Herpes simplex virus infection in the immunocompromised cancer patient.

REVIEW ARTICLE

Herpes Simplex Virus Infection in the Immunocompromised Cancer Patient By Carlos I. Bustamante and James C. Wade The development of infection remains a significant source of morbidity and mortality in the oncology patient. This patient population is at increased risk for infection because of alterations in cell-mediated immunity generated by the underlying neoplastic process and/or immunosuppressive therapy. Viral infection, particularly that attributable to herpes simplex virus (HSV), is being seen with increased frequency in the oncology patient. Because effective therapy is avail-

INFECTION

CONTINUES to be a significant cause of morbidity and mortality in cancer patients who are immunocompromised as a consequence of their underlying disease or various cancer treatment modalities. Major predisposing factors to infection include granulocytopenia, mucosal or integumentary damage, cellular immune dysfunction, humoral immune dysfunction, and iatrogenic procedures.' 6 Although these factors are independent, they are closely interrelated and may occur simultaneously. Each specific immune defect is associated with a specific group of infection sites and pathogens. Patients with granulocytopenia-associated integumentary or mucosal damage develop infections caused by bacteria and, subsequently, by fungal pathogens. The incidence and severity of these infections are dramatically influenced by both the degree and the duration of the neutropenia. Patients who are susceptible to a specific group of bacteria, fungi, protozoan elements, and viral pathogens include those with defects in cell-mediated immunity (thymus-derived lymphocytes) such as Hodgkin's disease, acute leukemia, or graft-versus-host disease; those with malnutrition; those with acquired immune deficiency syndrome; those who have undergone bone marrow transplantation; and those being treated with immunosuppressive agents such as corticosteroids, radiation, cyclosporine, or antithymocyte globulin. Viral infection, specifically that caused by the herpes group of viruses, is now recognized as an important cause of morbidity and mortality for patients with significant cellular immunosuppression. 7 2' Viral infection has become prominent in the complex clinical oncology setting, where immu-

able with the early use of antiviral agents, it is important to be aware of the potential for viral infection and to recognize the signs and symptoms that are evident early in its course. An overview of HSV infection is provided here, including discussion of the virus itself, its pathogenesis, its clinical spectrum, and current prophylactic and therapeutic approaches. J Clin Oncol 9:1903-1915. o 1991 by American Society of Clinical Oncology. nosuppression has been induced by antineoplastic therapy. Until recent years, viral infection remained elusive to conventional diagnostic and therapeutic approaches. However, advances in medical virology and antiviral development have resulted in significant improvement in the current diagnosis and management of such infection. Our understanding of the pathophysiologic events that lead to the reactivation of certain viral infections and the development of effective antiviral therapy have significantly enhanced our ability to treat successfully the majority of severely immunocompromised cancer patients who are undergoing intensive therapy. Given these recent advances, it is important to review current concepts of viral infection, especially as they relate to the immunocompromised oncology patient. Because of their prominence in this patient group, a discussion of oropharyngeal, esophageal, and respiratory tract infections caused by herpes simplex virus (HSV) will be provided, including descriptions of their clinical spectra, differential diagnoses, and current preventive and therapeutic approaches.

From the Section of Infectious Diseases and Microbiology, University of Maryland Cancer Center, Baltimore; and Divisions of Infectious Diseases and Oncology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD. Submitted January28, 1991; acceptedApril 17, 1991. Supported by an educationalgrant from Burroughs Wellcome Company. Address reprintrequeststo CarlosI Bustamante,MD, 16800 NWSecondAve, Suite 606, North Miami Beach, FL 33169. o 1991 by American Society of Clinical Oncology. 0732-183X/91/0910-0006$3.00/0

Journalof Clinical Oncology, Vol 9, No 10 (October), 1991: pp 1903-1915

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 10, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

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BUSTAMANTE AND WADE HERPESVIRUSES

