Varicella Zoster Virus (VZV) and Herpes Simplex Virus (HSV) in Solid Organ Transplant Patients

Authors

  • R. A. Zuckerman,

    1. Department of Medicine, Section of Infectious Disease and International Health, Dartmouth-Hitchcock Medical Center, Lebanon, NH
    2. Geisel School of Medicine at Dartmouth, Hanover, NH
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  • A. P. Limaye

    Corresponding author
    1. Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington
    • Department of Medicine, Section of Infectious Disease and International Health, Dartmouth-Hitchcock Medical Center, Lebanon, NH
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Corresponding author: Ajit P. Limaye,

limaye@u.washington.edu

Abstract

Varicella zoster virus (VZV) and the two herpes simplex viruses (HSV) are human α-herpesviruses that establish life-long latency in neural ganglia after initial primary infection. In the solid organ transplant (SOT) population, manifestations of VZV or HSV may be seen in up to 70% of recipients if no prophylaxis is used, some of them life and organ threatening. While there are effective vaccines to prevent VZV primary infection and reactivation in immunocompetent adults, these vaccines are contraindicated after SOT because they are live-virus vaccines. For HSV, prevention has focused primarily on antiviral strategies because the immunologic correlates of protection and control are different from VZV, making vaccine development more challenging. Current antiviral therapy remains effective for the majority of clinical VZV and HSV infections.

Abbreviations
ACV

acyclovir

CMI

cell-mediated immunity

CMV

cytomegalovirus

DFA

direct fluorescent antibody

FCV

famciclovir

FDA

Food and Drug Administration

HHV

human herpesvirus

HIV

human immunodeficiency virus

HSV

herpes simplex virus

HZ

herpes zoster

IVIG

intravenous immunoglobulin

PCR

polymerase chain reaction

PHN

postherpetic neuralgia

SOT

solid organ transplant

TK

thymidine kinase

VACV

valacyclovir

VZV

varicella zoster virus

Introduction

Human herpesviruses (HHV) are ubiquitous human pathogens. Varicella zoster virus (VZV or HHV-3) and the two herpes simplex viruses (HSV-1/HHV-1 and HSV-2/HHV-1) are the three pathogenic human α-herpesviruses and are characterized by transmission via mucoepithelial contact and establishing latency in neurons. When the human host is initially infected with these viruses (primary infection) there is a wide spectrum of clinical disease, but with immune control of the virus they eventually establish latency. Since VZV and HSV are highly genetically conserved across populations the broad clinical spectrum likely is a function of viral inoculum and host immune characteristics rather than strain differences. These may include host genetic and exogenous immunomodulatory factors [1]. Advances in the immunobiologics of solid organ transplantation have improved organ and patient survival but the targets of many of these agents are also important in the immune control of HHV infections. Consequently, continued vigilance in the evaluation of HHV infections in transplant patients is necessary.

Clinical Manifestations and Epidemiology (Table 1)

Primary infection

VZV

Clinically, primary varicella presents as a disseminated pruritic rash that often starts on the face and spreads down the trunk, with relative sparing of the hands and soles of the feet; mucosal involvement can occur. New lesions continue to appear for several days such that patients have lesions of various ages (papules, vesicles and crusted lesions) at the same time. Highly immunosuppressed patients may have more severe primary infection with rapid progression and multiorgan involvement. Prior to the introduction of the varicella vaccine in the United States in 1995, over 90% of the population acquired the disease in childhood [2]. Since then, a majority of US children and young adults have been vaccinated with the live Oka virus vaccine, which provides 88–98% protection against all forms of varicella [2]. Thus, only approximately 2–4% of adult SOT recipients are seronegative for VZV and therefore susceptible to primary infection [3].

Table 1. Clinical, epidemiology and risk factors for VZV and HSV infections in SOT patients
 ClinicalEpidemiologyRisk factors
  1. HSV = herpes simplex virus; VZV = varicella zoster virus; SOT = solid organ transplant; PHN = postherpetic neuralgia; CMI = cell-mediated immunity; CNS = central nervous system; MMF = mycofenolate mofetil; ALA = antilymphocyte antibody. See the text for references.

