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SYMPOSIUM: INFECTION (& IMMUNITY)

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.

Haematopoietic stem cell transplant procedure


Replacement of the defective haematopoietic stem cell with a
healthy allogeneic haematopoietic stem cell replaces nonfunctional cells in many primary immunodeficiency, nonmalignant haematological or metabolic diseases, or permits
development of cellular elements that were arrested by the
mutated gene. In malignant disease, chemotherapy- and
radiotherapy-induced marrow aplasia can be rescued by infusion
of autologous or allogeneic stem cells, with the advantage of
donor-versus-malignancy alloreactivity following an allogeneic
transplant procedure. Two tenets underline HSCT as an effective,
relatively safe clinical procedure:
 a combination of drugs, with or without antibodies, given
before infusion of stem cells, to destroy host haematopoiesis and peripheral immune cells, and to prevent rejection
of the graft e the conditioning regimen
 transplantation of sufficient stem cell inoculum to ensure
lifelong reconstitution of all haematopoietic lineages.
Stem cell donors include HLA-matched siblings or other
family members, HLA-matched or partially matched unrelated
donors, or HLA haplo-identical (often parental) donors, for
which extensive depletion of T lymphocytes from the inoculum is
necessary to prevent fatal GvHD, but increases the risk of viral
infection. Stem cell sources include bone marrow, G-CSF mobilized peripheral blood stem cells and umbilical cord blood stem
cells. Selection or depletion of specific cell populations from the
graft inoculum enables particular properties to be removed or
enhanced e.g. removal of GvHD-causing T lymphocytes, or selection of viral-specific cytotoxic T lymphocytes.

Keywords extracorporeal photopheresis; haematopoietic stem cell


transplantation; mesenchymal stem cells; minimal intensity conditioning;
T-lymphocyte depletion; virus-specific cytotoxic T lymphocytes

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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SYMPOSIUM: INFECTION (& IMMUNITY)

Infection through the transplant period

immunoglobulin infusions provide additional protection through


the transplant period. Trimethoprim-sulfamethoxazole prophylaxis protects against Pneumocystis jiroveci pneumonitis. A low
bacterial diet is recommended.

Three periods can be identified through the post-transplant


period when infection due to specific pathogens predominates
(Figure 1). The early phase covers the first month post-transplantation when the breakdown of mucous membrane barriers,
and chemotherapy-induced agranulocytosis and alymphocytosis
predispose to infections due to enteric gram-negative and -positive bacteria, Candida species and herpes virus. Recombinant GCSF reduces the period of agranulocytosis. When severe fungal
infections are present, patients may be treated with granulocyte
infusions, augmented by G-CSF, as well as appropriate antifungal
chemotherapy, until neutrophil engraftment occurs.
The second phase follows engraftment to around 100 days,
when indwelling venous catheters may become colonized,
particularly with gram-positive skin commensal bacteria. Infection from herpes viruses and adenovirus is a risk, from preexisting or newly acquired environmental infection, transfer of
infection from the donor inoculum, or reactivation of latent
infection and will be detected by regular PCR surveillance.
Fungal infection may also cause problems during this time.
Infection susceptibility may be compounded by administration of
immunosuppression to prevent or treat GvHD.
In the later phase following transplantation, after 100 days,
infection susceptibility is predominantly confined to encapsulated bacteria, particularly in those who are anatomically or
functionally asplenic, particularly following radiotherapy. However, in the presence of on-going acute or chronic GvHD, patients
also remain susceptible to viral and fungal infections secondary
to immunosuppressive treatment (Figure 2).

