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INTRODUCTIONVaricella-zoster virus (VZV), a herpesvirus, consists of a

double-stranded D N A g enome surrounded by a pro t e i n

tegument and contained within an icosahedral capsid and anouter lipid membrane envelope [1,2]. The VZV genome has69 distinct genes that encode proteins re q u i red for viru sattachment and entry into host cells, replication of viralD N A, and synthesis of new virions and their release orspread to adjacent uninfected cells (Figure 1).

V Z V, like ot her h uman herpesviruses, is a thr eat tohemato poietic cell transplant ation (HC T) recipients [3,4].D uring primary infection, w hich causes varicella, VZVestablishes latency in cells of the dorsal root sensory g anglia.Among adult H C T patients, most VZV infections representa reactivation of t he latent virus. Classic herpes zoster, w ithits dermatomal vesicular rash, is the most common clinicals y n d rome caused by VZ V reactivation, but some H C Trecipients have a generalized vesicular exanthema that

resembles varicella, syndromes of neuropathic pain, ororgan involvement that is not associated with any rash.

BIOLOGY OF VZV LATENCY AND REACTIVATIONN ew information about th e mechanisms of VZV patho-

genesis helps to explain t he risks associated with VZV re a c-

tivation in H C T recipients. The pathog enesis of VZVinfection involves 3 essential cellular tropisms: infectivityfor epithelial cells of the mucous membranes and skin, forc i rculating peripheral blood mononuclear cells, a nd forcells of th e sensory ga nglia.

VZV Infectivity for T Cells and SkinIn addition to causing characteristic skin lesions, VZV

can be detected in peripheral blood mononuclear cellsfrom healthy and immunocompromised patients with vari-cella an d fro m immunodefic ient pat ients w i th herpeszo s t er. Using the SC ID -hu mouse model, we have demon-strated that VZV infects C D 4+ and CD8+ human T cellsand thus shares pathogenic mechanisms characteristic ofthe lymphotropic and n e u ro t ropic herpesviruses (Figure

2) [5,6]. Infectivity for T cells is a critical component ofthe risk that VZ V presents in H C T recipients, since itunderlies susceptibility to cutaneous and visceral dissemi-nation. C onditions in the SC ID -hu model are similar tothose in the period immediately after H C T, since SC ID -hu mice lack the capacity to develop VZV-specific immu-n i t y. When VZ V reactivates in th e human host, it re p l i-cates eff ic iently in the skin, producing high t i ters ofinfectious virus in t he cutaneous vesicles. D uring acuteherpes zoster, T cells may become infected at the site of

Var ice l la -Zos ter V i rus : Pathogenes is , Immuni ty ,and C l in i ca l Management in Hematopo ie t i cCe l l Tr ansp lant Recip ien t s

Ann M . Arvin

Infectious D isease D ivision, Sta nford U niversity School of M edicine, St anford, C aliforn i a

C o rrespondence and reprint req uests: Ann M. Arvin, M D , G 311, Infectious D isease D ivision, St anford

U niversity Schoo l of Medicine, Stanf ord, C A 94305-5208; e-mail: arv i n a m @ s t a n fo rd.e du

(Received Febru ary 2, 2000; ac cepted Febru a ry 14, 2000)

ABSTRACTNew information about the mechanisms of varicella-zoster virus (VZV) pathogenesis and the host response to the

virus 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 deficiencies in VZV immunity in HCT recipients,

and inactivated varicella vaccine may be useful for the early reconstitution of adaptive immunity to VZV after HCT.

KEY WORDSVaricella-zoster viru s H ematopoietic cell transplantation L a t e n c y I m m u n o s u p p re s s i o n

B io logy o f B lood and Mar r ow Transp lan ta t i on 6 :219230 (2000 ) 2000 Am er ic an Soc ie t y fo r Bl ood an d Mar r ow Tr an sp lan t at i on

Studies of VZV pathogenesis and immuni ty in D r . Ar vins laboratory were

sponsored by grant s from the Nati onal I nsti tu te of A ll er gy and Infecti ous

D iseases (A I 20459 and AI 36884) and the National Cancer Institut e (PO1-

CA49605; Karl Bl ume, Pri ncipal Investi gator ); inactivated varicell a vaccine

for the evaluat ion of immune reconstit ut ion was provided by Merck.


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local cutaneous replication or may acquire virus fro mactively infected cells within the affected ganglia [7]. If thehost response is impaired, T cells can transport the virus tolungs, liver, brain, and other org a ns .

VZV infectivity for human T cells as well as skin isre q u i red for patho genesis, but our comparat ive a nalysesof VZV mutant strains that have altered expression ofp a rticular viral g enes demonstra te t hat these tropisms aremediated by d ifferent viral proteins, termed virulence deter-minants. VZV strains that lack glycoprotein C (gC) expres-sion have little or no capacity to replicate in skin. In con-trast, g C synthesis is not required for T-cell infection. Thus,gC is a specific determinant for VZV virulence in skin [6].In addition to the contribution of glycoproteins to VZV

pathogenesis, gene products that have no putat ive ordemonstrated role in viral entry into human cells haveemerged as key determinants of VZV virulence. The pro-teins encoded by the open reading frames (ORFs) 47 and66 are serine/threonine protein kinases [2]. We used VZVmutants that were constructed to block expression ofORF47 to demonstrate that this protein is essential for viralgrowth in human T cells and skin [8]. Absence of ORF66expression partially inhibited VZV infectivity for T cells butdid not impair replication in skin relative to t he intact virus.Infectivity for T cells and skin was re s t o red when themutant was re p a i red by inserting intact OR F47 back intothe genome. The ORF47 gene product is the first VZV pro-tein to be identified as necessary for T-cell tropism. LikegC , O RF47 is also essential fo r skin infectivity in vivo.