VZV   
PrimaryDisseminated pruritic rash, >98% symptomatic starts on face and spreads to trunk, spares hands and feet, lesions in various stages, more severe in immunocompromised. Rarely can causes end-organ damage (liver, CNS, lung, visceral)>90% VZV exposed in prevaccine era, vaccine 88–98% effective for prevention, 2–4% of SOT recipients are seronegativeSeronegative inhalation or direct contact. Allograft transmission rare
ReactivatedLocalized shingles: ≤2 unilateral dermatomes Disseminated: >2 dermatomes, or 2 noncontiguous, may be atypical or severe/disseminated in SOT patients, cranial nerve/ophthalmic involvement, PHN or superinfection as complicationsIncidence consistent for years after transplant (Figure 1) Lung>heart>kidney>liver PHN in 20–40%Decreased VZV-CMI, older age African American, more immunosuppression, MMF
HSV   
PrimaryVesicular and/or ulcerative lesions may extend locally in the orolabial, genital or perianal regions. More severe and prolonged in SOT. Dissemination rare (skin, liver, CNS)Prevalence HSV-1: 44% by age 19, 80% by 60 HSV-2: 1.6% by 19, 26.3% by 49. Infection from allograft rare. Acquisition after transplant uncommonContact with symptomatic or asymptomatic (shedding). Allograft transmission rare
ReactivatedAsymptomatic reactivation common. Lesions similar to primary infection. Disseminated disease rare35–68% incidence without prophylaxisMore immunosuppression, ALA and MMF

HSV

For HSV, a minority of immunocompetent persons develop symptomatic lesions with primary infection. However, in those who do have symptoms, HSV appears as classic vesicular and/or ulcerative lesions and may extend locally in the orolabial, genital or perianal regions [4, 5]. HSV seronegative SOT recipients may acquire primary HSV from intimate contacts. Rarely, primary HSV infection can be associated with more severe and disseminated disease, including skin, liver, CNS and other organs and is significantly more common in transplant and other immunocompromised persons. Primary infection from the allograft is rare but has been described in liver and kidney transplant recipients, as well as in other organ types [6-9]. The presentation is often fulminant with hepatitis and poor outcome. HSV-1 infection, the classic oro-labial virus, has a peak incidence from early childhood through adulthood, with prevalence in the United States of 44% in 12 to 19 year olds and approximately 80% by the age of 60 [10]. Because it is primarily sexually transmitted, HSV-2 seroprevalence increases rapidly at the age of onset of sexual activity and then progressively increases thereafter, infecting 1.6% of persons aged 14–19 years and 26.3% of persons aged 40–49 years in the United States [11]. HSV-1 is an increasing cause of genital lesions, though typically with less frequent recurrences [12, 13]. Thus, most transplant patients are latently infected with HSV-1 or HSV-2, or both, and are at therefore at risk for reactivated infection.

Reactivated infection

VZV

VZV, like other HHV, remains latent lifelong in trigeminal and dorsal root ganglia, and is generally symptomatic when reactivation occurs. The most common manifestation of VZV reactivation is cutaneous Herpes Zoster (HZ), or ‘shingles’ [14]. HZ most often presents as a painful vesicular rash that involves ≤2 adjacent unilateral dermatomes. Herpes zoster occurs at a relatively consistent incidence for years after transplant (Figure 1) [15]. In reported cohorts, lung recipients appear to be at highest risk (55.1 cases per 1000 person-years of follow-up) compared with heart (40.0), kidney (24.4) and liver (18.3) [15, 16]. This is significantly higher than the incidence of 3.6 per 1000 person years in the general population [17]. With the advent of primary immunization for varicella, HZ incidence has declined in the general population [18]. It remains to be determined if there will be a similar effect on the incidence of HZ in SOT recipients.

Figure 1.

Herpes zoster incidence in a multicenter cohort of solid organ transplant recipients [15].

Secondary complications of HZ include bacterial superinfection and postherpetic neuralgia (PHN), or chronic neuropathic pain at the site of the skin lesions [14]. Approximately 20–40% of transplant recipients with HZ will develop PHN, significantly greater than the rate in the general population [16].

Disseminated VZV is defined by a distribution of greater than two dermatomes, or involvement of two noncontiguous deromatomes and lesions that may mimic primary disease. SOT patients who have altered immune status may have atypical or severe clinical findings [19, 20]. Rarely, patients may develop invasive complications (CNS, visceral) without skin manifestations (zoster sine herpete) [21]. VZV reactivation may also present with ophthalmologic findings, with or without rash [22]. Herpes zoster ophthalmicus (HZO) and progressive outer retinal necrosis (PORN) are sight-threatening emergencies that require prompt ophthalmologic evaluation and treatment [22, 23]. The nasociliary nerve innervates the tip of the nose and the globe, so a vesicular rash on the nose (Hutchinson sign) should prompt consideration of ophthalmic involvement.

