Herpes Simplex Virus in Solid Organ Transplantation
2013; Elsevier BV; Volume: 13; Linguagem: Inglês
10.1111/ajt.12105
ISSN1600-6143
AutoresMarissa B. Wilck, Richard A. Zuckerman,
Tópico(s)Parvovirus B19 Infection Studies
ResumoHerpes simplex virus type-1 and 2 (HSV-1, HSV-2) are α-herpesviruses which establish latency in nerve root ganglia. Infection with HSV-1, the classic oro-labial herpes virus, is acquired from early childhood through adulthood, with prevalence in the United States of 44% in 12–19 year olds and approximately 80% by the age of 60 (1Schillinger JA Xu F Sternberg MR et al.National seroprevalence and trends in herpes simplex virus type 1 in the United States, 1976–1994.Sex Transm Dis. 2004; 31: 753-760Crossref PubMed Scopus (107) Google Scholar). Associated primarily with genital herpes, HSV-2 has a seroprevalence that increases rapidly at the age of sexual debut, infecting 1.6% of persons aged 14–19 years and 26.3% of persons aged 40–49 years in the United States (2Xu F Sternberg MR Kottiri BJ et al.Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States.JAMA. 2006; 296: 964-973Crossref PubMed Scopus (802) Google Scholar). In recent years, HSV-1 is an increasing cause of genital lesions, though typically with less frequent recurrences (3Engelberg R Carrell D Krantz E Corey L Wald A Natural history of genital herpes simplex virus type 1 infection.Sex Transm Dis. 2003; 30: 174-177Crossref PubMed Scopus (135) Google Scholar,4Roberts CM Pfister JR Spear SJ Increasing proportion of herpes simplex virus type 1 as a cause of genital herpes infection in college students.Sex Transm Dis. 2003; 30: 797-800Crossref PubMed Scopus (306) Google Scholar). Most adult transplant patients are infected with HSV-1 or HSV-2, or both, with prevalence similar to the distribution by age in the general population. A minority of immunocompetent persons infected with HSV develop symptomatic lesions; however, most will shed virus on mucosal surfaces (5Wald A Zeh JE Selke SA et al.Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons.N Engl J Med. 2000; 342: 844-850Crossref PubMed Scopus (529) Google Scholar). Compared with immunocompetent persons, solid organ transplant (SOT) recipients shed virus more frequently, have more frequent and severe clinical manifestations of HSV (6Greenberg MS Friedman H Cohen SG Oh SH Laster L Starr S A comparative study of herpes simplex infections in renal transplant and leukemic patients.J Infect Dis. 1987; 156: 280-287Crossref PubMed Scopus (79) Google Scholar,7Naraqi S Jackson GG Jonasson O Yamashiroya HM Prospective study of prevalence, incidence, and source of herpesvirus infections in patients with renal allografts.J Infect Dis. 1977; 136: 531-540Crossref PubMed Scopus (92) Google Scholar), and may be slower to respond to therapy. Most symptomatic HSV disease in adult transplant recipients results from reactivation of previously acquired virus, particularly early after transplantation and in the setting of antirejection therapy (8Pettersson E Hovi T Ahonen J et al.Prophylactic oral acyclovir after renal transplantation.Transplantation. 1985; 39: 279-281Crossref PubMed Scopus (55) Google Scholar, 9Seale L Jones CJ Kathpalia S et al.Prevention of herpesvirus infections in renal allograft recipients by low-dose oral acyclovir.JAMA. 1985; 254: 3435-3438Crossref PubMed Scopus (67) Google Scholar, 10Singh N Dummer JS Kusne S et al.Infections with cytomegalovirus and other herpesviruses in 121 liver transplant recipients: Transmission by donated organ and the effect of OKT3 antibodies.J Infect Dis. 1988; 158: 124-131Crossref PubMed Scopus (257) Google Scholar). Primary infection from the allograft is rare but described in liver, kidney and other organ transplant types (10Singh N Dummer JS Kusne S et al.Infections with cytomegalovirus and other herpesviruses in 121 liver transplant recipients: Transmission by donated organ and the effect of OKT3 antibodies.J Infect Dis. 1988; 158: 124-131Crossref PubMed Scopus (257) Google Scholar, 11Basse G Mengelle C Kamar N et al.Disseminated herpes simplex type-2 (HSV-2) infection after solid-organ transplantation.Infection. 