Varicella Zoster Virus in Transplant Recipients
Authors: Maha Assi, M.D., Scott James, M.D., David Kimberlin, M.D.
VIROLOGY
Varicella-zoster virus (VZV) is a double-stranded DNA virus member of the alphaherpesvirus family. The virus is highly temperature sensitive and depends on the envelope proteins for infectivity. It is spread as a cell-free virus into the susceptible host, but once within the infected host is transmitted by cell-to-cell spread (11).
EPIDEMIOLOGY
Primary infection with VZV results in varicella (chickenpox). It is highly transmissible by direct contact with a skin lesion and via respiratory droplets (50). Attack rates range from 30% in a classroom and up to 90% among household contacts (29). After the initial episode, VZV remains latent for life in cranial nerves and dorsal root ganglia and potentially can reactivate up to decades later as zoster (shingles) (23). Zoster is more common with older age and in individuals with decreased cell mediated immunity (27).
Varicella can occur throughout the year, but is more common in the spring (March through May) (50). Prior to the ability to prevent VZV infection by vaccination, chickenpox was a near-universal childhood disease, with 90% of adults in the US having acquired the infection before the age of 13. Since the introduction of the varicella vaccine in 1995, the majority of children and young adults have now been vaccinated (13), significantly altering the natural history of illness in both immunocompetent and immunodeficient populations.
VZV is the second most common viral pathogen in solid organ transplant (SOT) recipients (after cytomegalovirus), with a prevalence of about 29%. Varicella is rare in adult SOT recipients, as the majority is already seropositive (19, 43). On the other hand, zoster occurs in approximately 11% of SOT recipients within four years of transplant due to their required long term immunosuppressive regimens (4, 24). Several reports have linked treatment with mycophenolate mofetil (Cellcept), a commonly used medication for immunosuppression after transplantation, to increased incidence of zoster in SOT recipients (33). Herpes zoster classically occurs in the first 6 months after transplantation in SOT recipients. Recent data points towards increased rates of zoster with increasing time post transplant. This could probably be explained by discontinuation of antiviral prophylaxis, combined with increased length of immunosuppressive treatment (4).
CLINICAL MANIFESTATIONS PERTINENT TO TRANSPLANT RECIPIENTS
Varicella
Primary VZV infection usually manifests initially with fever and malaise, followed by a vesicular pruritic rash. Patients have lesions in different stages of development typically on the face, trunk and extremities (57). Transplant patients are at risk of extensive cutaneous involvement and visceral dissemination, which may lead to pneumonia, hepatitis, encephalitis, and disseminated intravascular coagulopathy. These complications cause a great deal of morbidity and are associated with a high mortality rate (17, 43)
Zoster
In healthy individuals, herpes zoster is most often unilateral involving one or two adjacent dermatomes. The trigeminal nerve, particularly the ophthalmic branch, is the most frequently affected dermatome, comprising 10-15% of cases. Pain and paresthesia within the involved dermatome usually precede by several days the development of lesions which are identical to those of varicella (37).
In immunocompromised patients, including SOT recipients, herpes zoster infection is often a more severe illness. In adult kidney transplant recipients, up to 8% of zoster cases can present with disseminated disease (4). Skin involvement can be more extensive, affecting several noncontiguous dermatomes and lesions may continue to appear for several weeks. Cutaneous dissemination (defined as more than five vesicular lesions beyond the primary dermatome) is more common in hematopoietic stem cell transplant (HSCT) than SOT recipients. Scabbing can be delayed for more than a month. Lesions can extend into the dermis and become hemorrhagic and necrotic. Visceral dissemination through viremic spread, similar to what is described in primary VZV infection, is also possible in up to 30% of cases, causing increased morbidity and mortality (37). Even in the absence of disseminated visceral disease, viremia often occurs in patients with isolated cutaneous VZV disease (14).
