Infection followinghaematopoietic stem celltransplantationAndrew R Gennery

Paraskevi Maggina

who develop infection through the transplant period are being intro-

SYMPOSIUM: INFECTION (& IMMUNITY)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 Pae-

diatric 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.duced. 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. Reduction or omission of sero-

therapy as part of the conditioning regimen preserves donor lymphocytes

and results in more rapid viral clearance. Weekly surveillance for herpes-

and 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 graft-

versus host disease enable a reduction in conventional immunosuppres-

sion, 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.

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 pri-

mary immunodeficiency (PID). Other diseases with disorderedAbstractHaematopoietic stem cell transplantation is offered to increasing numbers

of patients, with the potential of curing underlying disease. Whilst sur-

vival 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 patientsPAEDIATRICS AND CHILD HEALTH 24:6 236immunological function, or where the primary gene defect re-

sides 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 post-

transplant 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 graft-

versus 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.

Haematopoietic stem cell transplant procedure

Replacement of the defective haematopoietic stem cell with a

healthy allogeneic haematopoietic stem cell replaces non-

functional cells in many primary immunodeficiency, non-

malignant 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, givenbefore infusion of stem cells, to destroy host haematopoi-

esis and peripheral immune cells, and to prevent rejection

of the graft e the conditioning regimen

transplantation of sufficient stem cell inoculum to ensurelifelong 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 mobi-

lized 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 se-

lection of viral-specific cytotoxic T lymphocytes.

Preventative measures

The preparative conditioning regimen administered before infu-

sion of the stem cell product renders the patient aplastic until

haematopoiesis commences, leaving the patient extremely sus-

ceptible to infection. Protective isolation of the patient during the

most vulnerable period, in high-efficiency particulate air filtra-

tion or laminar airflow cubicles, helps to minimize infection from

airborne fungi and viruses. Scrupulous attention to hand disin-

fection 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 2013 Elsevier Ltd. All rights reserved.

therapy, particularly if respiratory viral infection has been identi-

load,

particularly in patients who are significantly immunocompro-

SYMPOSIUM: INFECTION (& IMMUNITY)mised. 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 pre-

existing circulating CMV-specific cytotoxic T lymphocytes.ganciclovir, foscarnet or cidofovir may help reduce the viralfied. 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 riske such patients should

be carefully screened prior to transplantation, using computerized

tomography, as well as bronchoalveolar lavage e suspicious le-

sions may require biopsy, to accurately identify the organism and

obtain chemotherapeutic sensitivities. A prolonged course of anti-

fungal treatment should be given before proceedingwithHSCT, and

surgical clearancemay 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 withimmunoglobulin infusions provide additional protection through

the transplant period. Trimethoprim-sulfamethoxazole prophy-

laxis protects against Pneumocystis jiroveci pneumonitis. A low

bacterial diet is recommended.

Maintenance of mucosal integrity

During the period of aplasia, the integrity of mucosal membranes

can be compromised, potentially allowing translocation of resi-

dent microbiota or colonizing micro-organisms into the blood-

stream, 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 developGvHD. 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 seemsmore

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 un-

dergoingHSCT, and sopatients should be carefully screenedprior to

commencing transplantation, including bronchoalveolar lavage at

time of anaesthetic during insertion of venous indwelling catheters.

For patientswith primary immunodeficiency, itmay not be possible

to clear infection until competent immunity has been achieved, and

many patients will commence the transplant procedure with on-

going 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 trans-

plantation, 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 chemo-PAEDIATRICS AND CHILD HEALTH 24:6 237Infection through the transplant period

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-trans-

plantation when the breakdown of mucous membrane barriers,

and chemotherapy-induced agranulocytosis and alymphocytosis

predispose to infections due to enteric gram-negative and -posi-

tive bacteria, Candida species and herpes virus. Recombinant G-

CSF 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. Infec-

tion from herpes viruses and adenovirus is a risk, from pre-

existing 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 encapsu-

lated bacteria, particularly in those who are anatomically or

functionally asplenic, particularly following radiotherapy. How-

ever, 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).

