219

B B & M T
I NTRODUCTI ON
Varicella-zoster virus (VZV), a herpesvirus, consists of a
double-stranded DNA genome surrounded by a pro t e i n
tegument and contained within an icosahedral capsid and an
outer lipid membrane envelope [1,2]. The VZV genome has
69 di sti nct genes that encode protei ns re q u i red for viru s
attachment and entry i nto host cel l s, repli cati on of vi ral
DNA, and synthesi s of new vi ri ons and thei r rel ease or
spread to adjacent uninfected cells (Figure 1).
V Z V, l i ke other human herpesvi ruses, i s a threat to
hematopoieti c cel l transplantation (HCT) recipi ents [3,4].
Duri ng pri mary i nfecti on, whi ch causes vari cel l a, VZV
establishes latency in cells of the dorsal root sensory ganglia.
Among adult HCT patients, most VZV infections represent
a reactivation of the latent virus. Classic herpes zoster, with
its dermatomal vesicular rash, is the most common clinical
s y n d rome caused by VZV reacti vati on, but some HCT
reci pi ents have a gener al i zed vesi cul ar exanthema that
resembl es vari cel l a, syndromes of neuropathi c pai n, or
organ involvement that is not associated with any rash.
BI OLOGY OF VZV LATENCY AND REACTI VATI ON
New i nformati on about the mechanisms of VZV patho-
genesi s helps to expl ain the ri sks associated with VZV re a c-
ti vati on i n H CT reci pi ents. The pathogenesi s of VZV
i nfecti on involves 3 essential cel lular tropi sms: i nfectivi ty
for epitheli al cells of the mucous membranes and skin, for
c i rcul ati ng peri pheral bl ood mononucl ear cel l s, and for
cells of the sensory gangli a.
VZV Infectivity for T Cells and Skin
In addition to causing characteristic ski n lesi ons, VZV
can be detected i n peri pheral bl ood mononucl ear cel l s
f rom healthy and i mmunocompromi sed patients wi th vari-
cel l a and from i mmunodefi ci ent pati ents wi th herpes
z o s t e r. Usi ng the SCI D-hu mouse model, we have demon-
strated that VZV i nfects CD4
+
and CD8
+
human T cell s
and thus shares pathogeni c mechanisms characteristic of
the lymphotropi c and n e u ro t ropic herpesvi ruses (Fi gure
2) [5,6]. I nfecti vi ty for T cell s is a critical component of
the ri sk that VZV presents i n H CT reci pi ents, si nce it
underl ies susceptibili ty to cutaneous and vi sceral dissemi-
nation. Conditions in the SCI D-hu model are simi lar to
those in the peri od i mmedi ately after HCT, since SCI D-
hu mi ce lack the capaci ty to develop VZV-specific immu-
n i t y. When VZV reacti vates i n the human host, i t re p l i -
cates effi ci entl y i n the ski n, pr oduci ng hi gh ti ter s of
i nfecti ous vi rus i n the cutaneous vesi cl es. During acute
herpes zoster, T cells may become i nfected at the si te of
Varicella-Zoster Virus: Pathogenesis, I mmunity,
and Clinical Management in Hematopoietic
Cell Transplant Recipients
Ann M. Arvin
I nfecti ous Disease Di vi sion, Stanford University School of Medici ne, Stanford, Cali forn i a
C o rrespondence and reprint requests: Ann M. Arvi n, MD, G311, I nfecti ous Disease Divi si on, Stanford
University School of Medi ci ne, Stanford, CA 94305-5208; e-mail : arv i n a m @ s t a n f o rd . e d u
(Recei ved Febru a ry 2, 2000; accepted Febru a ry 14, 2000)
ABSTRACT
New information about the mechanisms of varicella-zoster virus (VZV) pathogenesis and the host response to the
v i rus has improved our understanding of the threat that VZV reactivation may pose after hematopoietic cell trans-
plantation (HCT). Antiviral therapy compensates for some of the deciencies in VZV immunity in HCT re c i p i e n t s ,
and inactivated varicella vaccine may be useful for the early reconstitution of adaptive immunity to VZV after HCT.
KEY WORDS
Varicell a-zoster viru s Hematopoi eti c cell transpl antati on L a t e n c y I m m u n o s u p p re s s i o n
Biology of Blood and Marrow Transplantation 6:21 9 230 (2000)
2000 American Society for Blood and Marrow Transplantation
Studies of VZV pathogenesis and immunity in Dr. Arvins laboratory were
sponsored by grants fromtheNational Institute of Allergy and Infectious
Diseases(AI 20459 and AI36884) and theNational Cancer Institute(PO1-
CA49605; Karl Blume, Principal Investigator); inactivated varicella vaccine
for theevaluation of immunereconstitution wasprovided byMerck.
A.M. Arv i n
220
l ocal cutaneous repl i cati on or may acqui re vi rus fro m
actively infected cells wi thin the affected gangli a [7]. I f the
host response i s impai red, T cel ls can transport the vi rus to
lungs, li ver, brai n, and other org a n s .
VZV i nfecti vity for human T cel l s as wel l as ski n i s
re q u i red for pathogenesis, but our comparati ve analyses
of VZV mutant strai ns that have al tered expressi on of
p a rti cul ar viral genes demonstrate that these tropi sms are
mediated by different viral proteins, termed virulence deter-
minants. VZV strains that lack glycoprotein C (gC) expres-
sion have li ttl e or no capaci ty to replicate i n skin. I n con-
trast, gC synthesis is not required for T-cell infection. Thus,
gC is a specic determinant for VZV virulence in skin [6].
I n addi tion to the contri buti on of gl ycoprotei ns to VZV
pathogenesi s, gene products that have no putati ve or
demonstrated rol e i n vi ral entry i nto human cel l s have
e m e rged as key determinants of VZV vi rulence. The pro-
tei ns encoded by the open reading frames (ORFs) 47 and
66 a re serine/threonine protein ki nases [2]. We used VZV
mutants that were constructed to bl ock expr essi on of
ORF47 to demonstrate that this protein is essential for viral
g rowth in human T cells and skin [8]. Absence of ORF66
expression partially inhibited VZV infectivity for T cells but
did not impair replication in skin relative to the intact virus.