Post herpetic neuralgia is the most common neurologic manifestation of herpes zoster (21). Central nervous system complications have been reported mainly in immunocompetent elderly patients and in immunocompromised patients. In the latter, VZV produces a wide variety of clinical syndromes ranging from diffuse small vessel vasculopathy to meningoencephalitis (20).
There are several neurologic complications of zoster due to cranial nerve (CN) involvement. Herpes zoster ophthalmicus occurs when the ophthalmic division of CN V is affected, and occurs in 9% to 16% of cases of herpes zoster. The clinical manifestations include conjunctivitis, anterior uveitis, keratitis, and ophthalmitis (38). Ramsay Hunt Syndrome is a herpetic infection of the geniculate ganglion of the seventh cranial nerve (CN VII). Patients typically present with acute ear pain that radiates to the pinna. Other symptoms include vertigo, ipsilateral hearing loss, tinnitus and facial paralysis. Physical examination usually reveals peripheral facial nerve paresis with associated blisters in the distribution of the nervus intermedius. However the onset of the rash can be delayed for more than 10 days (35). Other unusual presentations have been described with complete absence of auricular lesions (47).
VZV encephalitis is an uncommon manifestation of varicella zoster infection, affecting only 0.1 to 0.2% of patients with VZV infection (16, 21). Among reported cases, most but not all transplant recipients had zoster rash that preceded or was concomitant with the VZV encephalitis (4, 2).
Acute retinal necrosis manifested by retinal vasculitis, confluent retinal necrosis, and acute vitritis produces devastating visual loss. It is seen in healthy and immunocompromised persons (18, 36). Progressive outer retinal necrosis (PORN) is mostly seen in AIDS patients but has also been described in HSCT recipients (28). It is characterized by early involvement of the outer retina, but paucity of intraocular inflammation (5). Other neurologic complications associated with herpes zoster include peripheral motor paralysis, transverse myelitis, and ascending paralysis. Guillain-Barré syndrome has been reported in 17 cases after reactivation of varicella–zoster virus and occurred few days to two months after the zoster rash (42, 42).
LABORATORY DIAGNOSIS
In the setting of acute infection (both varicella and zoster) rapid diagnosis is required to guide decisions about antiviral therapy in immunocompromised hosts, especially those with atypical presentations. VZV can be isolated in tissue culture, albeit less readily than herpes simplex virus. However, this method is not rapid enough to influence clinical decision making (10). The most practical test to virologically confirm acute VZV disease is detection of VZV antigen using a labeled monoclonal antibody. To perform this test, a scraping is obtained from the base of a vesicle and placed on a slide, from which viral antigens then are identified either by staining with fluorescein-conjugated monoclonal antibodies or with enzyme immunoassay methods (10). Another method is VZV DNA detection by in situ hybridization or polymerase chain reaction (PCR) (49). Several PCR assays are commercially available and can be used on different tissue samples including blood, cerebrospinal fluid (CSF), broncheoalveolar lavage, vesicle fluid, and tissue. A swab can be used to rub the base of an unroofed vesicle and then placed in viral transport media, which is then run for PCR detection of VZV DNA; this diagnostic modality is increasingly being used, and is a good adjunct test to perform in addition to antigen detection. Blood PCR has been used to diagnose disseminated infection in the absence of cutaneous lesions (15). Testing by blood PCR is particularly useful in establishing the diagnosis of a neurologic infection with VZV especially in the absence of a concomitant rash.
Serologic tests traditionally are used to determine immune status prior to transplantation. When positive, such tests confirm previous VZV infection in that individual. However, the sensitivity of serologic tests for VZV can be problematic. Commercially available assays for detection of antibody to VZV include the enzyme immunoassay (EIA) and latex agglutination (LA) test (48, 60). The gpELISA that has been used commonly in clinical studies is not commercially available (41). Commercially available EIA and LA tests are less sensitive and therefore unreliable in detecting immunity among vaccinated people. Additionally, the LA test can yield false positive results(6) . VZV IgG and IgM antibodies develop within three days following infection. However VZV IgM can also be detected in most patients with recurrent infection and therefore may not be useful in clinical practice (8).
