Varicella Zoster Virus (VZV)

EPIDEMIOLOGY AND RISK FACTORS

Epidemiology

Varicella zoster virus (VZV) is an exclusively human virus that belongs to the α-herpesvirus family. VZV is present worldwide and is highly infectious. Primary infection leads to acute varicella or “chickenpox”, usually from exposure either through direct contact with a skin lesion or through airborne spread from respiratory droplets.(1, 2) After initial infection, VZV establishes lifelong latency in cranial nerve and dorsal root ganglia, and can reactivate years to decades later as herpes zoster (HZ) or “shingles”.(3) More than 90% of adults in the United States acquired the disease in childhood, while the majority of children and young adults have been vaccinated with the live virus vaccine.(2, 4)

Primary varicella typically presents with fever, constitutional symptoms and a vesicular, pruritic, widely disseminated rash that primarily involves the trunk and face.(5) The symptoms usually resolve within 7 to 10 days, but in rare cases primary varicella leads to more severe disease and visceral invasion. Complications such as hepatitis, pancreatitis, pneumonitis, and encephalitis are infrequent but can be life-threatening; adults and very young children are more likely to develop such complications from primary infection.(6, 7) Rates of hospitalization and mortality due to varicella have dropped with the institution of routine childhood varicella vaccination.(8, 9)

Nearly all patients with HZ develop an exanthem of vesicular lesions in a dermatomal distribution. The annual incidence of HZ in the general population is 1.5 to 3.0 cases per 1,000 persons(2), and is estimated to occur in up to 20% of individuals during their lifetime.(10) Secondary complications such as bacterial superinfection and postherpetic neuralgia (PHN), or chronic neuropathic pain at the site of HZ lead to increased morbidity.(11)

Over 90% of adult solid organ transplant (SOT) recipients will be seropositive for VZV. Rates are lower in pediatric transplants (12, 13), but immunity will increase as uptake of varicella vaccine improves. Varicella is rare in adult SOT recipients, but can be devastating, with visceral involvement, severe skin disease, and disseminated intravascular coagulation.(14-19) Herpes zoster is a frequent infectious complication in SOT recipients with an incidence of approximately 8-11% during the first four years post transplant.(20-22) Invasive disease and dissemination similar to that seen in primary VZV infection are uncommon but have been reported in SOT and other immunocompromised populations, and level of immunosuppression may alter the risk of developing these complications.(17, 23, 24) Rates of PHN in SOT recipients may also be higher than in immunocompetent populations.(22)

Risk Factors

Primary Varicella

Susceptible patients are at risk for primary varicella. Studies have demonstrated that approximately 2-3% of adult SOT recipients are seronegative for VZV.(13, 25) Donor transmitted VZV infection is rare but has been reported in a case where the donor had recently been treated for primary varicella.(26)

Herpes Zoster

Patients with previous VZV disease or VZV vaccination are at risk for the development of HZ. Since there are no large prospective trials that have evaluated HZ in SOT, risk factors are not well defined. Similar to the general population, longitudinal studies have demonstrated that older transplant recipients are at greater risk for the development of HZ.(20, 21) In similar studies, heart and lung transplant patients have increased rates of HZ compared to other transplant recipients, possibly related at least in part to more intensive immunosuppression.(20, 22) The use of MMF has also been suggested as a potential risk factor for the development of HZ.(24, 27) It is unknown whether the development of HZ prior to transplant will lessen post-transplant VZV reactivation.