I nfecti vi ty for T cel l s and ski n was re s t o red when the
mutant was re p a i red by i nserting i ntact ORF47 back into
the genome. The ORF47 gene product is the rst VZV pro-
tei n to be i dentifi ed as necessary for T-cel l tropism. Like
gC, ORF47 is also essential for skin infectivity in vivo.
Among the human herpesviruses, VZV is related most
closel y to herpes simplex virus (HSV). The compari son of
VZV and HSV-1 infection in the SCI D-hu model revealed
signicant differences in T-cell and skin tropisms that corre-
l ate wi th the cl i nical experi ence of pathol ogi c effects i n
HCT recipients and other immunocompromised individuals
[6]. VZV caused extensive necrosis in deeper dermal layers
of ski n implants, whereas HSV-1 was conned to the epi-
d e rmis. I n contrast to VZV, HSV-1 was not infectious for
human CD4
+
or CD8
+
T cells, which is consistent with the
cl ini cal observation that HSV infection is rarely associated
with viremia, even in high-risk patients.
Classic herpes zoster results from transport of the viru s
along neuronal axons from the cellular sites of latency in dor-
sal root ganglia. However, disseminated VZV infection has
been diagnosed at autopsy i n HCT pati ents without cuta-
neous lesions [3]. This cl inical syndrome suggests that the
v i rus can enter T cells when they trafc through dorsal ro o t
gangl ia during VZV reactivation. Our studies usi ng pol y-
merase chain reaction (PCR) to detect the virus in peri pheral
blood mononuclear cells (PBMC) demonstrate that this event
is not unusual in HCT patients, especially during the r s t
100 days after transplantation (Figure 3) [9]. Activated T cells
a re more permissi ve for VZV i nfection in vi tro, so HCT
patients may be more likely to develop cell-associated infec-
tion because activated T cells persist in circulation for a pro-
longed interval after transplant [10-12]. The eval uation of
HCT recipients by VZV PCR assay demonstrated that VZV
reacti vation can occur wi thout cutaneous l esions and that
many patients resolve reactivation and viremia without devel-
oping si gns of visceral dissemination [9].
N e u ro t r opismof VZV
The hypothesis that herpes zoster results from the re a c-
tivation of latent virus acquired during vari cella was pro v e n
by restri cti on enzyme analysi s showing that a si ngl e VZV
strain caused both varicella and subsequent herpes zoster in
an i mmunocompromised child [13]. Duri ng varicell a, VZV is
postulated to move up neuronal axons from ski n lesions to
the correspondi ng sensory gangl ia. I mmunohi stochemi cal
stains of skin lesions demonstrate the presence of VZV pro-
teins in nerve termini , axons, and Schwann cells [14]. I n our
ani mal model experi ments, subcutaneous i nocul ati on of
guinea pigs with VZV was associated with spread of virus to
s e n s o ry ganglia [15]. Vi remia may also carry VZV to gang l i o n
cell s, as suggested by VZV spread to ganglia i n neonatal rats
i nocul ated i ntraperi toneal ly [16]. After earl ier confli cti ng
re p o rts, recent experi ments done with more sensi tive and
specifi c methods i ndi cate that VZV establi shes l atency i n
Figure 1. Diagramof varicella-zoster virus(VZV) and viral proteinsin VZV-infected cells.
VZV After HCT
221
B B & M T
Figure 2. Varicella-zoster virus(VZV) infection of T cellsand skin in theSCID-hu model. A: Infected T cellswithin a thymus/liver implant after inoculation
with VZV. a: Macrophagesengulf infected T cells. b: Day7, lymphocytedepletion. c: Day21, completedestruction. d: Mock-infected control. B: Virus-induced
changesin an infected skin implant. a: Infected cellsin epidermisand around hair follicles. b: Vesicular lesion involving dermis. c: Mock-infected control.
A
B
A.M. Arv i n
222
n e u ronal as well as satel lite cell s within dorsal root ganglia
[17-20]. How virus/cel l i nteracti ons resul t i n the mai nte-
nance of latency remains uncertain, but these mechani sms
must differ for VZV and HSV. VZV l atency is associated
with the expression of several viral gene products, i n contrast
to HSV, i n whi ch onl y anti sense l atency-associ ated tran-
scripts are detected. Transcripts of ORFs 21, 29, 62, and 63
have been detected, and there is evidence that proteins of
ORFs 4, 21, 29, and 62 are made in l atently i nfected cell s
[17,21]. VZV, like HSV, is presumed to persist in l atently
infected cell s as an episome, rather than by i ntegration into
cel lular DNA [22]; persistence must occur without transla-
tion of the ful l sequence of viral gene products, because
virion production woul d be expected to be associated with
cell lysis. Although the assessment of viral load in ganglia is
d i fcult, quanti tative DNA PCR analysis of human trigemi-
nal gangli a suggests the presence of about 250 VZV genome
equival ents per 10
5
cel ls [23]. The estimates of virus burd e n
suggest that VZV persists i n more cel ls of the tri geminal
than thoraci c gangl ia, whi ch coul d expl ain the re l a t i v e l y
higher incidence of facial zoster. When reactivation occurs,
extensive viral repli cation takes place wi thin the cell s of the
s e n s o ry gangl ia, produci ng pathol ogic changes i ncluding
extensive inammati on and necrosi s [24]. The virus moves to
the skin i nnervated by the involved ganglion via axonal trans-
p o rt, causi ng the dermatomal rash of typi cal herpes zoster.