HSV

Compared with VZV, HSV reactivation is a frequent occurrence (5–25% of days), the majority being asymptomatic [24]. Solid organ recipients shed virus frequently and also have more frequent and severe clinical manifestations of HSV [25]. Most symptomatic HSV disease occurs early after transplantation and in the setting of antirejection therapy [4, 5, 8]. Clinically evident HSV recurrences are characterized by lesions that are similar to primary infection. These lesions may be mistaken for HZ, particularly if they are on the buttock or atypical location; however, HZ usually covers a larger area of the dermatome than HSV. Additionally, if HZ does recur, then it is usually in a different location from prior recurrences, so recurrent lesions in the same location are more likely to be caused by HSV. Visceral or disseminated disease can occur, including disseminated cutaneous disease, esophagitis, hepatitis, CNS disease and pneumonitis [26, 27]. Fever, leucopenia and hepatitis are common presenting signs of disseminated disease. Pneumonitis is described in recipients of all organ types, but is most common in heart–lung recipients [27].

Risk factors (Table 1)

VZV—primary infection

Varicella zoster virus is highly infectious to seronegative persons and is primarily transmitted through respiratory droplets but can also be spread through direct contact with active skin lesions [14, 28, 29]. Rarely, virus may be aerosolized from patients with active skin lesions and transmitted to mucosal surfaces. Only one donor-transmitted infection has been reported [30]. The efficacy of VariZIG™in immunoprophylaxis for primary varicella is evidence that varicella-specific antibody likely provides some protection against primary infection, but humoral immunity is not important for protection against VZV reactivation [31]. In fact, VZV antibodies have been shown to be elevated in patients with disseminated disease, possibly due to stimulus by high levels of virus [32].

VZV—reactivated infection

Patients with previous VZV disease or VZV vaccination are at risk for the development of HZ [33], though vaccinated individual are less likely to develop HZ than those infected naturally [18]. Few systematic reviews have been done of risk factors for HZ after transplant; thus, a small number of specific risk factors outside of the traditional major factors of age and decreased VZV-CMI have emerged [15, 34]. In one review, African American patients have increased rates of HZ compared to other transplant recipients, possibly in part related to more intensive immunosuppression due to higher rates of rejection in African American transplant recipients [15]. Heart and lung transplant patients, presumably because of their higher immunosuppression requirements, appear to be at increased risk for HZ compared to other organ transplant recipients [3, 15, 16]. Studies have not been designed or powered to determine the risk of specific immunosuppressive agents or combinations; however, in two studies, mycofenolate mofetil (MMF) has been suggested as a potential risk factor for HZ [35, 36]. There has been some suggestion that use of the rapamycins with reduced calcineurin inhibitor exposure leads to decreased herpesvirus infections [37, 38], but the specific effect on VZV incidence has not been confirmed. When one considers the pathogenesis of HZ reactivation, the loss VZV-cell-mediated immunity (CMI) has been the primary risk factor in the development of disease [31, 39, 40]. Therefore, risk for HZ is traditionally highest when this CMI is diminished, such as in the use of immunosuppressive agents targeting CMI primarily as in the treatment of cell-mediated rejection episodes. One must also consider if boosting VZV-CMI may help to prevent HZ after transplant. To date there has been no study evaluating whether or not immunologic stimulus from a prior shingles episode or the use of pretransplant immunization decreases the risk of posttransplant HZ in SOT patients.

HSV—primary infection

In comparison with primary VZV that is transmitted through the respiratory route, primary HSV is transmitted through direct contact with infected mucoepithelial surfaces. Since asymptomatic shedding is frequent, HSV is most often acquired from persons without clinical lesions [41]. Knowledge of serostatus of the organ transplant candidate is important in determining whether the patient is at risk for primary HSV acquisition, either from the allograft or from close contacts after transplant. Primary HSV infection in SOT recipients tends to be clinically severe and prolonged due to lack of immunologic memory [42, 43].

HSV—reactivated infection

HSV seropositive recipients are at risk of clinical reactivation posttransplant in the absence of antiviral prophylaxis even if they have not had prior clinical HSV disease. The incidence of clinically apparent HSV disease in seropositive patients not receiving prophylaxis ranges from 35% to 68% [5, 8, 44]. Because severe HSV disease can occur in seropositive or in seronegative persons who newly acquire the infection, HSV should be considered in the differential diagnosis of clinically appropriate syndromes regardless of serostatus prior to transplant.

As with VZV, few studies have assessed the incidence of HSV reactivation with various immune suppression regimens. Historically, antilymphocyte antibodies and mycophenylate mofetil have been associated with increased risk of HSV reactivation after transplantation [8, 45, 46]. The effect of other agents has not been well studied.