Maintenance of mucosal integrity


During the period of aplasia, the integrity of mucosal membranes
can be compromised, potentially allowing translocation of resident microbiota or colonizing micro-organisms into the bloodstream, potentially leading to infection of indwelling venous
catheters or septicaemia. In addition to the risk to the patient of
infectious complications, the associated release of inflammatory
cytokines can further prime the patient to develop GvHD. The use
of keratinocyte-growth factor, if given during the conditioning
period, can prevent or reduce the severity of mucositis, thus
reducing the risk of microbe translocation, although it seems more
effective when radiation-based conditioning regimens are
employed, rather than those based on chemotherapy. Animal
studies have suggested a role for keratinocyte-growth factor in
enhancing thymopoiesis, reducing the lymphopenic period, but
human studies have so far failed to demonstrate this phenomenon.

Assessment and treatment of pre-existing infection


Pre-existing infections pose a particular problem for patients undergoing HSCT, and so patients should be carefully screened prior to
commencing transplantation, including bronchoalveolar lavage at
time of anaesthetic during insertion of venous indwelling catheters.
For patients with primary immunodeficiency, it may not be possible
to clear infection until competent immunity has been achieved, and
many patients will commence the transplant procedure with ongoing pre-existing infection, which significantly increases the risk
of complications and may alter the outcome. For those patients in
whom some protective immunity may be expected prior to transplantation, the transplant is best postponed if infection is detected
prior to chemotherapy commencing, in order to effectively treat the
infection. This may require postponement of timing of the chemotherapy, particularly if respiratory viral infection has been identified. For patients with prolonged neutropenia or neutrophil
dysfunction, or who have received prolonged immunosuppressive
treatment including corticosteroids and monoclonal antibodies,
invasive fungal infection is a particular risk e such patients should
be carefully screened prior to transplantation, using computerized
tomography, as well as bronchoalveolar lavage e suspicious lesions may require biopsy, to accurately identify the organism and
obtain chemotherapeutic sensitivities. A prolonged course of antifungal treatment should be given before proceeding with HSCT, and
surgical clearance may be required, particularly when blood supply
to the lesion is compromised.
Screening of viruses, particularly cytomegalovirus (CMV),
adenovirus and EpsteinBarr virus (EBV) by polymerase chain
reaction (PCR) should be performed prior to transplantation and
through the transplant course. Pre-transplant treatment with
ganciclovir, foscarnet or cidofovir may help reduce the viral load,
particularly in patients who are significantly immunocompromised. Prior knowledge of the recipients viral status pre-HSCT
will help in the choice of donor e a CMV positive recipient will
benefit most from a donor who is also CMV positive, and has preexisting circulating CMV-specific cytotoxic T lymphocytes.

PAEDIATRICS AND CHILD HEALTH 24:6

Routine viral surveillance and treatment


In children, three viral pathogens are of particular concern:
 Cytomegalovirus
Reactivation has been reported in 40e70% of HSCT recipients
who are seropositive or have a seropositive donor. Viraemia can
be associated with organ disease, particularly pneumonitis,
hepatitis, colitis and retinitis.
 EpsteinBarr virus
Infection is a major concern, following HSCT, particularly
during periods of lymphopenia. Prior to the introduction of rituximab therapy, between 11 and 26% of transplant recipients
developed EBV-related B-lymphoproliferative disease.
 Adenovirus
Disseminated infection leads to pneumonitis, hepatitis, and
colitis. Mortality rates of up to 50% are reported.
The widespread introduction of surveillance screening for viruses by PCR of blood, stool and respiratory secretions has facilitated pre-emptive treatment with antiviral drug therapy, and, when
possible, early withdrawal of immunosuppression, before viral
disease occurs. However, particularly in conjunction with GvHD,
viral disease remains the single most important factor influencing
mortality after allogeneic transplantation in children. A recent
study looked at the impact of viral infections post-HSCT in the
modern era of viral surveillance screening. Pre-existing adenovirus
infection, CMV or EBV seropositivity and in-vivo T-lymphocyte
depletion using serotherapy were significant risk factors for viral
reactivation in blood. Reduced intensity conditioning was found to
be a risk factor for EBV reactivation, as previously described. Acute

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SYMPOSIUM: INFECTION (& IMMUNITY)