I MMUNE EVASI ON AND THE HOST RESPONSE
TO VZV I NFECTI ON
Whether the host response contributes di rectly to pre-
s e rvi ng VZV latency at the cellular level is not known. Neu-
rons or satellite cells that harbor VZV are assumed to re m a i n
invisible to the immune system duri ng latency, or adverse
consequences would result from the cumulative destru c t i o n
of neuronal cell s. Nevertheless, the high incidence of herpes
zoster in HCT recipients who are latently infected because of
chil dhood varicella and lose antigen-specic immuni ty during
HCT provides compelling evidence that immunologic mech-
anisms modulate the frequency of symptomatic episodes of
VZV reacti vation. Under ord i n a ry ci rcumstances, h e r p e s
zoster re p resents a useful strategy of the virus, ensuri ng its
persistence in the human population. Cutaneous re c u rre n c e s
give VZV an opportunity for transmission to susceptible close
contacts while causing only a self-limited skin rash with some
n e u ropathic pain, which i s uncomfortable but not li fe-thre a t-
eni ng to the heal thy i ndi vi dual . H erpes zoster i nfecti on
reveals the l imi tations of immune survei ll ance even i n the
immunocompetent host, since it occurs despi te circ u l a t i n g
V Z V- s p e c i c memory T cells. To evade establi shed immu-
n i t y, repli cate in skin cel ls, and release infectious virus into
vesicular uid, VZV virus, it is thought, has evolved ways to
avoid antigen-specic T-cell re s p o n s e s .
I mmune Evasion
Li ke other herpesviruses, VZV encodes gene pro d u c t s
that downregul ate major hi stocompati bi l i ty compl ex
(MHC) class I expressi on on fi brobl asts and T cel l s (A.
A b e n d r oth, I . L i n, A.M.A., unpubl i shed data) [ 25] .
Restricted class I expression i nterf e res wi th recogniti on of
VZV-infected cells by CD8
+
T cells. Although the viral pr o-
tei n or proteins that mediate cl ass I downregulation have
not been identied, we found that MHC class I molecules
exit from the endoplasmic reticulum (ER) but are retained
in the Gol gi (A. Abendroth, I . Li n, A.M.A., unpubl i shed
data). I n contrast, HSV blocks transport of class I proteins
from the ER by effects of I CP47, the product of a gene that
is not found in the VZV genome [26]. Because MHC class I
molecules are expressed on almost all mammalian cells and
function to present foreign peptides to CD8
+
T cells, inter-
ference with their transport to the cell surface makes VZV-
infected cells more difcult to eliminate by this arm of the
antiviral immune response.
I n addi tion to li mi ting MHC class I trafficking to the
cell surface, VZV-infected cells are resistant to the upregu-
l ation of MHC cl ass I I expressi on eli cited by i nterf e ro n
( I F N ) - [27]. MHC cl ass I I molecules present pepti des to
s u p p o rt the cl onal expansi on of CD4
+
T cel ls. Wi th the
excepti on of B cel ls, monocytes, and thymic epi thel ium,
most cells do not express MHC cl ass I I proteins consti tu-
tively, but exposure to I FN- triggers rapid upregulation of
these proteins on membranes of many cell types. VZV- s p ecic
m e m o ry CD4
+
T cel ls are programmed to synthesize and
rel ease I FN- when sti mul ated by vi ral anti gen [7]. Our
analysi s of VZV effects on this pathway revealed that the
block of I FN-induced MHC class I I expression occurred
at the level of gene transcripti on withi n the i nfected cel l
( F i g u re 4). Exami nation of skin biopsi es taken from earl y
herpes zoster lesions demonstrated that VZV-infected cells
did not express MHC class I I in vivo, suggesting a mecha-
nism that transiently protects VZV-infected cells despite cir-
culating VZV memory CD4
+
T cells. This effect is transient
most likely because synthesis and transport of MHC class I I
mol ecules to the cel l surface are normal when uni nfected
cells are exposed to I FN-. As herpes zoster progresses, the
re c ruitment of VZV-speci fic CD4
+
T cell s that pro d u c e
I FN- to the cutaneous site of VZV replication should con-
t rol the cel l-to-cel l spread of the vi rus. Even i f the vi ru s
enters adjacent uninfected cells, I FN- released by memory
C D 4
+
T cells shoul d make these secondarily i nfected cell s
detectable by effector T cells.
Figure 3. Detection of polymerasechain reaction product after amplication
of DNA fromperipheral blood mononuclear cells. Samplesfrom3 bonemar-
row transplant (BMT) patientswhohad subclinical cell-associated viremia are
shown in 1A, 1C and 1D; samplesfrom5 BMT patientswithout detectable
VZV viremia areshown in 1B and 2C-F. Samples1F and 2B aretheVZV
DNA controls; sample2A is PBMC froma healthy immunedonor control.
Reprinted with permission [8].
A
1
2
B C D E F
VZV After HCT
223
B B & M T
A n t i gen-Specific T-Cell Frequencies in Ada p t i ve
I mmunityto VZV
The escape of VZV from immune surveillance is associ-
ated wi th decl i ni ng numbers of VZV-speci fi c memor y
T cells in the latently infected host [28]. Conversely, the risk
of herpes zoster i s decreased when VZV-specifi c T- c e l l
responses are detected. Among HCT recipients and other
pati ents with cell ul ar i mmunodeciencies, prol onged peri-
ods of l ymphopenia and the l oss of VZV-speci fi c T cel ls
predict an interval of high risk for VZV reactivation [3,9,29-
38]. The most severely immunocompromised patients, such
as HCT recipients, are most suscepti bl e to herpes zoster.
Among these patients, memory T cellswhich can prolifer-
ate i n response to VZV anti gen, make cytoki nes such as
I F N -, tumor necrosis factor (TNF)- or i nterleuki ns, or
have cytotoxi c acti vi ty agai nst VZV-i nfected cel l sfal l
below the threshol d of detection [37]. Otherwi se heal thy
elderly individuals have a higher risk of VZV reactivation as
a result of immunosenescence; these individuals have some
V Z V-speci fi c T cel l s but l ower frequencies of re s p o n d e r
T cells than younger adults. I n contrast to correlation with
loss of cellular immunity, a prospective analysis of the risk of
herpes zoster and VZV antibody titers in the HCT donor or
recipient revealed no relationship [39].