Herpesviruses constitute a group of largeenvelope, DNA-containing viruses. The members of this group that cause human infection are HSV types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus 6.20-28 All human herpesviruses have an internal core containing double-stranded DNA. All members of this group of viruses can also establish latent states within certain types of cells that they infect. HSV-1 and HSV-2 grow in a variety of human and animal cell lines, have a worldwide distribution, and cause a wide variety of infections in the normal, nonimmunocompromised host, affecting the urogenital tract, skin, mucous membranes, and CNS. Recurrent infection occurs frequently with both HSV-1 and HSV-2 and is generally secondary to endogenous reactivation of virus rather than to 2 exogenous reinfection. 1-23 HSV Infection in the Normal Host In the normal host, initial exposure to HSV-1 or HSV-2 causes primary infection that frequently is associated with systemic signs and symptoms and involvement of various mucosal and extramucosal sites, with a potential for associated complications.21,22,24,26,27 Both types of viruses can lead to

orofacial, genital, cutaneous, ocular, visceral, CNS, and peripheral nervous system involvement. In

general, HSV-1 is responsible for orolabial infection, whereas genital infection is more frequently secondary to infection with HSV-2.28,2 9 In normal hosts, first-episode infection tends to be more severe and prolonged than recurrent episodes of infection. The clinical manifestations depend on the anatomic site, the age of the patient, and the antigenic type involved. HSV-1 usually infects children between the ages of 2 and 10, but it can cause infection in neonates, or the primary infection can be delayed until adolescence or young adulthood. Transmission results from contact with active ulcerative lesions or with secretions from asymptomatic HSVexcreting individuals. Both HSV-1 and HSV-2 can be transmitted from cutaneous lesions and from salivary or genital tract secretions. The incubation period is relatively short, ranging from 1 to 26 days, with a median range of 6 to 8 days. The rate of infection recurrence is dependent on the antigenic type and the site of infection. Genital HSV-2

infection is twice as likely to reactivate as is genital HSV-1 infection, whereas orolabial HSV-1 infection recurs more frequently than orolabial HSV-2 infection. The most frequent clinical manifestations of first-episode HSV-1 infection are gingival stomatitis and pharyngitis. Lesions may involve the hard and soft palates, gingiva, tongue, lips, and facial area, with associated ulcerative and exudative pharyngotonsillitis. Other symptoms include fever, malaise, myalgia, cervical lymphadenopathy, and an inability to eat. After primary HSV-1 infection, the virus remains dormant in the trigeminal ganglia, and asymptomatic excretion or clinical reactivation may occur. In the normal host, clinical reactivation of HSV is usually limited to recurrence on the external facial skin of the nasolabial junction. 2 2 ,23 Recurrent mucosal, intraoral, or pharyngeal infection is uncommon in the nonimmunocompromised host. The predominant HSV-2 clinical entity is genital herpes. Primary genital HSV-2 infection may be asymptomatic or may be associated with a clinical presentation characterized by fever, headache, malaise, myalgia, pain, itching, dysuria, vaginal and urethral discharge, tender inguinal adenopathy, and bilateral involvement of the external genitalia, characterized by vesicles, pustules, and/or painful, erythematous ulcers. Viremia and aseptic meningitis can occur during primary HSV-2 infection. The rate of recurrence of genital HSV infection varies widely in the adult, nonimmunocompromised general population.2 9 It is also important to note that HSV-2 can be transmitted to neonates via contact with herpetic lesions in the birth canal. Exposure to the virus can lead to a spectrum of illnesses, ranging from subclinical to severe systemic disease. Measures should be implemented during delivery to minimize the risk of infection of the neonate with HSV-2. Complications of primary oropharyngeal and/or genital HSV infection in the normal host include herpetic whitlow, keratitis, chorioretinitis, acute necrotizing retinitis, visceral dissemination to organs (eg, esophagus, lungs, and liver), and hematogenous dissemination. However, these potential complications are an uncommon phenomena in the normal host. CNS and peripheral nervous system HSV infections include HSV-1 encephalitis and HSV-2 meningitis, which could be a complication of primary HSV-2 infection. Other rare


