Herpes Simplex Virus in Transplant Recipients
Authors: Scott H. James, MD, David W. Kimberlin, MD
VIROLOGY
Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are members of the alpha herpesvirus subfamily of the Family Herpesviridae. The virion of herpes simplex viruses consists of four components: 1) a core containing a single linear, double-stranded DNA molecule approximately 152 kbp in size; 2) an icosahedral capsid made up of 162 capsomeres; 3) an amorphous, though tightly adherent, tegument surrounding the capsid; and 4) a lipid bilayer envelope containing viral glycoprotein spikes surrounding the capsid-tegument complex. The DNA consists of two covalently linked components, designated simply as L (long) and S (short), each consisting of unique regions (UL and US) flanked by inverted repeats (45).
The genomes of HSV-1 and HSV-2 are approximately 50% homologous and as such, there is considerable cross-reactivity between antigenically related polypeptides of both HSV types (44). Type-specific polypeptides do exist, however, such as glycoprotein G (gG-1 and gG-2 for HSV-1 and HSV-2, respectively), allowing for differentiation of the two virus types via the host’s antigen-specific antibody response. Restriction endonuclease fingerprinting as well as DNA sequencing can also distinguish between HSV-1 and HSV-2 (6, 61).
Key steps in viral replication within infected cells include attachment to the cell surface, entry of the viral genome into the nucleus, transcription, DNA synthesis, capsid assembly, DNA packaging, and envelopment as new virions pass though the trans-Golgi network. Glycoproteins protruding from the viral envelope mediate attachment and penetration into host cells, and also induce host immune response.
EPIDEMIOLOGY
Humans are the only known natural reservoir of herpes simplex viruses, and the virus is transmitted via close personal contact. Seroprevalence studies indicate that HSV-1 and HSV-2 infections are common worldwide, in both developed and undeveloped countries (53). Prevalence of HSV antibodies increases with age, though earlier acquisition of infection is seen with HSV-1 compared to HSV-2, and in people of lower socioeconomic status for both HSV-1 and HSV-2 (37, 59). More than 90% of adults have acquired HSV-1 infection by their fifth decade of life, though only a minority develop clinically apparent disease at the time of acquisition (10).
Previous studies have documented a worldwide HSV-2 epidemic with increasing seroprevalence in developed countries (11, 15). More recent seroepidemiologic studies performed as a part of the National Health and Nutrition Examination Surveys (NHANES), however, have shown a slight decrease in HSV-1 and HSV-2 seroprevalence rates in the United States during the period from 1999 to 2004 compared to a previous period of 1988 to 1994. HSV-2 seroprevalence dropped from 21% to 17% in adolescents and adults age 14-49 years old during this timeframe, while HSV-1 seroprevalence fell from 62% to approximately 58%. This study also indicated that HSV-1 had become a more common cause of genital infection than in the previous time period (69). Another analysis of the NHANES data evaluating HSV-1 seroprevalence in children age 6-13 years old during 1999-2002 found a rate of 31%. Younger age, non-hispanic white ethnicity, birthplace within the United States, and living at or above the poverty line were all variables associated with a lower rate of infection (68).
Solid organ transplantation (SOT) recipients have historically had pre-transplant HSV seropositivity rates and age distributions similar to the general population (35). Post-transplantation HSV disease may occur as a primary infection acquired in the community or resulting from an infected donor organ, but the majority of cases are due to reactivation of latent HSV infection (as described below) in seropositive SOT recipients (47, 50). In the absence of antiviral prophylaxis, reactivation of latent HSV infection has been reported to cause symptomatic disease in 75% of seropositive kidney recipients and 40% of liver recipients (38, 51). The use of antiviral agents as a prophylactic measure in SOT recipients has helped to reduce the incidence of HSV disease in this population. A review of studies evaluating the utility of acyclovir prophylaxis in the early post-transplant period (range 2-12 weeks after SOT) as compared to placebo or historical control demonstrated a reduction in the rates of symptomatic HSV infections, from 30%-50% to 0-10% in kidney recipients and from 46-80% to 9-16% in heart recipients (52).