2008; 36: 62-64Crossref PubMed Scopus (35) Google Scholar, 12Dummer JS Armstrong J Somers J et al.Transmission of infection with herpes simplex virus by renal transplantation.J Infect Dis. 1987; 155: 202-206Crossref PubMed Scopus (67) Google Scholar, 13Goodman JL Possible transmission of herpes simplex virus by organ transplantation.Transplantation. 1989; 47: 609-613Crossref PubMed Scopus (22) Google Scholar). Patients may present early after transplant with a fulminant course with hepatitis and poor outcome. HSV seronegative SOT recipients may also acquire HSV from intimate contacts. The most common clinical presentation of HSV is orolabial, genital or perianal disease (8Pettersson E Hovi T Ahonen J et al.Prophylactic oral acyclovir after renal transplantation.Transplantation. 1985; 39: 279-281Crossref PubMed Scopus (55) Google Scholar,9Seale L Jones CJ Kathpalia S et al.Prevention of herpesvirus infections in renal allograft recipients by low-dose oral acyclovir.JAMA. 1985; 254: 3435-3438Crossref PubMed Scopus (67) Google Scholar). Lesions can be classic vesicular and/or ulcerative and may extend locally. Visceral or disseminated disease can occur, including disseminated mucocutaneous disease, esophagitis, hepatitis and pneumonitis (14Kusne S Schwartz M Breinig MK et al.Herpes simplex virus hepatitis after solid organ transplantation in adults.J Infect Dis. 1991; 163: 1001-1007Crossref PubMed Scopus (144) Google Scholar,15Smyth RL Higenbottam TW Scott JP et al.Herpes simplex virus infection in heart-lung transplant recipients.Transplantation. 1990; 49: 735-739Crossref PubMed Scopus (68) Google Scholar). Fever, leucopenia and hepatitis are the most common presenting signs of disseminated disease. Pneumonitis is described in recipients of all organ types, but is most common in heart–lung transplant recipients (15Smyth RL Higenbottam TW Scott JP et al.Herpes simplex virus infection in heart-lung transplant recipients.Transplantation. 1990; 49: 735-739Crossref PubMed Scopus (68) Google Scholar). Rarely, visceral disease may occur in the absence of cutaneous or mucosal findings. Keratitis (infection of the cornea) is the most common manifestation of HSV in the eye (16Cook SD Herpes simplex virus in the eye.Br J Ophthalmol. 1992; 76: 365-366Crossref PubMed Scopus (29) Google Scholar). Keratitis presents in a variety of pathophysiologic entities. Superficial infection has historically been thought to result from HSV infection in the trigeminal nerve. However, other, pathology may be the result of deeper infection of corneal tissues (e.g. stromal keratitis) with resultant inflammatory reaction and/or immune mediated responses to remaining antigen (17Inoue Y Immunological aspects of herpetic stromal keratitis.Semin Ophthalmol. 2008; 23: 221-227Crossref PubMed Scopus (24) Google Scholar). Recipient HSV IgG serostatus should be determined prior to transplant (II-1). It should be noted that there is limited utility in testing infants and children in the first 6–12 months of life when they may still harbor maternal antibodies. HSV seropositive recipients are at risk of clinical reactivation posttransplant in the absence of antiviral prophylaxis even if they had not had prior clinical HSV disease. The incidence of clinically apparent HSV disease in HSV-seropositive adult transplant patients who are not receiving antiviral prophylaxis ranges from 35% to 68% (9Seale L Jones CJ Kathpalia S et al.Prevention of herpesvirus infections in renal allograft recipients by low-dose oral acyclovir.JAMA. 1985; 254: 3435-3438Crossref PubMed Scopus (67) Google Scholar,10Singh N Dummer JS Kusne S et al.Infections with cytomegalovirus and other herpesviruses in 121 liver transplant recipients: Transmission by donated organ and the effect of OKT3 antibodies.J Infect Dis. 1988; 158: 124-131Crossref PubMed Scopus (257) Google Scholar,18Lowance 