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HERPES SIMPLEX VIRUS INFECTION

manifestations of HSV infection include polyneuritis, transverse myelitis, Guillain-Barr6 syndrome, 3 and death." Role of immunity. In the normal, nonimmunocompromised host, the immune system plays a significant role in determining the severity of infection, maintenance of latency, and frequency of HSV recurrence.31 37 A majority of recurrent infections are due to endogenous reactivation of virus and are associated with fewer mucocutaneous lesions and a shorter median time for healing than the primary infection.26 Within this context, both the cell-mediated and the antibody-mediated immune responses are thought to be clinically important, with multiple cell populations, primarily comprised of T cells, being the first line of defense against HSV. The neutropenic patient seems to be at risk for HSV infection by virtue of associated lymphopenia. Lymphokines, such as interferons, and the presence of adequate antibodydependent cell-mediated cytotoxicity are also of primary importance in modulating the immune response to HSV infection. The role of humoral antibodies in regulating the response to HSV is less clear. Patients with frequently recurring HSV infection have high levels of neutralizing antibodies, suggesting that these antibodies do not afford protection against clinical disease but may identify a group of patients at increased risk for recurrence.3841

The seroprevalence of HSV-1 infection in the general population is in excess of 70%, and the prevalence of HSV-2 varies with socioeconomic status, occupation, and age, but is approximately 25%.42,43 For this reason, a history of clinical HSV infection and/or the presence of neutralizing antibodies for HSV-1 or HSV-2 are important considerations in the management of individuals who develop cancer and must undergo immunosuppressive chemotherapy and radiation therapy. Although serologies are most definitive, a history of recurrent orofacial or genital HSV infection is approximately 50% sensitive and will closely approximate 100% with regard to specificity. In some patients, such a history can be used in lieu of serotesting." HSV Infection in the CompromisedHost HSV infection that occurs in a patient with a hematologic malignancy will often be localized and self-limited and may differ little from the

infection that occurs in patients with intact immune defenses." However, depending upon the specific underlying illness, the disease activity, and the temporal relationship to initiation of cytotoxic immunosuppressive therapy, infection that is almost exclusively recurrent in origin may be more frequent, severe, and protracted in its course. The presence of circulating anti-HSV antibodies is an indication of potential risk of recurrent infection. Patients receiving bone marrow transplants who are seropositive for antibody to HSV before transplantation have an 80% chance of reactivation of the HSV infection within the first 5 weeks after transplant. In evaluating HSV-seropositive patients with acute leukemia who were undergoing induction chemotherapy with cytarabine and daunorubicin, Saral et al44 found that 25% developed HSV infection during their induction period. These results are similar to those from the prospective study of patients with acute leukemia that had been reported earlier by Lam et al."3 When Saral et al reanalyzed the occurrence of infection among patients with antibody titers of 1:16 or greater, they found that 61% of this cohort of patients became infected with HSV within a median of 18 days after the initiation of induction chemotherapy. We have evaluated 130 consecutive adults with acute leukemia undergoing induction or reinduction therapy at the University of Maryland Cancer Center and found that 48% of these patients developed an HSV reactivation a median of 17 days after the initiation of induction therapy. In patients who were analyzed for the presence of HSV antibody before the initiation of therapy, 66% of seropositive patients experienced a reactivation of infection, whereas none of the seronegative patients became infected. Mucocutaneous lesions associated with positive cultures were felt to warrant antiviral therapy in 89% of these patients, with the majority of the infections being purely intraoral. The risk for patients with non-Hodgkin's lymphoma and other intensively treated solid tumors is less well known. However, data from studies performed by Lam et al and Hann et al45 suggest that the risk may be as high as 25% for seropositive patients. Recurrent HSV infection in immunocompromised cancer patients, particularly those with hematologic malignancy, tends to be more frequent, severe, and prolonged than in nonimmunosuppressed individuals. Patients may experience