CLINICAL MANIFESTATIONS
In immunocompetent individuals, HSV infections most commonly are asymptomatic or present as orolabial or genital herpes (24, 25). Symptomatic disease occurs as a first episode which heals in 10 to 21 days, followed by the establishment of viral latency and risk of subsequent episodes of reactivation. Cell-mediated immunity plays an important role in host defense and containment of infection (26). Individuals with impaired cell-mediated immunity, such as SOT recipients, are subject to more frequent episodes of reactivation, prolonged duration of symptoms and shedding, increased severity of infection, and a greater potential for dissemination (17). In the absence of antiviral prophylaxis, seropositive SOT recipients often experience reactivation of latent HSV infection within the first month after transplantation (50), with approximately half of these occurring in the form of orolabial or genital lesions. Life-threatening HSV disease is uncommon beyond the first two months following transplantation (17).
The clinical presentation of mucocutaneous reactivation of HSV disease in SOT recipients is initially similar to reactivation of disease in an immunocompetent person. Painful erythematous papules erupt on the surface of the skin and quickly progress to the characteristic vesicular lesions filled with clear fluid, often appearing in a cluster. These fragile vesicles typically burst, but if they do not, an influx of inflammatory cells may cause the lesions to develop into pustules. After rupturing, each lesion will appear as a shallow ulcer on an erythematous base. Mucosal lesions typically have no vesicles and progress straight to ulcerations. The ulcers are usually gray/white, approximately 1-3mm in diameter, and will crust over as they begin to heal, with the total process lasting as little as 8-10 days (equivalent to the disease course of an immunocompetent patient) or as long as 6 weeks (67). Rarely, immunocompromised patients develop areas where ulcerations have coalesced to form large, deep, chronic mucocutaneous ulcerations that are difficult to treat.
As stated, mucocutaneous lesions make up the majority of HSV disease in transplant populations, and of these, orolabial lesions are the most common presentation – reportedly up to 85% of all HSV disease in the early post-transplant period (33). Most orolabial infections are mild and do not progress to severe disease (39), although pain alone may lead to significant morbidity in the form of anorexia. Lesions can affect the gingiva, buccal mucosa, tongue, hard palate, posterior pharynx, lips, and the skin surrounding the mouth. Lesions may also be seen on the chin and anterior neck due to spread of the infectious agent via saliva. Complications of orolabial HSV disease may include secondary bacterial infections of the oral cavity or spread of the infection leading to esophagitis or pneumonitis. For patients on certain chemotherapeutic anti-rejection agents, it may be difficult to distinguish orolabial HSV disease from mucositis. The presence of labial or perioral lesions is suggestive of HSV, but in cases limited to nonspecific intraoral findings, viral culture or polymerase chain reaction (PCR) may be necessary to diagnose HSV (17).
Anogenital lesions are the second most common presentation of HSV disease in SOT recipients, and are usually due to reactivation of latent HSV-2 in the sacral ganglia (17). For men, the typical herpetic lesions may involve the glans and shaft of the penis, the perianal area, and less commonly, the buttocks or thighs. Lesions due to reactivation of HSV in women most commonly occur on the vulva, labia, or vaginal introitus. The lesions are painful and may be associated with local paresthesia. As with orolabial disease, anogenital herpes in SOT recipients is most often similar in scope to the recurrent herpes lesions of an immunocompetent host, but may also be associated with coalescence of ulcerations and prolongation of healing for several months (7). Although orolabial and anogenital HSV infections in SOT recipients are usually self-limited, it should be recognized that they are capable of local invasion or widespread dissemination. These more complicated infections are less common, but can cause significant morbidity and mortality. In one study evaluating liver transplant recipients, of those who had HSV infection in the early post-transplant period, 91% were limited to mucocutaneous disease but the remaining 9% of patients infected (3 out of 35) had fatal disseminated disease (28). Spread of the infection in these more severe cases usually occurs either by direct extension of mucocutaneous lesions or through viremic dissemination. Direct extension occurs more commonly in the form of orolabial lesions spreading beyond the posterior pharynx and into the respiratory or gastrointestinal tracts. Viremic spread is more common and may lead to multiorgan involvement, especially of the visceral organs. Cutaneous lesions are not required for viremia and spread to visceral organs, making the diagnosis of this potentially fatal complication difficult (29). Disseminated HSV infection resulting from primary infection due to transplantation of a solid organ from a seropositive donor into a seronegative recipient has also been reported (27, 29).
