

Wehr et al. – Case

Yousry et al., 1998


Tahan et al., 2000

CYTOMEGALOVIRUS TREATMENT IN THE


13, 2015 [43]

14, 2015 [43]

28, 2015 [43]


AUTHOR/YEAR

CONTEXT OF PRIMARY
2015 [43]

IMMUNODEFICIENCY
to CVID.
[68]

[71]

Treatment of CMV disease is often challenging,


due to the limited selection and toxic nature of
a
b

668 www.co-infectiousdiseases.com Volume 34  Number 6  December 2021

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.


Cytomegalovirus in primary immunodeficiency Godsell et al.

available therapies. This issue is exacerbated in the by lymphocyte defects or viral infection. An evidence
context of PID, where it is unlikely that clinicians base for CMV screening is needed, given the signifi-
will be able to alter the outcome of CMV disease cant challenges of treating CMV disease in the con-
through withdrawal of immunosuppression or facil- text of PID. However, studies in this area are
itated natural reconstitution of the immune system, hampered by the relative rarity and heterogeneity
as occurs following HSCT. of PID. A targeted study of the CVID population
Ganciclovir-related neutropenia is a common presents an appealing starting point for such work,
side effect of this therapy, occurring in up to 42% given the high morbidity and mortality of CMV
of those requiring CMV treatment [85]. Up to a third disease described in this literature review.
of patients with CVID develop autoimmune cytope-
nias [86], complicating the use of both valganciclovir Acknowledgements
and ganciclovir. Unreliable oral absorption of valgan- We would like to acknowledge the invaluable and ongo-
ciclovir due to PID-associated enteropathy may lead ing support of the Royal Melbourne Hospital Clinical
to sub-therapeutic drug levels, which over time may Immunology & Allergy Unit, Infectious Diseases Unit,
contribute to viral resistance, creating an argument Day Medical Centre nurses, and our patients.
for the measurement of drug blood levels where
possible. The high rates of co-morbid inflammatory Financial support and sponsorship
pathology in CVID and ongoing need for immuno- None.
suppression can lead to prolonged sub-optimal use of
antivirals and recurrent CMV complications. Conflicts of interest
Novel anti-CMV drugs such as letermovir and
S.C. reports grants, personal fees and nonfinancial sup-
maribavir are associated with less myelosuppression
port from CSL and nonfinancial support from Sanofi
and nephrotoxicity than older agents such as (val)-
outside the submitted work. J.S. has received research
ganciclovir and foscarnet [87,88]. Patient factors,
funding from Gilead Sciences and the NHMRC. M.Y has
particularly enteropathy and irreversible immuno-
received honoraria from MSD. In the past 5 years, J.A.D.
suppression, have been shown to complicate the
has received honoraria for educational presentations
use of these newer anti-CMV therapeutics in PID.
from Astra-Zeneca, GSK, Novartis & CSL. She has served
Emergence of letermovir resistance has been recently
on advisory boards for Sanofi-Aventis, Novartis, GSK,
documented in the context of late-onset combined
Astra-Zeneca, Immunosis and CSL. She has undertaken
immunodeficiency, with multiple breakthroughs in
contracted or investigator initiated research on behalf of:
CMV replication observed despite letermovir therapy
& GSK, Novartis, Immunosis, AstraZeneca, Sanofi-Aven-
[89 ]. Marabavir has been successfully used to achieve
tis, Grifols, CSL, BioCryst & Equilium. She has a per-
viral suppression in a separate case of diffuse refrac-
sonal superannuation shareholding in CSL and received
tory CMV enteritis complicating late onset combined
book royalties from ‘Fast Facts: Asthma’. C.S. has served
immunodeficiency, although its use was limited by
as a medical advisor to Grifols and Takeda and has
difficulties accessing the drug [90]. Passive immuno-
undertaken contracted or investigator initiated research
therapy in the form of pathogen specific immuno-
on behalf of: Takeda, Grifols, CSL & Immunosis. V.B. &
globulin or adoptive T lymphocytes are still being
J.G. report no disclosures.
assessed as potential therapies for resistant refractory
CMV. Their use in PID has typically occurred post-
HCST, and has yielded promising results for some, REFERENCES AND RECOMMENDED
but not all, patients [55,91]. These cases serve to
READING
highlight PID as an important circumstance to Papers of particular interest, published within the annual period of review, have
be considered in the development of novel been highlighted as:
& of special interest
CMV therapeutics. && of outstanding interest