ANTIretroVIRAL THERAPY
Immunocompromised patients with primary varicella infection should be treated with intravenous (IV) acyclovir at 10 mg/kg every 8 hours (Table 1) (39). Maximum benefit is achieved with early initiation of therapy, especially within 24 h of rash onset. However, treatment should still be given even beyond the initial 24 hours of symptoms onset (40). A switch to oral acyclovir or valacyclovir can be made once the patient is clinically improved. Reduction in immunosuppressive therapy should be considered especially in the severely ill patients. Steroid dosing may need to be maintained or increased to avoid adrenal insufficiency (39).
Localized uncomplicated dermatomal zoster can be treated as an outpatient with oral acyclovir (pediatric dose: 20 mg/kg four times a day; adult dose: 800 mg 5 times a day), valacyclovir (pediatric dose: 20 mg/kg three times a day; adult dose: 1g three times a day), or famciclovir (adult dose: 500 mg three times a day) (31, 39). Intravenous acyclovir (10 mg/kg every 8 hrs) is reserved for patients with disseminated skin infection or organ invasive disease (e.g., pneumonia, hepatitis, encephalitis). SOT recipients with herpes zoster ophthalmicus, Ramsay-Hunt syndrome, or those undergoing treatment for acute rejection should also be preferably treated with IV acyclovir, as above. In addition, patients with Zoster ophthalmicus should have an ophthalmology consult, as they are at risk of losing eyesight (39).
Antivirals are to be given for at least 7 days or until lesions are crusted (39). In SOT recipients, treatment may need to be prolonged as crusting of lesions is usually delayed.
In the rare patient with acyclovir-resistant VZV, the alternative drug is foscarnet 40 mg/kg IV every eight hours for 10 days (44). The major disadvantage associated with foscarnet is the potential for significant metabolic and renal toxicity.
Intravenous immunoglobulin (IVIG) has been used in severely ill patients but there is no evidence of improved outcome (52, 53). The same applies to VZV immunoglobulin and therefore routine use of immunoglobulins is not recommended for treatment of VZV (39).
VACCINES
Indications
VARIVAX (Merck) is a live attenuated Oka VZV vaccine used to prevent chickenpox (34). Pre transplant vaccination is indicated in seronegative individuals, with 2 doses given at least 4 weeks apart (39). Protective varicella titers have been reported in 49 to 100 percent of children on dialysis. Post transplantation, recipients with protective titers developed neither varicella nor herpes zoster (9, 54). However, this would delay transplantation by a minimum of 4 weeks and preferably 3 months to avoid the risk of uncontrolled proliferation of the attenuated strain with high dose immunosuppression. Zostavax (Merck), the herpes zoster vaccine, is not recommended for patients with chronic conditions such as renal failure or end stage liver disease. It has 15 times more plaque forming units of live-virus than the varicella vaccine and therefore could cause disseminated disease in immunosuppressed patients (22, 32). Although two studies have shown no significant adverse effects associated with post transplant administration of a live-virus varicella vaccine in pediatric SOT populations (30, 56) routine post transplant live-virus vaccination is not currently recommended (39).
ANTIVIRAL PROPHYLAXIS
Primary Prophylaxis
In the first 3 to 6 months after transplant most patients receive CMV prophylaxis with ganciclovir or valganciclovir, which will also provide protection against VZV reactivation (Table 2) (25). For patients not receiving CMV prophylaxis (or once CMV prophylaxis is discontinued), oral acyclovir or its pro-drug, valacyclovir, used primarily for HSV prophylaxis, will also prevent VZV reactivation in most patients (39). Although transplant recipients are always at greater risk of reactivation due to lifelong immunosuppression, there is no current indication to routinely extend prophylaxis beyond the first 6 months (39).
Secondary Prophylaxis
Exposure to VZV is considered significant with household contact or an indoor non transient face to face contact. If hospitalized, significant exposure includes sharing the same hospital room or face to face contact with an infectious staff member, patient, or visitor (40). Seronegative SOT recipients with such exposures could benefit from immunoglobulin infusions and oral antiviral therapy (39).