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 (657) Google Scholar). Because severe HSV disease can occur in HSV-seropositive or in seronegative persons who newly acquire the infection, HSV infection should be considered in the differential diagnosis of clinically appropriate syndromes regardless of serostatus prior to transplantation. Knowledge of serostatus may be important to determine the possibility of primary HSV acquisition, either from the allograft or from natural sources after transplant, which may be more clinically severe and prolonged due to lack of immunologic memory (19Corey L Holmes KK Genital herpes simplex virus infections: Current concepts in diagnosis, therapy, and prevention.Ann Intern Med. 1983; 98: 973-983Crossref PubMed Scopus (119) Google Scholar,20Nichols WG Boeckh M Carter RA Wald A Corey L Transferred herpes simplex virus immunity after stem-cell transplantation: Clinical implications.J Infect Dis. 2003; 187: 801-808Crossref PubMed Scopus (37) Google Scholar). The incidence of HSV reactivation with specific immunosuppressive regimens has not been formally assessed. Historically, use of anti-CD3 antibody muromonab (OKT3) and mycophenolate mofetil have been associated with an increased risk of HSV reactivation after transplantation (10Singh N Dummer JS Kusne S et al.Infections with cytomegalovirus and other herpesviruses in 121 liver transplant recipients: Transmission by donated organ and the effect of OKT3 antibodies.J Infect Dis. 1988; 158: 124-131Crossref PubMed Scopus (257) Google Scholar,21Tang IY Maddux MS Veremis SA Bauma WD Pollak R Mozes MF. Low-dose oral acyclovir for prevention of herpes simplex virus infection during OKT3 therapy.Transplant Proc. 1989; 21: 1758-1760PubMed Google Scholar,22Buell C Koo J. Long-term safety of mycophenolate mofetil and cyclosporine: A review.J Drugs Dermatol. 2008; 7: 741-748PubMed Google Scholar). There have been no evaluations to date comparing different induction regimens (T cell depleting agents such as rabbit-antithymocyte globulin or alemtuzumab vs. nondepleting agents such as basiliximab or daclizumab) or maintenance immunosuppressive regimens with regards to HSV reactivation rates. However, there are some data to suggest use of the mTOR inhibitors (e.g. rapamycin) with reduced calcineurin inhibitor exposure leads to reduced herpes virus infections (23Pliszczynski J Kahan BD Better actual 10-year renal transplant outcomes of 80% reduced cyclosporine exposure with sirolimus base therapy compared with full cyclosporine exposure without or with concomittant sirolimus treatment.Transplant Proc. 2011; 43: 3657-3668Crossref PubMed Scopus (13) Google Scholar,24Brennan DC Legendre C Patel D et al.Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: Pooled analysis of three clinical trials.Am J Transplant. 2011; 11: 2453-2462Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). Although most patients present with typical orolabial and genital lesions, HSV in immunocompromised hosts may be atypical, thus, laboratory confirmation may be helpful. HSV grows well in tissue culture so that most isolates are identified within 5 days. Timing of sampling is important with mucocutaneous lesions: for example, sampling of genital lesions >5 days old had a yield of less than 35% (25Lafferty WE Krofft S Remington M et al.Diagnosis of herpes simplex virus by direct immunofluorescence and viral isolation from samples of external genital lesions in a high-prevalence population.J Clin Microbiol. 1987; 25: 323-326Crossref PubMed Scopus (107) Google Scholar). Direct fluorescent antibody (DFA) testing of mucocutaneous lesions, bronchoalveolar lavage (BAL) and other clinical samples, can provide rapid results. Compared with virus isolation the sensitivity has been reported between 60% and 75% and specificity of 85–99% (25Lafferty WE Krofft S Remington M et al.Diagnosis of herpes simplex virus by direct immunofluorescence and viral isolation from samples of external genital lesions in a high-prevalence population.J Clin Microbiol. 