HSV esophagitis may be difficult to distinguish clinically from other etiologies of esophagitis in the transplant population (Candida, cytomegalovirus) since all may present with similar symptoms. Because HSV esophagitis typically occurs as a direct extension of orolabial disease, findings of disease in the oral cavity may help narrow the differential diagnosis in an SOT patient presenting with dysphagia or odynophagia. Endoscopic examination and biopsy showing shallow ulcerations with surrounding erythema and confirmatory viral culture or polymerase chain reaction (PCR) are the most reliable methods of diagnosis. Not surprisingly, orogastric or nasogastric tubes in patients with orolabial disease increase the risk of HSV esophagitis.
HSV pneumonia in SOT recipients is associated with significant morbidity and mortality (13, 39). Patients receiving heart and/or lung allografts are more likely to have HSV pneumonia than recipients of other types of solid organs (54). HSV pneumonia usually occurs as a direct extension from oral secretions in patients with orolabial disease, with tracheal intubation being a risk factor for lung involvement (12, 49). The clinical presentation is similar to that of pneumonias caused by other etiologies (fever, dyspnea, cough, hypoxia, leukocytosis, and radiographic evidence of focal or multifocal infiltrates), so biopsy and viral culture or PCR of deep lung specimens obtained via bronchoscopy may be required for diagnosis. Isolation of HSV from sputum alone may indicate nothing more than oral colonization, so it is important to take into account the presence or absence of histopathologic signs of infection when making the diagnosis (12). HSV pneumonia caused by viremic spread rather than direct extension is possible as well, but this scenario more commonly occurs in the context of multiorgan dissemination and presents with a more diffuse pneumonitis on chest radiography (43).
As with the immunocompetent host, anogenital herpes in the transplant population may be associated with a benign and self-limited lymphocytic aseptic meningitis. This meningitis does not usually progress to herpes simplex encephalitis (HSE). Although HSE has been reported after solid organ transplantation (18), it is a rare finding and does not occur with increased frequency in the transplant population (39).
Viremic dissemination of HSV, either from reactivation or primary infection, may involve spread to multiple organs such as the liver, adrenal glands, gastrointestinal tract, lungs, skin, and bone marrow. Disseminated HSV infections are difficult to diagnose in the absence of orolabial, anogenital, or other cutaneous disease and are associated with significant mortality. This systemic syndrome occurs within the first month after transplantation and is marked by fever and findings specific to the organs involved (e.g. hepatitis, pneumonia, cutaneous lesions). Signs of sepsis may also be present, including hypotension, metabolic acidosis, and disseminated intravascular coagulopathy (DIC), all of which are associated with increased mortality (29). In the early post-transplant period, clinicians must have a low index of suspicion for disseminated HSV infections since rapid diagnosis as well as early, aggressive antiviral therapy and supportive care can be lifesaving. Antiviral prophylaxis during the first month after transplantation has been shown to reduce the incidence of symptomatic HSV infections, preventing many of these potentially fatal infections from occurring in the first place (52).
LABORATORY DIAGNOSIS
In the presence of characteristic mucocutaneous HSV lesions, clinical diagnosis alone may be considered reliable. It should be recognized, however, that lesions may present with an atypical appearance, may mimic skin ulcerations due to other etiologies, or may be located in inaccessible areas such as the urethra. Laboratory diagnosis should therefore be used to confirm HSV suspected cases.
Viral culture is the definitive method of diagnosing HSV infections. For mucocutaneous lesions, the sensitivity of viral culture is greatest in the earlier stages of disease (vesicles or ulcerations rather than crusted lesions) (36). To perform the viral culture, a swab should be used to swab the base of an unroofed vesicle or an ulcer, and then immediately placed in viral transport media and taken to a viral diagnostic laboratory as soon as possible. If any delay in transport is anticipated, it is best to keep the specimen on ice. If shipping is required, the specimen can be kept at 4oC for up to 48 hours if necessary (17). Tissue specimens taken from diagnostic biopsies may also be prepared in such a way to make viral culture possible. Specimens should be inoculated into an appropriate mammalian cell culture system and incubated while monitoring for the characteristic cytopathic effects (CPE) that indicate viral replication. If HSV is present, these cytologic changes commonly occur within 24 to 48 hours, though some cultures may take up to 5 to 7 days. For culture specimens in which CPE has been identified, confirmation of the finding and identification of the virus type is achieved by staining with type-specific monoclonal antibodies. Besides mucocutaneous lesions and tissue specimens, viral culture may also be used to isolate HSV from urine, stool, nasopharynx, throat, conjunctiva, and cerebrospinal fluid (CSF), although the yield from CSF may be low (45).
