Varicella Zoster Virus (VZV) in Solid Organ Transplant Recipients

Abstract

Varicella zoster virus (VZV) is an exclusively human virus that belongs to the a-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 (1Sawyer MH Chamberlin CJ Wu YN Aintablian N Wallace MR Detection of varicella-zoster virus DNA in air samples from hospital rooms.J Infect Dis. 1994; 169: 91-94Crossref PubMed Scopus (148) Google Scholar, 2Gnann Jr, JW Whitley RJ Clinical practice. Herpes zoster.N Engl J Med. 2002; 347: 340-346Crossref PubMed Scopus (662) Google Scholar). 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’ (3Gilden DH Kleinschmidt-DeMasters BK LaGuardia JJ Mahalingam R Cohrs RJ Neurologic complications of the reactivation of varicella-zoster virus.N Engl J Med. 2000; 342: 635-645Crossref PubMed Scopus (650) Google Scholar). 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 (2Gnann Jr, JW Whitley RJ Clinical practice. Herpes zoster.N Engl J Med. 2002; 347: 340-346Crossref PubMed Scopus (662) Google Scholar, 4Marin M Guris D Chaves SS Schmid S Seward JF Prevention of varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2007; 56: 1-40PubMed Google Scholar). Primary varicella typically presents with fever, constitutional symptoms and a vesicular, pruritic, widely disseminated rash that primarily involves the trunk and face (5Heininger U Seward JF Varicella.Lancet. 2006; 368: 1365-1376Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar). The symptoms usually resolve within 7–10 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 (6Varicella-related deaths among adults-United States, 1997.MMWR Morb Mortal Wkly Rep. 1997; 46: 409-412PubMed Google Scholar, 7Guess HA Broughton DD Melton 3rd, LJ Kurland LT Population-based studies of varicella complications.Pediatrics. 1986; 78: 723-727Crossref PubMed Google Scholar). Rates of hospitalization and mortality due to varicella have dropped with the institution of routine childhood varicella vaccination (8Nguyen HQ Jumaan AO Seward JF Decline in mortality due to varicella after implementation of varicella vaccination in the United States.N Engl J Med. 2005; 352: 450-458Crossref PubMed Scopus (353) Google Scholar, 9Davis MM Patel MS Gebremariam A Decline in varicella-related hospitalizations and expenditures for children and adults after introduction of varicella vaccine in the United States.Pediatrics. 2004; 114: 786-792Crossref PubMed Scopus (179) Google Scholar). 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 1.5–3.0 cases per 1000 persons (2Gnann Jr, JW Whitley RJ Clinical practice. Herpes zoster.N Engl J Med. 2002; 347: 340-346Crossref PubMed Scopus (662) Google Scholar), and is estimated to occur in up to 20% of individuals during their lifetime (10Straus SE Ostrove JM Inchauspe G et al.NIH conference. Varicella-zoster virus infections. Biology, natural history, treatment, and prevention.Ann Intern Med. 1988; 108: 221-237Crossref PubMed Scopus (333) Google Scholar). Secondary complications such as bacterial superinfection and postherpetic neuralgia (PHN), or chronic neuropathic pain at the site of HZ, lead to increased morbidity (11Johnson RW The future of predictors, prevention, and therapy in postherpetic neuralgia.Neurology. 1995; 45: S70-S72Crossref PubMed Google Scholar). Over 90% of adult solid organ transplant (SOT) recipients will be seropositive for VZV. Rates are lower in pediatric transplants (12Crespo JF Gorriz JL Avila A et al.Prevalence of past varicella zoster virus infection in candidates for kidney transplantation: Vaccination in seronegative patients.Transplant Proc. 2002; 34: 77Crossref PubMed Scopus (13) Google Scholar, 13Geel AL Landman TS Kal JA Van Doomum GJ Weimar W Varicella zoster virus serostatus before and after kidney transplantation, and vaccination of adult kidney transplant candidates.Transplant Proc. 2006; 38: 3418-3419Crossref PubMed Scopus (34) Google Scholar), 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 (14Pandya A Wasfy S Hebert D Allen UD Varicella-zoster infection in pediatric solid-organ transplant recipients: A hospital-based study in the prevaricella vaccine era.Pediatr Transplant. 