1987; 25: 323-326Crossref PubMed Scopus (107) Google Scholar, 26Pouletty P Chomel JJ Thouvenot D Catalan F Rabillon V Kadouche J Detection of herpes simplex virus in direct specimens by immunofluorescence assay using a monoclonal antibody.J Clin Microbiol. 1987; 25: 958-959Crossref PubMed Scopus (19) Google Scholar, 27Caviness AC Oelze LL Saz UE Greer JM Demmler-Harrison GJ Direct immunofluorescence assay compared to cell culture for the diagnosis of mucocutaneous herpes simplex virus infections in children.J Clin Virol. 2010; 49: 58-60Crossref PubMed Scopus (20) Google Scholar). Polymerase chain reaction (PCR) assays are up to fourfold more sensitive than tissue culture for diagnosing mucocutaneous HSV and have replaced viral culture as the preferred diagnostic test (28Wald A Huang ML Carrell D Selke S Corey L Polymerase chain reaction for detection of herpes simplex virus (HSV) DNA on mucosal surfaces: Comparison with HSV isolation in cell culture.J Infect Dis. 2003; 188: 1345-1351Crossref PubMed Scopus (257) Google Scholar, 29Kimberlin DW Lakeman FD Arvin AM et al.Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.J Infect Dis. 1996; 174: 1162-1167Crossref PubMed Scopus (212) Google Scholar, 30Ramaswamy M McDonald C Smith M et al.Diagnosis of genital herpes by real time PCR in routine clinical practice.Sex Transm Infect. 2004; 80: 406-410Crossref PubMed Scopus (66) Google Scholar, 31Filen F Strand A Allard A Blomberg J Herrmann B Duplex real-time polymerase chain reaction assay for detection and quantification of herpes simplex virus type 1 and herpes simplex virus type 2 in genital and cutaneous lesions.Sex Transm Dis. 2004; 31: 331-336Crossref PubMed Scopus (58) Google Scholar, 32Cone RW Hobson AC Brown Z et al.Frequent detection of genital herpes simplex virus DNA by polymerase chain reaction among pregnant women.JAMA. 1994; 272: 792-796Crossref PubMed Scopus (117) Google Scholar), culture and DFA remain options for mucocutaneous lesions. The use of PCR in cerebrospinal fluid to diagnose HSV encephalitis is the diagnostic test of choice, with a sensitivity of 98% and specificity approaching 100% (33Lakeman FD Whitley RJ Diagnosis of herpes simplex encephalitis: Application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.J Infect Dis. 1995; 171: 857-863Crossref PubMed Scopus (583) Google Scholar). HSV DNA is also detected in the blood of immunocompetent patients with primary ulcerative infection (34Johnston C Magaret A Selke S Remington M Corey L Wald A Herpes simplex virus viremia during primary genital infection.J Infect Dis. 2008; 198: 31-34Crossref PubMed Scopus (59) Google Scholar) and in those with significant reactivation disease (34Johnston C Magaret A Selke S Remington M Corey L Wald A Herpes simplex virus viremia during primary genital infection.J Infect Dis. 2008; 198: 31-34Crossref PubMed Scopus (59) Google Scholar,35Berrington WR Jerome KR Cook L Wald A Corey L Casper C Clinical correlates of herpes simplex virus viremia among hospitalized adults.Clin Infect Dis. 2009; 49: 1295-1301Crossref PubMed Scopus (60) Google Scholar); however, the clinical significance of finding HSV DNA in the blood outside of patients with clinical syndromes consistent with disseminated disease has not been well established (36Zuckerman RA The clinical spectrum of herpes simplex viremia.Clin Infect Dis. 2009; 49: 1302-1304Crossref PubMed Scopus (11) Google Scholar). Tissue histopathology with immunocytochemistry for HSV, can be helpful and is recommended to confirm a diagnosis where PCR or other tests (e.g. culture) may represent contamination from another site (e.g. BAL contaminated from oropharynx). Serologic testing is rarely useful for diagnosing acute infections as most patients will be HSV seropositive and IgM positivity in HSV infection may indicate reactivation and not new acquisition. Nevertheless, serology (by IgG) is useful to acquire pretransplant for appropriate posttransplant risk stratification.Table 1:Laboratory