Nucleic acid amplification methods of DNA detection, such as PCR, are increasing in their utility. PCR has been shown to be 3 to 4 times more sensitive than viral culture for diagnosis of HSV in mucosal surfaces, and it has already replaced viral culture as the gold standard for diagnosis in central nervous system disease (31, 64). PCR offers a relatively rapid turnaround and also allows for less stringent specimen transport since detection of DNA is not dependent upon actively replicating virus.
Direct fluorescent antibody (DFA) is another modality for diagnosis of HSV, especially for mucocutaneous lesions. DFA offers rapid diagnosis similar to that of the Tzanck smear (less than one hour), but it has greater sensitivity and can also give type-specific diagnoses (17). DFA requires scraping at the base of the unroofed vesicle or ulcer in order to acquire cells. The specimen is immediately applied to a glass slide, which is then fixed and stained with HSV-1 and HSV-2 specific fluorescein-labeled monoclonal antibodies. Enhancement when the fixed and stained specimen is viewed under a fluorescent microscope indicates the presence of virus.
Serology may be used during the pre-transplantation period to determine whether a patient has latent HSV infection, but it is generally not useful in the diagnosis of acute disease. A possible exception is the confirmation of seroconversion during primary infection by evaluating acute and convalescent serum antibody titers. Recent commercially available serologic immunoassays are superior to previous generations of assays in that they are type-specific. This specificity is due to the fact that the current assays detect antibodies against glycoprotein G, which is an envelope protein that provides antigenic distinction between HSV-1 (gG-1) and HSV-2 (gG-2) (2, 8).
PATHOGENESIS
Initial HSV infection is established by viral replication in the cells of mucocutaneous surfaces that have come into direct contact with a person shedding the virus. As replication occurs, the virus enters sensory nerve endings and is transported in a retrograde fashion to nerve cell bodies in the dorsal root ganglia, where it enters a latent state. Based upon their usual sites of infection, HSV-1 most commonly establishes latency in the trigeminal ganglion while HSV-2 most commonly seeds sacral ganglia S2 to S5 (3, 45). Periodic reactivation from latency may be triggered by stimuli such as ultraviolet light, trauma, fever, immunosuppression, or stress (though no specific trigger need be evident with each recurrence). Upon reactivation, HSV travels centrifugally from the ganglia through peripheral sensory nerves and to the corresponding skin or mucosal surfaces, where viral replication resumes. Infected epithelial cells become distended and transform into multinucleated giant cells as their plasma membranes degenerate. Cell lysis releases clear fluid that is laden with viruses, cellular debris, and inflammatory cells, causing eruption of characteristic vesicles.
Once latency is established in the dorsal root ganglia, an equilibrium between persistence of the viral genome and the host immune response exists. A previous model of viral quiescence has been challenged by recent investigations indicating that latent HSV within neural ganglia may have persistent low-level expression of a limited array of viral genes (22). CD8+ T cell and cytokine-mediated host immune responses play a major, though not yet completely defined, role in establishing and maintaining latency (58). Due to impaired cell-mediated immunity, latently infected immunocompromised patients, including SOT recipients, experience more frequent and more severe recurrences of disease compared to immunocompetent individuals (10).
ANTIVIRAL THERAPY
Drug of Choice
Acyclovir is the drug of choice for treatment of HSV infections in both immunocompetent and immunocompromised populations. Initial investigations into the utility of intravenous (IV) acyclovir in transplant recipients with mucocutaneous HSV disease established the drug’s safety and efficacy. Mucocutaneous lesions in transplant patients treated with acyclovir were shown to have a reduced duration of viral shedding, more rapid resolution of pain, and faster healing time of the lesions when compared to placebo (34). Oral acyclovir has also been shown to be safe and effective in the treatment of immunocompromised HSV patients with mucocutaneous disease (48). Valacyclovir and famciclovir are oral agents with better bioavailability than acyclovir that may be used as well (see Alternative Therapy). Although no randomized, controlled trials have evaluated the use of acyclovir in SOT recipients with visceral or disseminated HSV infections, sufficient reports exist to establish IV acyclovir as the drug of choice in these life-threatening clinical settings (4, 16, 20, 29).