Diagnosis

Clinical findings are a cornerstone for the diagnosis of the majority of VZV and HSV infections, but because of the varied nature of clinical presentation in transplant recipients, supportive diagnostics are important. Similar diagnostic tests are available for the two viruses, and each test has its advantages and disadvantages (Table 2). Rapid diagnostic methods are essential to clinical management and include direct fluorescent assays (DFA) and polymerase chain reaction (PCR) [47, 48]. DFA is performed on scrapings taken from the base of a lesion or other tissue specimen, and is a rapid and reliable method for diagnosing VZV and HSV disease, and for differentiating the two. PCR testing is the most sensitive test [49, 50], can also be done on blood and other fluids (e.g. spinal, bronchoalveolar lavage, vitreous), but may not be available with rapid turnaround at all centers. HSV grows much better in tissue culture than VZV, and most isolates are identified within 5 days. Shell vial culture (a more rapid culture using permissive cells) is more sensitive than tissue culture for VZV, is available within 48 h and is very specific [51]; however, culture has historically been less sensitive than PCR [50, 52, 53]. Tissue histopathology can be helpful with immunocytochemistry for HSV and VZV. All transplant recipients should have serology for VZV and HSV prior to transplant to assist in guidance of peritransplant prevention (see below). VZV and HSV seropositive patients are at risk for reactivation disease. Disseminated VZV disease usually occurs as a reactivation disease so most patients are seropositive. Negative serology (including IgM) in the setting of acute primary infection does not rule out primary infection given its lack of sensitivity in the SOT population. As a result, serologic testing is not indicated in the diagnosis of acute clinical HSV and VZV infection, but is important as a screening tool prior to transplant to predict risk posttransplant and to identify patients for whom VZV vaccination is appropriate. HSV and VZV serologic testing are not routinely done in donors because the results will not affect clinical care. Immunity is not transferred and donor serology does not predict the rare case of allograft transmission of either virus.

Table 2. Laboratory methods for diagnosis of VZV and HSV
TestAdvantageDisadvantage
Direct fluorescent• Rapidly available• Lower sensitivity than PCR
Antibody (DFA)• Virus specific• Limited sample types (need cells to stain; e.g. not CSF)
PCR• Most sensitive• Not available at all centers
 • Done on most sample types 
Culture• Type specific• Takes longer
 • Able to isolate virus for drug susceptibility• Less sensitive
 testingHSV—only ∼25% of PCR positive
  Depends on level of virus [50]
  VZV—<10% sensitive [52]
Tzank smear• Rapid• Requires experience
 • Direct visualization• Nonspecific (HSV or VZV)
Histopathology with• Can prove tissue-invasive disease• Samples more difficult to acquire
immunohistochemistry • Long turnaround
Serology• Useful to guide pre-transplant risk stratification and prevention• Not useful posttransplant, insensitive marker for acute infection
  • False-positive IgM with HSV reactivation

Treatment (see Table 3)

Varicella

Primary, disseminated and visceral varicella require the early initiation of intravenous acyclovir 10 mg every 8 h to optimize clinical outcomes [54, 55]. While some experts support reduction in immunosuppression, there have been no controlled trials of this approach and the overall risk to the patient with regard to the likelihood of organ rejection, adrenal insufficiency and the possibility of allowing for the development of a more robust inflammatory response need to be considered. VZV-specific immune globulin preparations are difficult to obtain rapidly, are expensive, and have not been systematically studied in the setting of disseminated disease; however, some clinicians have reported the use of nonspecific immunoglobulins (IVIG), the efficacy of which has not been established [56].

Table 3. Treatment of VZV and HSV in solid organ transplant patients (81,100)
Clinical disease VZVHSVComments
  1. Dosages are for GFR≥ 50, adjustment is necessary for renal insufficiency.

  2. HSV = herpes simplex virus; VZV = varicella zoster virus; ACV = acyclovir; VACV = valacyclovir; FCV = famciclovir; SOT = solid organ transplant; po = per orally; iv = intravenously; tid = three times a day; bid = twice daily.

Localized mucocutaneousACV800 mg po 5 ×/day400 mg po tid• Prompt initiation of therapy is associated
 VCV1 g po tid1 g po bidwith improved outcomes
 FCV500 mg po tid500 mg po bid• Therapy should be continued until complete crusting (VZV) or healing (HSV) of all lesions
Disseminated mucocutaneous or invasive disease, primary varicella visceral, CNS ophthalmic VZV Ramsey–Hunt syndrome lesions involving the face ACV iv 10 mg/kg q 8 hACV iv 5–10 mg/kg q 8 h• IV therapy can be changed to oral therapy once the patient has significantly improved• IV therapy should be given for at for at least 7 days, but may need to be given for longer in patients with extensive involvement or CNS disease• Ophthalmology consultation is recommended for patients with ophthalmic involvement
Acyclovir resistant disease Foscarnet iv 80–120 mg/kg/day in 2–3 divided dosesIntravenous cidofovirCutaneous HSV: Topical cidofovir or trifluridineInvestigational agents: lipid ester cidfovir, helicase-primase inhibitors • Acyclovir resistance may be seen in HSV and is rare in VZV• Resistance testing is recommended before initiating therapy unless there is strong clinical evidence for lack of response