2001; 5: 153-159Crossref PubMed Scopus (32) Google Scholar, 15Furth SL Sullivan EK Neu AM Tejani A Fivush BA Varicella in the first year after renal transplantation: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS).Pediatr Transplant. 1997; 1: 37-42PubMed Google Scholar, 16Rodriguez-Moreno A Sanchez-Fructuoso AI Calvo N et al.Varicella infection in adult renal allograft recipients: Experience at one center.Transplant Proc. 2006; 38: 2416-2418Crossref PubMed Scopus (36) Google Scholar, 17Fehr T Bossart W Wahl C Binswanger U Disseminated varicella infection in adult renal allograft recipients: Four cases and a review of the literature.Transplantation. 2002; 73: 608-611Crossref PubMed Scopus (100) Google Scholar, 18Feldhoff CM Balfour Jr, HH Simmons RL Najarian JS Mauer SM Varicella in children with renal transplants.J Pediatr. 1981; 98: 25-31Abstract Full Text PDF PubMed Scopus (114) Google Scholar, 19McGregor RS Zitelli BJ Urbach AH Malatack JJ Gartner Jr, JC Varicella in pediatric orthotopic liver transplant recipients.Pediatrics. 1989; 83: 256-261Crossref PubMed Google Scholar). HZ is a frequent infectious complication in SOT recipients with an incidence of approximately 8–11% during the first 4 years posttransplant (20Pergam S, Boeckh M, Maynard C, Forsberg C, Limaye A, Young B. Increased Risk of Herpes Zoster in a Multi-center VA Healthcare System Cohort of Solid Organ Transplant Recipients. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/ 46th Annual Infectious Diseases Society of America Conference, Washington, DC, October 25–28, 2008; Abstract 1330.Google Scholar, 21Arness T Pedersen R Dierkhising R Kremers W Patel R Varicella zoster virus-associated disease in adult kidney transplant recipients: Incidence and risk-factor analysis.Transpl Infect Dis. 2008; 10: 260-268Crossref PubMed Scopus (69) Google Scholar, 22Gourishankar S McDermid JC Jhangri GS Preiksaitis JK Herpes zoster infection following solid organ transplantation: Incidence, risk factors and outcomes in the current immunosuppressive era.Am J Transplant. 2004; 4: 108-115Crossref PubMed Scopus (201) Google Scholar). 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 (17Fehr T Bossart W Wahl C Binswanger U Disseminated varicella infection in adult renal allograft recipients: Four cases and a review of the literature.Transplantation. 2002; 73: 608-611Crossref PubMed Scopus (100) Google Scholar, 23Koc Y Miller KB Schenkein DP et al.Varicella zoster virus infections following allogeneic bone marrow transplantation: Frequency, risk factors, and clinical outcome.Biol Blood Marrow Transplant. 2000; 6: 44-49Abstract Full Text PDF PubMed Scopus (190) Google Scholar, 24Lauzurica R Bayes B Frias C et al.Disseminated varicella infection in adult renal allograft recipients: role of mycophenolate mofetil.Transplant Proc. 2003; 35: 1758-1759Crossref PubMed Scopus (54) Google Scholar). Rates of PHN in SOT recipients may also be higher than in immunocompetent populations (22Gourishankar S McDermid JC Jhangri GS Preiksaitis JK Herpes zoster infection following solid organ transplantation: Incidence, risk factors and outcomes in the current immunosuppressive era.Am J Transplant. 2004; 4: 108-115Crossref PubMed Scopus (201) Google Scholar). 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 (13Geel AL Landman TS Kal JA Van Doomum GJ Weimar W Varicella zoster virus serostatus before and after kidney transplantation, and vaccination of adult kidney transplant candidates.Transplant Proc. 2006; 38: 3418-3419Crossref PubMed Scopus (34) Google Scholar, 25Geel A Zuidema W Van Gelder T Van Doornum G Weimar W Successful vaccination against varicella zoster virus prior to kidney transplantation.Transplant Proc. 2005; 37: 952-953Crossref PubMed Scopus (29) Google Scholar). Donor transmitted VZV infection is rare but has been reported in a case where the donor had recently been treated for primary varicella (26Fall AJ Aitchison JD Krause A Hasan A Hamilton JR Gould FK Donor organ transmission of varicella zoster due to cardiac transplantation.Transplantation. 