Innate Host Responses to VZV
Despite the correl ati on between loss of VZV- s p e c i f i c
m e m o ry T cel l s and the ri sk of VZV re c u rrence, the
absence of detectabl e responses for prol onged peri ods
appears to be a necessary, but not sufci ent, conditi on for
VZV reacti vation from l atency. This observation suggests
that nonspecifi c anti vi ral immuni ty hel ps to restri ct the
symptoms of VZV reactivation. I n contrast to virus-specic
T-cell immunity, natural killer (NK) cell activity comparable
to that of healthy subjects is recovered during the rst few
months after HCT [39]. When eval uated for cytotoxici ty
agai nst VZV-infected targets, some HCT reci pients had a
predominance of NK cells expressing CD16 surface antigen,
and infected cells were lysed by class I and class I indepen-
dent mechani sms [9]. I FN - i s made by N K cel l s and
monocytes wi thout requi r i ng the presence of anti gen-
specic T cells and has direct antiviral activity against VZV.
A functional role for this protein was suggested by the ef-
cacy of exogenous I FN- in reducing the severity of recur-
rent VZV infections in immunocompromised patients when
given within 72 hours after the appearance of the cutaneous
rash [40]. Nonspecic cytotoxic responses and induction of
antiviral cytokines may function to control VZV replication
before the recovery of virus-specic T cells after HCT.
Granulysi n is a newl y described cytolyti c protein made
by NK cells as wel l as by anti gen-specic CD8
+
T cells [41].
Our recent exper i ments demonstrate that granul ysi n
i n c reases the death rate of VZV-infected cells in vi tro [42].
When VZV-infected cel ls were exposed to granulysin, syn-
thesis of infectious virus was reduced dramatically and death
of VZV-i nfected cel l s was accel erated. VZV i nfecti on of
f i b roblasts in the absence of granul ysin caused downre g u-
lated surface expression of the cellular protein fas and inhib-
ited susceptibility of i nfected cel ls to apoptosis triggered by
anti -fas i mmunoglobul i n M (I gM). Granulysi n rel ease by
NK cel ls re p resents an i nnate i mmune response that may
reverse thi s vi rus-induced block of apoptosis, resulti ng i n cell
death before large numbers of infectious virions can be syn-
thesized. Secretion of granulysi n by NK cells may enhance
the early destructi on of VZV-infected cell s in the absence of
m e m o ry T cells that medi ate adaptive immune responses.
RECONSTI TUTI ON OF VZV-SPECI FI C T-CELL I MMUNI TY
AFTER HCT
H CT pati ents have a gr adual re c o v e ry of memory
T cells that recognize VZV antigens (Figure 5) (A. Hata, L.
Zerboni, M. Sommer, A.A. Kaspar, C. Cl ayberg e r, A.M.
K re n s k y, A.M.A., unpubl ished data) [7,9,30]. Detecti on of
VZV memor y T cel l s i s usual l y possi bl e by 9 to 12
months after HCT and correl ates with a reducti on i n the
Figure 4. Interferencebyvaricella-zoster virus(VZV) with interferon (IFN)-induced upregulation of major histocompatibilitycomplex classII expression via
theStat signal transduction pathway. Reprinted with permission [26].
A.M. Arv i n
224
overall ri sk of herpes zoster and its complications. Never-
theless, the recovery of adaptive immunity to VZV may not
occur until after the patient has experienced herpes zoster.
Once VZV reacti vation occurs, most HCT reci pi ents are
effectively resensitized to the virus. I n the earliest study of
the reconsti tution of VZV T-cell immuni ty, Meyers et al .
[43] detected T-lymphocyte proliferation to VZV in 16 of
18 pati ents (89%) after symptomatic re c u rrences of VZV
versus 15 of 29 patients (51%) who did not develop herpes
z o s t e r. Almost half of the HCT reci pi ents re c o v e red VZV
immunity with no clinical signs of recurrence. Thus, innate
immune mechanisms may be adequate to control viral repli-
cation while naive T cel ls are induced to become antigen-
specic or while the few remaining antigen-specic T cells
undergo suf cient clonal expansion. This pattern of recon-
stituti on suggests that the subcl inical epi sodes of re a c t i v a-
tion, documented by VZV PCR, may provide the stimulus
to re s t o re adapti ve immuni ty to VZV [9]. Pre t r a n s p l a n t
immunity in both donor and recipient may also facilitate the
recovery of VZV-specic T cells [43].
I n additi on to proli ferative and cytokine responses, at
later times after HCT, patients also devel op cytotoxic T l ym-
phocytes (CTL) that can recognize and lyse autologous tar-
get cel ls that express VZV proteins [9]. I n our experi ence,
50% of HCT patients had VZV- s p e c i c CTL function when
tested a mean of 155 days after transplant (Figure 6). How-
e v e r, the mean precursor frequency of T lymphocytes that
recognized the VZV I E62 protein or glycoprotein E (for-
merl y desi gnated gp I ) was more than 2-fol d lower among
HCT reci pients than the frequency of CTL that re c o g n i z e d
these viral proteins i n PBMC from healthy immune subjects.
I n these experi ments, the proliferation of CD4
+
T cells was
reduced signicantly compared with that of healthy subjects;
C D 8
+
T cel l s predomi nated i n VZV-stimulated cul ture s ,
re ecting the relative i ncrease in circulating CD8
+
T cell s
that is common after HCT [44]. Although CD8
+
T lympho-
cytes have been dened as the classi c cytotoxic effector cell,
human CD4
+
cells also function effectivel y as antiviral CTL
agai nst many viruses, incl uding VZV [45]. The diminished
C D 4
+
T-cell response to VZV anti gen may account for the
low frequencies of CTL precursors specic for the I E62 or
gE protei ns i n HCT reci pi ents compar ed wi th heal thy,
V Z V-immune individuals.