Herpes zoster

Mild localized cutaneous HZ can be treated with oral acyclovir (800 mg five times a day), valacyclovir (1 g three times a day) or famciclovir (500 mg three times a day) [57]. Treatment is given for a minimum of 7 days, and may need to be continued for longer in the compromised host whose lesions may not crust over quickly. Adjunctive therapies to prevent PHN have not been evaluated in SOT patients. Patients with localized disease involving the face (trigeminal and geniculate ganglions) should be considered for IV acyclovir therapy (10 mg/kg every 8 h) given the potential for ocular (herpes zoster ophthalmicus) and facial nerve (Ramsay–Hunt syndrome) complications [58].

HSV

As with VZV, disseminated, visceral or extensive cutaneous or mucosal HSV disease should be treated with intravenous acyclovir, though the dose is usually lower at 5–10 mg every 8 h [6, 26, 59-61]. Early initiation of acyclovir therapy is associated with improved outcome for HSV disease in transplantation [6], and can be life saving in cases of HSV hepatitis or dissemination. As with VZV, reduction in immunosuppression should be considered for life-threatening HSV disease. More limited mucocutaneous disease can be treated with oral acyclovir, valacyclovir or famciclovir. Therapy should be continued until complete healing of the lesions.

Resistance

Resistance to nucleoside analogs occurs more frequently for HSV than VZV. In fact, there are very few clinical reports of acyclovir resistance through thymidine kinase (TK) and DNA polymerase mutations in VZV [62, 63] and little therapeutic experience [64]. On the other hand, nucleoside analog resistance is found in about 4–7% of immunocompromised patients with HSV [65-67]. Very few studies have looked at SOT-specific resistance rates. In a surveillance study for HSV resistance in France, 2.5% or isolates in SOT patients were resistant to ACV [68]. In another study in Northwest England, two of 20 (10%) heart or lung transplant recipients in were found to have resistant isolates [69]. Thus, resistance rates appear similar in the SOT population to other immunocompromised populations. Acyclovir resistance needs to be considered in patients whose lesions are not responding clinically to appropriate doses of acyclovir therapy. Initial evaluation should include laboratory confirmation of HSV disease and acyclovir susceptibility done on a viral isolate. Foscarnet should be used in patients in whom acyclovir resistance is documented [70]. Topical or intravenous cidofovir and topical trifluridine have also been associated with improvement [71]. To the extent possible, doses of immunosuppressive therapy should be reduced in patients with acyclovir resistant disease. Recurrent acyclovir-resistant HSV disease may require repeated courses of foscarnet. However, after complete healing, the subsequent recurrences may be again susceptible to acyclovir therapy. Novel therapies that are being evaluated include a new lipid-ester formulation of cidofovir and a new helicase-primase inhibitor, ASP2151 [72].

Prevention (see Figure 2)

Posttransplant antiviral therapy for VZV and HSV

Antiviral therapy prevents VZV and HSV reactivation in solid organ transplant patients [16, 73]. When used as universal prophylaxis for cytomegalovirus (CMV) prevention, valgancyclovir, ganciclovir, acyclovir and valacyclovir prevent VZV and HSV reactivation [73]. HSV-specific prophylaxis should be considered for all HSV-1 and HSV-2 seropositive organ recipients not receiving antiviral medication for CMV prevention. Therapies used for HSV prevention are generally considered adequate to prevent VZV. In the unusual circumstance of a patient who is not receiving CMV antiviral prophylaxis and is also HSV seronegative, the use of prophylaxis is not specifically recommended, but some clinicians may choose to give antiviral prophylaxis to prevent the rare case of HSV transmission from an organ [6] or to prevent VZV reactivation. However, the risk for VZV reactivation persists for years after transplant (Figure 1) and the relative benefits of extended duration therapy have not been established in this population. Thus, short duration of VZV-specific prophylaxis is not likely to prevent the majority of cases of HZ. Close clinical monitoring with early antiviral therapy at first onset is also an option. This is an area in need of research.

Figure 2.

VZV and HSV prevention in solid organ transplant patients.

