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Infection in Haematology
Indirect Effects of Cytomegalovirus Infection
Götz Ulrich Grigoleit,
1
Markus Kapp
2
and Hermann Einsele
3
1. Senior Physician; 2. Resident Physician; 3. Full Professor, Internal Medicine, and Director,
Medical Clinic II, Julius Maxmilians University Würzburg
Abstract
Primary cytomegalovirus (CMV) infection often presents as an asymptomatic self-limiting disease in immunocompetent individuals and is
followed by latent persistence in different host tissues. However, solid organ transplant (SOT) recipients and patients undergoing allogeneic
haematopoietic stem cell transplantation (alloHSCT) are at risk of life-threatening complications caused by CMV infection. Direct effects (or
CMV disease) are marked by viral proliferation in a variety of tissues and organs. Clinical manifestations that are observed after SOT and
alloHSCT are gastroenteritis, pneumonitis, hepatitis, uveitis, retinitis, encephalitis and graft rejection. In contrast to the direct effects,
indirect effects are a consequence of the maintenance of persistent low-level viral replication and have been associated with an increased
risk of rejection and graft dysfunction, graft-versus-host disease, accelerated atherosclerosis, opportunistic infections, malignancies, post-
transplant diabetes and Guillain-Barré syndrome. This article aims to summarise these indirect effects of CMV, their possible causes and
possible treatment strategies.
Keywords
Cytomegalovirus, indirect effects, immune modulation
Disclosure: The authors have no conflicts of interest to declare.
Received: 13 October 2008 Accepted: 30 June 2009
Correspondence: Götz Ulrich Grigoleit, Medizinische Klinik und Poliklinik II, Building C11, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
E: grigoleit_g@klinik.uni-wuerzburg.de
Human cytomegalovirus (HCMV) is a DNA virus that is part of the Immunomodulatory Effects of
herpesviridae family. Infections are common, with the worldwide Cytomegalovirus Infection
seroprevalence for CMV ranging from approximately 60 to 100%.
1
The replication of CMV may cause a variety of indirect effects due
In immunocompetent individuals, primary CMV infection is often to the interaction with the host immune system. In both SOT and
an asymptomatic and self-limiting disease. If symptomatic, it often alloHSCT patients, the therapeutic effect of immunosuppressive
occurs as a mononucleosis-like syndrome with fever, lymphadenopathy therapy to control rejection may be enhanced by the production of
and splenomegaly. Primary infection is followed by persistence in a immunosuppressive CMV proteins and the immunosuppressive
latent form in different host tissues. There is increasing evidence effects of antiviral agents. Activation of the immune system by viral
that CMV can induce alterations of T-cell function in elderly proteins may lead to the development of rejection and acute or
individuals, e.g. oligoclonal T-cell expansions, narrowing of the T-cell chronic GvHD.
receptor repertoire and accumulation of T-cell subpopulations with
altered functional activity.
2–5
Immunosuppressive effects of CMV infection are caused by CMV
replication-induced changes in lymphocytes, monocytes and
However, CMV infection is still a common and life-threatening dendritic cells (DCs) (see Figure 2) that change their ability to
complication in solid organ transplant (SOT) recipients as well as respond, their ability to produce cytokines and their antigen-
in patients undergoing allogeneic haematopoietic stem cell presenting capacity.
15,16
T-cell recognition, activation and expansion
transplantation (alloHSCT). These patients are harmed by both direct are altered via different pathways.
and indirect effects of CMV infection (see Figure 1). Direct effects
are marked by viral proliferation in a variety of tissues and organs. This suppression of an adequate immune response is one factor
Clinical syndromes that are observed after SOT and HSCT are explaining the common association of CMV infection with other
gastroenteritis, pneumonitis, hepatitis, uveitis, retinitis, encephalitis opportunistic infections (i.e. invasive aspergillosis, Pneumocystis
and graft rejection. In contrast to the direct effects, indirect effects jirovecii pneumonia) or other nosocomial infections, such as fungal
are a consequence of the maintenance of persistent low-level viral and bacterial infections. Further correlation with other herpesviridae
replication and have been associated with an increased risk of has been demonstrated for CMV (e.g. Epstein-Barr virus [EBV]).
17
rejection and graft dysfunction, graft-versus-host disease (GvHD),
accelerated atherosclerosis, opportunistic infections, malignancies, Other indirect effects of CMV, such as graft rejection or GvHD, can
post-transplant diabetes and Guillain-Barré syndrome.
6–14
be explained not by the immunosuppressive effect of CMV
© TOUCH BRIEFINGS 2009 41
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