Among the human herpesviruses, VZV is related mostclosely to herpes simplex virus (H SV). The comparison ofVZV and H SV-1 infection in the SCI D -hu model revealedsignificant differences in T-cell and skin t ropisms that corre-late with the clinical experience of pathologic effects inH C T recipients and other immunocompromised individuals[6]. VZV caused extensive necrosis in deeper dermal layersof skin implants, whereas H SV-1 was confi ned to th e epi-de rmis. In con trast t o VZ V, H SV-1 was not infectious forhuman CD 4+ or CD 8+ T cells, which is consistent with the

clinical observation that H SV infection is rarely associatedwith viremia, even in high-risk patients.

C lassic herpes zoster results from t ransport o f the virusalong neuronal axons from the cellular sites of latency in dor-sal root gang lia. H owever, disseminated VZV infection hasbeen diagnosed at autopsy in HCT patients without cuta-neous lesions [3]. This clinical syndrome suggests that thevirus can enter T cells when they traffic through dorsal rootganglia during VZV reactivation. Our studies using poly-merase chain reaction (PCR) to detect the virus in peripheralblood mononuclear cells (PBMC) demonstrate that this eventis not unusual in H C T patients, especially during t he fi r st100 days after transplantation (Figure 3) [9]. Activated T cellsa re more permissive for VZ V infection in vitro, so H C T

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 evaluation ofH C T recipients by VZV PC R assay demonstrated that VZVreactivation can occur without cutaneous lesions and thatmany patients resolve reactivation and viremia without devel-oping signs of visceral dissemination [9].

Ne u ro tr opism of VZVThe hypothesis that herpes zoster results from the re ac-

tivation of latent virus acquired during varicella was provenby restriction enzyme analysis showing that a single VZVstrain caused both varicella and subsequent herpes zoster inan immunocompromised child [13]. D uring varicella, VZV ispostulated to move up neuronal axons from skin lesions to

the corresponding sensory ganglia. Immunohistochemicalstains of skin lesions demonstrate the presence of VZV pro-teins in nerve termini, axons, and Schwann cells [14]. In ouranimal mo del experiments, subcutaneous inoculation ofguinea pigs with VZV was associated with spread of virus tosensory ganglia [15]. Viremia may also carry VZV to ganglioncells, as suggested by VZV spread to ganglia in neonatal ratsinoculated intraperitoneally [16]. After earlier conflictingre p o rts, recent experiments done w ith more sensitive andspecific methods indicate that VZV establishes latency in

Figure 1. D iagram of var icell a-zoster vi rus (VZV ) and vir al proteins in VZV -i nfected cell s.


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Figure 2. Var icell a-zoster vi rus (VZV ) infecti on of T cell s and skin in the SCID -hu model. A : Infected T cell s wi thi n a thymus/li ver implant aft er inoculat ion

wi th VZV. a: M acrophages engul f infected T cell s. b: Day 7, l ymphocyte depletion. c: Day 21, complete destr uction. d: Mock- infected contr ol. B: Virus-induced

changes in an infected skin implant . a: Infected cell s in epidermis and around hai r foll icles. b: Vesicular l esion involv ing dermi s. c: Mock- in fected contr ol.

A

B


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neuronal as well as satellite cells within dorsal root ganglia[17-20]. H ow virus/cell interact ions result in t he maint e-nance of latency remains uncertain, but these mechanismsmust differ fo r VZ V and H SV. VZV latency is associatedwith the expression of several viral gene products, in contrastto HSV, in which only antisense latency-associated tran-scripts are detected. Transcripts of ORFs 21, 29, 62, and 63

have been detected, and there is evidence that proteins ofORFs 4, 21, 29, and 62 are made in latently infected cells[17,21]. VZ V, like H SV, is presumed to persist in lat ent lyinfected cells as an episome, rather than by integration intocellular D N A [22]; persistence must occur wit hout t ransla-tion of the full sequence of viral gene products, becausevirion production would be expected to be associated withcell lysis. Although the assessment of viral load in ganglia isdiffi cult, quantitat ive D N A P C R analysis of human trigemi-nal ganglia suggests the presence of about 250 VZV genomeequivalents per 105 cells [23]. The estimates of virus burdensuggest that VZV persists in more cells of the trigeminalthan tho racic gang lia, which could explain the re l a t i v e l yhigher incidence of facial zoster. When reactivation occurs,extensive viral replication takes place within the cells of the

s e n s o ry ganglia, producing patholo gic changes includingextensive inflammati on and necrosis [24]. The virus moves tothe skin innervated by the involved ganglion via axonal trans-port, causing the dermatomal rash of typical herpes zoster.