Acyclovir is an acyclic nucleoside analogue with antiviral activity against the herpesvirus family, especially HSV-1 and HSV-2. Once taken into an infected cell, acyclovir is phosphorylated by the virally encoded thymidine kinase. Acyclovir monophosphate then undergoes two further phosphorylation steps by cellular kinases, at which point acyclovir triphosphate is able to selectively and competitively inhibit viral DNA polymerase. In addition to this inhibition, acyclovir triphosphate exhibits a second mechanism of action in that it also incorporates itself into the elongating DNA product, causing chain termination.
When taken in its oral form, acyclovir has poor bioavailability, in the range of 15-21% (63). It has a wide distribution throughout the body, with the highest levels attained in the kidneys, lungs, liver, heart, and vesicular fluid of the skin lesions. The CSF concentration of acyclovir is approximately 50% of the serum concentration. In both the IV and oral formulations, acyclovir is generally well tolerated. Dose adjustment is required for both oral and IV acyclovir in patients with impairment of renal function. An obstructive nephropathy due to deposition of acyclovir crystals in the renal tubules may occur if the agent is given intravenously to a patient with underlying renal disease, dehydration, or if the infusion is too rapid. This nephrotoxicity is usually reversible by discontinuation of the agent. In instances when the serum concentration of acyclovir becomes elevated (such as with nephrotoxicity or other underlying renal disease), patients may also develop a reversible neurotoxicity (19). Significant drug interactions include increased risk of nephrotoxicity when used with other nephrotoxic agents such as cyclosporine, as well as the potential to increase serum concentrations of methotrexate, with which acyclovir competes for renal excretion.
Acyclovir resistance is primarily caused by alterations in the viral thymidine kinase such that acyclovir cannot undergo the initial phosphorylation required for its antiviral activity. Infections caused by acyclovir-resistant HSV have not yet become a significant problem in the general population, with a reported prevalence of <1% (9, 57). Immunocompromised patients (including patients with HIV/AIDS), however, have been reported to have a prevalence of acyclovir-resistant HSV strains as high as 7% (57). In the transplant population, hematopoietic stem cell transplant patients have slightly lower resistance rates (2-5%), while SOT recipients have an even lower prevalence (though still higher than the immunocompetent population) (17). Transplant recipients with HSV infections presenting as chronic and progressive mucocutaneous disease should be considered suspicious for possible acyclovir-resistant strains, especially if they are failing acyclovir therapy. In these cases, new viral cultures should be obtained and sent for antiviral susceptibility testing.
Specific Infections
Mucocutaneous Infection
Transplant patients with mucocutaneous HSV infection (including orolabial, anogenital, or any other areas of skin) may be treated with IV acyclovir (5mg/kg/dose given every 8 hours), oral acyclovir, or one of the alternative oral antiviral agents with better bioavailability (valacyclovir or famciclovir), depending upon extent of disease, proximity to the transplant, and degree of immunosuppression (Tables 1 and 2). Treatment of mucocutaneous disease should continue until all lesions are healed, a course that typically lasts 7-14 days. Superficial lesions that spread in an invasive manner, such as esophagitis or pneumonia arising from orolabial infection, should be treated aggressively with IV acyclovir.
Visceral/Disseminated Infection
Due to the potentially life-threatening nature of these infections, early diagnosis and aggressive treatment is critical. Any suspected disseminated or visceral organ HSV disease should be treated with high dose IV acyclovir (10mg/kg/dose given every 8 hours) (Tables 1 and 2). While published data evaluating optimal treatment duration for severe HSV infections in the SOT population are lacking, antiviral courses are often 14-21 days to ensure full resolution of clinical and laboratory abnormalities.
Herpes Simplex Encephalitis (HSE)
Though no more common in the transplant population than in the general population, HSE has been reported in SOT recipients (18). If untreated, HSE is associated with significant mortality, and those who do survive are often left with neurologic deficits. Treatment of HSE should consist of IV acyclovir given at a dose of 10mg/kg/dose every 8 hours for 14-21 days. Some experts have advocated higher doses of 15mg/kg/dose every 8 hours, but neurotoxicity may be a limiting factor in using this dosage.