Whether re c o v e ry of T cells that recognize part i c u l a r
VZV proteins affects the risk of herpes zoster is not known,
because onl y I E62- and gE-specifi c responses have been
Figure 6. Precursor frequenciesof cytotoxicT lymphocytesspecicfor theimmediateearlyprotein (IE62) and glycoprotein I (gpI) of varicella-zoster virusin bone
marrow transplant recipientsand healthysubjects. Mean SD for precursor frequencyestimatesareindicated next totheindividual data points() generated by
testing individual hematopoieticcell transplant recipientsand healthyimmunesubjects. Reprinted with permission [8].
Figure 5. Lymphocytetransformation responsesof marrow transplant recipi-
ents tovaricella-zoster virus (VZV) antigen. All patients and donors had a
history of VZV infection. The9 patientswhohad circulating myeloblastsor
lymphoblasts beforetransplant areindicated by triangles (). The25th to
75th percentileof thenormal responsetoVZV antigen is indicated by the
hatched area, and the horizontal lines enclosea 95% rangeof normal
responses.
Time after transplantation (days)
VZV After HCT
225
B B & M T
quantitated. I n the intact host, helper and cytotoxic T- c e l l
responses specifi c for the I E63 protei n are mai ntai ned for
decades after pri mary VZV i nfecti on [46]. Recovery of
responses to the immediate early proteins may be part i c u-
larly important, because these viral gene products are made
i n i nfected cel l s before vi ral pr ogeny are synthesi zed.
Recognition by the adaptive immune system could result in
lysis of infected cells at early times after virus entry, blocking
cell-to-cell spread or release of infectious virus.
Evaluation of Inactivated Varicella Vaccine f o r
Reconstitution of VZV Imm u n i t y
Based on the evi dence that natural VZV re a c t i v a t i o n
induces recovery of VZV-specic T cells, we have evaluated
whether the inactivated varicella vaccine could substitute for
the resensi tizati on caused by VZV reactivation after HCT
and modify the incidence or severity of herpes zoster [37].
Administering the live attenuated varicella vaccine to elderly
individuals enhances VZV-specic immunity and immuniza-
tion and is being evaluated as a strategy to reverse immuno-
senescence in this population [37]. Heat inactivation of the
live attenuated varicella vaccine provides an acceptable vac-
ci ne for eval uati on i n severel y i mmunocompr o m i s e d
patients. We have completed 2 trials of inactivated varicella
vaccine in HCT recipients. I n the rst, a single-dose regi-
men of inactivated varicella vaccine was found to i nduce a
transient boost in T-cell responses but did not result in clin-
i cal benefi t. When the vacci ne was gi ven at 1, 2, and 3
months after HCT, we observed enhanced cell -medi ated
immunity and decreased severity of herpes zoster in a popu-
lation including autologous and allogeneic transplant recipi-
ents (Figure 7). Patients i n the vacci ne group devel oped
VZV reactivation but had minimal cutaneous disease and no
persistent postherpeti c neuralgi a. With re g a rd to re c o v e ry
of cytokine responses, I FN- production was associated with
the r e c o v e ry of VZV-speci fi c T-cel l prol i ferati on and
i n c reased wi th ti me after transpl antation. I nterleuki n-10
p roduction was also observed consistently after HCT and
was highest in patients whose T-cell proliferation response
was restored. The experience with the 3-dose regimen fur-
ther supports the signicance of VZV-specic T-cell immu-
nity in maintaining the equilibrium between the latent virus
and host. Our current study is desi gned to assess whether
earlier VZV immune reconstitution in HCT recipients can
be achieved by immunizing recipients before as well as after
transplantation.
VZV RESEARCH AND CLI NI CAL OBSERVATI ONS
Of importance i s the rel ationshi p between studi es of
VZV pathogenesis and immunity and observations about the
clini cal syndromes associ ated wi th VZV reacti vation after
H C T. Cl inical experience demonstrates that the i mmuno-
logic impai rment experienced by HCT recipients results in
an attack rate of 13% to 55% for symptomatic VZV re a c t i-
vation during the rst year [3,29-37] (Table). I n contrast, the
annual i ncidence of herpes zoster among heal thy adul ts i s
0.5% [1]. Although the preci se viral mechanisms that trigger
reactivation are not known, cli nical observations document
that the di ff e rences between patterns of VZV and H SV
interactions with dorsal root ganglia cell s duri ng latency are
associ ated wi th a l onger i nterval to VZV r e a c t i v a t i o n
[4,35,36]. HSV-1 di sease typical ly occurs about 2 to 3 weeks
after HCT, whereas VZV re c u rrences present at a median of
5 months. Most VZV re c u rrences appear 2 to 10 months
after transplantation, although some cases are di agnosed as
early as week 1. Analyses of risk factors such as al logeneic
versus autol ogous transpl ant, graft- ver sus-host di sease
(GVHD), underlying disease, and pre-BMT irradiation are
equivocal in establ ishing denitive associati ons. The patients
underl ying disease does not appear to inuence VZV re a c t i-
vation, but in 1 study, a history of symptomatic herpes zoster
b e f o re transpl antati on i n Hodgki ns di sease patients was
associated wi th a hi gher risk of early herpes zoster after
autol ogous H CT [31]. Thi s observati on suggests that
re-establishment of l atency may be incomplete in the context
of continued or increased immunosuppression.
L o c al i z ed Herpes Zoster
A dermatomal rash is the most common clinical pre s e n t a-
tion of VZV infection in HCT recipients who are sero p o s i t i v e
at the time of transplant, accounting for 85% of cases in 231
HCT recipients in the study by Locksley et al. [3]. The rash of
localized herpes zoster is usually preceded by pain and paras-
thesias in the involved dermatome [1,34,47]. These symptoms
a re undoubtedly a manifestation of viral replication that occurs
in the sensory ganglia and may begin many days before the
cutaneous rash appears. In some cases, the pain syndrome is
not fol l owed by the typi cal zoster rash, but subsequent
enhanced immune responses suggest a recent VZV re a c t i v a-
tion; this syndrome is re f e rred to as zoster sine herpete [48].