IMMUNE EVASION AND THE HOST RESPONSETO VZV INFECTION

Whether the host response contributes directly to pre-serving VZV latency at the cellular level is not known. Neu-rons or satellite cells that harbor VZV are assumed to re maininvisible to the immune system during latency, or adverseconsequences would result from the cumulative destructionof neuronal cells. Nevertheless, the high incidence of herpes

zoster in H C T recipients who are latently infected because ofchildhood varicella and lose antigen-specifi c immunity duringH C T provides compelling evidence that immunologic mech-anisms modulate the frequency of symptomatic episodes ofVZ V reactivation. U nder ord i n a ry circumstances, h e r p e szoster represents a useful strategy of the virus, ensuring itspersistence in the human population. C utaneous recurrencesgive VZV a n opportunity for transmission t o susceptible closecontacts while causing only a self-limited skin rash with someneuropathic pain, which is uncomfortable but not life-threat-ening to th e healthy individual. H erpes zoster infectionreveals the limitations of immune surveillance even in theimmunocompetent host, since it occurs despite circ ul a tingVZV-specifi c memory T cells. To evade established immu-nity, replicate in skin cells, and release infectious virus into

vesicular fluid, VZV virus, it is thought, has evolved ways toavoid antigen-specifi c T-cell responses.

Imm une EvasionLike other herpesviruses, VZ V encodes gene pro ducts

that downregulate major histocompatibi l i ty complex(MH C ) class I expression on fibro blasts and T cells (A.A b e n d rot h, I . L in, A.M .A., unpublished dat a) [25].Restricted class I expression interf eres with recognition ofVZV-infected cells by C D 8+ T cells. Although the viral pr o-

tein or proteins that mediate class I downregulation havenot been identified, we found tha t MH C class I moleculesexit from the endoplasmic reticulum (ER) but are retainedin the G olgi (A. Abendroth , I. Lin, A.M.A., unpublisheddata). In contrast, H SV blocks transport of class I proteinsfrom the E R by effects of ICP 47, the product of a gene thatis not found in t he VZV genome [26]. Because MH C class I

molecules are expressed on almost all mammalian cells andfunction to present foreign peptides to C D 8+ T cells, inter-ference with their transport to the cell surface makes VZV-infected cells more difficult to eliminate by this arm of theantiviral immune response.

In addition to limiting MH C class I trafficking to thecell surface, VZV-infected cells are resistant to the upregu-lation of MH C class II expression elicited by interf e ro n( I FN ) - [27]. MH C class II molecules present peptides tos u p p o rt th e clonal expansion of C D 4+ T cells. With theexception of B cells, monocytes, and thymic epithelium,most cells do not express MH C class II proteins constitu-tively, but exposure to IFN-triggers rapid upregulation ofthese proteins on membranes of many cell types. VZV-specificme m ory CD4+ T cells are programmed to synthesize and

release IFN -when stimulated by viral antigen [7]. Ouranalysis of VZV effects on this pathway revealed that theblock of IFN-induced M H C class II expression occurredat the level of gene transcription within the infected cell(F i g u re 4). Examination of skin biopsies ta ken fr om earlyherpes zoster lesions demonstrated that VZV-infected cellsdid not express MH C class II in vivo, suggesting a mecha-nism that transiently protects VZV-infected cells despite cir-culating VZV memory C D 4+ T cells. This effect is transientmost likely because synthesis and transport of M H C class IImolecules to the cell surface are normal when uninfectedcells are exposed to IFN-. As herpes zoster progresses, there c ruitment of VZV-specific C D 4+ T cells tha t pro d u c eIFN-to the cutaneous site of VZV replication should con-

t rol the cell-to-cell spread of the virus. Even i f the viru senters adjacent uninfected cells, IFN-released by memoryC D 4+ T cells should make these secondarily infected cellsdetectable by effector T cells.

Figure 3. Detecti on of polymerase chain reacti on product after amplificati on

of DNA fr om per ipheral blood mononuclear cell s. Samples fr om 3 bone mar-

row t ransplant (BM T) pati ents who had subcli nical cell -associated vi remia are

shown i n 1A , 1C and 1D ; samples fr om 5 BM T pati ents wit hout detectable

VZ V vir emia are shown in 1B and 2C-F. Samples 1F and 2B are the VZ V

DNA contr ols; sample 2A is PBMC f rom a healt hy immune donor contr ol.

Repri nted wit h permission [8] .

A

1

2

B C D E F


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A n t i gen-Specific T-Cell Frequencies in Ada pti veImm unity to VZV

The escape of VZV from immune surveillance is associ-ated with declining numbers of VZV-specific memoryT cells in the latently infected host [28]. Conversely, the riskof herpes zoster is decreased w hen VZ V-specific T- c e l lresponses are detected. Among H C T recipients and ot herpatients with cellular immunodeficiencies, prolonged peri-ods of lymphopenia and the loss of VZV-specific T cellspredict an interval of high risk for VZ V reactivation [3,9,29-38]. The most severely immunocompromised patients, suchas H C T recipients, are most susceptible to herpes zoster.Among these patients, memory T cellswhich can prolifer-

ate in response to VZV antigen, make cytokines such asI FN -, tumor necrosis factor (TNF)- or interleukins, orhave cytotoxic activity against VZV-infected cellsfallbelow the threshold of detection [37]. Otherwise healthyelderly individuals have a higher risk of VZV reactivation asa result of immunosenescence; these individuals have someV Z V-specific T cells but low er freq uencies of re s p o n d e rT cells than younger adults. In contrast to correlation withloss of cellular immunity, a prospective analysis of the risk ofherpes zoster and VZV antibody tit ers in the H C T donor orrecipient revealed no relationship [39].