Alternative Therapy
Due to oral acyclovir’s poor bioavailability and frequent dosing interval, other agents have been developed as better alternatives for oral therapy of mild to moderate HSV infections (Tables 1 and 2). Valacyclovir is the L-valyl ester prodrug of acyclovir and has significantly improved bioavailability, in the range of 50-70% (23, 55). Since it is converted to acyclovir by first-pass metabolism in the liver and intestine, valacyclovir has the same mechanism of action, spectrum of activity, and resistance patterns as acyclovir. Famiciclovir is the diacetyl ester prodrug of penciclovir, which is a nucleoside analogue with a spectrum of activity comparable to acyclovir. Penciclovir has a mechanism of activity similar to that of acyclovir in that it is phosphorylated by viral and cellular kinases prior to acting as a competitive inhibitor of viral DNA polymerase, though unlike acyclovir, it does not act to terminate the elongation of the DNA chain. Ingestion of oral famciclovir yields a penciclovir bioavailability of 77%, and though penciclovir is less potent than acyclovir, its prolonged intracellular half-life results in effective antiviral activity (14). Because of the advantages afforded by their improved pharmacokinetic profiles, while at the same time maintaining efficacy and tolerability, valacyclovir and famciclovir have replaced oral acyclovir as the mainstays of treatment for the mild to moderate mucocutaneous HSV infections in SOT recipients (17). Ganciclovir, valganciclovir, foscarnet, and cidofovir are other antiviral agents with activity against herpesviruses. Although these agents are more commonly used to treat other members of the herpesvirus family, especially cytomegalovirus (CMV), each are active against HSV and may be considered for treatment of HSV in the transplant population. Clinical scenarios in which these agents may be considered include HSV and CMV co-infection and in some cases of acyclovir-resistant HSV infections, depending upon the mechanism of antiviral resistance. In the case of co-infection, it may be preferable to use a single agent to treat both infections, in which case ganciclovir or its oral prodrug valganciclovir would be effective against both HSV and CMV (note that acyclovir has no significant activity towards CMV). Patients infected with acyclovir-resistant strains of HSV, most of which involve an alteration of thymidine kinase, may benefit from treatment with foscarnet or cidofovir since each of these agents inhibit viral DNA polymerase independent of thymidine kinase activity. Foscarnet and cidofovir are each associated with a dose-dependent nephrotoxicity and therefore should be used with caution.
ADJUNCTIVE THERAPY
There are currently no widely accepted adjuvant therapies for HSV in routine use. Consideration has been given to the use of monoclonal antibodies as a form of passive immunotherapy to compliment antiviral therapy. Initial animal models were promising, but as of yet no human trials have been completed (5, 30). Other efforts to provide passive immunotherapy using polyclonal immunoglobulin preparations have not proven beneficial (17).
ENDPOINTS FOR MONITORING THERAPY
Transplant patients with mucocutaneous HSV disease usually require at least 7-14 days of treatment, though lesions that have become extensive and chronic require a longer course. The standard endpoint for treatment of mucocutaneous disease is when all lesions have healed over and there is no evidence of invasive spread (e.g. no esophagitis or pneumonitis). Visceral HSV disease, either affecting an isolated organ or as a part of a disseminated process, requires a more prolonged antiviral course. No clinical studies exist to help determine optimal treatment endpoints for visceral or disseminated HSV infections.
VACCINES
No vaccines for HSV-1 or HSV-2 are commercially available at this time. If an effective HSV vaccine were to become available, there would be a potential benefit to vaccinating seronegative patients prior to transplantation. While this would not address the more prevalent issue of reactivation of latent infection after transplantation, it could prevent acquisition of primary HSV infection during a time when these patients are immunologically vulnerable.
Numerous efforts have been made to develop an HSV vaccine using several different methods including inactivated virus, live attenuated virus, viral subunits, and more recently, recombinant viruses (45). Many of these attempts showed promising results in their early phases of development, but none have come to fruition in human trials. Clinical trials are continuing with several different types of vaccine candidates, but two in particular seem promising: an HSV-2 glycoprotein D subunit vaccine and a genetically engineered replication-defective HSV-2 vaccine (21, 56).
ANTIVIRAL PROPHYLAXIS
In the absence of antiviral prophylaxis, seropositive SOT recipients are at high risk of having latent HSV infections reactivate into symptomatically evident disease, which can be associated with significant morbidity and mortality. Early clinical trials evaluating IV acyclovir prophylaxis administered in bone marrow transplant populations showed significant decreases in the incidence of HSV disease in seropositive patients when compared to placebo (32, 46). Oral acyclovir has also been shown to be effective in preventing HSV disease after bone marrow transplantation (62). Clinical trials and reported experiences also support the use of acyclovir prophylaxis in SOT recipients, demonstrating considerable reductions in the incidence of HSV disease in the early post-transplant period (1, 40, 42).