F i gu r e 7. T-cell proliferation tovaricella-zoster antigen in bonemarrow
transplant recipientsparticipatingin thestudyof the3-doseregimen of inacti-
vated varicella vaccine. Themean stimulation index (SI) SE tovaricella-
zoster antigen in vaccinerecipientstestedimmediatelybeforeimmunization at 1
month after transplantation andat 2, 3, 4, 5, and12 months() and responses
of unvaccinated patientsat thesametimeintervals after HCT (). *Time
points with a statisticallysignicant (P <.05) differencein mean SI between
vaccinatedandunvaccinated patients. Reproducedwith permission [37].
A.M. Arv i n
226
The dermatomal distribution of the cutaneous lesions of local-
ized herpes zoster re ects the persistence of VZV in dorsal
root gangli a and its transport down neuronal axons in the
course of reactivation. The rash consists of clusters of vari-
cella-like vesicles in 1 or several sites anteriorly and posteriorly
withi n the dermatome. Having been deli vered to cutaneous
epi thel ial cell s via neuronal pathways, the vi rus i s abl e to
s p read from cell to cell within the epidermis and dermis, as
evident from the fact that discrete vesicles typically enlarge to
f o rm confl uent l esions [47]. Del ayed or inadequate host
responses resul t i n an average ti me for cessati on of new
lesion formati on of 8 days, compared with 3 to 5 days in the
n o rmal host; the time to complete healing is also pro l o n g e d .
Some HCT patients may have a chronic cutaneous re a c t i v a-
tion of VZV that persists for months, indicating continued
viral replication in ganglia and skin that is unchecked by the
host response [34]. Bacterial superinfection and local scarr i n g
a re also common in HCT recipients with herpes zoster, occur-
ring with an incidence of 17% and 19%, re s p e c t i v e l y.
F a i l u re of the host response to overcome the i mmune
evasion mechanisms of the virus and stop replication results
in particular complications when VZV reactivation involves
cranial nerves. Corneal damage, facial scarring, facial palsy,
and heari ng l oss with vesti bul ar symptoms are common
[3,29-36]. Oral l esi ons of the pal ate may develop without
any cutaneous lesions when the second branch of cranial
n e rve V is affected. Herpes zoster i nvolving cranial nerv e s
can also be associated with the serious central nervous sys-
tem compl ication re f e rred to as cerebral angi i tis, a syn-
d rome of cerebral vascul ar infl ammati on wi th thro m b o s i s
and mi cro i n f a rcts. Cerebral angi itis can result in extensi ve
thrombosis with contralateral hemiparesis [49]. The patho-
logic changes are granulomatous inammation of the arter-
ial wal l, mononucl ear cel l i nfiltrates, and vascular necro s i s
associated with the detection of VZV i n endotheli al cel ls
and smooth muscl e cell s of the affected arteri es. I n some
cases, VZV replication can extend from the dorsal ganglia to
involve the anterior horn cells of the spinal cord, with asso-
ciated abnormali ties evident by magneti c resonance imag-
ing. Under these circumstances, inammation and necrosis
may produce permanent motor decits [50].
Postherpetic neuralgia (PHN) is the most common com-
pli cati on of herpes zoster i n immunocompetent as wel l as
i m m u n o c o m p romised patients. Postherpetic pain is described
as any pain that persists after resoluti on of the rash or, alter-
n a t i v e l y, only pain that persi sts more than 2 months after
cutaneous healing. As a result, estimates of the incidence of
postherpetic neuralgia depend on the deni tion used. HCT
recipients appear to be at higher risk of PHN. Locksley et al.
[3] observed PHN in 25% of HCT reci pi ents, compare d
with an expected i ncidence of about 9% in healthy individu-
als; Koc et al. observed PHN and peri pheral neuropathy in
68% of HCT patients [37].
Cutaneous and Visceral Dissemination
Heightened susceptibility to viral dissemination is fur-
ther evidence of the impact of diminished immunity on the
pathogenesis of VZV infections after HCT. When options
for antiviral therapy were limited, 21% of HCT recipients
with recur rent VZV had visceral dissemination of the virus
and 12% di ed from compl i cati ons of re c u rrent VZV [3].
The current risk of morbidity and mortality caused by VZV
infection cannot be compared with the original analyses of
VZV-related disease after BMT, because antiviral therapy is
now available. Nevertheless, more recent studies document
a high risk of cutaneous dissemination (15%-23%) and vis-
ceral involvement (5%-14%) in HCT recipients. For exam-
pl e, Schuchter et al . [31] found that 15% of autol ogous
BMT recipients had cutaneous di ssemi nati on, 5% had vi s-
ceral di ssemi nati on, and 25% had neurologi c sequelae,
including PHN.
Because i t i s a sign that VZV has i nfected circul ati ng
T cells, cutaneous dissemination provides a marker for risk of
vi sceral disseminati on. However, visceral dissemination al so
occurs in patients whose cutaneous lesions are localized to the
p r i m a ry dermatome. I n addition, some patients have no pri-
m a ry dermatomal involvement but present with diffuse VZV
lesions resembling vari cel la. This syndrome, re f e rred to as
atypical nonlocalized zoster, accounted for 21% of re c u rre n t
VZV episodes in 1 series of HCT recipients [32].