Innate Host Responses to VZVD espite the correlation between loss of VZV- s p e c i f i c

m e m o ry T cells an d th e risk of VZ V re c u rrence, th e

absence of detectable responses for prolonged periodsappears to be a necessary, but not sufficient, condition forVZV reactivation from latency. This observation suggeststhat nonspecific antiviral immunity helps to restrict thesymptoms of VZV reactivation. In cont rast to virus-specifi cT-cell immunity, natural killer (NK) cell activity comparableto that of healthy subjects is recovered during the first fewmonths aft er H C T [39]. Wh en evaluated for cyto toxicityagainst VZ V-infected targets, some HC T recipients had apredominance of N K cells expressing C D 16 surface antigen,

and infected cells were lysed by class I and class Iindepen-dent mechanisms [9]. IF N - is made by NK cells andmonocytes without requiring the presence of antigen-specific T cells and has direct an tiviral activity against VZV.A functional role for this protein was suggested by the effi-cacy of exogenous IFN- in reducing the severity of recur-rent VZV infections in immunocompromised patients whengiven within 72 hours after the appearance of the cutaneousrash [40]. Nonspecific cytotoxic responses and induction ofantiviral cytokines may function to control VZV replicationbefore the recovery of virus-specifi c T cells after H C T.

G ranulysin is a newly described cytolytic protein madeby N K cells as well as by antigen-specific C D 8+ T cells [41].

Our recent experiments demonstrate that granulysinincreases the death rate of VZV-infected cells in vitro [42].When VZV-infected cells were exposed to granulysin, syn-thesis of infectious virus was reduced dramatically and deathof VZV-infected cells was accelerated. VZV infection offib roblasts in t he ab sence of g ranulysin caused dow nregu-lated surface expression of the cellular protein fas and inhib-ited susceptibility of infected cells to apoptosis triggered byanti-fas immunoglobulin M (IgM). G ranulysin release byNK cells rep resents an innat e immune response tha t mayreverse this virus-induced block of apoptosis, resulting in celldeath before large numbers of infectious virions can be syn-thesized. Secretion of granulysin by NK cells may enhancethe early destruction of VZV-infected cells in the absence ofmemory T cells that mediate adaptive immune responses.

RECONSTITUTION OF VZV-SPECIFIC T-CELL IMMUNITYAFTER HCT

H C T patients have a gradual re c o v e ry of memoryT cells that recognize VZV antigens (Figure 5) (A. H ata, L .Zerbo ni, M. Sommer, A.A. K aspar, C . C layberg e r, A.M.Kren s k y, A.M .A., un published data) [7,9,30]. D etect ion ofVZV memory T cel ls is usual ly possible by 9 to 12months after H C T and correlates with a reduction in the

Figure 4. Int erf erence by vari cella- zoster vir us (VZV ) wi th int erf eron (I FN )-induced upregulat ion of major histocompati bil i ty complex class II expression v ia

the Stat signal t ransducti on pathway. Repri nted wit h permission [26].


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overall risk 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.O nce VZV reactivation occurs, most H C T recipients areeffectively resensitized to the virus. In the earliest study ofthe reconstitution of VZV T-cell immunity, Meyers et al.

[43] detected T-lymphocyte proliferation to VZV in 16 of18 pat ients (89%) aft er sympt omat ic re cu rrences of VZVversus 15 of 29 patients (51%) who did not develop herpeszoster. Almost half of the H C T recipients rec overed VZVimmunity with no clinical signs of recurrence. Thus, innateimmune mechanisms may be adequat e to cont rol viral repli-cation while naive T cells are induced to become antigen-

specific or while the few remaining antigen-specific T cellsundergo sufficient clonal expansion. This pattern of recon-stitution suggests that the subclinical episodes of react i v a-tion, documented by VZV PCR, may provide the stimulusto re s t o re adapt ive immunity to VZ V [9]. P re t r a n s p l a n timmunity in both donor and recipient may also facilitate therecovery o f VZ V-specifi c T cells [43].

In addition to proliferative and cytokine responses, atlater t imes after H C T, patients also develop cytotoxic T lym-phocytes (CTL) that can recognize and lyse autologous tar-get cells that express VZV proteins [9]. In our experience,50% of H C T patients had VZV-specific C TL function whentested a mean of 155 days after transplant (Figure 6). How-ever, the mean precursor frequency of T lymphocytes thatrecognized the VZV IE62 protein or glycoprotein E (for-

merly designated gp I) was more than 2-fold lower amongH C T recipients than the frequency of C TL t hat recognizedthese viral proteins in PB MC from healthy immune subjects.In t hese experiments, the proliferation of C D 4+ T cells wasreduced significantly compared w ith t hat of healthy subjects;C D 8+ T cells predominat ed in VZV-stimulated culture s ,reflecting the relative increase in circulating C D 8+ T cellsthat is common after HC T [44]. Although C D 8+ T lympho-cytes have been defined as the classic cytoto xic effector cell,human CD4+ cells also function effectively as antiviral C TLagainst many viruses, including VZV [45]. The diminishedC D 4+ T-cell response to VZV antigen may account for thelow f requencies of C TL precursors specific fo r the IE 62 orgE prot eins in H C T recipients compared with healthy,

VZV-immune individuals.Whether reco ve ry of T cells th at recognize part i c ularVZV proteins affects the risk of herpes zoster is not known,because only IE62- and gE-specific responses have been

Figure 6. Precur sor fr equencies of cytotoxic T lymphocytes specific for t he immediate earl y protein (IE62) and glycoprotein I (gp I ) of var icell a-zoster v irus in bone

mar row tr ansplant recipients and healt hy subjects. Mean SD for pr ecur sor fr equency esti mates are indicated next to the indiv idual data poin ts () generated by

testi ng indiv idual hematopoieti c cell tr ansplant r ecipients and healt hy immune subjects. Repri nted wit h permission [8].