methods for diagnosis of HSVTestAdvantageDisadvantageDirect fluorescent antibody (DFA)• Rapidly available• Lower sensitivity than PCR• Virus-specific• Limited sample types (needs cells to stain; e.g. not CSF)PCR• Most sensitive• Not available at all centers• Done on most sample types• Positive result, other than in CSF, requires interpretationCulture• Type-specific• Takes longer• Able to isolate virus for drug susceptibility testing• Less sensitive, only ∼25% of PCR positive depends on level of virus (Ref. 23Pliszczynski J Kahan BD Better actual 10-year renal transplant outcomes of 80% reduced cyclosporine exposure with sirolimus base therapy compared with full cyclosporine exposure without or with concomittant sirolimus treatment.Transplant Proc. 2011; 43: 3657-3668Crossref PubMed Scopus (13) Google Scholar)Tzank smear• Rapid• Requires experience• Direct visualization• Nonspecific (HSV or VZV)Histopathology with immunohistochemistry• Can prove tissue-invasive disease• Samples more difficult to acquire • Long turnaroundSerology• Useful to guide pretransplant risk stratification and prevention• Not useful posttransplant, insensitive marker for acute infection• False-positive IgM with HSV reactivation Open table in a new tab Diagnosis of HSV keratitis remains primarily a clinical diagnosis based on characteristic features of the corneal lesion on slit lamp microscopy. Referral to an ophthalmologist is requisite for appropriate diagnosis and treatment of HSV ocular disease (Table 1). Currently, many transplant recipients receive antiviral medication to prevent CMV replication (see CMV guidelines). Ganciclovir (Grade I for HSV prevention), acyclovir (I), valacyclovir (I) and valganciclovir (III), prevent most HSV replication when given in standard doses for CMV prevention. HSV-specific prophylaxis should be considered for all HSV-1 and HSV-2 seropositive organ recipients not receiving antiviral medication for CMV prevention (Grade I). Some centers use EBV-specific prophylaxis in pediatric transplant recipients not receiving prophylaxis for CMV infection. The antivirals used for EBV prevention also likely prevent HSV reactivation, so additional prophylaxis may not be necessary (Grade III). In the unusual circumstance of a patient who is not receiving CMV antiviral prophylaxis and is also HSV seronegative, the risk of early posttransplant HSV infection is not well defined, though probable cases of HSV transmission from organs have been described (11Basse G Mengelle C Kamar N et al.Disseminated herpes simplex type-2 (HSV-2) infection after solid-organ transplantation.Infection. 2008; 36: 62-64Crossref PubMed Scopus (35) Google Scholar). In this setting, some clinicians may choose to give antiviral prophylaxis while others may consider close clinical monitoring (Grade III). Immunosuppression intensification for organ rejection has been associated with HSV recurrence, though usually not life threatening. Limited data suggest that prophylaxis during rejection episodes treated with OKT3 is effective (21Tang IY Maddux MS Veremis SA Bauma WD Pollak R Mozes MF. Low-dose oral acyclovir for prevention of herpes simplex virus infection during OKT3 therapy.Transplant Proc. 1989; 21: 1758-1760PubMed Google Scholar); and the utility of HSV prophylaxis is likely similar for other types of immunosuppressive regimens (Grade II-2). Patients may also be receiving antivirals for CMV prophylaxis during treatment of rejection so HSV-specific prophylaxis may not be required. 