2000; 70: 211-213PubMed Google Scholar). 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 (20Pergam S, Boeckh M, Maynard C, Forsberg C, Limaye A, Young B. Increased Risk of Herpes Zoster in a Multi-center VA Healthcare System Cohort of Solid Organ Transplant Recipients. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/ 46th Annual Infectious Diseases Society of America Conference, Washington, DC, October 25–28, 2008; Abstract 1330.Google Scholar, 21Arness T Pedersen R Dierkhising R Kremers W Patel R Varicella zoster virus-associated disease in adult kidney transplant recipients: Incidence and risk-factor analysis.Transpl Infect Dis. 2008; 10: 260-268Crossref PubMed Scopus (69) Google Scholar). 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 (20Pergam S, Boeckh M, Maynard C, Forsberg C, Limaye A, Young B. Increased Risk of Herpes Zoster in a Multi-center VA Healthcare System Cohort of Solid Organ Transplant Recipients. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/ 46th Annual Infectious Diseases Society of America Conference, Washington, DC, October 25–28, 2008; Abstract 1330.Google Scholar, 22Gourishankar S McDermid JC Jhangri GS Preiksaitis JK Herpes zoster infection following solid organ transplantation: Incidence, risk factors and outcomes in the current immunosuppressive era.Am J Transplant. 2004; 4: 108-115Crossref PubMed Scopus (201) Google Scholar). The use of mycophenolate mofetil (MMF) has also been suggested as a potential risk factor for the development of HZ (24Lauzurica R Bayes B Frias C et al.Disseminated varicella infection in adult renal allograft recipients: role of mycophenolate mofetil.Transplant Proc. 2003; 35: 1758-1759Crossref PubMed Scopus (54) Google Scholar, 27Satoh S Tada H Murakami M et al.The influence of mycophenolate mofetil versus azathioprine and mycophenolic acid pharmacokinetics on the incidence of acute rejection and infectious complications after renal transplantation.Transplant Proc. 2005; 37: 1751-1753Crossref PubMed Scopus (37) Google Scholar). It is unknown whether the development of HZ prior to transplant will lessen posttransplant VZV reactivation. 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 (2Gnann Jr, JW Whitley RJ Clinical practice. Herpes zoster.N Engl J Med. 2002; 347: 340-346Crossref PubMed Scopus (662) Google Scholar). 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 (28Volpi A Severe complications of herpes zoster.Herpes. 2007; 14: 35-39PubMed Google Scholar). Immunocompromised patients with HZ may develop disseminated skin lesions that can mimic primary varicella during periods of prominent immunosuppression (2Gnann Jr, JW Whitley RJ Clinical practice. Herpes zoster.N Engl J Med. 2002; 347: 340-346Crossref PubMed Scopus (662) Google Scholar, 17Fehr T Bossart W Wahl C Binswanger U Disseminated varicella infection in adult renal allograft recipients: Four cases and a review of the literature.Transplantation. 2002; 73: 608-611Crossref PubMed Scopus (100) Google Scholar). SOT recipients are more likely to present atypically (29Oh KH Ahn C Kim YS et al.Atypical generalized zoster with suspicious esophageal involvement and early relapse in an adult renal transplant recepient.Transplant Proc. 2002; 34: 1174-1177Crossref PubMed Scopus (7) Google Scholar, 30Hovens MM Vaessen N Sijpkens YW De Fijter JW Unusual presentation of central nervous system manifestations of Varicella zoster virus vasculopathy in renal transplant recipients.Transpl Infect Dis. 2007; 9: 237-240Crossref PubMed Scopus (18) Google Scholar), and can rarely develop invasive complications without skin lesions (30Hovens MM Vaessen N Sijpkens YW De Fijter JW Unusual presentation of central nervous system manifestations