Routine viral surveillance and treatment

In children, three viral pathogens are of particular concern:

CytomegalovirusReactivation 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 virusInfection is a major concern, following HSCT, particularly

during periods of lymphopenia. Prior to the introduction of rit-

uximab therapy, between 11 and 26% of transplant recipients

developed EBV-related B-lymphoproliferative disease.

AdenovirusDisseminated infection leads to pneumonitis, hepatitis, and

colitis. Mortality rates of up to 50% are reported.

The widespread introduction of surveillance screening for vi-

ruses by PCR of blood, stool and respiratory secretions has facili-

tated pre-emptive treatmentwith 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 conditioningwas found to

be a risk factor for EBV reactivation, as previously described. Acute 2013 Elsevier Ltd. All rights reserved.

Pre-engraftmen

Post-engraftment Late PhaseengraftmenDays 0 - +30

Bacteria

Gram ve and Gram +ve bacteria Encapsulated bacteria

Fungi

Aspergillus species, Toxoplasma, Candida species

Pneumocystis jroveci

Enteric and respiratory viruses

Epstein Barr virus (PTLD)

Adenovirus

Viruses Herpes simplex virus

Cytomegalovirus

pos

Days +30 - +100 Days +100 - >+180

Human Herpes 6 virus

in

SYMPOSIUM: INFECTION (& IMMUNITY)Days

Figure 1 Timeline through haematopoietic stem cell transplantation period0 30 60GvHD (grade II)was significantly associatedwith adenovirus andEBV reactivation.

Cytomegalovirus

Recently published guidelines recommend prophylaxis with

acyclovir, in conjunction with weekly monitoring of CMV load in

Foundation UK.

Figure 2 Computerized tomography of (a) thorax and (b) cranium in a patient

receiving a number of immunosuppressive agents, including infliximab. Biopsy

to amphotericin, which the patient was receiving as prophylaxis. Courtesy of

PAEDIATRICS AND CHILD HEALTH 24:6 238Varicella zoster virus

90 120 150 180

t transplantation

dicating when specific infections are most likely. Courtesy of the Bubblethe blood by PCR. Ganciclovir (or valganciclovir if gastrointes-

tinal absorption is normal) is recommended first line treatment,

with foscarnet used as an alternative in the presence of neu-

tropenia, or previous treatment-failure. Cidofovir is recom-

mended as third line treatment in patients unresponsive to, or

intolerant of, both ganciclovir and foscarnet. Immunoglobulin

post-HSCT. The patient had developed graft-versus host disease and was

of the chest lesion demonstrated Scedosporium apiospermum, resistant

the Bubble Foundation UK.

2013 Elsevier Ltd. All rights reserved.

actor

(Allogeneic HSCT with in-vivo or ex-vivo T-cell depletion, unre-

s the

virus-specific enzyme, thymidine kinase, which is not expressed

SYMPOSIUM: INFECTION (& IMMUNITY)in EBV-positive tumours during viral latency. Additional treat-

ment 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 anti-

bodies 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 dehy-

drogenase. Biopsy of suspect lesions will help confirm the diag-

nosis, and stage clinical and histological disease. Reduction of

immunosuppression may be enough to enable cytotoxic T lym-

phocytes to regain control of the B-lymphoproliferation, but is

not always feasible. An alternative strategy is to remove the EBV-

driven B lymphocytes. Rituximab, a chimeric murine/humanestablished, acyclovir alone is ineffective, because it targetlated donor graft or unrelated cord blood graft, grade IIIeIV

GvHD, severe lymphopenia

third

using

cell lines bi-specific for adenovirus and EBV. More recently, a

SYMPOSIUM: INFECTION (& IMMUNITY)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 T-

lymphocyte 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 photo-

pheresis, mononuclear cells are treated with the photosensitizing

agent 8-methoxypsoralen and irradiated with ultraviolet light A

(UVA 320e400 nm) in an extracorporeal system before re-

infusion. 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.