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 (Grade III). However, persons may acquire HSV from asymptomatic individuals so care should be taken in intimate contact, particularly during periods of most intense immune suppression (Grade III). Condoms may be effective, but do not completely protect against HSV transmission (37Martin ET Krantz E Gottlieb SL et al.A pooled analysis of the effect of condoms in preventing HSV-2 acquisition.Arch Intern Med. 2009; 169: 1233-1240Crossref PubMed Scopus (108) Google Scholar). A majority of persons infected with HSV have never had symptomatic lesions, 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 (Grade III). In serodiscordant couples, daily antiviral therapy taken by the seropositive partner has been shown to prevent HSV-2 transmission to the seronegative partner (38Corey L Wald A Patel R et al.Once-daily valacyclovir to reduce the risk of transmission of genital herpes.N Engl J Med. 2004; 350: 11-20Crossref PubMed Scopus (607) Google Scholar), so this may be considered as an option (Grade III), 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. The only randomized trials of HSV prophylaxis in SOT recipients were published in the 1980s and showed effective HSV suppression with acyclovir administered at doses of 200 mg three (9Seale L Jones CJ Kathpalia S et al.Prevention of herpesvirus infections in renal allograft recipients by low-dose oral acyclovir.JAMA. 1985; 254: 3435-3438Crossref PubMed Scopus (67) Google Scholar) or four (8Pettersson E Hovi T Ahonen J et al.Prophylactic oral acyclovir after renal transplantation.Transplantation. 1985; 39: 279-281Crossref PubMed Scopus (55) Google Scholar) times a day. In a meta-analysis comparing these regimens with higher doses of acyclovir and valacyclovir for CMV prevention, HSV was well suppressed at all evaluated doses of acyclovir, with no difference between these “low-dose” (<1 g/day) and the higher dose regimens (39Fiddian 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-S115Crossref PubMed Scopus (40) Google Scholar); Table 2). In this meta-analysis, the use of acyclovir resulted in a significant reduction (OR, 0.17; 95% CI, 0.12–0.24; p < 0.001) in HSV disease (39Fiddian 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-S115Crossref PubMed Scopus (40) Google Scholar).Table 2:Recommendations for HSV prevention and treatment in HSV seropositive solid organ transplant recipientsIndicationTreatmentEvidenceCommentsPreventionAdult:CMV prophylaxis1CMV prophylaxis with recommended doses of ganciclovir, valganciclovir, valacyclovir or acyclovir are adequate for HSV prevention. Due to lack of SOT-specific studies, the level of evidence is extrapolated from populations of other patients with similar levels of immune compromise. Dosages are for GFR ≥ 50, adjustment is necessary for renal insufficiency. orGrade I• Administer for at least 1 monthACV 400–800 mg p.o. 2×/dayGrade I• During treatment of rejection episodes (for at least 1 month)VACV 500 mg p.o. bidFCV 500 mg p.o. bidGrade IGrade IPediatric:ACV 30–80 mg/kgp.o. in 3 divided dosesVACV 15–30 mg/kg/p.o. tidGrade III• For recurrent infection: Lower doses for recurrent labialis, higher doses for recurrent genital or ocular disease.TreatmentMucocutaneous diseaseAdult:ACV 400 mg p.o. 3×/dayVACV 1 g p.o. 2×/dayFCV 500 mg p.o. 2×/dayACV 5 mg/kg i.v. every 8 h (if unable to take p.o.)Grade IGrade IGrade I• Because prompt initiation of therapy is associated with improved outcome, therapy should be started based on clinical diagnosis, pending laboratory confirmation• Therapy should be continued until complete healing of all lesions or at least 5–7 daysPediatric:ACV 10 mg/kg i.v. every 8 h• Severe mucocutaneous.ACV 1000 mg/day p.o. in 3–5 divided doses for 7–14 days• Limited disease. Treat for 7–14 days.Severe, visceral/disseminated/CNS diseaseAdult:ACV 10 mg/kg i.v. every 8 hGrade II-1• i.v. Therapy should be continued until resolution of disease, or 14 days, then oral medication may be given. For CNS infection may consider 21 days of IV therapy.Pediatric:ACV IV 60 mg/kg/day in 3 divided dosesGrade II-2• Continue for 21 days for disseminated or CNS infection.HSV KeratitisTopical: Ganciclovir 0.15%Trifluorothymidine 1%Acyclovir 3% ointment (Grade III)Acyclovir, 400 mg five times dailyValacyclovir and FamciclovirOral:• Topical steroids should also be considered for stromal keratitis.Grade I• Ganciclovir given 5 × a day until healing then 3 × daily for 1 week• One drop every 2 h for 2 weeks. Limited by epithelial