BUSTAMANTE AND WADE

1906 multiple large mucocutaneous ulcers that may persist for weeks to months at nasolabial, oropharyngeal, or genital mucosal sites. In the absence of antiviral therapy, viral shedding may persist, and lesions may progress with significant morbidity as well as increased risk of bacterial and fungal superinfection. In patients who are undergoing bone marrow transplantation or who are receiving remission-induction chemotherapy for acute leukemia, the healing of HSV lesions is often delayed until the circulating granulocytes recover.1419 At the University of Maryland Cancer Center, 90% of the patients with HSV reactivation warranted antiviral therapy with acyclovir because of significant morbidity associated with mucocutaneous lesions. Therefore, a suppressive antiviral regimen of acyclovir is now routinely initiated at this institution at the start of chemotherapy in patients who have a history of HSV reactivation or in whom HSV antibodies are present. Clinical presentation and patterns of infection. The primary sites of HSV infection in the compromised host remain the nasolabial and genital mucocutaneous areas. Visceral and disseminated infection, although infrequent, may occur when immunosuppression and mucosal trauma are present.""49 Localized endogenous viral reactivation at sites of mucosal disruption has been well documented and can be particularly prevalent in individuals with chemotherapy-induced oral mucositis, in those who have a dental prosthesis, in patients with acute exacerbation of chronic periodontal disease, and in patients in whom nasogastric tubes have been inserted or who have been tracheally intubated through either the nasal or oral passages. These multiple factors can contribute to significant oropharyngeal or tracheobronchial mucosal breakdown and, consequently, allow the proliferation of local and invasive HSV infection, including pharyngitis, esophagitis, tracheobronchitis, pneumonia, visceral disseminated disease, and viremia.6,4 8 Oropharyngeal HSV infection. Viral infection after chemotherapy or bone marrow transplantation can result in considerable oral disease. HSV is the primary causative agent, although VZV and CMV have also been reported.5 51' Considerable patient discomfort involving pain and decreased oral intake can have a significant deleterious effect on the patient's overall condition. Intraoral HSV lesions are frequently multiple vesicles that quickly

rupture, causing the development of confluent ulceration, with extensive involvement of the hard and soft palates and the oropharynx, and subsequent exudative necrosis (Fig 1). These ulcerative lesions frequently become colonized with superimposed pathogens such as aerobic gram-positive cocci, Candida albicans, and/or enteric gramnegative bacteria. Associated extraoral lesions are common, especially along the commissures and vermilion border of the lips and on the filtrum, and they follow a similar pattern of vesicular and ulcerative stages. Differential diagnosis includes chemotherapy- and irradiation-induced mucositis, ulcerative or exudative candidal or bacterial infection, non-HSV viral infection, acute and chronic periodontal infection, necrotizing gingivitis, graftversus-host disease, Stevens-Johnson syndrome, and infiltration with leukemia or other cancers. Other possible noninfectious etiologies may include Behqet's syndrome and various vasculitides, which are less frequent in immunocompromised cancer patients.5 ° The severity of oropharyngeal HSV infection is greatest in patients with granulocytopenia, particularly in those with hematologic malignancy. Patients with acute myelogenous leukemia who are receiving induction or reinduction chemotherapy frequently develop bacterial and fungal oropharyngeal infection with associated bacteremia. In such circumstances, HSV infection, along with intensive chemotherapy, may play a significant role in causing mucosal disruption and facilitating superinfection. This coinfection phenomenon may explain the usual polymicrobial etiology of oropharyngeal infection and its associated morbidity. The diagnosis of such infection involves a comprehensive work-up, and its treatment usually requires a multidrug regimen. Asymptomatic shedding of HSV from throat cultures without obvious mucosal lesions may also occur. While the role of asymptomatic HSV infection is not clear, it may eventually predispose to esophageal or respiratory tract infection. Prophylaxis with acyclovir is a routine approach used in patients who are undergoing bone marrow transplantation, but its use in leukemic patients treated with chemotherapy has not been widespread. The presence of asymptomatic oropharyngeal HSV shedding may precede the development of clinically important infection. For this reason, treatment of those patients who are not receiving


1907


Fig 1. Clinical manifestation of intraoral lesions secondary to HSV infection. (A) Multiple hard palate ulcerations. (B) Intraoral white plaques often assumed to be secondary to mucocutaneous candidiasis. (C, D) Intraoral infection with gingival ulcerations and gingival papillae necrosis. Pearly margins are characteristic. (E) Diffuse mucosal disruption compatible with chemotherapy- or radiation-induced mucositis. (F) HSV and Candida infection in a patient with acute myelogenous leukemia presenting with gingival hyperplasia and secondary bacterial infection.

suppressive antiviral therapy may prove to be a useful approach to the prevention of progressive disease, dissemination, and superinfection. HSV infection of the respiratory tract. Frequently, the nasal mucosa is a site of reactivation of HSV and, in immunosuppressed patients, may be associated with extensive bilateral nasal mu-

cosal involvement with vesicular, ulcerative, and exudative lesions with hemorrhagic necrosis, which may obstruct the nasal passages and cause extensive involvement of the nasolabial junction as well as the skin of the facial area. Epistaxis and secondary bacterial superinfection with cellulitis and bacteremia may complicate this clinical pic-