DIAGNOSIS

In general, both primary varicella and HZ have typical clinical presentations that allow for a presumptive clinical diagnosis. 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. One distinctive feature is that new lesions appear for several days such that patients have papules, vesicles, and crusted lesions at the same time. HZ most often presents as a painful vesicular rash that involves ≤2 adjacent unilateral dermatomes.(2) Presentations may vary as patients may present with pain as a prodrome to the development of lesions, and pain may be less frequently seen in children and young adults. Herpes zoster ophthalmicus (trigeminal ganglion), Ramsay-Hunt syndrome (herpes zoster oticus – geniculate ganglion), and other unique HZ presentations have been described elsewhere.(28)

Immunocompromised patients with HZ may develop disseminated skin lesions that can mimic primary varicella during periods of prominent immunosuppression.(2, 17) SOT recipients are more likely to present atypically (29, 30), and can rarely develop invasive complications without skin manifestations.(30) In SOT recipients, who may develop a multitude of other infectious and non-infectious rashes, laboratory testing is even more important than in the normal host, as diagnosis may be more difficult to establish on clinical grounds alone.

Definitive laboratory testing can be used for atypical cases of VZV or HZ and should routinely be used for suspected disseminated or visceral disease. Rapid diagnostic methods, including polymerase chain reaction (PCR) and direct fluorescent assays (DFA), are the methods of choice.(31) PCR testing, the most sensitive test for VZV (32), can be used for detecting invasive disease, and detects VZV in vesicle fluid, serum, spinal fluid, and other tissues. DFA is performed on scrapings taken from the base of a skin lesion, and is a rapid and reliable method for diagnosing VZV disease. While viral culture is specific and can help distinguish VZV from other viral pathogens, it provides slower results and is much less sensitive.(33) Since serologic testing can lead to false-negative results in immunocompromised patients or in early infection, and to false-positive results following a blood transfusion, it should not be used for diagnosing acute infections in this population.(31)

TREATMENT (see Table 1)

Table 1.

Recommendations for VZV Treatment in Solid Organ Transplant Recipients

Disease	Treatment	Evidence	Comments
Outpatient Treatment
Herpes Zoster			Valacyclovir and Famcicovir is not FDA approved for treatment of herpes zoster, but is commonly used in clinical practice Valacyclovir is only recommended for children ≥2 to 18 years of age Antivirals are typically given for at least 7 days or until lesions have crusted over, which may be delayed in immunocompromised hosts IV acyclovir is recommended in children <2 yrs of age [10 mg/kg IV every 8 hours] or those who cannot tolerate oral therapy
Localized (Dermatomal)	Acyclovir 800 mg PO five times daily (adults and children ≥ 12 yrs) 20 mg/kg PO four times daily (pediatrics > 2 years; max of 800 mg/dose) OR Valacyclovir 1 gram PO three times daily (adults) 20 mg/kg PO three times daily (pediatric >2 and ≤18) years)† OR Famciclovir 500 mg PO three times daily (adults only)	Evidence II-1
Inpatient Treatment
Acute Varicella	Acyclovir 10 mg/kg IV every 8 hours	Evidence II-2	IV therapy can be changed to oral therapy once the patient has significantly improved Careful monitoring of renal function is needed while on IV therapy, and dosing should be adjusted for renal insufficiency
Herpes Zoster Disseminated or Invasive Disease or Herpes zoster ophthalmicus or Ramsay-Hunt syndrome/Herpes zoster oticus	Acyclovir‡ 10 mg/kg IV every 8 hours	Evidence II-2 or III*	In disseminated disease 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 Consideration for switch to oral therapy dependent on patient's clinical status

^*Data supporting IV therapy for herpes zoster ophthalmicus and oticus are Evidence level III

^†FDA approved dosing for children only in varicella not herpes zoster

^‡Higher dosing [20mg/kg IV every 8 hours] has been suggested for treatment of herpes zoster in children <12 years (reference 31)

Varicella

Post-transplant patients who develop primary varicella are at risk for developing severe disease and should be treated with intravenous acyclovir.(34-36) (Evidence II-1) Therapy initiated early in the course of the illness, especially within 24-hours of rash onset, maximizes efficacy.(31) Reduction in immunosuppressive therapy should be considered (Evidence III)(18), but to facilitate an appropriate stress response, steroid dosing should be maintained or may need to be temporarily boosted based on clinical findings. Neither non-specific intravenous immunoglobulin (IVIG) nor VZV immunoglobulin likely add additional benefits to those with established disease and are therefore not recommended.(31) However, IVIG has been used in those with severe disease (Evidence III).(17, 37, 38)