1. Bousfiha AA, Jeddane L, Ailal F, et al. Primary immunodeficiency diseases


worldwide: more common than generally thought. J Clin Immunol 2013;
CONCLUSION 33:1–7.
2. Abolhassani H, Azizi G, Sharifi L, et al. Global systematic review of primary
There is scant prospective evidence to guide diagnosis immunodeficiency registries. Expert Rev Clin Immunol 2020; 16:717–732.
and management of CMV in the context of PID. We 3. Bousfiha A, Jeddane L, Picard C, et al. Human inborn errors of immunity: 2019
& update of the IUIS phenotypical classification. J Clin Immunol 2020;
recommend that clinicians tailor their approach 40:66–81.
based on the underlying immune deficit, with a high This update on the 2013 PID classification adds 65 newly recognised clinical and
genetic primary immunodeficiency diagnoses to the current schema.
index of suspicion to seek diagnostic confirmation 4. Jeffrey Modell Foundation 10 Warning Signs of Primary Immunodeficiency for
and low threshold for treatment when managing Adults. 2009. http://www.info4pi.org/aboutPI/pdf/Adult10WarningSignsFI-
NAL.pdf. [Accessed 10 July 2021].
patients with a history of significant iatrogenic 5. Seale H, MacIntyre CR, Gidding HF, et al. National serosurvey of cytome-
immunosuppression or a PID diagnosis characterised galovirus in Australia. Clin Vaccine Immunol 2006; 13:1181–1184.

0951-7375 Copyright ß 2021 Wolters Kluwer Health, Inc. All rights reserved. www.co-infectiousdiseases.com 669

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.