Preengraftmen
Days 0 - +30

Post-engraftment
Days +30 - +100

Late Phase
Days +100 - >+180

Gram ve and
Gram +ve bacteria

Bacteria

Encapsulated bacteria

Aspergillus species, Toxoplasma, Candida species


Fungi

Pneumocystis jroveci

Enteric and respiratory viruses


Human Herpes 6 virus
Adenovirus
Epstein Barr virus (PTLD)
Cytomegalovirus
Viruses

Herpes simplex virus

30

Varicella zoster virus

90

60

120

150

180

Days post transplantation


Figure 1 Timeline through haematopoietic stem cell transplantation period indicating when specific infections are most likely. Courtesy of the Bubble
Foundation UK.

GvHD (grade II) was significantly associated with adenovirus and


EBV reactivation.

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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SYMPOSIUM: INFECTION (& IMMUNITY)

(normal or CMV-specific hyperimmune) is not recommended as


prophylaxis, but should be used in patients with primary immunodeficiency. However, CMV disease developing from a primary infection should be treated with ganciclovir or foscarnet
monotherapy and intravenous immunoglobulin. Patients in
whom CMV disease develops whilst on pre-emptive therapy or
who have clinically progressive disease, require drug resistance
testing. Increased drug doses should be given and combination
therapy considered. Reduction in immunosuppression, particularly in corticosteroid dose, is strongly recommended when
possible. CMV-safe blood products should be given when recipient and donor are CMV-negative, either derived from CMV IgGnegative donors or achieved by leucodepletion. In the UK, universal leucodepletion has mainly replaced blood products
collected from CMV-negative donors since May 2012, although
these products are available on request.

monoclonal antibody that targets CD20, a B lymphocyte-specific


surface molecule has been used in prophylaxis and treatment of
EBV-disease. Because CD20 expression is not confined to the
malignant cells, normal B cells are also destroyed and so rituximab should be used as pre-emptive therapy for PTLD when
there is a high risk of subsequent lymphoma. In high-risk cases,
where there is malignant transformation of B lymphocytes, or
patients have failed to respond to alternative treatments,
chemotherapy with regimens used to treat lymphoma, such as
cyclophosphamide, doxorubicin, vincristine, and prednisone is a
therapeutic option. In the HSCT setting, once T lymphocyte immunity is restored, EBV is controlled, and there is little risk of
disease recurrence. However, in the setting of poor immune
reconstitution and on-going GvHD the prognosis is poor. Disease
of the central nervous system is also associated with a poor
outlook.

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.

Preservation of immune function through transplantation


Given that the risk of infection is highest immediately following
chemotherapy and infusion of the inoculum until engraftment
and the commencement of myelopoiesis, strategies to reduce the
period and severity of aplasia will reduce this risk. Replete stem
cell sources that contain mature cells of all lineages, as well as
precursors and stem cells are more effective at countering
infection than products that have been manipulated.
A number of non-myeloablative or reduced intensity conditioning regimens are now employed, that are less toxic than
conventional myeloablative treatments. Fungal infections are a
particular problem in patients with phagocytic defects. In a
recent study of 58 high-risk patients undergoing HSCT for
chronic granulomatous disease, 14 had invasive fungal disease e
two died, but none of fungal complications. A minimal intensity
antibody-based regimen was trialled in 16 high-risk PID patients
e in 14, neutrophil recovery occurred at a median of 9.5 days
(range 1e15). The use of serotherapy as part of the preconditioning regimen causes in-vivo depletion of graft T lymphocytes, reducing the risk of GvHD, but increasing the length of
time to appearance of donor T lymphocytes, and the risk of
infection. Three studies have reported on omitting or reducing
the dose of serotherapy in patients receiving umbilical cord blood
stem cells for PID. In these studies, T lymphocytes appeared
much more quickly than following conventional cord blood
transplantation, resulting in faster clearance of viral infection.
In HLA-mismatched transplants, removal of mature T lymphocytes is necessary to prevent GvHD, but leaves the patient
alymphopenic, for at least 120 days, until thymopoiesis develops,
leaving the patient susceptible, as T lymphocyte immunity is
required to clear viral infection. Extensive depletion of all cellular
elements other than the haematopoietic stem cell risks incomplete donor chimaerism, and an increased risk of viral disease.
New techniques are being used to selectively remove specific
elements of the inoculum, depleting harmful GvHD-causing
mature T lymphocytes, whilst retaining cellular precursors and
mature Natural Killer lymphocytes, thus retaining antiviral activity and enabling control of viral disease. A more recent
development selectively depletes CD3 T lymphocytes that express a T lymphocyte receptor composed of ab chains (more
likely to cause GvHD), but retain those with a receptor composed