Antiviral dosing

Early trials of HSV-specific prophylaxis in SOT recipients showed effective HSV suppression with acyclovir administered at low doses given three and four times a day [4, 5]. Subsequent metaanalysis showed that these regimens were as effective as higher dose regimens used for CMV prophylaxis [73]. Higher doses of acyclovir administered less frequently (e.g. 400–800 mg 2×/day) have been shown to be safe and effective in other similarly immunocompromised populations (e.g. hematopoietic stem cell transplant, HIV), and are recommended for SOT recipients due to their safety and ease of administration [61, 74, 75]. Additionally, these regimens have been shown to be effective in preventing VZV reactivation in the same populations. Patients with a history of frequent severe clinical HSV reactivations prior to transplant should be given doses in the higher range. Valacyclovir given once daily was found to be inferior to twice daily when given for HSV suppression in HIV patients so once daily valacyclovir is generally not recommended in immunocompromised patients [76].

Duration of HSV-specific prophylaxis

The majority of severe HSV disease occurs within the first month after transplant [5], so prophylaxis should continue for at least a month. For patients receiving CMV antiviral prophylaxis, HSV prevention does not need to be continued after this therapy is completed unless the recipient experiences frequent symptomatic reactivation after prophylaxis is stopped. In patients who experience bothersome clinical recurrences after discontinuation of antiviral therapy, suppressive antiviral therapy should be continued until such time as the level of immunosuppression can be decreased. Of note, suppressive therapy can be safely continued for many years and is associated with less frequent acyclovir resistant HSV than episodic therapy in immunocompromised patients [75], and thus is the preferred approach. If cessation of prophylaxis is unsuccessful, then lifelong suppressive therapy may be necessary.

Immunosuppression intensification for organ rejection has been associated with VZV and HSV recurrence. Resumption of prophylaxis during rejection episodes is recommended [45].

VZV-Specific Prevention

Pretransplant vaccination

Seronegative organ transplant candidates without contraindications should be given live attenuated Oka varicella vaccine (Varivax®, Merck & Co, Inc., USA). Though there are limited data in recipients other than kidney and liver transplant patients, this live vaccine appears to be safe and effective in most patients with organ failure prior to transplant [77-79]. Seroconversion after vaccination is reduced in end-stage kidney and liver disease [78, 80], so two doses should be given prior to transplantation if practical with a minimum interval of 4–6 weeks in between [81]. Patients should be vaccinated at least 2 weeks but preferably greater than 4 weeks prior to transplant. Serology should be done after immunization, with consideration of subsequent doses for patients who do not respond to the initial series [78]. Additional research is needed to determine optimal vaccination strategies and immune markers of protection.

The first trials evaluating the safety of the pretransplant use of the Oka/Merck shingles vaccine (Zostavax®, Merck & Co., Inc., USA) to prevent and/or attenuate the complications of HZ after transplant are ongoing (NCT00940940, NCT01137669). Pretransplant patients without contraindications who are eligible for the vaccine based on current recommendations should be considered for the vaccine if given greater than 4 weeks prior to transplant. In the rare event that a patient receives vaccination soon before transplant, antiviral therapy is recommended after transplant as the Oka strain is susceptible to acyclovir.

Posttransplant vaccination

Seronegative patients who do not receive and/or respond to vaccination pretransplant are at risk for primary infection after transplant. Varivax has been given to seronegative children after transplant on low levels of immunosuppression with some efficacy and little toxicity [79, 82]; however because of reports of disseminated disease after immunization and a lack of systematic evaluation of safety and efficacy, it is not generally recommended in adults [83]. It is important to ensure all close contacts are protected from acquiring primary VZV and potentially exposing the SOT recipient (see the Infection Control section below).

Vaccination with Zostavax has been shown to attenuate the risk and incidence of complications from HZ in immunocompetent individuals [84] but until further research is done, it is currently contraindicated in the immunosuppressed SOT population due to the risk of disseminated disease as it is a live-virus preparation. A heat-inactivated (Merck V212) vaccine has shown some promise in preventing HZ in hematologic autologous transplant [40]; however, there are no current trials underway in the solid organ transplant population.

Infection control

VZV is highly transmissible, so infection control is an important part of any primary prevention method. In the community setting, close contacts and family members 12 months or older should be vaccinated for VZV if they have never received the vaccine, have no history of varicella or HZ, and have no contraindications to vaccination. Vaccinated individuals are less contagious when they develop varicella and secondary attack rates are much lower [85]. The risk of transmission of the Oka vaccine strain to transplant recipients is low compared to the benefit of avoiding the risk of severe VZV disease if an unprotected contact were to expose the SOT recipient to primary varicella. Close contacts of transplant patients who receive live attenuated VZV immunization should keep the vaccination site covered and avoid direct contact with the transplant recipient if lesions develop. Transplant recipients should be isolated from vaccinated contacts who develop a varicella-like rash, particularly those with >50 lesions, as vaccine associated rashes can result in transmission [85].