Antimicrobial agents: viral

6. Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence 36. Stowe RP, Kozlova EV, Yetman DL, et al. Chronic herpesvirus reactivation
and demographic characteristics associated with infection. Rev Med Virol occurs in aging. Exp Gerontol 2007; 42:563–570.
2010; 20:202–213. 37. Dorman SE, Uzel G, Roesler J, et al. Viral infections in interferon-g receptor
7. Orasch C, Conen A. Severe primary cytomegalovirus infection in the immuno- deficiency. J Pediatr 1999; 135:640–643.
competent adult patient: a case series. Scand J Infect Dis 2012; 44:987–991. 38. Hamdoun O, Mulla AA, Zaabi SA, et al. Unique mutation in SP110 resulting in
8. Eddleston M, Peacock S, Juniper M, Warrell DA. Severe cytomegalovirus hepatic veno-occlusive disease with immunodeficiency. Case Rep Pediatr
infection in immunocompetent patients. Clin Infect Dis 1997; 24:52–56. 2020; 2020:1–4.
9. Kanno M, Chandrasekar PH, Bentley G, et al. Disseminated cytomegalovirus 39. Pai S-Y. Treatment of primary immunodeficiency with allogeneic transplant
disease in hosts without acquired immunodeficiency syndrome and without and gene therapy. Hematology 2019; 2019:457–465.
an organ transplant. Clin Infect Dis 2001; 32:313–316. 40. Vora SB, Englund JA. Cytomegalovirus in immunocompromised children. Curr
10. Wreghitt TG, Teare EL, Sule O, et al. Cytomegalovirus infection in immuno- Opin Infect Dis 2015; 28:323–329.
competent patients. Clin Infect Dis 2003; 37:1603–1606. 41. Walter JE, Heimall J. CMV-seropositive mothers of SCID: to breastfeed or
11. Drutman SB, Mansouri D, Mahdaviani SA, et al. Fatal cytomegalovirus infec- not? J Allergy Clin Immunol Pract 2019; 7:2866–2867.
tion in an adult with inherited NOS2 deficiency. N Engl J Med 2020; 42. Richards S, Gennery AR, Davies EG, et al. Diagnosis and management of
382:437–445. severe combined immunodeficiency in Australia and New Zealand. J Paediatr
12. Crough T, Khanna R. Immunobiology of human cytomegalovirus: from bench Child Health 2020; 56:1508–1513.
to bedside. Clin Microbiol Rev 2009; 22:76–98. 43. Wehr C, Gennery AR, Lindemans C, et al. Multicenter experience in hema-
13. Thakkar A, Gonzalez-Lugo JD, Goradia N, et al. Seroconversion rates follow- topoietic stem cell transplantation for serious complications of common
ing COVID-19 vaccination amongst patients with cancer. Cancer Cell 2021; variable immunodeficiency. J Allergy Clin Immunol 2015; 135:988–997. e6.
39:1081–1090.e2. 44. Cohen JI. Herpesviruses in the activated phosphatidylinositol-3-kinase-d
14. Benedict CA, Loewendorf A, Garcia Z, et al. Dendritic cell programming by syndrome. Front Immunol 2018; 9:237.
cytomegalovirus stunts naive T Cell responses via the PD-L1/PD-1 pathway. J 45. Coulter TI, Chandra A, Bacon CM, et al. Clinical spectrum and features of
Immunol 2008; 180:4836–4847. activated phosphoinositide 3-kinase d syndrome: a large patient cohort study.
15. Andrews DM, Scalzo AA, Yokoyama WM, et al. Functional interactions J Allergy Clin Immunol 2017; 139:597–606. e4.
between dendritic cells and NK cells during viral infection. Nat Immunol 46. Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity:
2002; 4:175–181. 2019 update on the classification from the International Union of Immuno-
16. Fielding CA, Weekes MP, Nobre LV, et al. Control of immune ligands by logical Societies Expert Committee. J Clin Immunol 2020; 40:24–64.