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BUSTAMANTE AND WADE

ture. Intranasal mucosal and facial lesions may persist for weeks despite aggressive antiviral therapy and may not entirely resolve until the patient's underlying immunodeficiency improves, usually upon bone marrow recovery. Nasolabial and facial lesions are common in patients who first present with acute myelogenous leukemia"3 and may be associated with extensive HSV lesions at other dermal sites as a result of autoinoculation (ie, herpetic whitlow). Such infection requires aggressive intervention with acyclovir therapy, as well as the use of broad-spectrum antibiotics for associated bacterial superinfection. Involvement of the tracheobronchial tree may occur as part of a viremic infection or, more frequently, as part of a localized process initiated by endogenous viral shedding and mucosal disruption. HSV infection involving the respiratory tract may go unrecognized clinically, as there may be no apparent cutaneous manifestation. HSV pneumonia represents approximately 5% of nonbacterial pneumonia and most frequently occurs in allogeneic marrow transplant recipients, from whom lung biopsy and autopsy specimens are obtained for viral isolation.52 It has been proposed that a precipitating event for such infection is tracheobronchial mucosal trauma due to endotracheal intubation. The cytotoxic effects of radiation and chemotherapy may also affect the regenerating mucosal barrier cells of the tracheobronchial tree and the alimentary tract and may be a significant predisposing factor for both pneumonia and alimentary tract HSV infection. Of 20 patients with HSV pneumonia reported by the Infectious Diseases Group from Seattle, WA, 52 17 had hematologic malignancies and 16 had undergone bone marrow transplantation. Cough, fever, and hypoxia were common symptoms, and the chest roentgenogram showed either focal or multifocal infiltrates or diffuse interstitial pneumonitis. Preceding or coincident mucocutaneous lesions were seen in 17 of the 20 patients. Concomitant disseminated fungal, CMV, or bacterial infection was also common. HSV pneumonia is usually preceded by oral mucosal HSV infection or endotracheal intubation, along with mucosal disruption due to cytotoxic chemotherapy or radiation therapy. Hematogenous dissemination of HSV infection from oral or genital mucocutaneous sites may

result in visceral infection and bilateral diffuse interstitial HSV pneumonitis. HSVesophagitis. Esophagealinfection is a common problem in immunocompromised patients with cancer who undergo intensive chemotherapy or bone marrow transplantation. Predisposing factors include mucosal trauma secondary to chemotherapy and/or radiation, graft-versus-host disease, and mechanical trauma secondary to nasogastric intubation. Symptoms may include odynophagia, dysphagia, chest pain, nausea and vomiting, fever, and bleeding. The underlying etiology is frequently that of a mixed polymicrobial infection with bacteria, fungi (usually Candida species), and HSV. CMV may also be involved and is generally associated with gastric and enteric ulcerations as well as esophagitis, particularly in the human immunodeficiency virus (HIV)-infected patient. On endoscopy, the esophageal mucosa appears grossly abnormal, and three stages of mucosal damage have been described. The first is a discrete raised vesicle, usually seen in the distal esophagus, with otherwise normal-appearing mucosa. The finding of such vesicles is almost always diagnostic of HSV. The next stage of HSV esophagitis is coalescence into larger (0.5 to 2.0 cm) lesions with raised borders, and the third stage is diffuse mucosal necrosis without welldefined borders or vesicles. McDonald et a151 recently described their findings in immunosuppressed bone marrow graft recipients with suspected clinical esophagitis. Of 46 endoscopic procedures in 39 patients, 21 showed esophageal infection. Single organisms were responsible for 17 infections (seven CMV, six HSV, and four fungal). HSV was found in four additional patients as part of a mixed infection. In that study, bacterial esophagitis was rare. Buss and Scharyj reviewed the autopsy records of 56 adult patients in whom postmortem examination had shown evidence of HSV infection involving nongenital viscera. 53 Herpetic esophageal ulcerations were found in 50 cases; the majority of these patients had hematologic neoplasias and/or had received corticosteroid therapy. At the University of Maryland Cancer Center, 76 consecutive patients were examined endoscopically for symptomatic esophagitis. In 67 patients, visual changes compatible with esophageal inflammation were found, and an infectious etiology for