toxicityGrade IGrade IIIAvoids topical toxicityNo comparative or dose finding studies.Acyclovir-resistant HSVFoscarnet 80–120 mg/kg/day IV in 2–3 divided doses until healing is completeGrade I• Resistance should be laboratory-confirmed, although empiric therapy can be startedIntravenous cidofovirGrade II-3• Reduce immunosuppression, if possibleTopical cidofovirGrade IIITopical trifluridineGrade II-3ACV = acyclovir; CMV = cytomegalovirus; FCV = famciclovir; HSV = herpes simplex virus; i.v. = intravenously; p.o. = per orally; SOT = solid organ transplant; VACV = valacyclovir.1 CMV prophylaxis with recommended doses of ganciclovir, valganciclovir, valacyclovir or acyclovir are adequate for HSV prevention.Due to lack of SOT-specific studies, the level of evidence is extrapolated from populations of other patients with similar levels of immune compromise. Dosages are for GFR ≥ 50, adjustment is necessary for renal insufficiency. Open table in a new tab ACV = acyclovir; CMV = cytomegalovirus; FCV = famciclovir; HSV = herpes simplex virus; i.v. = intravenously; p.o. = per orally; SOT = solid organ transplant; VACV = valacyclovir. Compared with these initial HSV prevention trials in SOT, 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 (Grade II). Because SOT-specific studies have not been done, the level of evidence reported herein is extrapolated from studies performed in populations of other patients with similar levels of immune compromise (40Boeckh M Kim HW Flowers ME Meyers JD Bowden RA Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation—A randomized double-blind placebo-controlled study.Blood. 2006; 107: 1800-1805Crossref PubMed Scopus (194) Google Scholar, 41Erard V Wald A Corey L Leisenring WM Boeckh M Use of long-term suppressive acyclovir after hematopoietic stem-cell transplantation: Impact on herpes simplex virus (HSV) disease and drug-resistant HSV disease.J Infect Dis. 2007; 196: 266-270Crossref PubMed Scopus (83) Google Scholar, 42Workowski KA Berman SM Sexually transmitted diseases treatment guidelines. 2006.MMWR Recomm Rep. 2006; 55: 1-94PubMed Google Scholar). Patients with a history of frequent severe clinical HSV reactivations prior to transplant should be given doses in the higher range (Grade III). Valacyclovir given twice daily was found to be superior to once daily when used as prophylaxis against HSV in immunocompromised patients so once daily administration is generally not recommended (43Conant MA Schacker TW Murphy RL Gold J Crutchfield LT Crooks RJ Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: Two randomized trials.Int J STD AIDS. 2002; 13: 12-21Crossref PubMed Scopus (92) Google Scholar). Dosage adjustment for renal insufficiency is necessary if GFR is <50. Famciclovir, the oral prodrug of penciclovir, is also effective in preventing recurrent HSV in immunocompromised and immunocompetent hosts (44Diaz-Mitoma F Sibbald RG Shafran SD Boon R Saltzman RL Oral famciclovir for the suppression of recurrent genital herpes: A randomized controlled trial. Collaborative Famciclovir Genital Herpes Research Group.JAMA. 1998; 280: 887-892Crossref PubMed Scopus (139) Google Scholar,45Schacker TW Hu HL Koelle DM et al.Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons. A double-blind, placebo-controlled trial.Ann Intern Med. 1998; 128: 21-28Crossref PubMed Scopus (167) Google Scholar) and is an alternate option for prophylaxis. HSV prophylaxis in pediatric patients is not universal. Dosing for seropositive patients or patients who have had prior occurrences is derived from studies of HIV positive and stem cell transplant recipients. For children ≥2 years of age requiring oral therapy a typical quantity is 600–1000 mg/day in 3–5 divided doses. For intravenous therapy, 5 mg/kg every 8 h is recommended (46American Academy of PediatricsHerpes Simplex.in: Pickering LK Red Book: 2009 Report of the Committee on Infectious Diseases.28th ed. American Academy of Pediatrics, Elk G
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