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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SYMPOSIUM: INFECTION (& IMMUNITY)

of gd chains, which confer antiviral and antitumour activity. A


similar technique depletes CD45RA T lymphocytes, but leaves
the CD45RA fraction, which contains memory cells with
antiviral specificity e clinical trials using this technique are in
progress.

intracellularly to cidofovir diphosphate after cleavage of its lipid


moiety and phosphorylation by intracellular kinases. It is
absorbed in the small intestine and transported throughout the
body as a phospholipid. Unlike cidofovir, CMX001 is not
concentrated in renal proximal tubules, and is therefore unlikely
to have renal toxicity. A recently published trial demonstrated
that the incidence of CMV-associated events was significantly
lower in HSCT patients who received prophylactic CMX001, than
placebo, including some receiving immunosuppression for
GvHD. The drug was well tolerated, and there was no increased
myelosuppression or nephrotoxicity, common toxic effects
observed in patients who receive ganciclovir, valganciclovir,
foscarnet, or cidofovir. The role of CMX001 in the treatment of
CMV, and adenovirus disease is yet to be explored, but as
myelosuppression and nephrotoxicity significantly impact on
treatment with current agents, it holds great promise.

Immunomodulatory treatments for GvHD


The most significant transplant-induced complication is GvHD,
caused when mature alloreactive donor cells are activated
against recipient tissue antigens. Methylprednisolone at a dose of
2 mg/kg remains the first line treatment for acute GvHD, and
complete response rates of 25e50% can be expected. For patients who fail first line treatment, a number of second and third
line immunosuppressive agents are available, but all significantly
increase the risk of infection, which is a common cause of
morbidity and mortality in patients with steroid non-responsive
GvHD.
Two treatment modalities have novel mechanisms, which
appear to be predominantly immunomodulatory, rather than
immunosuppressive. Mesenchymal stromal cells (MSC) are a
population of adherent cells that can differentiate into multiple
mesenchymal lineages, including adipose tissue, cartilage and
bone. Ex vivo expanded MSCs have potent inhibitory effects on Tlymphocyte proliferation in response to polyclonal activation as
well as to alloantigens, and prevent generation of cytotoxic T
lymphocytes towards allogeneic targets. They inhibit monocyte
to dendritic cell differentiation and promote regulatory T
lymphocyte generation. In a study of 37 patients receiving MSC
for the treatment of steroid resistant severe GvHD, deaths from
viral infection were significantly less in those responding to MSC
therapy, than in those who did not respond. Critically, patients
receiving MSC to treat severe GvHD are able to mount T
lymphocyte-directed antiviral responses.
Extracorporeal photopheresis may act by immunomodulation,
rather than immunosuppression. During extracorporeal photopheresis, mononuclear cells are treated with the photosensitizing
agent 8-methoxypsoralen and irradiated with ultraviolet light A
(UVA 320e400 nm) in an extracorporeal system before reinfusion. Apoptosis of lymphocytes induces monocytes to
develop into tolerogenic dendritic cells, controlling GvHD, and
facilitating a reduction in conventional immunosuppression
which enables viral-specific T lymphocytes to clear virus.

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

PAEDIATRICS AND CHILD HEALTH 24:6

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2013 Elsevier Ltd. All rights reserved.