Herpes Zoster

Localized non-severe dermatomal HZ can be treated with oral valacyclovir or famciclovir as an outpatient with close follow-up.(39, 40) (Evidence II-1) Two notable exceptions would be VZV reactivation within the trigeminal ganglion (herpes zoster ophthalmicus) which may be sight-threatening, and involvement of the geniculate ganglion (herpes zoster oticus / Ramsay-Hunt syndrome) which can lead to facial palsy. These patients should preferably receive IV acyclovir therapy, and in cases of trigeminal involvement, prompt ophthalmologic consultation to avoid major morbidity (Evidence III). Disseminated or organ invasive disease should be treated like primary varicella with IV acyclovir (Evidence II-2).(34, 36)

PREVENTION (see Table 2)

Table 2.

Recommendations for VZV Prevention in Solid Organ Transplant Recipients

Strategy	Pre-Transplant	Post-Transplant	Dosing	Comments
Primary Prevention
Antiviral Prophylaxis				Dosing based on HSV prevention. Evidence in other populations for effectiveness against VZV, however limited data in SOT recipients. IV acyclovir is recommended in children <2 yrs of age [5 mg/kg IV every 8 hours] or those who cannot tolerate oral therapy Alternate less frequent dosing (BID) for acyclovir has been described but has not been evaluated in SOT populations Lifelong risk of HZ limits use of these agents for long-term prevention. Patients receiving CMV prophylaxis generally should be protected from VZV reactivation Valacyclovir is only recommended for children 2 to <18 years of age and has not been studied as a prophylactic agent in children post-SOT
Acyclovir (and pro-drugs)	N/A	Consider, short term prophylaxis if patients not receiving CMV prophylaxis (Evidence III)	Acyclovir 600-1000 mg/day PO in 3-5 divided doses (adults and children ≥ 2 yrs) Max dose in children is 80 mg/kg/day not to exceed 1000 mg OR Valacyclovir 500 mg PO twice daily (adults only)§
Vaccination				Vaccination has been shown to be safe in ESRD and ESLD patients Seroconversion rate reduced in immunosuppressed individuals Caution should be used in post-transplant patients since live virus vaccine Second dose can be given 4 weeks after first (see package insert for administration)
Varicella Vaccine (Varivax®)	YES, if seronegative (Evidence II-1)	Consider if susceptible in select populations (Evidence III)	Varivax® 0.5 mL administered SQ
Zoster Vaccine (Zostavax®)	No for most transplant recipients (Evidence III), unless patient meets label indications (Evidence I)	No (Evidence III)	N/A	Follow label indications, as no evidence that vaccine is safe in severe organ dysfunction or post-transplant If patient meets label indications can be considered, but should be given at least 3-4 weeks prior to transplant.
Secondary Prevention (Post-exposure)
Immunoprophylaxis				VariZIG is only available through IND protocol† Must be given as soon as possible – no efficacy if given more than 96 hours post-exposure Not 100% effective in clinical studies of preventing VZV, so close observation is suggested If varicella develops, patient should be treated with antiviral therapy
VZV immunoglobulin (VZIG, VariZIG™)	YES, if seronegative (Evidence II-1)	YES, if susceptible (Evidence II-1)	VariZIG 125 units/10 kg body weight in single IM dose (Max dose is 625 units, min 125 units)
IV immunoglobulin (non-specific IVIG)	Consider, if VZIG or VariZIG not available (Evidence III)	Consider, if VZIG or VariZIG not available (Evidence III)	IVIG 400 mg/kg IV single dose	Amount of anti-VZV antibodies in IVIG is variable, and should only be considered if VZV specific immunoglobulin therapy is not available
Antiviral Prophylaxis				Given 7-10 days after exposure for 7 days Alternatively, some experts recommend dosing being given days 3-22 after exposure (or till day 28 if given immunoprophylaxis) Caution with patients with underlying renal dysfunction as dosing may need to be reduced IV acyclovir is recommended in children <2 yrs of age [10 mg/kg IV every 8 hours] or those who cannot tolerate oral therapy Valacyclovir is only recommended for children 2 to <18 years of age and has not been studied as a prophylactic agent in children post-SOT
Acyclovir‡ (and pro-drugs)	Consider, if VZIG or VariZIG not available or in addition to immunoprophylaxis (Evidence III)	Consider, if VZIG or VariZIG not available or in addition to immunoprophylaxis (Evidence III)	Acyclovir 800 mg PO four times daily( adults) 20 mg/kg PO four times daily (maximum 800 mg four times a day, ≥ 2 yrs of age) OR Valacyclovir 1 gram PO three times daily (adults)