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the changes was determined in 39; in seven of these cases, the changes were due to HSV infection, either as a single pathogen or as a component of a polymicrobial process.5 4 In this study, the visual findings were nondiagnostic. Concomitant throat cultures showed low sensitivity but a high specificity and a positive predictive value of 60%. While the pathogenesis of HSV esophagitis is not clear, it has been proposed that it may represent the spread of virus from oropharyngeal sites of reactivation to areas of mucosal disruption in the esophagus. However, the recent isolation of HSV from the vagus nerve ganglia of humans suggests that herpetic esophagitis could represent a site directly affected by reactivation of latent HSV.5 5 Disseminated HSV infection. This remains an uncommon but well-documented entity. Visceral involvement of liver, lungs, adrenal glands, gastrointestinal tract, CNS, and skin has been reported in immunocompromised patients. It has been observed that viral dissemination is a more frequent complication of primary infection when circulating antibodies are absent. Cellular immune dysfunction is also a major risk factor for disseminated visceral involvement. The role of cellular immune dysfunction as a risk factor for CNS infection, specifically HSV encephalitis, is not clear, but the frequency among immunocompromised hosts is not dramatically different from that reported in the general population. (A discussion of disseminated HSV visceral infection is not within the scope of this article.) Diagnosisof HSVInfection The diagnosis of HSV infection is usually made without difficulty on the basis of clinical grounds in patients who have typical nasolabial, pharyngeal, or genital HSV lesions. Patients who present with atypical nasal mucosal lesions, facial cellulitis, exudative pharyngitis, acute periodontal infection, or esophagitis are treated primarily for infection due to bacterial or fungal pathogens, with the possibility of underlying HSV etiology usually disregarded. Increased awareness and expertise on the part of the treating physician are required to heighten the index of suspicion of HSV as a pathogen frequently associated with these clinical presentations. The laboratory diagnosis of HSV should be evaluated from two different perspectives. The

first goal is to identify patients who are seropositive for HSV before the development of clinical reactivation. HSV antibody can be detected by a variety of techniques, including complement fixation, microneutralization, and enzyme immunoassay.40, 41,56 ,57 These techniques are highly sensitive and reliable and can be used to screen for past HSV infection to determine whether acyclovir prophylaxis should be administered before bone marrow transplantation, organ transplantation, and induction chemotherapy for acute leukemia. The second objective is to identify those patients who are actively shedding HSV and who may have a well-established infection requiring aggressive antiviral therapy. HSV-1 and HSV-2 grow in a wide variety of tissue culture cells, inducing characteristic cytopathic effects in up to 90% of cultures within 72 hours of inoculation. 5859 Type-specific monoclonal antibodies for HSV-1 and HSV-2 are commercially available. The clinical source, collection, and handling of the specimens are of paramount importance in viral recovery. The specimens should be collected as soon as possible in the course of the illness, since the probability of isolating HSV decreases with time after lesions develop. The highest isolation rates are obtained from vesicle fluid (80% to 90%), and the rates decrease as the ulcerative phase of the lesion becomes crusted and resolves (• 25%). In obtaining a specimen of a herpetic ulcer, the swab should be firmly rubbed against the ulcer and then immediately immersed in diluent or transport medium. The swab should be rolled vigorously and the excess fluid removed by pressing the swab against the side of the tube. HSV can be recovered from virtually any tissue or body fluid, including saliva, tracheobronchial secretion, and spinal and bronchoalveolar lavage fluid. Clinical specimens can also be examined by fluorescent antibody testing, indirect immunoperoxidase testing, or enzyme immunoassay using monoclonal antibodies. These have the advantages of lower cost and the potential for a rapid diagnosis, and usually do not require cell-culture capabilities. The newly introduced centrifugation techniques, followed by direct fluorescent antibody staining with monoclonal antibodies, are rapid and sensitive but are used preferentially for the diagnosis of CMV, which usually takes longer


