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Infection following
haematopoietic stem cell
transplantation
immunological function, or where the primary gene defect resides in the haematopoietic stem cell are also amenable to
correction with allogeneic HSCT. Expanding unrelated donor
registries, molecular tissue typing, graft engineering techniques,
safer chemotherapy conditioning regimens and improved posttransplant care mean that for some conditions, survival and
cure can be greater than 90%. The most significant causes of
transplant-related morbidity and mortality in the modern era are
infectious complications, which may be associated with graftversus host disease (GvHD). This review will focus on recent
developments that reduce the risk of infectious disease, as well as
detecting and treating post-transplant infectious complications.
Andrew R Gennery
Paraskevi Maggina
Abstract
Haematopoietic stem cell transplantation is offered to increasing numbers
of patients, with the potential of curing underlying disease. Whilst survival rates have significantly improved over recent years, with survival
for some procedures over 90%, infection remains a significant cause of
morbidity and mortality. Strategies to improve the outcome of patients
who develop infection through the transplant period are being introduced. Minimal intensity conditioning regimens reduce the period of
bone marrow aplasia when patients are most at risk of developing lifethreatening bacterial or fungal infection. Reduction or omission of serotherapy as part of the conditioning regimen preserves donor lymphocytes
and results in more rapid viral clearance. Weekly surveillance for herpesand adenovirus infection enables pre-emptive treatment before disease
develops e new antiviral treatments are currently being trialled. Cellular
therapies are more effective at countering viral infection. New methods of
graft manipulation remove T lymphocytes more likely to cause GvHD, but
retain Natural Killer cells and specific T lymphocyte subsets more likely to
exhibit antiviral activity. Immunomodulatory methods of treating graftversus host disease enable a reduction in conventional immunosuppression, which allows control of viral infection. New methods of generating
virus-specific cytotoxic T lymphocytes will facilitate donor banking of
such cells to treat patients with third party lymphocyte infusions.
Introduction
For an increasing number of patients, haematopoietic stem cell
transplantation (HSCT) is a realistic treatment option to treat,
and cure disease, including haematological malignancy or primary immunodeficiency (PID). Other diseases with disordered
Preventative measures
The preparative conditioning regimen administered before infusion of the stem cell product renders the patient aplastic until
haematopoiesis commences, leaving the patient extremely susceptible to infection. Protective isolation of the patient during the
most vulnerable period, in high-efficiency particulate air filtration or laminar airflow cubicles, helps to minimize infection from
airborne fungi and viruses. Scrupulous attention to hand disinfection for staff caring for the patient is critical. The use of masks,
hats, gowns and overshoes is more contentious, although aprons
help to prevent cross-contamination of infection from cubicle to
cubicle. Meticulous patient hygiene is important to minimize
infection from microbiota. An exclusion policy for non-essential
staff, and limiting visitors during the most vulnerable period help
prevent infection. Prophylactic antimicrobials and normal
Andrew R Gennery MD MRCP FRCPCH DCH Dip Med Sci is Clinical Reader in
Paediatric Immunology & Haematopoietic Stem Cell Transplantation at
the Institute of Cellular Medicine and Consultant Paediatrician at the
Great North Childrens Hospital, Newcastle upon Tyne, UK. Conflict of
interest: none.
Paraskevi Maggina MD is a Clinical Fellow at the Department of Paediatric Immunology, Great North Childrens Hospital, Newcastle upon
Tyne, UK, and the Allergy & Clinical Immunology Research Center,
University of Athens (NKUA), Athens, Greece. Conflict of interest: none.