When virus-i nfected T cells have entered the circ u l a t i o n ,
the virus can reach many vi sceral organs. The most common
sites for further viral infecti on are the lungs and liver, re s u l t-
i ng i n VZV pneumonia, hepatitis, and intravascular coagu-
l o p a t h y. Fatal VZV infecti ons are most often due to vi ral
pneumonia [51]. The risk of VZV dissemination is incre a s e d
Incidenceof Varicella-Zoster Virus(VZV) InfectionsAfter HCT
Clinical Presentation
VZV Localized Atypical
Year Reference UnderlyingDisease Transplant Type n Infection(%) Zoster (%) Zoster (%) Varicella(%)
1980 [8] Leukemia Allogeneic/syngeneic 33 21
1982 [10] Leukemia/aplastic anemia Allogeneic/syngeneic 98 52
1985 [1] Leukemia/aplastic anemia Allogeneic 1394 17 85 15 0
1986 [11] Hematological malignancy Allogeneic 73 36 91 7 2
1989 [7]* Leukemia/solid tumors Autologous 236 23 75 13 18
1989 [12] Leukemia/lymphoma Autologous 153 28 77 20 2
1991 [13] Hodgkinsdisease Autologous 28 32 100 0 0
1992 [36] Leukemia/lymphoma/other Autologous/allogeneic 51 31 100 0 0
2000 [38] Leukemia/lymphoma/other Allogeneic 100 41 80 20

*Thisstudyevaluated pediatricpatientsonly.

17% had varicella-likecutaneousinvolvement and 3% had visceral dissemination.

VZV After HCT
227
B B & M T
in patients with acute GVHD, and VZV has also been identi-
ed as a cause of late interstitial pneumonia in HCT patients
wi th chronic GVHD [52]. Some HCT recipients pre s e n t
with si gns of vi sceral dissemination 24 to 96 hours before the
d e rmatomal rash becomes evident [53-57]. The fact that vis-
ceral dissemination has been observed in HCT patients with-
out any si gns of cutaneous di sease demonstrates that cel l-
associ ated viremia can occur without replication of the vi ru s
in skin, presumably by entry of virus i nto T cells that trafc
t h rough sensory ganglia [3]. I mmunosuppression also pre d i s-
poses to CNS infection, which manifests clinically as menin-
goencephaliti s, duri ng VZV reactivation [58]. Vi sceral dis-
semi nati on i ncreases the mortali ty of VZV re a c t i v at i o n
s u b s t a n t i a l l y, from 7% to 55%. Mortali ty is usually due to
pneumonia, but the risk of fatal infection is highest among
patients who develop both pneumonia and encephalitis.
Second Episodes of Herpes Zoster
Some HCT recipients have recur rences of herpes zoster
within days after antiviral therapy is stopped, indicating the
failure to reestablish latency in the short term. When zoster
has resol ved, however, second episodes are unusual . Onl y
2% of patients in 1 l arge seri es had 2 epi sodes of herpes
zoster, occurring an average of 25 months (range 4-41) after
transplantation [3]. These data confirm the importance of
reconstituted VZV immunity in maintaining latency.
I MPLI CATI ONS FOR THE MANAGEMENT OF VZV
I NFECTI ONS I N HCT RECI PI ENTS
D i agn o s i s
The unusual cl inical manifestati ons of re c u rrent VZV
i n HCT recipients re q u i re a high i ndex of suspi cion for
VZV as a potenti al etiology. Reli ance on rapi d, sensiti ve
methods for laboratory diagnosis i s essential in many cases.
These methods i ncl ude di r ect i mmunofl uor e s c e n c e ,
enzyme immunoassay, and PCR, as well as more rapi d and
sensiti ve viral culture methods such as shell vial assays [59].
S e rologic approaches to the diagnosi s of acute VZV re a c t i-
vati on are not rel iabl e because VZV I gG anti bodi es are
p resent in all latently i nfected indivi dual s, VZV I gM assays
a re di fficult to standardize, i ntermittent detection of I gM
antibodies is re p o rted i n i ndi viduals wi th no evi dence of
reactivation, and some pati ents have herpes zoster without
eliciti ng I gM anti bodies.
Antiviral Tr e at me n t
Acyclovi r has been shown to be effective for the tre a t-
ment of re c u rrent VZV i nfecti on in immunocompro m i s e d
patients in placebo-controll ed trial s and extensive cl inical
experi ence [47]. Antivi ral treatment compensates for the
delayed host response and resul ts i n shorter time to cessati on
of new lesi on formation, more rapid crusti ng and heal ing,
and prevention of cutaneous and visceral dissemination. Acy-
cl ovir therapy i ni ti ated withi n 72 hours after the onset of
VZV reactivati on can be expected to reduce the duration of
new l esi on formation in HCT pati ents to approximately 3
days. On average, early antiviral treatment should cause the
cessation of acute pain wi thi n 4 days, crusting of lesions by 7
days, and compl ete heal ing by 2 to 3 weeks. Although early
acyclovir treatment is likely to produce the best results, clini-
cal benet can still occur when therapy is del ayed for more
than 3 days [60]. I n 1 series, none of 29 i mmunocompro-
mi sed patients whose therapy was initiated more than 3 days
after the onset of the rash had pro g ressi ve herpes zoster,
c o m p a red with 3 of 17 patients in the placebo gro u p .
Although the drug eliminates the life-threatening compli-
cations of VZV reactivation in most patients, relapse of her-
pes zoster is a clinical problem in some HCT patients who
a re treated with acyclovir. I n 1 series, 5 of 40 patients (12%)
developed new lesions; in 3 of the 5 patients, relapse occurre d
less than 4 days after treatment was stopped [61]. Early acy-
clovir therapy may delay the re c o v e ry of VZV- s p e c i c immu-
nity in some patients. Nevertheless, most patients respond to
t reatment with a second course of acyclovir.
Although acyclovir is clearly benecial for the treatment
of acute herpes zoster, i ts effect on the i ncidence of PHN
has been more di fficult to establ ish. Among HCT re c i p i-
ents, 9 of 40 (20%) patients had recurrence of pain after ces-
sation of therapy [62].