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BUSTAMANTE AND WADE

than HSV to grow in conventional cell-culture lines.' Managementof HSVInfection A number of antiviral agents have been evaluated in placebo-controlled trials, but few have shown significant clinical benefit in the management of HSV infection. Before the development of acyclovir, vidarabine was the standard therapy for severe oropharyngeal, esophageal, and CNS HSV infection, including encephalitis. Since its introduction, acyclovir has become the only antiviral agent with proven efficacy for the prophylactic and therapeutic management of HSV infection in normal and immunocompromised hosts. Acyclovir, an acyclic purine nucleoside analogue, is a potent inhibitor of HSV-1, HSV-2, and VZV. The activity of acyclovir is highly selective against viruses that encode for viral thymidine kinase capable of phosphorylating acyclovir to a monophosphate; the acyclovir monophosphate is subsequently converted to an acyclovir triphosphate by cellular enzymes.61 Therefore, the triphosphorylation of acyclovir occurs primarily in HSVinfected cells. Acyclovir triphosphate acts as a more potent inhibitor of viral DNA polymerases than of cellular polymerases, acting as a DNA chain terminator and causing viral inactivation. This selectivity of acyclovir for HSV-infected cells also explains the relatively low toxicity of this agent. Acyclovir is generally well tolerated after intravenous (IV) administration, but local pain and phlebitis have been reported. Peak serum concentration after a dose of 9 mg/kg body weight is approximately 9 ýpg/mL, while the median infective dose (IDso) of susceptible HSV-1 and HSV-2 strains is generally lower than 1 Rg/mL. Oral acyclovir, however, is poorly absorbed, and its bioavailability is approximately 20%. Its plasma half-life is approximately 3 hours, and 85% to 90% of the drug is excreted unchanged in the urine. Oral acyclovir may cause nausea, which generally resolves with continued use. Topical acyclovir 5% ointment may cause burning, but it is otherwise well tolerated. It should not be applied to mucosal surfaces; its use should be limited to the skin. Reversible renal dysfunction has been seen in approximately 5% of patients treated with IV acyclovir at a dosage of 5 mg/kg every 8 hours. This has been attributed to crystalline nephropa-

thy, characterized by crystallization of acyclovir in renal tubules. The use of acyclovir has also been reported to cause neurotoxicity, including lethargy, tremor, delirium, and seizures, and to result in an abnormal electroencephalogram.62 '63 Neurotoxicity induced by acyclovir is frequently heralded by a resting or intentional tremor. Toxicities are avoidable with adequate hydration with 800 to 1,000 cc of fluid per each gram of acyclovir administered daily. Prevention of HSV Infection Acyclovir prophylaxis has been shown to be highly effective in preventing reactivation of HSV infection in immunocompromised seropositive patients, particularly those with acute leukemia who are undergoing chemotherapy or patients being prepared for bone marrow transplantation. The IV formulation of acyclovir was first used as prophylaxis against HSV infection and found to be highly effective.64-71 Saral et al"5 administered acyclovir to patients with acute myelogenous leukemia who were undergoing induction chemotherapy. Acyclovir prophylaxis began 4 days after the initiation of chemotherapy and continued for 1 month. None of the 14 acyclovir recipients, compared with 11 of the 15 placebo recipients, sustained recurrent HSV infection. Although quantification was difficult, it was noted that the observed mucositis among these patients, presumably due to the intensive chemotherapy, was dramatically less severe for acyclovir recipients. Similar efficacy with the IV preparation had been reported by Saral et al among bone marrow transplant recipients who were seropositive for antibody to HSV. IV acyclovir prophylaxis has routinely used a dosage of 250 mg/m 2 every 12 hours. This dose provides virologic suppression in greater than 90% of recipients. IV dosing of 250 mg/m 2 once a day, however, has been associated with greater than 25% viral reactivation and is not an acceptable prophylactic regimen. Doses of 75 to 125 mg/m2 every 12 hours may be effective based on the pharmacokinetics of acyclovir, although controlled studies have not yet been performed. Oral acyclovir is also highly effective as prophylaxis. Acyclovir given at a dosage of 400 mg (two 200-mg tablets every 4 hours, five times daily) has been compared with placebo for prophylaxis of HSV infection after marrow transplantation in a prospective, randomized double-blind trial.67 Acy-