of Varicella zoster virus vasculopathy in renal transplant recipients.Transpl Infect Dis. 2007; 9: 237-240Crossref PubMed Scopus (18) Google Scholar). In SOT recipients, who may develop a multitude of other infectious and noninfectious 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 (31American Academy of Pediatrics. Varicella-Zoster Infections. In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book 2006: Report of the Committee on Infectious Diseases, 27th Ed. Elk Grove Village, IL: American Academy of Pediatrics, 2006.Google Scholar). PCR testing, the most sensitive test for VZV (32Taha YA Quinlivan M Scott FT et al.Are false negative direct immnufluorescence assays caused by varicella zoster virus gE mutant strains?.J Med Virol. 2004; 73: 631-635Crossref PubMed Scopus (11) Google Scholar), 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 (33Coffin SE Hodinka RL Utility of direct immunofluorescence and virus culture for detection of varicella-zoster virus in skin lesions.J Clin Microbiol. 1995; 33: 2792-2795Crossref PubMed Scopus (66) Google Scholar). Because 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 (31American Academy of Pediatrics. Varicella-Zoster Infections. In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book 2006: Report of the Committee on Infectious Diseases, 27th Ed. Elk Grove Village, IL: American Academy of Pediatrics, 2006.Google Scholar). Posttransplant patients who develop primary varicella are at risk for developing severe disease and should be treated (Table 1) with intravenous acyclovir (34Balfour Jr, HH McMonigal KA Bean B Acyclovir therapy of varicella-zoster virus infections in immunocompromised patients.J Antimicrob Chemother. 1983; 12: 169-179Crossref PubMed Google Scholar, 35Carcao MD Lau RC Gupta A Huerter H Koren G King SM Sequential use of intravenous and oral acyclovir in the therapy of varicella in immunocompromised children.Pediatr Infect Dis J. 1998; 17: 626-631Crossref PubMed Scopus (36) Google Scholar, 36Shepp DH Dandliker PS Meyers JD Treatment of varicella-zoster virus infection in severely immunocompromised patients. A randomized comparison of acyclovir and vidarabine.N Engl J Med. 1986; 314: 208-212Crossref PubMed Scopus (218) Google Scholar) (Evidence II-1). Therapy initiated early in the course of the illness, especially within 24-h of rash onset, maximizes efficacy (31American Academy of Pediatrics. Varicella-Zoster Infections. In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book 2006: Report of the Committee on Infectious Diseases, 27th Ed. Elk Grove Village, IL: American Academy of Pediatrics, 2006.Google Scholar). Reduction in immunosuppressive therapy should be considered (Evidence III) (18Feldhoff CM Balfour Jr, HH Simmons RL Najarian JS Mauer SM Varicella in children with renal transplants.J Pediatr. 1981; 98: 25-31Abstract Full Text PDF PubMed Scopus (114) Google Scholar), but to facilitate an appropriate stress response, steroid dosing should be maintained or may need to be temporarily boosted based on clinical findings. Neither nonspecific intravenous immunoglobulin (IVIG) nor VZV immunoglobulin likely add additional benefits to those with established disease and are therefore not recommended. (31American Academy of Pediatrics. Varicella-Zoster Infections. In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book 2006: Report of the Committee on Infectious Diseases, 27th Ed. Elk Grove Village, IL: American Academy of Pediatrics, 2006.Google Scholar) Even so, IVIG has been used in those with severe disease (Evidence III) (17Fehr T Bossart W Wahl C Binswanger U Disseminated varicella infection in adult renal allograft recipients: Four cases and a review of the literature.Transplantation. 