Figure 5. Lymphocyte tr ansformat ion r esponses of marrow tr ansplant recipi-

ents to vari cell a-zoster v i rus (VZV ) ant igen. A ll pati ents and donors had a

history of VZV i nfecti on. The 9 pati ents who had circulati ng myeloblasts or

lymphoblasts before transplant ar e indi cated by tr iangles (). The 25t h to

75th percentil e of the normal r esponse to VZ V anti gen i s indicated by the

hatched ar ea, and the hor i zontal li nes enclose a 95% r ange of normal

responses.

Time after transplantation (days)


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quantitated. In the intact host, helper and cytotoxic T-cellresponses specific for the IE63 protein are maintained fordecades after primary VZV infection [46]. Recovery ofresponses to the immediate early proteins may be particu-larly important, because these viral gene products are made

in infected cells before viral progeny are synthesized.Recognition by the adaptive immune system could result inlysis of infected cells at early times after virus entry, blockingcell-to-cell spread or release of infectious virus.

Evaluation of Inactivated Varicella Vaccine f o rReconstitution of VZV Imm u n i t y

Ba sed on the evidence that natural VZ V re a c t i v a t i o ninduces recovery of VZV-specific T cells, we have evaluatedwhether the inact ivated varicella vaccine could substitute forthe resensitization caused by VZV reactivation aft er H C Tand modify the incidence or severity of herpes zoster [37].Administering the live attenuated varicella vaccine to elderlyindividuals enhances VZV-specific immunity and immuniza-tion and is being evaluated as a strategy to reverse immuno-

senescence in t his population [37]. H eat inactivation of t helive attenuated varicella vaccine provides an acceptable vac-cine for evaluat ion in severely immun ocom pro m i s e dpatients. We ha ve completed 2 t rials of inactivated varicellavaccine in H C T recipients. In the fi rst, a single-dose regi-men of inactivated varicella vaccine was found to induce atransient boost in T-cell responses but did not result in clin-ical benefit. When the vaccine was given at 1, 2, and 3mont hs after H C T, we observed enhanced cell-mediatedimmunity and decreased severity of herpes zoster in a popu-

lation including auto logous and allogeneic transplant recipi-ents (Figure 7). Patients in the vaccine group developedVZV reactivation but had minimal cutaneous disease and nopersistent postherpetic neuralgia. With re g ard to recov e ryof cyto kine responses, IF N -production was associated w ithth e re c o v e ry of VZ V-specific T-cell prolif erat ion andi n c reased w ith time after tra nsplantat ion. Int erleukin-10

p roduction w as also observed con sistently after H C T an dwas highest in patients whose T-cell proliferation responsewas restored. The experience with the 3-dose regimen fur-ther supports the signifi cance of VZ V-specifi c T-cell immu-nity in maintaining the equilibrium between the latent virusand host. Our current study is designed to assess whetherearlier VZV immune reconstitution in H C T recipients canbe achieved by immunizing recipients before as well as aftertransplantation.

VZV RESEARCH AND CLINICAL OBSERVATIONSOf importance is the relationship between studies of

VZV pathogenesis and immunity and observations about theclinical syndromes associated with VZV reactivation after

H C T. C linical experience demonstr ates th at the immuno-logic impairment experienced by H C T recipient s results inan attack rate of 13% to 55% for symptomatic VZV re acti-vation dur ing the fi rst year [3,29-37] (Table). In contr ast, theannual incidence of herpes zoster among healthy adults is0.5% [1]. Although the precise viral mecha nisms that trig gerreactivation are not known, clinical observations documentthat the d iff e rences between pat terns of VZV and H SVinteractions with dorsal root ganglia cells during latency areassociat ed with a longer interval to VZV re a c t i v a t i o n[4,35,36]. H SV-1 disease typically occurs abo ut 2 to 3 weeksafter H C T, whereas VZV recurrences present at a median of5 months. Most VZV rec u rrences appear 2 t o 10 mont hsafter transplantation, although some cases are diagnosed as

early as week 1. Analyses of risk factors such as allogeneicversus autologous transplant, graft-versus-host disease(GVH D ), underlying disease, and pre-BMT irradiation areequivocal in establishing definitive associations. The patientsunderlying disease does not appear to influence VZV reacti-vation, but in 1 study, a history of symptomatic herpes zosterb e f o re tra nsplantat ion in H odgkins disease pat ients wasassociated with a higher risk of early herpes zoster afterautolog ous HC T [31]. This observation suggests thatre-establishment of latency may be incomplete in the contextof continued or increased immunosuppression.