The efcacy of oral acyclovir for herpes zoster in HCT
patients has not been rmly established, and its bioavailabil-
ity is low. The oral route of administration is appropriate for
patients who are carefully selected based on their presenta-
ti on with l ocali zed herpes zoster only, at longer interv a l s
after HCT. Acyclovir has been shown to be a safe agent in
m o re than a decade of clinical experience and is tolerated
well by HCT patients, al though side effects are more fre-
quent than i n other popul ati ons. I n 1 series, nausea and
vomiting, which is particularly associated with elevated crea-
tinine, occurred i n 40% of treated patients [61]. Nephro-
toxic effects, dened as a 50% rise in serum creatinine, were
also more common than in other patient populations; 10%
to 25% of HCT patients receiving acyclovir were reported
to have abnormal serum creatinine, but these elevations may
have been caused by other medications given concurrently.
Because acyclovir is excreted by glomerular ltration, other
d rugs that affect renal function, such as cycl ospori ne, can
increase plasma drug concentrations. Acyclovir dosage must
be adjusted in relation to creatinine clearance. Acute neuro-
toxi ci ty associ ated wi th acycl ovi r treatment has been
reported in patients with impaired renal clearance. I n most
i nstances, abnormal l i ver functi on tests i n pati ents wi th
VZV reactivation are li kel y to indi cate vi ral hepati tis, not
drug toxicity. Acyclovir does not have hematologic toxicity
and does not interfere with engraftment in HCT recipients.
Valaciclovir and famciclovir are nucleoside analogs that
resembl e acycl ovi r in thei r stru c t u re and mechani sms of
acti on; al l 3 drugs i nterf e re wi th vi ral thymi di ne ki nase
acti vi ty [63,64]. Val aci clovi r and famci clovi r are absorbed
much more effecti vel y after oral administrati on than acy-
clovir and have a comparable safety prole. Although con-
trolled trials to establish their clinical efcacy have not been
done in HCT patients, valaciclovir and famciclovir are use-
ful al ternatives to acycl ovir i n those patients with herpes
zoster for whom oral therapy i s consi dered appro p r i a t e .
They require only 3 doses per day but are more expensive
than acyclovir and do not have signicantly enhanced ef-
cacy compared wi th the recommended dosage of oral acy-
clovir in otherwise healthy individuals.
VZV resistance to acyclovir has not been common in HCT
recipients, but it has been re p o rted in patients with acquire d
A.M. Arv i n
228
i m m u n o d e ciency syndrome [65]. When VZV re a c t i v a t i o n
occurs in HCT recipients, it may resolve slowly or recur short l y
after antiviral therapy is stopped. In most cases, this clinical pat-
t e rn is related to limitations in the host response, for which the
d rug compensates only part i a l l y, and does not re p resent the
e m e rgence of acyclovir resistance. Because most resistant VZV
strains have mutations in thymidine kinase, acycl ovir, valaci-
c l o v i r, and famciclovir are all equally ineffective [47,65,66]. Fos-
c a rnet has antiviral activity against VZV strains that are not
inhibited by acyclovir, but its clini cal use is complicated by
potential l iver toxi city and emergence of resistance [67]. I n
some cases, acyclovir- resistant VZV strains emerge during ther-
a p y, a risk that is associated particularly with prolonged, low-
dose regimens, but VZV isolates from later re c u rrences may
have re c o v e red susceptibility to acyclovir. Ganciclovir and acy-
clovir have equivalent antiviral activity against VZV in vitro ,
but ganciclovir efcacy has not been evaluated in patients with
herpes zoster because it is more toxic than the primary dru g s .
Based on in vitro analysis, ganciclovir given to CMV- i n f e c t e d
HCT recipients might ameliorate concurrent VZV infection.
Koc et al . [37] found that patients receiving ganciclovir had
delayed onset of VZV reactivation until after 4 months.
Al though the l ive attenuated vari cel l a vacci ne i s not
indicated for administration after HCT, some children who
have received this vaccine may become transplant recipients.
The risk i s significantly l ess than naturall y acquired VZV
i nfecti on, but the vacci ne vi rus can establ i sh l atency and
reactivation may occur [68]. Because the vaccine is prepared
from the Oka strain of VZV, which retains susceptibility to
acyclovir and related antiviral agents, vaccine-related herpes
zoster can be treated with acyclovir.
Varicella-Zoster Imm u n ogl o b u l i n
Vari cel la-zoster immunoglobulin (VZI G) contains high
titers of VZV I gG and is indicated for immediate postexpo-
s u re prophylaxis of high-risk patients who have not had VZV
infection and have cl ose contact wi th vari cell a or herpes
z o s t e r. VZI G i s not used i n patients wi th herpes zoster,
because VZV I gG titers are maintai ned despi te the loss of
cell-mediated immunity to the virus. There is no indication
that passive antibody prophylaxis increases existing antibody
titers or reduces the risk of VZV reactivation after HCT [38].
The cl ini cal experi ence is that HCT reci pients exposed to
varicella or herpes zoster are rarel y rei nfected with the viru s ,
even when no VZV- s p e c i c T-cell responses are detectable.
The persistence of VZV IgG may protect against exogenous
re e x p o s u res to the virus, by neutralization or other antibody-
medi ated mechanisms, even though antibodies fail to block
reactivation of the patients endogenous virus.
Antiviral Pr o p hy l ax i s
Although daily acyclovir prophylaxis inhibits the reacti-
vation of VZV, antiviral drugs are not usually given to HCT
recipients for VZV suppression. Herpes zoster, especi all y
when it occurs shortly after HCT, may cause disseminated
di sease; however, prompt i ni tiation of acycl ovi r therapy,
given when symptoms of VZV reacti vation appear, i s an
effective alternative to continued administration of antiviral
drugs. I n 2 studies of acyclovir prophylaxis after HCT, VZV
reactivation was managed effectively among placebo subjects
who were given intravenous acyclovir at the onset of symp-
toms [69-71]. Giving antiviral agents daily at the low doses
used for prophyl axis may faci l itate the selecti on of VZV
strai ns that are thymidine ki nasenegati ve and there f o re
resistant. I n addi ti on, the cumulative attack rate for VZV
reactivation in treated and pl acebo patients was equivalent
over a 1- year ti me peri od, i ndi cati ng that suppre s s i o n
required a constant presence of the drug in tissues.
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