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237
Preengraftmen
Days 0 - +30
Post-engraftment
Days +30 - +100
Late Phase
Days +100 - >+180
Gram ve and
Gram +ve bacteria
Bacteria
Encapsulated bacteria
Pneumocystis jroveci
30
90
60
120
150
180
the blood by PCR. Ganciclovir (or valganciclovir if gastrointestinal absorption is normal) is recommended first line treatment,
with foscarnet used as an alternative in the presence of neutropenia, or previous treatment-failure. Cidofovir is recommended as third line treatment in patients unresponsive to, or
intolerant of, both ganciclovir and foscarnet. Immunoglobulin
Cytomegalovirus
Recently published guidelines recommend prophylaxis with
acyclovir, in conjunction with weekly monitoring of CMV load in
Figure 2 Computerized tomography of (a) thorax and (b) cranium in a patient post-HSCT. The patient had developed graft-versus host disease and was
receiving a number of immunosuppressive agents, including infliximab. Biopsy of the chest lesion demonstrated Scedosporium apiospermum, resistant
to amphotericin, which the patient was receiving as prophylaxis. Courtesy of the Bubble Foundation UK.
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Adenovirus
European guidelines for the diagnosis and treatment of patients
with leukaemia or undergoing HSCT who have adenovirus disease are available. Weekly surveillance screening by PCR of
blood, stool and respiratory secretions should be performed
during the at-risk period. Prophylactic antiviral therapy is not
recommended with the currently available antiviral drugs. Patients who develop viraemia and have at least one risk factor
(Allogeneic HSCT with in-vivo or ex-vivo T-cell depletion, unrelated donor graft or unrelated cord blood graft, grade IIIeIV
GvHD, severe lymphopenia <200 cells/mL) should receive preemptive antiviral treatment with cidofovir 3e5 mg/kg/week
initially for 2e3 weeks and then fortnightly. Immunosuppression
should be reduced whenever possible. Patients with probable or
proven adenoviral disease should be treated with intravenous
cidofovir.
EpsteinBarr virus
EpsteinBarr virus-related disease in the setting of HSCT takes
the form of EBV-driven post-transplant B-lymphoproliferative
disease (PTLD) due to failure of EBV-specific cytotoxic T
lymphocyte control. Prophylactic treatment with acyclovir and
normal immunoglobulin may decrease the incidence of PTLD by
limiting intercellular virus transmission. However, once PTLD is
established, acyclovir alone is ineffective, because it targets the
virus-specific enzyme, thymidine kinase, which is not expressed
in EBV-positive tumours during viral latency. Additional treatment is targeted at restoring the balance between proliferating
EBV-infected B lymphocytes and the cytotoxic T lymphocyte
response, or targeting the B lymphocytes with monoclonal antibodies or chemotherapy. Symptoms of disease include fever and
symptoms due to local lymphoproliferation, which may include
respiratory, gastrointestinal or hepatic, urological or neurological
symptoms. Transplant-associated B-lymphoproliferative disease
is often extranodal. Associated findings include a monoclonal
gammopathy, raised b2 microglobulin and raised lactate dehydrogenase. Biopsy of suspect lesions will help confirm the diagnosis, and stage clinical and histological disease. Reduction of
immunosuppression may be enough to enable cytotoxic T lymphocytes to regain control of the B-lymphoproliferation, but is
not always feasible. An alternative strategy is to remove the EBVdriven B lymphocytes. Rituximab, a chimeric murine/human
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Cellular therapies
Restoration of T lymphocyte-specific immunity is required to
control and clear viral disease following HSCT, hence the greatest
risk is found in those receiving T-lymphocyte depleted stem cell
sources, or who require significant and prolonged immunosuppression to control GvHD. The infusion of unfractionated lymphocytes from donors can clear EBV-PTLD in recipients who had
previously received T-lymphocyte depleted grafts. A bank of
EBV-specific cells established and used to successfully treat,
predominantly solid organ transplant recipients, demonstrated
the efficacy of this approach, and has also been used to treat
patients with primary immunodeficiency presenting with lymphoproliferative disease.
The infusion of HLA-matched virus-specific T lymphocytes
derived from the stem cell donor is an attractive treatment option
to treat HSCT-recipients with viral infection. However, treating
HSCT recipients with, third party, HLA mismatched viral-specific
cytotoxic T lymphocytes risks causing GvHD because of the lack
of recipient immunocompetence. Additionally, the requirement
for banks of lymphocytes with different antiviral specificity
would be overcome if pools of cells from donors had multiple
specificities, particularly against CMV, EBV and adenovirus.