L ocal i z ed Herpes ZosterA dermatomal rash is the most common clinical presenta-

tion of VZV infection in HC T recipients who are seropositive

at the time of transplant, accounting for 85% of cases in 231H C T recipients in the study by Locksley et al. [3]. The rash oflocalized herpes zoster is usually preceded by pain and paras-thesias in the involved dermatome [1,34,47]. These symptomsare undoubtedly a manifestation of viral replication that occursin the sensory ganglia and may begin many days before thecutaneous rash appears. In some cases, the pain syndrome isnot followed by the typical zoster rash, but subsequentenhanced immune responses suggest a recent VZV reactiva-tion; t his syndrome is referred to as zoster sine herpete [48].

Fi gu r e 7. T-cell pr oli ferati on to var icell a-zoster anti gen in bone mar row

tr ansplant recipients part icipating in the study of the 3-dose regimen of inacti -

vated vari cell a vaccine. The mean sti mul ation index (SI) SE to vari cel la-

zoster anti gen i n vaccine recipients tested immediately before immuni zati on at 1

month after t ransplantation and at 2, 3, 4, 5, and 12 months() and r esponses

of unvaccinated patients at t he same ti me interval s after HCT (). *Time

points with a stat isti cally significant (P < .05) di fference in mean SI between

vaccinated and unvaccinated patient s. Reproduced wi th permission [37].


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The dermatomal distribution of the cutaneous lesions of local-ized herpes zoster reflects the persistence of VZV in dorsalroot ganglia and its transport down neuronal axons in thecourse of reactivation. The rash consists of clusters of vari-

cella-like vesicles in 1 or several sites anteriorly and posteriorlywithin the dermatome. H aving been delivered to cutaneousepithelial cells via neuronal pathways, the virus is able tospread from cell to cell within the epidermis and dermis, asevident from the fact that discrete vesicles typically enlarge tof o rm conf luent lesions [47]. D elayed o r inadeq uate h ostresponses result in an average time for cessation of newlesion formation of 8 days, compared with 3 to 5 days in thenormal host; the time to complete healing is also pro longed.Some H C T patients may have a chronic cutaneous reactiva-tion of VZV that persists for months, indicating continuedviral replication in ganglia and skin that is unchecked by thehost response [34]. Bacterial superinfection and local scarringare also common in H C T recipients with herpes zoster, occur-

ring with an incidence of 17% and 19%, respectively.Fai l ure of the host response to overcome the immuneevasion mechanisms of the virus and stop replication resultsin particular complications when VZV reactivation involvescranial nerves. C orneal damage, facial scarring, facial palsy,and hearing loss with vestibular symptoms are common[3,29-36]. Oral lesions of the palate may develop withoutany cutaneous lesions when the second branch of cranialnerve V is affected. H erpes zoster involving cranial nervescan also be associated with the serious central nervous sys-tem complication re f e rred to as cerebral ang iitis, a syn-d rome of cerebral vascular inflammation w ith thro m b o s isand microinf arcts. C erebral angiitis can result in extensivethrombosis with contralateral hemiparesis [49]. The patho-logic changes are granulomatous inflammation of the arter-

ial w all, mononuclear cell infiltrat es, and vascular necro s isassociated with the detection of VZV in endothelial cellsand smooth muscle cells of the affected arteries. In somecases, VZV replication can extend from t he dorsal ganglia toinvolve the anterior horn cells of the spinal cord, with asso-ciated abnormalities evident by magnetic resonance imag-ing. U nder these circumstances, inflammat ion and necrosismay produce permanent motor deficits [50].

P ostherpetic neuralgia (P H N) is the most common com-plication of herpes zoster in immunocompetent as well as

immunocompromised patients. P ostherpetic pain is describedas any pain that persists after resolution of the rash or, alter-na ti v e l y, on ly pain th at persists more than 2 mont hs aftercutaneous healing. As a result, estimates of the incidence of

postherpetic neuralgia depend on t he defi nition used. H CTrecipients appear to be at higher risk of PH N. Locksley et al.[3] observed P H N in 25% of H C T recipients, compare dwith an expected incidence of about 9% in healthy individu-als; Koc et al. observed PHN and peripheral neuropathy in68% of H C T patients [37].

Cutaneous and Visceral DisseminationH eightened susceptibility to viral dissemination is fur-

ther evidence of the impact of diminished immunity on thepathogenesis of VZV infections after H C T. When optionsfor ant iviral therapy w ere limited, 21% of H C T recipientswith recurrent VZV had visceral dissemination of the virusand 12% died from complications o f re c u rrent VZV [3].

The current risk of morbidity and mortality caused by VZVinfection cannot be compared with the original analyses ofVZV-related disease after B MT, because antiviral therapy isnow available. Nevertheless, more recent studies documenta high risk of cutaneous dissemination (15%-23%) and vis-ceral involvement (5%-14%) in H C T recipients. For exam-ple, Schuchter et al. [31] found that 15% of autologousBMT recipients had cutaneous dissemination, 5% had vis-ceral dissemination, and 25% had neurologic sequelae,including PH N.

Because it is a sign that VZV has infected circulatingT cells, cutaneous dissemination provides a marker for risk ofvisceral dissemination. H owever, visceral disseminat ion alsooccurs in patients whose cutaneous lesions are localized to theprimary dermatome. In addition, some patients have no pri-

mary dermatomal involvement but present with diffuse VZVlesions resembling varicella. This syndrome, ref erred to asatypical nonlocalized zoster, accounted for 21% of recurrentVZV episodes in 1 series of H C T recipients [32].