VZV= Varicella zoster virus, HSV = Herpes simplex virus, SOT = Solid organ transplant, ESRD= End-stage renal disease, ESLD=End-stage liver disease

^†Contact information for VariZIG is available online at: (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm55e224a1.htm)

^‡Valacyclovir is preferred as oral acyclovir may have poor bioavailability and unpredictable absorption

Primary Prophylaxis

Antiviral therapy

Oral acyclovir and its pro-drugs have been shown to prevent VZV reactivation in other immunosuppressed populations.(41) During the early post-transplant period, many current regimens used for cytomegalovirus (CMV) prevention will likely prevent VZV reactivation, and therefore additional antiviral prophylaxis for VZV is not needed during active CMV prophylaxis [valganciclovir, ganciclovir, or high dose acyclovir] (42-44) In patients who do not receive CMV prophylaxis, short term antivirals [acyclovir, valganciclovir] given for herpes simplex (HSV) prophylaxis may also be effective against VZV during the period immediately post-transplant (Evidence III). Since the length of immunosuppression is life-long in most SOT recipients, an increased risk for HZ is continuous after transplantation (20-22). While effective for short-term use (45), insufficient data exist to recommend routine use or long-term VZV prophylaxis in SOT recipients (Evidence III).

Pre-Transplant Vaccination

Potential transplant patients who are susceptible to VZV, should be given varicella vaccination with the live attenuated Oka vaccine (Varivax^®, Merck & Co, Inc., USA) provided no contraindications are present (Evidence II-1). Multiple non-randomized studies in subjects with end-stage renal disease have demonstrated that the Oka vaccine is safe and effective prior to transplant.(25, 46-48) While fewer data are available in subjects with end-stage liver disease, the Oka vaccine also appears to be safe if given pre-transplant to these patients.(49, 50) (Evidence II-2) Little data exists for other pre-transplant patients but the vaccine is likely safe in these populations (Evidence III).(51) Patients with end-stage organ disease have reduced seroconversion rates to varicella vaccination [~60%](46-48), so two doses should be given prior to transplantation if practical with a minimal interval of 4 to 6 weeks.(44, 52, 53) Patients should be vaccinated at least 2 to 4 weeks prior to transplant (53), but if the vaccine is given in conjunction with measles, mumps, rubella vaccine (MMR and Varicella combined vaccine [ProQuad^®, Merck & Co., Inc, USA]) it should be administered at least 4 weeks prior to transplant.

The newly licensed HZ vaccine (Zostavax^®, Merck & Co., Inc., USA) contains approximately ten times more plaque forming units of live-virus then do current Oka varicella vaccines so, poses a risk of disseminated disease in immunosuppressed patients and should not be used post-SOT. This vaccine has not been studied in patients with end-organ disease and is currently not recommended for post-transplant patients (Evidence III).

Post-Transplant Vaccination

Live-virus vaccines are generally not recommended in immunocompromised hosts. However, the Oka varicella vaccines have been shown to be safe in select children undergoing chemotherapy and small studies have demonstrated that they can be given safely to post-transplant recipients receiving immunosuppression.(54-56) While vaccination has been given safely to small numbers of susceptible SOT recipients (56), until further controlled trials, available vaccines are currently not routinely recommended post-transplant (Evidence III).