Such approaches have been shown to be effective as therapy
for refractory CMV, EBV and adenovirus infections, as well as
prophylaxis. HSCT patients have been successfully treated using
cell lines bi-specific for adenovirus and EBV. More recently, a
clinical trial using cell lines active against CMV, adenovirus or
EBV demonstrated efficacy with viral clearance and no significant GvHD. However, the substantial ex vivo manipulation
required to generate these cells in initial studies, including the
use of dendritic cells or genetically modified antigen-presenting
cells is financially costly, and impractical on any thing other
than a single patient basis, and non-compliant with current Good
Manufacturing Practice (GMP) regulation and standards. Additionally, when the donor lacks viral immunity because of lack of
previous exposure, or following the use of umbilical cord blood
stem cells, this approach is not possible. New techniques using
direct selection of virus-specific T lymphocytes from seropositive
donors require minimal ex vivo manipulation. This means that
the cells product can be more rapidly and economically produced
in the event of an urgent clinical indication, and in an environment more readily compliant with GMP standards.
Future perspectives
Chemotherapeutics
Current treatment options, particularly antiviral treatments, are
associated with organ toxicities. Whilst the introduction of
cidofovir has significantly improved the treatment of adenoviral
disease, renal toxicities can limit therapy. On the day of cidofovir
administration, nephro-protective measures should be taken
including hyperhydration and oral probenecid. Ideally, other
nephrotoxic drugs should be avoided, but even with these
measures, patients often suffer significant nephrotoxicity.
CMX001 is an orally bioavailable lipid acyclic nucleoside
phosphonate that has potent antiviral activity against herpes viruses, polyomaviruses and adenoviruses. CMX001 is approximately 400 times more potent than cidofovir in vitro against
CMV, including ganciclovir-resistant strains. It is converted
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Conclusion
Infection remains a significant problem through the transplant
period for some patients. New chemotherapeutic agents with less
adverse effects may reduce morbidity from treatment. Innovative
manipulation of stem cell grafts, coupled with less ablative
conditioning regimens and the potential widespread application
of virus-specific T lymphocyte therapy will likely reduce longterm morbidity and mortality.
A
FURTHER READING
Ball LM, Bernardo ME, Roelofs H, et al. Multiple infusions of mesenchymal
stromal cells induce sustained remission in children with steroidrefractory, grade III-IV acute graft-versus-host disease. Br J Haematol
2013; 163: 501e9.
Emery V, Zuckerman M, Jackson G, et al. British Committee for Standards in Haematology; British Society of Blood and Marrow Transplantation, UK Virology Network. Management of cytomegalovirus
infection in haemopoietic stem cell transplantation. Br J Haematol
2013; 162: 25e39.
Goldberg JD, Zheng J, Castro-Malaspina H, et al. Palifermin is efficacious in recipients of TBI-based but not chemotherapy-based allogeneic hematopoietic stem cell transplants. Bone Marrow Transpl
2013; 48: 99e104.
ngo
r T, Teira P, Slatter M, et al. on behalf of the Inborn Errors Working
Gu
Party of the European Society for Blood and Marrow Transplantation.
Reduced-intensity conditioning and HLA-matched haemopoietic stemcell transplantation in patients with chronic granulomatous disease: a
prospective multicentre study. Lancet 2013 Oct 22; http://dx.doi.org/
10.1016/S0140-6736(13)62069-3 [Epub ahead of print]. pii:
S0140e6736(13)62069-3.
Hiwarkar P, Gaspar HB, Gilmour K, et al. Impact of viral reactivations in the
era of pre-emptive antiviral drug therapy following allogeneic haematopoietic SCT in paediatric recipients. Bone Marrow Transpl 2013;
48: 803e8.
Lane JP, Evans PT, Nademi Z, et al. Low dose serotherapy improves early
immune reconstitution after cord blood transplantation for primary
immunodeficiencies. Biol Blood Marrow Transpl 2013 Nov 10; http://
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