members of a cytomegalovirus gene expansion suppresses natural killer cell 47. Slade CA, Bosco JJ, Giang TB, et al. Delayed diagnosis and complications of
activation. Elife 2017; 6:e22206. predominantly antibody deficiencies in a cohort of australian adults. Front
17. Halenius A, Gerke C, Hengel H. Classical and nonclassical MHC I molecule Immunol 2018; 9:694.
manipulation by human cytomegalovirus: so many targets—but how many 48. Aghamohammadi A, Abolhassani H, Hirbod-Mobarakeh A, et al. The uncom-
arrows in the quiver? Cell Mol Immunol 2014; 12:139–153. mon combination of common variable immunodeficiency, macrophage activa-
18. Poole E, King CA, Sinclair JH, Alcami A. The UL144 gene product of human tion syndrome, and cytomegalovirus retinitis. Viral Immunol 2012;
cytomegalovirus activates NFkB via a TRAF6-dependent mechanism. Embo J 25:161–165.
2006; 25:4390–4399. 49. Agrawal S, Khokhar A, Gupta S. Cytomegalovirus colitis in primary hypo-
19. Klenerman P, Oxenius A. T cell responses to cytomegalovirus. Nat Rev gammaglobulinemia with normal CD4þ T cells: deficiency of CMV-specific
Immunol 2016; 16:367–377. CD8þ T Cells. Front Immunol 2019; 10:399.
20. Sylwester AW, Mitchell BL, Edgar JB, et al. Broadly targeted human cyto- 50. Aird A, Lagos M, Vargas-Hernández A, et al. Novel heterozygous mutation in
megalovirus-specific CD4þ and CD8þ T cells dominate the memory com- NFKB2 is associated with early onset CVID and a functional defect in NK cells
partments of exposed subjects. J Exp Med 2005; 202:673–685. complicated by disseminated CMV infection and severe nephrotic syndrome.
21. Lang A, Nikolich-Zugich J. Functional CD8 T cell memory responding to persistent Front Pediatr 2019; 7:303.
latent infection is maintained for life. J Immunol 2011; 187:3759–3768. 51. Bonetti LR, Losi L, Gregorio CD, et al. Cytomegalovirus infection of the upper
22. Utzschneider DT, Legat A, Marraco SAF, et al. T cells maintain an exhausted gastrointestinal tract: a clinical and pathological study of 30 cases. Scand J
phenotype after antigen withdrawal and population reexpansion. Nat Immunol Gastroentero 2011; 46:1228–1235.
2013; 14:603–610. 52. Buckner FS, Pomeroy C. Cytomegalovirus disease of the gastrointestinal tract
23. Jonjić S, Pavić I, Polić B, et al. Antibodies are not essential for the resolution of in patients without AIDS. Clin Infect Dis 1993; 17:644–656.
primary cytomegalovirus infection but limit dissemination of recurrent virus. J 53. Cabot RC, Scully RE, Mark EJ, et al. Case 7-1995 — A 58-year-old man with
Exp Med 1994; 179:1713–1717. common variable immunodeficiency, splenomegaly, and hemolytic anemia. N
24. Revello MG, Lazzarotto T, Guerra B, et al. A randomized trial of hyperimmune Engl J Med 1995; 332:663–671.
globulin to prevent congenital cytomegalovirus. N Engl J Med 2014; 54. Chua I, Quinti I, Grimbacher B. Lymphoma in common variable immunode-
370:1316–1326. ficiency; interplay between immune dysregulation, infection and genetics.
25. Kruger RM, Paranjothi S, Storch GA, et al. Impact of prophylaxis with cytogam Curr Opin Hematol 2008; 15:368–374.
alone on the incidence of CMV viremia in CMV-seropositive lung transplant 55. Ciccocioppo R, Comoli P, Gallia A, et al. Autologous human cytomegalovirus-
recipients. J Hear Lung Transplant 2003; 22:754–763. specific cytotoxic T cells as rescue therapy for ulcerative enteritis in primary
26. Mansfield SA, Dwivedi V, Elgharably H, et al. Cytomegalovirus immunoglo- immunodeficiency. J Clin Immunol 2014; 34:681–685.