SYMPOSIUM: INFECTION (& IMMUNITY)

dx.doi.org/10.1016/j.bbmt.2013.11.005 [Epub ahead of print]. pii:


S1083e8791(13)00524-7.
Leen AM, Bollard CM, Mendizabal AM, et al. Multicenter study of banked
third-party virus-specific T cells to treat severe viral infections after
hematopoietic stem cell transplantation. Blood 2013; 12: 5113e23.
Lindemans CA, Chiesa R, Amrolia PJ, et al. The impact of thymoglobulin
prior to pediatric unrelated umbilical cord blood transplantation on
immune-reconstitution and clinical outcome. Blood 2013 Nov 1 [Epub
ahead of print].
Marty FM, Winston DJ, Rowley SD, et al. CMX001-201 Clinical Study Group.
CMX001 to prevent cytomegalovirus disease in hematopoietic-cell
transplantation. N Engl J Med 2013; 369: 1227e36.
Matthes-Martin S, Feuchtinger T, Shaw PJ, et al. Fourth European Conference on Infections in Leukemia. European guidelines for diagnosis
and treatment of adenovirus infection in leukemia and stem cell
transplantation: summary of ECIL-4 (2011). Transpl Infect Dis 2012;
14: 555e63.
Qasim W, Gilmour K, Zhan H, et al. Interferon-g capture T cell therapy for
persistent Adenoviraemia following allogeneic haematopoietic stem
cell transplantation. Br J Haematol 2013; 161: 449e52.
Schumm M, Lang P, Bethge W, et al. Depletion of T-cell receptor alpha/beta and CD19 positive cells from apheresis products with the CliniMACS device. Cytotherapy 2013; 15: 1253e8.
Slatter M, Nademi Z, Patel S, et al. Haploidentical hematopoietic stem cell
transplantation can lead to viral clearance in severe combined immunodeficiency. J Allergy Clin Immunol 2013; 131: 1705e8.
Teschner D, Distler E, Wehler D, et al. Depletion of naive T cells using
clinical grade magnetic CD45RA beads: a new approach for GVHD
prophylaxis. Bone Marrow Transpl 2013 Aug 12; http://dx.doi.org/10.
1038/bmt.2013.114 [Epub ahead of print].
Worth A, Conyers R, Cohen J, et al. Pre-emptive rituximab based on viraemia and T cell reconstitution: a highly effective strategy for the
prevention of EpsteineBarr virus-associated lymphoproliferative disease following stem cell transplantation. Br J Haematol 2011; 155:
377e85.

Two direct selection techniques which are most clinically


applicable are:
 selection according to binding of class I HLA-peptide
multimers
 selection according to induction of cytokine secretion in
response to viral proteins or peptides.
Of these, the latter has been developed, using gamma-capture, where viral-specific T lymphocytes secrete interferon
gamma in response to stimulation with appropriate viral antigen.
Antiinterferon gamma antibody, attached to an organic iron bead
may be used to select these cells as they are passed through a
magnetic column e a commercially available closed system is
now available to perform this, facilitating the establishment of
banks of viral-specific cytotoxic T lymphocytes generated from
virus-immune individuals with common HLA types. These cells
can be frozen and stored which will expand this treatment to
many more patients.

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://

PAEDIATRICS AND CHILD HEALTH 24:6

Clinical practice points


C

241

Infection remains a significant cause of morbidity and mortality


in patients undergoing HSCT.
Minimal intensity conditioning regimens reduce the period of
bone marrow aplasia when patients are most at risk of
developing life-threatening bacterial or fungal infection.
Weekly surveillance for herpes- and adenovirus infection enables pre-emptive treatment before disease develops.
New methods of T-lymphocyte depletion of the graft retain
Natural Killer cells and specific T lymphocyte subsets more
likely to exhibit antiviral activity.
Immunomodulatory methods of treating graft-versus 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 to treat patients with third
party lymphocyte infusions.

2013 Elsevier Ltd. All rights reserved.

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