In the hospital, patients with varicella or HZ should be placed on airborne and contact isolation, and VZV susceptible close contacts (e.g. seronegative and/or without history of vaccination or disease) should be immunized as soon as possible if not contraindicated (preferably within 3 days of exposure with possible efficacy as late as 5 days postexposure) or given appropriate VZV prophylaxis [86]. Patients should be isolated until at least all lesions are crusted, which can be delayed in immunocompromised patients [86]. In addition to postexposure prophylaxis, exposed susceptible patients should remain in airborne and contact precautions from day 10 to 21 after exposure to the index patient, and those who receive VariZIG should remain in precautions until day 28 [86]. Patients with localized zoster lesions should also have them covered as this can potentially decrease transmission risk [87]; however, secondary transmission from HZ via airborne route or direct contact remains a concern [88].

Postexposure prophylaxis

Seronegative transplant recipients are at risk for developing severe primary varicella infection after exposure and should, after a significant exposure, receive postexposure prophylaxis. In the outpatient environment significant exposure to VZV has been defined as exposure to a household contact or nontransient face-to-face contact indoors. In the hospital significant exposure to VZV is defined as exposure in the same 2- to 4-bed room, face-to-face contact with an infectious staff member or patient, or a visit by a person deemed contagious [86]. Though less common, VZV can be acquired by direct contact with a person who has active skin lesions since individual lesions have high titers of viral DNA [89]. There are case reports of airborne acquisition of VZV from patients with localized HZ [90].

Options for postexposure prophylaxis include passive immunoprophylaxis and/or antiviral therapy. The only currently available VZV-specific immune globulin preparation is VariZIGTM (Cangene Corporation, Winnipeg, Canada). The United States Food and Drug Administration (FDA) requires an investigational new drug application through an expanded access protocol and patient informed consent to give this product. The FDA recently expanded the time after exposure before which VariZIG needs to be administered from 96 h to 10 days [91], making it more feasible for some centers to acquire the drug in the recommended window. While efficacy is greatest when the drug is given as soon as possible after exposure, there is good evidence for efficacy in preventing and/or attenuating disease if it is given up to 10 days after exposure [91]. VariZIG is available through a single US distributor (FFF Enterprises; Temecula, California). Although not studied in clinical trials, nonspecific pooled IVIG has been suggested as an alternate postexposure prophylaxis when VariZIG is not available; combination use of IVIG with antiviral therapy in immunocompromised patients can also be considered [92].

The use of antiviral agents as postexposure prophylaxis has not been evaluated in randomized clinical trials in immunocompromised patients, but should be considered as adjunctive therapy in patients receiving immunoprophylaxis or in patients who are unable to receive immunoprophylaxis. The value of acyclovir as postexposure prophylaxis has been demonstrated in a study of immunocompetent children [93] and has been suggested to be effective (in addition to immunoprophylaxis) in a small study of high-risk children which included five kidney transplant recipients [94]. Due to the unpredictable absorption and low bioavailability of oral acyclovir, valacyclovir, which has improved bioavailability, may be preferred for prophylaxis. Current recommendations are for patients to receive acyclovir or valacyclovir for a 7-day course of therapy beginning 7 to 10 days after varicella exposure [86]. Alternatively, some experts believe that those who are highly immunosuppressed should receive longer antiviral prophylaxis from days 3 to 22 after known exposure and from days 3 to 28 if given immunoprophylaxis since immunoprophylaxis may delay the onset of disease [95]. Vaccination is not currently recommended as a part of secondary prevention of VZV in organ transplant recipients.

HSV-Specific Prevention

Prevention of primary infection

Unfortunately, a vaccine to prevent primary HSV infection has been elusive; therefore current prevention techniques are focused on behavioral and antiviral methods to prevent acquisition of HSV. Seronegative transplant recipients should be counseled regarding the risks of HSV-1 and HSV-2 acquisition. It is important to avoid contact with persons with active lesions as these patients are most infectious. However, persons may acquire HSV from asymptomatic individuals so care should be taken in intimate contact, particularly during periods of most intense immune suppression. Condoms may be effective, but do not completely protect against HSV transmission [96]. A majority of persons infected with HSV have never had symptoms, so the virus may be acquired from persons who have never had lesions. Where appropriate, HSV-2 seronegative transplant recipients in new sexual relationships should consider having their partner tested for HSV-2. In serodiscordant couples, daily antiviral therapy taken by the seropositive partner has been shown to prevent HSV-2 transmission to the seronegative partner [41], so this may be considered as an option, but has not been evaluated in the SOT population. There are no controlled studies looking at the efficacy of postexposure prophylaxis to prevent HSV acquisition so it is not routinely recommended.