Secondary Prophylaxis

Post-Exposure Prophylaxis

Seronegative transplant recipients are at risk for developing varicella after primary exposure and should, after a significant exposure, receive post-exposure prophylaxis (Evidence II-1). In the outpatient environment significant exposure to VZV has been defined as exposure to a household contact or nontransient face–to-face contact indoors with a playmate or other contact. 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.(31) VZV can be spread from a person with active varicella or HZ to a person who has never had chickenpox through direct contact with the rash since individual lesions have high titers of viral DNA. There is also evidence that VZV may be spread through an airborne route even from localized HZ.(1, 57-59)

Options for post-exposure prophylaxis include passive immunoprophylaxis and/or antiviral therapy. Varicella zoster immune globulin (VZIG) is no longer available in most centers, and currently a new non-licensed VZV immune globulin VariZIG™ (Cangene Corporation, Winnipeg, Canada) may be the only VZV specific immunoprophylaxis available.(4) Available only through an investigational new drug application, lack of rapid access may further limit the use of VariZIG at many centers.(60) If available, VZIG or VariZIG is recommended in susceptible patients exposed to VZV and should be given as soon as possible but within at least 96 hours of exposure. (Evidence II-1).(31)

Immunoprophylaxis alone does not prevent all immunosuppressed patients from developing clinical varicella but lessens the severity of disease.(61-63) Although not studied in clinical trials, non-specific IVIG has been suggested as an alternate post-exposure prophylaxis when VariZIG is not available (31); combination use of IVIG with antiviral therapy in immunocompromised patients can also be considered (Evidence III).

The use of antiviral agents as post-exposure 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 were unable to receive immunoprophylaxis prior to 96 hours after their exposure (Evidence III). The value of acyclovir as post-exposure prophylaxis has been demonstrated in a study of immunocomponent children(64) and has been suggested to be effective (in addition to VZIG) in a small study of high-risk children which included 5 kidney transplant recipients.(65) Due to the unpredictable absorption and low bioavailability of oral acyclovir (66, 67), valacyclovir, which has improved bioavailability (68), may be preferred for prophylaxis (Evidence III). 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 (Evidence III).(31) Alternatively, some experts believe 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 (Evidence III).(69, 70)

INFECTION CONTROL ISSUES

All patients admitted to the hospital with varicella or HZ should be placed on airborne and contact isolation, and close contacts that are susceptible to VZV should be immunized as soon as possible (preferably within 3 days of exposure with possible efficacy as late as 5 days post-exposure) or given appropriate VZV prophylaxis (Evidence II-B).(31) Patients should be isolated until at least all lesions are crusted, which can be delayed in immuncompromised patients.(31) In addition to post-exposure 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 or IVIG should remain in precautions until day 28.(31) Patients with localized zoster lesions should also have them covered as this can potential decrease transmission risk.(59)

Since secondary cases of VZV in a household setting can be more severe due to exposure to a higher titer of virus (71), prevention is critically important. Vaccinated individuals are 50% less contagious when they develop varicella and secondary attack rates are much lower.(72) Close contacts and family members 12 months or older should be vaccinated for VZV if they have never received the vaccination, have no history of varicella or HZ, and have no contraindications to vaccination (Evidence III). 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.(72)

RESEARCH ISSUES

Further epidemiologic data regarding specific transplant and host related factors that increase the risk of the developing of HZ in SOT are needed. Future studies are needed to evaluate the safety and efficacy of post-transplant vaccination for HZ in seropositive recipients, and to assess the use of antiviral therapy as post-exposure prophylaxis. Newer inactivated vaccines are being developed and will need to be studied in the SOT population.(73) The development of new immunosuppressive agents will need to be evaluated both in terms of altering risk post-transplant as well as their effect on vaccine efficacy.