Pediatr Blood Cancer 2008;51:451–452

HIGHLIGHTby Roderick Skinner, FRCPCH

1* and Sophie Hambleton, Dphil2*

Prevention of Varicella in Children With Cancer: Is it Time toReconsider our Strategy?

(Commentary on Manley et al., page 540)

C hickenpox (varicella zoster virus [VZV] infection) is one of

the commonest potentially serious viral infections in children

with malignancy. By contrast with their immunocompetent peers,

such children are at greatly increased risk for severe, prolonged and

complicated varicella. Before the advent of effective antiviral

therapy, varicella infection was associated with a mortality rate

of around 7% in children receiving chemotherapy for malignancy

[1]. Deaths occurred as a result of severe complications such as

pneumonitis, hepatitis, encephalitis, and visceral involvement

(e.g., of pancreas, bowel or spleen), which collectively affected

about 30% of these children. The typical vesicular skin lesions of

varicella may be absent or minimal despite such complications,

even in fatal disseminated disease, emphasising the threat posed to

immunocompromised children by this infection [2].

Heightened susceptibility to severe varicella is associated with

impaired cellular immune responses against VZV. Breakdown of

VZV-specific cellular immunity is also responsible for the greatly

increased incidence of herpes zoster (shingles) during immuno-

suppressive treatment in VZV-seropositive children. Not surpris-

ingly, the extent and duration of immunosuppression affects the risk

of VZV disease; for example, lymphopenia has been demonstrated

to be a risk factor for the development of pneumonitis after varicella

infection [3]. Children with acute lymphoblastic leukaemia (ALL)

are particularly vulnerable [3,4] due to the severe and prolonged

immunosuppression that results from contemporary treatment

protocols for this malignancy. In addition, recent steroid treatment

[5] and more intensive chemotherapy regimens, especially haemo-

poietic stem cell transplantation [6], appear to be associated with

increased severity of varicella.

Fortunately, effective antiviral treatment is now available.

Intravenous aciclovir usually provides rapid control of varicella,

even in immunocompromised patients [7]. Nevertheless, it remains

preferable to prevent VZV infection in these highly vulnerable

children rather than to have to treat established infection sub-

sequently. A variety of strategies to prevent severe varicella include

reduction of VZVexposure, universal protection by vaccination and

post-exposure prophylaxis against varicella. In the USA, VZV

circulation has plummeted since the introduction of universal

childhood immunisation against varicella. This is expected to offer

both herd immunity and personal protection against varicella in

those who subsequently develop malignancy, but its impact in this

group has not yet been reported. In those not already protected,

varicella vaccine is immunogenic and effective during maintenance

chemotherapy for paediatric ALL with a low risk of vaccine

complications [8]. However, this practice has not found widespread

use owing to concerns about the requirement to stop chemotherapy

for 2 weeks when the vaccine is given, as well as reports of

rare but serious adverse events. Targeted immunisation of VZV-

seronegative family members and health care professionals is

recommended in an effort to reduce VZV transmission to vulnerable

children [9,10].

The two principle means of post-exposure prophylaxis with

relevance for immunosuppressed children are intramuscular

varicella zoster immunoglobulin (VZIG) [3,11] and oral aciclovir

[12]. The majority of the published literature concerning post-

exposure prophylaxis of VZV relates to VZIG, particularly in

the immunocompromised. However, the UK Royal College of

Paediatrics and Child Health’s Best Practice Statement on the

Immunisation of Immunocompromised Children (2002) acknowl-

edged the increasing clinical experience of aciclovir prophylaxis

(at least in the UK) by recommending the use of either aciclovir or

VZIG for prophylaxis in immunocompromised children, including

those treated for cancer or leukaemia [9]. However, failures

may occur after either strategy [2,13]. There is an urgent need to

document more fully the efficacy of aciclovir and to compare it

with that of VZIG in order to identify the optimum method of post-

exposure prophylaxis in immunosuppressed children, including

those treated with chemotherapy.

Post-exposure prophylaxis is not currently recommended in

the UK for individuals with prior evidence of VZV immunity

(seropositivity), except after haemopoietic stem cell transplanta-

tion; furthermore, routine retesting of initially seropositive patients

has not been advocated. This practice reflects clinical experience

that it is uncommon for children who are VZV-seropositive at

diagnosis to develop varicella [11], even during ongoing immuno-

suppressive treatment. Furthermore, it is uncertain whether VZIG

will increase VZVantibody titres in an already seropositive patient,

and hence whether VZIG will offer any additional benefit [10].

However, the report by Manley et al. from the Paediatric Oncology

� 2008 Wiley-Liss, Inc.DOI 10.1002/pbc.21680

——————Department of Paediatric and Adolescent Oncology, Royal Victoria

Infirmary, Newcastle upon Tyne Hospitals NHS Foundation

Trust, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United

Kingdom; 2Department of Paediatric Immunology, Newcastle General

Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust,

Westgate Road, Newcastle upon Tyne NE4 6BE, United Kingdom

*Correspondence to: Dr. Roderick Skinner, Department of Paediatric

and Adolescent Oncology, Royal Victoria Infirmary, Newcastle upon

Tyne Hospitals NHS Foundation Trust, Queen Victoria Road,

Newcastle upon Tyne NE1 4LP, United Kingdom.

E-mail: roderick.skinner@ncl.ac.uk

Received 23 May 2008; Accepted 27 May 2008

Unit in Liverpool, UK describes nine children with ALL who

developed chickenpox despite previously documented VZV

seropositivity at diagnosis of leukaemia. Retesting at the time

of or after the chickenpox episode showed that five of these

children had lost VZV-specific antibodies. This experience calls into

question the assumption that children who are seropositive at

commencement of immunosuppressive treatment remain protected.

Second episodes of varicella, attributed to reinfection, have been

described in previously VZV-seropositive leukaemic children [14],

and even occasionally in apparently immunocompetent children

[15]. The attrition of varicella vaccine-induced humoral immunity

during cancer chemotherapy has also been noted [16]. Although

Manley et al. suggest that varicella occurred in previously

seropositive children due to reduction or loss of VZV immunity as

a consequence of the immunosuppressive nature of ALL treatment,

it is feasible that their observation may have alternative explana-

tions. For example, could the initial seropositivity at diagnosis

in these patients have been due to blood product transfusions

received before testing [17]? An accompanying clinical history of

varicella would help clarify this point. Nevertheless, Manley’s

data is worrying, especially in an era where the intensity (and hence

immunosuppressive potential) of ALL treatment is increasing.

As the authors have concluded, it will be very instructive to perform

a prospective study of VZV serology, immunological markers

(especially lymphocyte subset numbers) and varicella / zoster

infection patterns in children with ALL. This will help determine

whether prior VZV immunity is indeed lost during contemporary

ALL treatment and hence whether this needs to be accounted for in

post-exposure prophylaxis guidelines.

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452 Skinner and Hambleton