Acyclovir is the preferred agent for prophylaxis of HSV infections in SOT patients, although it is appropriate to use ganciclovir or valganciclovir as a single agent in patients requiring prophylaxis for both CMV and HSV (Table 3). Valacyclovir and famciclovir have also been used successfully for prophylaxis against HSV recurrences, although valacyclovir appears to be the superior of the two (60, 65).
Common strategies for prophylaxis against HSV infections include universal prophylaxis for all transplant recipients and targeted prophylaxis of seropositive patients. Targeted prophylaxis is based on the idea that seronegative transplant recipients are at less risk for HSV disease since they do not have latent HSV infection. Seronegative transplant recipients are at risk for severe disease if they acquire primary HSV infection, however, so universal prophylaxis would be of benefit in this scenario. When prophylaxis is initiated, it should continue for at least one month after transplantation (35). Clinical judgment should be used to determine if a patient requires a longer duration of prophylaxis. Factors that may necessitate a longer prophylactic course include a history of frequent orolabial or anogenital recurrences prior to transplantation or if a period of intensified anti-rejection therapy is needed.
INFECTION CONTROL MEASURES
HSV is transmitted via direct contact with infected secretions, whether oral, genital, or vesicular. Patients with mucocutaneous lesions should therefore be maintained on contact precautions. HSV is not typically spread by aerosolization or fomites (41). If lesions are confined to one area only and are well covered, standard precautions alone may suffice. Patients who have visceral disease but no external mucocutaneous lesions may be on standard precautions as well. Practitioners should be aware, however, that even asymptomatic individuals may shed HSV in oral secretions at any time, so standard precautions should always be followed (66).
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Table 1. Antiviral Therapy for HSV Infections in Adult SOT Patients
| Antiviral Agent | Mucocutaneous Infection | Visceral/Disseminated Infection | Herpes Simplex Encephalitis |
|---|---|---|---|
| Acyclovir | 5mg/kg/dose IV q8h 400mg PO qid | 10mg/kg/dose IV q8h | 10mg/kg/dose IV q8h |
| Valacyclovir | 500mg PO bid | n/aa | n/a |
| Famciclovir | 500mg PO bid | n/a | n/a |
a Not applicable
Table 2. Antiviral Therapy for HSV Infections in Pediatric SOT Patientsa
| Antiviral Agent | Mucocutaneous Infection | Visceral/Disseminated Infection | Herpes Simplex Encephalitis |
|---|---|---|---|
| Acyclovir | <12 years old: 10mg/kg/dose IV q8 hours
≥12 years old: 5-10mg/kg/dose IV q8 hours All ages: 80 mg/kg/day PO in 4 divided doses; maximum dose 3200 mg/day |
10mg/kg/dose IV q8 hours
(some experts recommend 15 mg/kg/dose IV q8 hours, monitoring for nephrotoxicity and neurotoxicity) |
10mg/kg/dose IV q8 hours
(some experts recommend 15 mg/kg/dose IV q8 hours, monitoring for nephrotoxicity and neurotoxicity) |
| Valacyclovir | 20 mg/kg/dose PO bid or tid; maximum dose, 1000 mg/doseb, c | n/ad | n/a |
| Famciclovir | Insufficient data | n/a | n/a |
b http://us.gsk.com/products/assets/us_valtrex.pdf
c Kimberlin D, Jacobs R, Weller S, van der Walt J, Heitman C, Man C, Bradley J. Pharmacokinetics and safety of extemporaneously compounded valacyclovir oral suspension in pediatric patients from 1 month to 12 years of age. Clinical Infectious Diseases. 2009 (In Press).
d Not applicable
Table 3. Antiviral Prophylaxis for HSV Infections in SOT Patients
| Antiviral Agent | Adult Dose (with normal renal function) | Pediatric Dose (with normal renal function) |
|---|---|---|
| Acyclovir | 250mg/m2/dose IV q12 hours
5mg/kg/dose IV q12 hours400mg PO bid |
All ages: 5mg/kg/dose IV q8 hours
≥2 years old: 600-1000mg/ day PO in 3-5 divided doses |
| Valacyclovir | 500mg PO bida | 20mg/kg/dose PO bid or tid (limited data) |
| Famciclovir | 500mg PO bid | Insufficient data |
| Ganciclovir | 5mg/kg/dose IV q12 hours | 5mg/kg/dose IV q12 hours |
| Valganciclovir | 900mg PO daily | Insufficient data |
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