bulin G titers do not predict reactivation risk in immunocompetent hosts. J 56. Costantino G, Mondello P, Previti M, et al. Pan-digestive tract colonization by
Med Virol 2019; 91:836–844. cytomegalovirus in common variable immunodeficiency. Int Arch Allergy
27. Poole E, Sinclair J. Sleepless latency of human cytomegalovirus. Med Micro- Immunol 2014; 164:30–31.
biol Immun 2015; 204:421–429. 57. Elordui JP, Gonzalez PA, Sagastagoitia JO, de Z, et al. Infliximab como
28. Goodrum F. Human cytomegalovirus latency: approaching the gordian knot. tratamiento de la enteropatı́a severa en un paciente con inmunodeficiencia
Ann Rev Virol 2015; 3:1–25. común variable e infección por citomegalovirus. Gastroenterol Hepatol 2018;
29. Simon CO, Holtappels R, Tervo H-M, et al. CD8 T cells control cytomega- 41:163–164.
lovirus latency by epitope-specific sensing of transcriptional reactivation. J 58. Ishikawa K, Ando Y, Narita M, et al. Cytomegalovirus retinitis during immu-
Virol 2006; 80:10436–10456. notherapy for common variable immunodeficiency. J Infect 2002; 44:55–56.
30. Imlay H, Dasgupta S, Boeckh M, et al. Risk factors for cytomegalovirus 59. Kathi P, Tama M, Reddy V, et al. Acute gastrointestinal bleeding due to
reactivation and association with outcomes in critically ill adults with sepsis: cytomegalovirus colitis in a patient with common variable immunodeficiency.
a pooled analysis of prospective studies. J Infect Dis 2020; 223:2108–2112. ACG Case Rep J 2018; 5:e40.
31. Lachance P, Chen J, Featherstone R, Sligl WI. Association between cyto- 60. Koźlik P, Kosałka J, Gała˛zka K, et al. Cytomegalovirus gastroenteritis
megalovirus reactivation and clinical outcomes in immunocompetent critically with pyloric stenosis and persistent malabsorption in a patient with
ill patients: a systematic review and meta-analysis. Open Forum Infect Dis common variable immunodeficiency. Pol Arch Intern Med 2018;
2017; 4:ofx029. 128:783–784.
32. Cook CH, Trgovcich J. Cytomegalovirus reactivation in critically ill immuno- 61. Kuntz M, Goldacker S, Blum HE, et al. Analysis of bulk and virus-specific
competent hosts: a decade of progress and remaining challenges. Antivir Res CD8þ T cells reveals advanced differentiation of CD8þ T cells in patients
2011; 90:151–159. with common variable immunodeficiency. Clin Immunol 2011; 141:177–186.
33. Stéphan F, Clergue F, Méhari D, et al. Evaluation by polymerase chain reaction 62. Magalhães-Costa P, Bispo M, Chagas C. Cytomegalovirus enterocolitis in a
of cytomegalovirus reactivation in intensive care patients under mechanical patient with common variable immunodeficiency: A capsule endoscopy-aided
ventilation. Intensive Care Med 1996; 22:1244–1249. diagnosis. Gastroenterol Hepatol Engl Ed 2016; 39:336–338.
34. Chakravarti B, Abraham GN. Aging and T-cell-mediated immunity. Mech 63. Medlicott SAC, Coderre S, Horne G, Panaccione R. Multimodal immuno-
Ageing Dev 1999; 108:183–206. suppressant therapy in steroid-refractory common variable immunodeficiency
35. Hemmersbach-Miller M, Alexander BD, Pieper CF, Schmader KE. Age sprue: a case report complicating cytomegalovirus infection. Int J Surg Pathol
matters: older age as a risk factor for CMV reactivation in the CMV seros- 2006; 14:101–106.
tatus–positive kidney transplant recipient. Eur J Clin Microbiol 2020; 64. Nasa M, Mishra SR, Lipi L, Sud R. Common variable immunodeficiency
39:455–463. syndrome with chronic diarrhoea. BMJ Case Rep 2019; 12:e228240.