When virus-infected T cells have entered the circulation,the virus can reach many visceral organs. The most commonsites for further viral infection are the lungs and liver, result-ing in VZV pneumonia, hepatitis, and intravascular coagu-l o p a t h y. F atal VZV infections a re most often due to viralpneumonia [51]. The risk of VZV dissemination is increased

Incidence of Var icell a-Z oster Vi rus (VZV ) In fecti ons Af ter HCT

Clinical Presentation

VZV Localized AtypicalYear 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 01986 [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] Hodgkins disease 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

*T his study evaluated pediat r ic patients only.17% had vari cell a-l ike cutaneous involvement and 3% had visceral dissemi nati on.


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in patients with acute G VH D , and VZV has also been identi-fi ed as a cause of late interstitial pneumonia in HC T patientswith chronic G VH D [52]. Some H C T recipients pre s e n twith signs of visceral dissemination 24 to 96 hours before thedermatomal rash becomes evident [53-57]. The fact that vis-ceral dissemination has been observed in HC T patients with-out any signs of cutaneous disease demonstrates that cell-

associated viremia can occur without replication of the virusin skin, presumably by entry of virus into T cells that trafficthrough sensory g anglia [3]. Immunosuppression also predis-poses to CNS infection, which manifests clinically as menin-goencephalitis, during VZV reactivation [58]. Visceral dis-seminat ion increases the morta lity of VZV re a c t i v at i o nsubstantia lly, from 7% to 55%. Mortality is usually due topneumonia, but the risk of fatal infection is highest amongpatients who develop both pneumonia and encephalitis.

Second Episodes of Herpes ZosterSome H C T recipients have recur rences of herpes zoster

within days after antiviral therapy is stopped, indicating thefailure to reestablish latency in the short term. When zosterhas resolved, however, second episodes are unusual. Only

2% of patients in 1 large series had 2 episodes of herpeszoster, occurring an average of 25 months (range 4-41) aftertransplantation [3]. These data confirm the importance ofreconstituted VZV immunity in maintaining latency.

IMPLICATIONS FOR THE MANAGEMENT OF VZVINFECTIONS IN HCT RECIPIENTSD iagn o si s

The unusual clinical manifestat ions of re current VZVin H C T recipients re q u i re a high index of suspicion f orVZV as a potential etiology. Reliance on rapid, sensitivemethods for laboratory diagnosis is essential in many cases.These met hod s includ e dir ect immun of luor e s c e n c e ,

enzyme immunoassay, and PCR, as well as more rapid andsensitive viral culture methods such as shell vial assays [59].Serologic approaches to the diagnosis of acute VZV reacti-vation are not reliable because VZ V IgG antibodies arepresent in all latently infected individuals, VZV IgM assaysare difficult to standardize, intermittent detection of IgMant ibodies is re p o rted in individuals with no evidence ofreactivation, and some patients have herpes zoster withouteliciting IgM antibodies.

Antiviral Tr e at m e ntAcyclovir has been shown to be effective for the treat-

ment of recurrent VZV infection in immunocompro misedpatients in placebo-controlled trials and extensive clinicalexperience [47]. Antiviral treatment compensates for the

delayed host response and results in shorter time to cessationof new lesion formation, more rapid crusting and healing,and prevention of cutaneous and visceral dissemination. Acy-clovir therapy initiated within 72 hours after the onset ofVZV reactivation can be expected to reduce the duration ofnew lesion format ion in H C T patients to approximately 3days. On average, early antiviral treatment should cause thecessation of acute pain within 4 days, crusting of lesions by 7days, and complete healing by 2 to 3 weeks. Although earlyacyclovir treatment is likely to produce the best results, clini-

cal benefi t can still occur when t herapy is delayed for morethan 3 days [60]. In 1 series, none of 29 immunocompro-mised patients whose therapy was initiated more than 3 daysafter the onset of the rash ha d pro g ressive herpes zoster,compared with 3 of 17 patients in the placebo group.

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 HC T patients whoare treated with acyclovir. In 1 series, 5 of 40 patients (12%)developed new lesions; in 3 of the 5 pat ients, relapse occurredless than 4 days after treatment was stopped [61]. Early acy-clovir therapy may delay the recovery of VZV-specifi c immu-nity in some patients. Nevertheless, most patients respond totreatment w ith a second course of acyclovir.

Although acyclovir is clearly benefi cial for t he treatmentof acute herpes zoster, its effect on the incidence of PH Nhas b een more difficult to establish. Among H C T re c ip i-ents, 9 of 40 (20%) patients had recurrence of pain after ces-sation of therapy [62].