Knowledge Gaps

Epidemiology

As immunosuppressive agents and regimens change, ongoing epidemiologic research is necessary to determine if specific agents are associated with altered risk for VZV and HSV reactivation. As the population ages, more individuals will be coming to transplant who have been primarily vaccinated for VZV as opposed to having had natural infection. Continued epidemiologic research regarding risks for HZ and the possibility VZV reinfection for those with waning immunity will be necessary.

Diagnosis

VZV and HSV diagnostics have improved substantially with the advent of PCR. However, not all centers have PCR testing for VZV and HSV readily available for various specimen types. Additionally, the appropriate clinical use of PCR testing needs further clarification. For example, HSV PCR testing may be positive from typically ‘sterile’ sites in the setting of other acute illnesses [97]. Formative research needs to be done to determine the clinical and epidemiologic significance of these positive tests [98].

Treatment

Acyclovir remains an extraordinarily safe and effective agent with little resistance in both VZV and HSV. However, the higher IC50 for VZV can make therapy challenging for certain patients. Thus, the pipeline for antiherpes medication development should include mechanisms for early research into drug efficacy for treatment of SOT patients. This would specifically need to include the evaluation of medication levels and interactions with immunosuppressive therapies. The novel helicase-primase inhibitors are not yet being evaluated in SOT patients. The transplant community needs to continue efforts at collaborative multi-center studies to improve access to diverse patient populations.

Prevention

Primary VZV prevention works when vaccines are given pretransplant, but response rates to the current vaccine preparations are suboptimal and the immune correlates of vaccine response have not been well defined in SOT patients. We still use antibody response as a marker for prior exposure and protection from primary infection with VZV; however, we know that alternative immune responses are necessary for protection and some previously VZV exposed transplant recipients may be seronegative but experience HZ after transplant [34]. Further research into improving vaccine response and determining the appropriate markers for protection in the SOT population are necessary. Adjuvant vaccine algorithms should also be evaluated in the SOT population.

In contrast to VZV, HSV-specific vaccines have been difficult to develop. This is due to major differences in the immune control of HSV as compared with VZV. VZV vaccination produces robust antibody and CMI responses in immune competent hosts which both prevent primary infection and reactivation. It appears that HSV prevention and control are more complex than for VZV, so both preventive and therapeutic HSV vaccine trials have been disappointing to date [99]. While VZV-CMI is the primary driver to prevent reactivation of varicella, control of HSV is a function of complex local and systemic innate and adaptive immune responses. Future HSV vaccine studies will need to incorporate measures of protection that may be altered in the SOT population. As previously noted, further research needs to be done regarding antiviral treatment (used by both recipients and their partners) to prevent primary infection with HSV leading into and after transplant.

With >20% of transplant recipients experiencing zoster reactivation during their lifetime, and up to 45% of those developing PHN, it is imperative to do more research to prevent HZ. This should include different vaccine products given both pre and posttransplant and also in the discovery of immune correlates of protection and consideration of modification of regimens to optimize infection prevention. The long-term use of acyclovir is common in the stem cell transplant patient population where lifelong immunosuppression is not the norm as it is in the SOT population. Future research should evaluate immunologic triggers for VZV and HSV reactivation and the limited use of antivirals during periods of highest risk. With current technologies, we should move to identify immune correlates of risk for HHV reactivation so that care may be individualized in the future.

Disclosure

The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. R.A.Z. has received research grant funding from Astellas Pharma. A.P.L. has received consulting, research support, and/or speaking fees from: Astellas Pharma, Merck, BioRad, Novartis, Genentech and Amgen.

Questions

  1. True/false: Varicella (Zoster) may recur in the same location frequently in SOT patients
  2. The best diagnostic test to prove tissue invasive disease from HSV or VZV is
    1. Culture
    2. DFA
    3. Histopathology
    4. Serology
  3. Which of the following regimens should NOT be used to prevent reactivation of VZV and HSV in SOT patients
    1. Valgancyclovir when given for CMV prevention
    2. Acyclovir 800 mg p.o. bid
    3. Famciclovir 500 mg p.o. bid
    4. Valacyclovir 1 g nodaily
  4. True/False: Zostavax is recommended for patients >60 years old after SOT to prevent shingles

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