2002; 73: 608-611Crossref PubMed Scopus (100) Google Scholar, 37Sulliger JM Imbach P Barandun S et al.Varicella and herpes zoster in immunosuppressed children: Preliminary results of treatment with intravenous immunoglobulin.Helv Paediatr Acta. 1984; 39: 63-70PubMed Google Scholar, 38Vales-Albertos LJ Andrade-Sierra J Gomez-Navarro B et al.Nonspecific immunoglobulin and granulocyte-macrophage colony-stimulating factor use in complicated varicella zoster: The first case report in a renal transplant recipient.Transplantation. 2006; 81: 809-810Crossref PubMed Scopus (12) Google Scholar).Table 1Recommendations for VZV treatment in solid organ transplant recipientsDiseaseTreatmentEvidenceCommentsOutpatient treatmentHerpes Zoster Localized (Dermatomal)Acyclovir 800 mg PO five times daily (adults and children ≥ 12 years) 20 mg/kg PO four times daily (pediatrics > 2 years; max. of 800 mg/dose) OR Valacyclovir 1 g PO three times daily (adults) 20 mg/kg PO three times daily (pediatric >2 and ≥18) years)†FDA approved dosing for children only in varicella not herpes zoster. OR Famciclovir 500 mg PO three times daily (adults only)Evidence II-1• Valacyclovir and Famcicovir are 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 years of age [10 mg/kg IV every 8 h] or those who cannot tolerate oral therapyInpatient treatmentAcute VaricellaAcyclovir 10 mg/kg IV every 8 h¶Careful monitoring of renal function is needed while on IV therapy, and dosing should be adjusted for renal insufficiency.Evidence II-2• IV therapy can be changed to oral therapy once the patient has significantly improvedHerpes Zoster Disseminated or Invasive Disease or Herpes zoster ophthalmicus or Ramsay-Hunt syndrome/Herpes zoster oticusAcyclovir‡Higher dosing [20 mg/kg IV every 8 h] has been suggested for treatment of herpes zoster in children <12 years (31). 10 mg/kg IV every 8 h¶Careful monitoring of renal function is needed while on IV therapy, and dosing should be adjusted for renal insufficiency.Evidence II-2 or III*Data supporting IV therapy for herpes zoster ophthalmicus and oticus are Evidence level 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 [20 mg/kg IV every 8 h] has been suggested for treatment of herpes zoster in children <12 years (31American Academy of Pediatrics. Varicella-Zoster Infections. In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book 2006: Report of the Committee on Infectious Diseases, 27th Ed. Elk Grove Village, IL: American Academy of Pediatrics, 2006.Google Scholar).¶ Careful monitoring of renal function is needed while on IV therapy, and dosing should be adjusted for renal insufficiency. Open table in a new tab Localized nonsevere dermatomal HZ can be treated with oral valacyclovir or famciclovir as an outpatient with close follow-up (39Tyring S Belanger R Bezwoda W Ljungman P Boon R Saltzman RL A randomized, double-blind trial of famciclovir versus acyclovir for the treatment of localized dermatomal herpes zoster in immunocompromised patients.Cancer Invest. 2001; 19: 13-22Crossref PubMed Scopus (79) Google Scholar, 40Arora A Mendoza N Brantley J Yates B Dix L Tyring S Double-blind study comparing 2 dosages of valacyclovir hydrochloride for the treatment of uncomplicated herpes zoster in immunocompromised patients 18 years of age and older.J Infect Dis. 2008; 197: 1289-1295Crossref PubMed Scopus (23) Google Scholar) (Evidence II-1). Two notable exceptions would be VZV reactivation within the trigeminal ganglion (herpes zoster ophthalmicus) that may be sight-threatening, and involvement of the geniculate ganglion (herpes zoster oticus/Ramsay-Hunt syndrome) that 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) (34Balfour Jr, HH McMonigal KA Bean B Acyclovir therapy of varicella-zoster virus infections in immunocompromised patients.J Antimicrob Chemother. 1983; 12: 169-179Crossref PubMed Google Scholar, 36Shepp DH Dandliker PS Meyers JD Treatment of varicella-zoster virus infection in severely immunocompromised patients. A randomized comparison of acyclovir and vidarabine.N Engl J Med. 1986; 314: 208-212Crossref PubMed Scopus (218) Google Scholar). Antiviral therapy: Oral acyclovir and its pro-drugs have been shown to prevent (Table 2) VZV reactivation in other immunosuppressed populations (41Erard V Guthrie KA Varley C et al.One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: No evidence of rebound varicella-zoster virus disease after drug discontinuation.Blood. 