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 vi-

ruses, polyomaviruses and adenoviruses. CMX001 is approxi-

mately 400 times more potent than cidofovir in vitro against

CMV, including ganciclovir-resistant strains. It is convertedtients who fail first line treatment, a number of second andof gd chains, which confer antiviral and antitumour activity. A

similar technique depletes CD45RA T lymphocytes, but leavesthe CD45RA fraction, which contains memory cells withantiviral specificity e clinical trials using this technique are in

progress.

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 pa-PAEDIATRICS AND CHILD HEALTH 24:6 240clinical trial using cell lines active against CMV, adenovirus or

EBV demonstrated efficacy with viral clearance and no signifi-

cant 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. Addi-

tionally, 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 environ-

ment more readily compliant with GMP standards.prophylaxis. HSCT patients have been successfully treatedintracellularly 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.

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 immunosup-

pression to control GvHD. The infusion of unfractionated lym-

phocytes 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 lym-

phoproliferative 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 2013 Elsevier Ltd. All rights reserved.

Two direct selection techniques which are most clinically 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 Con-

ference 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 Clin-

iMACS device. Cytotherapy 2013; 15: 1253e8.

SYMPOSIUM: INFECTION (& IMMUNITY)applicable are:

selection according to binding of class I HLA-peptidemultimers

selection according to induction of cytokine secretion inresponse to viral proteins or peptides.

Of these, the latter has been developed, using gamma-cap-

ture, 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 long-

term 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 steroid-

refractory, 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 Stan-

dards in Haematology; British Society of Blood and Marrow Trans-

plantation, 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 effica-

cious in recipients of TBI-based but not chemotherapy-based allo-

geneic hematopoietic stem cell transplants. Bone Marrow Transpl

2013; 48: 99e104.

Gungor T, Teira P, Slatter M, et al. on behalf of the Inborn Errors Working

Party of the European Society for Blood and Marrow Transplantation.

Reduced-intensity conditioning and HLA-matched haemopoietic stem-

cell 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 hae-

matopoietic 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 241Slatter M, Nademi Z, Patel S, et al. Haploidentical hematopoietic stem cell

transplantation can lead to viral clearance in severe combined im-

munodeficiency. 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 vir-

aemia and T cell reconstitution: a highly effective strategy for the

prevention of EpsteineBarr virus-associated lymphoproliferative dis-

ease following stem cell transplantation. Br J Haematol 2011; 155:

377e85.

Clinical practice points

C Infection remains a significant cause of morbidity and mortality

in patients undergoing HSCT.

C 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.

C Weekly surveillance for herpes- and adenovirus infection en-

ables pre-emptive treatment before disease develops.

C New methods of T-lymphocyte depletion of the graft retain

Natural Killer cells and specific T lymphocyte subsets more

likely to exhibit antiviral activity.

C Immunomodulatory methods of treating graft-versus host

disease enable a reduction in conventional immunosuppres-

sion, which allows control of viral infection.

C New methods of generating virus-specific cytotoxic T lympho-

cytes will facilitate donor banking to treat patients with third

party lymphocyte infusions. 2013 Elsevier Ltd. All rights reserved.

Infection following haematopoietic stem cell transplantationIntroductionHaematopoietic stem cell transplant procedurePreventative measuresMaintenance of mucosal integrity

Assessment and treatment of pre-existing infectionInfection through the transplant periodRoutine viral surveillance and treatmentCytomegalovirusAdenovirusEpstein--Barr virus

Preservation of immune function through transplantationImmunomodulatory treatments for GvHDFuture perspectivesChemotherapeuticsCellular therapies

ConclusionFurther reading