The effi cacy of oral acyclovir for herpes zoster in HC Tpatients has not been fi rmly established, and its bioavailabil-ity is low. The oral rout e of administration is appropriate for

patients who are carefully selected based on their presenta-tion with localized herpes zoster only, at longer interv a l safter H C T. Acyclovir has been shown to be a safe agent inm o re t han a decade of clinical experience and is tolerat edwell by H C T patients, although side effects are more fre-quent than in other populations. In 1 series, nausea andvomiting, w hich is particularly associated wit h elevated crea-tinine, occurred in 40% of treated patients [61]. Nephro-toxic effects, defined as a 50% rise in serum creatinine, werealso more common than in other patient populations; 10%to 25% of H C T patients receiving acyclovir were reportedto have abnormal serum creatinine, but these elevations mayhave been caused by other medications given concurrently.Because acyclovir is excreted by glomerular filtration, other

d rugs tha t a ffect renal function, such as cyclosporine, canincrease plasma drug concentrations. Acyclovir dosage mustbe adjusted in relation t o creatinine clearance. Acute neuro-toxicity associated wit h acyclovir treatment has beenreported in patients with impaired renal clearance. In mostinstances, abnormal liver function tests in patients withVZV reactivation are likely to indicate viral hepatitis, notdrug toxicity. Acyclovir does not have hematologic toxicityand does not interfere with engraft ment in H C T recipients.

Valaciclovir and famciclovir are nucleoside analogs thatresemble a cyclovir in their stru c t u re and mechanisms ofaction; all 3 drug s interf e re with viral t hymidine kinaseactivity [63,64]. Valaciclovir and famciclovir are absorbedmuch more effectively after oral administration than acy-clovir and have a comparable safety profi le. Although con-

trolled trials to establish their clinical effi cacy have not beendone in H C T patients, valaciclovir and fa mciclovir are use-ful alternatives to acyclovir in those patients with herpeszoster for wh om oral thera py is considered appro p r i a t e .They require only 3 doses per day but are more expensivethan acyclovir and do not have significantly enhanced effi-cacy compared with the recommended dosage of oral acy-clovir in otherw ise healthy individuals.

VZV resistance to acyclovir has not b een common in H CTrecipients, but it has been reported in patients with acquired


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immunod efi ciency syndrome [65]. When VZV reactiv ationoccurs in HC T recipients, it may resolve slowly or recur shortlyafter antiviral therapy is stopped. In most cases, this clinical pat-tern is related to limitations in the host response, for which thedrug compensates only partially, and does not represent theemergence of acyclovir resistance. Because most resistant VZVstrains have mutations in thymidine kinase, acyclovir, valaci-

clovir, and famciclovir are all equally ineffective [47,65,66]. Fos-carnet has antiviral activity against VZV strains that are notinhibited by acyclovir, but its clinical use is complicated bypotential liver toxicity and emergence of resistance [67]. Insome cases, acyclovir-resistant VZV strains emerge during ther-apy, a risk that is associated particularly with prolonged, low-dose regimens, but VZV isolates from later recurrences mayhave recovered susceptibility to acyclovir. G anciclovir and acy-clovir have equivalent antiviral activity against VZV in vitro ,but ganciclovir efficacy has not been evaluated in patients withherpes zoster because it is more toxic than the primary drugs.Based on in vitro analysis, ganciclovir given to CMV-infectedH C T recipients might ameliorate concurrent VZV infection.Koc et al. [37] found that patients receiving ganciclovir haddelayed onset of VZ V reactivation until after 4 months.

Although the live attenuated varicella vaccine is notindicated for administration aft er HC T, some children whohave received this vaccine may become transplant recipients.The risk is significantly less than naturally acquired VZVinfection, but the vaccine virus can establish latency andreactivation may occur [68]. Because the vaccine is preparedfrom the Oka strain of VZV, which retains susceptibility toacyclovir and related antiviral ag ents, vaccine-related herpeszoster can be t reated with acyclovir.

Varicella-Zoster Imm u n oglobu l i nVaricella-zoster immunoglobulin (VZIG ) contains high

titers of VZV IgG and is indicated for immediate postexpo-sure prophylaxis of high-risk patients who have not had VZV

infection and have close contact with varicella or herpesz o s t e r. VZI G is not used in patients with herpes zoster,because VZV I gG titers are maintained despite the loss ofcell-mediated immunity to the virus. There is no indicationthat passive antibody prophylaxis increases existing antibodytiters or reduces the risk of VZV react ivation after H C T [38].The clinical experience is that H C T recipients exposed tovaricella or herpes zoster are rarely reinfected with the virus,even when no VZV-specifi c T-cell responses are detecta ble.The persistence of VZV IgG may protect against exogenousreexposures to the virus, by neutralization or other antibody-mediated mechanisms, even though antibodies fail to blockreactivation of the pa tients endogenous virus.

Antiviral Pr o phy laxis

Although daily acyclovir prophylaxis inhibits the reacti-vation of VZV, antiviral drugs are not usually given to H C Trecipients for VZ V suppression. H erpes zoster, especiallywhen it occurs shortly after H C T, may cause disseminateddisease; however, prompt initiation of acyclovir therapy,given when symptoms of VZV reactivation appear, is aneffective alternative to continued administration of antiviraldrugs. In 2 studies of acyclovir prophylaxis after H C T, VZVreactivation was ma naged effectively among placebo subjectswho were given intravenous acyclovir at the onset of symp-

toms [69-71]. G iving antiviral agents daily at the low dosesused for prophylaxis may facilitate the selection of VZVstrains tha t are th ymidine kinasenegative and th ere f o reresistant. In addition, the cumulative attack rate for VZVreactivation in treated and placebo patients was equivalentover a 1-year time period, indicat ing th at suppre s s i o nrequired a constant presence of the drug in t issues.

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