Varicella zoster immune globulin (VZIG) was found to be somewhat effective in either preventing infection or lessening the severity of disease in immunosuppressed children with household exposures to varicella (60), but is no longer available. A new varicella zoster immune globulin product, VariZIG (Cangene Corporation, Winnipeg, Canada), is available by expanded access protocol, but its efficacy has not been tested in clinical trials (1). The dose is 125 units/10 kg body weight, with a minimum dose of 125 units (1 vial) and a maximum dose of 625 units (five vials), to be given within 96 hours of exposure ((12, 39). If VariZIG is not administered within this time frame, the Centers for Disease Control and Prevention suggest the use of IVIG (27).
Antiviral therapy has not been well studied for post exposure prophylaxis in immunocompromised patients. Acyclovir has been suggested to be effective as secondary prophylaxis in conjunction with VZV IgG in a small study of high-risk children including five kidney transplant recipients (43). Current recommendations include acyclovir or valacyclovir (for better absorption) for 7 days, beginning 7–10 days after varicella exposure (39). Other regimens suggested by expert opinions include prophylaxis to be given from days 3 to 22 after known exposure or from days 3 to 28 if the patient is given immunoprophylaxis (7, 57).
INFECTION CONTROL MEASURES
Hospitalized patients with varicella, disseminated zoster, and immunocompromised patients with dermatomal zoster should be placed on airborne (negative pressure room) and contact isolation precautions. Patients are to remain in isolation until lesions have crusted, which could be delayed in immunosuppressed individuals (45, 55). Seronegative exposed SOT recipients should receive appropriate secondary prophylaxis and be placed in isolation between days 10 and 21 post exposure, or until day 28 if immunoglobulins are given (39). Household exposure to vaccinated individuals who develop a vaccine associated rash can also potentially transmit varicella (46). Susceptible transplant recipients should be isolated from such contacts to avoid disseminated disease.
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Table 1. Treatment of Varicella Zoster Virus Infection
| Indication | Drug and Adult Dose | Drug and Pediatric Dose | Duration |
|---|---|---|---|
| Primary varicella | Acyclovir 10 mg/kg IV Q8h | Acyclovir 10 mg/kg IV q8h | Antivirals are to be given for at least 7 days or until lesions are custed.
In SOT recipients treatment might need to be prolonged as crusting of lesions is usually delayed or for more invasive disease.
|
| Localized Zoster | Acyclovir 800 mg PO 5 times a day
Valacyclovir 1g PO TID Famciclovir 500 mg PO TID |
Acyclovir 20 mg/kg PO 4 times a day
Valacyclovir 20 mg/kg PO TID |
|
Disseminated Zoster Organ invasive disease
Zoster ophthalmicus Ramsey-Hunt Syndrome |
Acyclovir 10 mg/kg IV Q8h | Acyclovir 10 mg/kg IV Q8h |
Table 2. Varicella Zoster Virus Prophylaxis
| Indication | Drug | Adult Dose | Duration |
|---|---|---|---|
| Primary prophylaxis | Ganciclovir (If CMV prophylaxis indicated) | 1 g PO three times a day | First 3 months post transplant |
| Valganciclovir (If CMV prophylaxis indicated) | 900 mg PO once a day | ||
| Acyclovir | 600-1000 mg/day (over 3-5 doses) | First 6 months post transplant (if not on CMV prophylaxis) | |
| Valacyclovir | 500 mg PO twice a day | ||
| Secondary prophylaxis | VariZIG | 125 units/10 kg IM once (625 units maximum, 125 units minimum) | Within 96 hours of exposure |
| IVIG | 400 mg/kg IV once | After 96 hours of exposure | |
| Acyclovir | 800 mg PO Four times a day | For 7 days, starting on day 7-10 post exposure | |
| Valacyclovir | 1g PO three times a day |
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Ho D, Newland JG, Arvin AM. Varicella-Zoster Virus
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