670 www.co-infectiousdiseases.com Volume 34  Number 6  December 2021

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.


Cytomegalovirus in primary immunodeficiency Godsell et al.

65. Raeiszadeh M, Kopycinski J, Paston SJ, et al. The T cell response to persistent 79. Oksenhendler E, Gérard L, Fieschi C, et al. Infections in 252 patients with
herpes virus infections in common variable immunodeficiency. Clin Exp common variable immunodeficiency. Clin Infect Dis 2008; 46:1547–1554.
Immunol 2006; 146:234–242. 80. Gracia-Guindo MDCD, Ruiz-Fuentes MDC, Galindo-Sacristán P, et al. Cyto-
66. Sewell WA, Marshall SE, Mullighan CG, Bird AG. A hypogammaglobulinae- megalovirus infection monitoring based on interferon gamma release assay in
mic man with respiratory failure. Postgrad Med J 1998; 74:503–504. kidney transplantation. Transplant Proc 2018; 50:578–580.
67. Stack E, Washington K, Avant GR, Eisen GM. Cytomegalovirus enteritis in 81. Rezahosseini O, Møller DL, Knudsen AD, et al. Use of T cell mediated immune
common variable immunodeficiency. South Med J 2004; 97:96–101. functional assays for adjustment of immunosuppressive or antiinfective agents
68. Tahan V, Dobrucali A, Canbakan B, et al. CASE REPORT: cytomegalovirus in solid organ transplant recipients: a systematic review. Front Immunol 2020;
infection of gastrointestinal tract with multiple ulcers and strictures, causing 11:567715.
obstruction in a patient with common variable immunodeficiency syndrome. 82. Rogers R, Saharia K, Chandorkar A, et al. Clinical experience with a novel
Digest Dis Sci 2000; 45:1781–1785. assay measuring cytomegalovirus (CMV)-specific CD4þ and CD8þ T-cell
69. Ünal B, Başsorgun Cİ. Gön€ ulc€
u SÇ, et al. Cytomegalovirus colitis with immunity by flow cytometry and intracellular cytokine staining to predict
common variable immunodeficiency and Crohn’s disease. Case Rep Med clinically significant CMV events. Bmc Infect Dis 2020; 20:58.
2015; 2015:1–4. 83. Yong MK, Cameron PU, Slavin M, et al. Identifying cytomegalovirus complica-
70. Witte T, Werwitzke S, Schmidt RE. CMV complications in common variable tions using the quantiferon-CMV assay after allogeneic hematopoietic stem
immunodeficiency. Immunobiology 2000; 202:194–198. cell transplantation. J Infect Dis 2017; 215:1684–1694.
71. Yousry TA, Strupp M, Br€ uning R. Common variable immunodeficiency leading 84. Yong MK, Lewin SR, Manuel O. Immune monitoring for CMV in transplanta-
to spinal subacute combined degeneration monitored by MRI. J Neurology tion. Curr Infect Dis Rep 2018; 20:4.
Neurosurg Psychiatry 1998; 64:663–666. 85. Venton G, Crocchiolo R, F€ urst S, et al. Risk factors of Ganciclovir-related
72. Kim E, Asmar BI, Thomas R, Abdel-Haq N. Cytomegalovirus viremia and neutropenia after allogeneic stem cell transplantation: a retrospective mono-
&& resistance patterns in immunocompromised children: An 11-year experience. centre study on 547 patients. Clin Microbiol Infect 2014; 20:160–166.
Pediatr Hemat Oncol 2019; 37:1–10. 86. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and
Description of fatal outcomes with multidrug resistant CMV in the context of PID, mortality in common variable immune deficiency over 4 decades. Blood 2012;
highlighting the challenges managing CMV disease in this context. 119:1650–1657.
73. Yong MK, Ananda-Rajah M, Cameron PU, et al. Cytomegalovirus reactivation 87. Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cyto-
is associated with increased risk of late-onset invasive fungal disease after megalovirus in hematopoietic-cell transplantation. N Engl J Med 2017;
allogeneic hematopoietic stem cell transplantation: a multicenter study in the 377:2433–2444.
current era of viral load monitoring. Biol Blood Marrow Transplant 2017; 88. Marty FM, Alexander B, Brissot E, et al. A phase 3 randomized study of
23:1961–1967. maribavir (MBV) versus investigator-assigned antiviral therapy (IAT) for the
74. Kralickova P, Mala E, Vokurkova D, et al. Cytomegalovirus disease in patients treatment (Tx) of refractory/resistant (R/R) cytomegalovirus (CMV) infection in
with common variable immunodeficiency: three case reports. Int Arch Allergy hematopoietic cell transplant (HCT) or solid organ transplant (SOT) recipi-
Immunol 2014; 163:69–74. ents; 2021. Abstract LBA2. https://tct.confex.com/tct/2021/meetingapp.cgi/
75. Durand CM, Marr KA, Arnold CA, et al. Detection of cytomegalovirus DNA in Paper/18096. [Accessed 2 July 2021].
plasma as an adjunct diagnostic for gastrointestinal tract disease in kidney 89. Popping S, Dalm VASH, L€ ubke N, et al. Emergence and persistence of
and liver transplant recipients. Clin Infect Dis 2013; 57:1550–1559. & letermovir-resistant cytomegalovirus in a patient with primary immunodefi-
76. Rizvi F, Zainaldain H, Rafiemanesh H, et al. Autoimmunity in common variable ciency. Open Forum Infect Dis 2019; 6:ofz375.
immunodeficiency: a systematic review and meta-analysis. Exp Rev Clin Emergence of letermovir resistance with prolonged treatment in PID.
Immunol 2020; 16:1227–1235. 90. Bright PD, Gompels M, Donati M, Johnston S. Successful oral treatment of
77. Cunningham-Rundles C. The many faces of common variable immunodefi- Ganciclovir resistant cytomegalovirus with Maribavir in the context of primary
ciency. Hematol Am Soc Hematol Educ Program 2012; 2012:301–305. immunodeficiency: frst case report and review. J Clin Virol 2017; 87:12–16.
78. Chapel H, Lucas M, Lee M, et al. Common variable immunodeficiency 91. Naik S, Nicholas SK, Martinez CA, et al. Adoptive immunotherapy for primary
disorders: division into distinct clinical phenotypes. Blood 2008; 112: immunodeficiency disorders with virus-specific T lymphocytes. J Allergy Clin
277–286. Immunol 2016; 137:1498–1505. e1.

0951-7375 Copyright ß 2021 Wolters Kluwer Health, Inc. All rights reserved. www.co-infectiousdiseases.com 671

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

You might also like