2007; 110: 3071-3077Crossref PubMed Scopus (158) Google Scholar). During the early posttransplant 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] (42Lowance D Neumayer HH Legendre CM et al.Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group.N Engl J Med. 1999; 340: 1462-1470Crossref PubMed Scopus (649) Google Scholar, 43Gane E Saliba F Valdecasas GJ et al.Randomised trial of efficacy and safety of oral ganciclovir in the prevention of cytomegalovirus disease in liver-transplant recipients. The Oral Ganciclovir International Transplantation Study Group [corrected].Lancet. 1997; 350: 1729-1733Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar, 44Humar A Reactivation of viruses in solid organ transplant patients receiving cytomegalovirus prophylaxis.Transplantation. 2006; 82: S9-S14Crossref PubMed Scopus (55) Google Scholar). 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 posttransplant (Evidence III). Because the length of immunosuppression is life-long in most SOT recipients, an increased risk for HZ is continuous after transplantation (20Pergam S, Boeckh M, Maynard C, Forsberg C, Limaye A, Young B. Increased Risk of Herpes Zoster in a Multi-center VA Healthcare System Cohort of Solid Organ Transplant Recipients. 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/ 46th Annual Infectious Diseases Society of America Conference, Washington, DC, October 25–28, 2008; Abstract 1330.Google Scholar, 21Arness T Pedersen R Dierkhising R Kremers W Patel R Varicella zoster virus-associated disease in adult kidney transplant recipients: Incidence and risk-factor analysis.Transpl Infect Dis. 2008; 10: 260-268Crossref PubMed Scopus (69) Google Scholar, 22Gourishankar S McDermid JC Jhangri GS Preiksaitis JK Herpes zoster infection following solid organ transplantation: Incidence, risk factors and outcomes in the current immunosuppressive era.Am J Transplant. 2004; 4: 108-115Crossref PubMed Scopus (201) Google Scholar). While effective for short-term use (45Fiddian P Sabin CA Griffiths PD Valacyclovir provides optimum acyclovir exposure for prevention of cytomegalovirus and related outcomes after organ transplantation.J Infect Dis. 2002; 186: S110-115Crossref PubMed Scopus (40) Google Scholar), insufficient data exist to recommend routine use or long-term VZV prophylaxis in SOT recipients (Evidence III).Table 2Recommendations for VZV prevention in solid organ transplant recipientsStrategyPretransplantPosttransplantDosingCommentsPrimary PreventionAntiviral prophylaxisAcyclovir (and pro-drugs)N/AConsider, 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 years) max. dose in children is 80 mg/(kg day) not to exceed 1000 mg OR• Dosing based on HSV prevention. Evidence in other populations for effectiveness against VZV, however limited data in SOT recipients.Valacyclovir 500 mg PO twice daily (adults only)§• IV acyclovir is recommended in children <2 years of age [5 mg/kg IV every 8 h] 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-SOTVaccinationVaricella Vaccine (Varivax®)YES, if seronegative (Evidence II-1)Consider if susceptible in select populations (Evidence III)Varivax® 0.5 mL administered SQ• Vaccination has been shown to be safe in ESRD and ESLD patients• Seroconversion rate reduced in immunosuppressed individuals• Caution should be used in posttransplant patients since live virus vaccine• Second dose can be given 4 weeks after first (see package insert for administration)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 posttransplant• If patient meets label indications can be considered, but should be given at least 3–4 weeks prior to transplantSecondary prevention (postexposure)Immunoprophylaxis 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)• VariZIG i