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clovir, which was begun 1 week before transplantation, was continued 4 weeks after transplantation. In that study, only five of 24 acyclovir-treated patients developed HSV infection during prophylaxis, compared with 17 of 25 who received placebo (P < .01). In those patients who took a minimum of 40% of the prescribed dose, acyclovir was 96% virologically effective and 100% clinically effective during the period of oral administration. More recently, the Seattle Marrow Transplant Group has shown that using an oral acyclovir dosing of 800 mg twice daily provides greater than 90% virologic efficacy, suggesting that this dosing regimen may also provide effective prophylaxis, with decreased cost and improved compliance. However, a combination of the IV and oral formulations may be required for patients with cancer, with the IV formulation of acyclovir being used during periods of coincidental nausea, vomiting, or dysphagia and the oral regimen being highly effective as an alternative to IV therapy for most ambulatory immunosuppressed patients at risk for infection reactivation. In summary, acyclovir prophylaxis has been shown to be highly effective for seropositive patients who are undergoing induction chemotherapy for acute leukemia or are being prepared for bone marrow transplantation, and it is recommended in all such patients. Routinely, we have reserved prophylaxis among other seropositive patients with cancer until a single documented HSV infection complicating chemotherapy has been identified. Once effectively treated, prophylaxis has then been continued throughout all subsequent courses of chemotherapy. The optimal duration of HSV prophylaxis is not clear, but in large part, continuation of the prophylaxis until antineoplastic therapy has been completed and immunosuppression has been reversed is appropriate. In patients who are receiving induction chemotherapy for acute leukemia, acyclovir should be administered during episodes of profound neutropenia and throughout courses of consolidation and maintenance chemotherapy. Marrow transplant recipients should receive acyclovir for a minimum of 4 to 6 weeks after transplantation. Treatment of HSVInfection The importance of treating HSV infection in patients with malignancy has been debated. Baglin et a172 have evaluated this aspect by reviewing 72

episodes of fever that occurred in 43 patients with hematologic malignancy. HSV infection was documented by positive cultures in 24 of the 43 patients. Of the evaluated 72 episodes of fever, 48 were not associated with positive HSV cultures, and 32 of the 48 (67%) responded to antibacterial antibiotics alone. However, only three of the 24 episodes of fever associated with positive cultures for HSV responded to antibacterial antibiotics. The high incidence of antibiotic-resistant fever in neutropenic patients with HSV infection indicates the importance of recognizing this clinical entity and using effective antiviral therapy. Both oral and IV acyclovir have been shown to be effective in the treatment of acute and chronic mucocutaneous HSV infection in immunosuppressed patients. 7'3 74 Acyclovir is well tolerated, and most symptomatic recurrences of HIV infection have been successfully suppressed during periods of treatment with either oral or IV acyclovir. A number of double-blind, placebo-controlled trials conducted in patients with malignancy or patients who had undergone bone marrow transplantation have demonstrated significant clinical efficacy for this agent. The Seattle Marrow Transplant Group administered IV acyclovir at a dosage of 750 mg/m2 daily for 7 days or placebo to transplant recipients with HSV infection. Of the 17 acyclovir-treated patients, 13 had a beneficial clinical response compared with only two of the 17 given placebo. Duration of positive cultures was shorter for acyclovir recipients, as was the median time to resolution of pain, crusting of all lesions, and most importantly, total healing. 74 Shepp et a173 showed that oral acyclovir (400 mg five times daily for 10 days) is more effective than placebo for culture-proven recurrent mucocutaneous HSV infection. Oral acyclovir significantly shortened the median duration of viral shedding, reduced new lesion formation, and shortened the duration of pain, time to resolution of pain, and the achievement of total healing. The period of viral shedding for acyclovir recipients was a median of 2 days, with the time required for healing being just slightly longer than 1 week. Results with oral acyclovir were quite similar to those seen with the IV formulation (Table 1). Again, a combination of IV and oral therapy may be the optimal approach in an attempt to tailor therapy based on the patient's clinical status and the presence of nau-


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BUSTAMANTE AND WADE Table 1. Treatment of HSV Infection With Acyclovir 73

Orao

IV74

Parameter

Median days to (range) Negative cultures First decrease in pain Cessation of pain Crusting of all external lesions Total healing

Acyclovir

3 6 10 7 14

(1-8) (1-10) (7-21) (2-28)t (6-28)t

Placebo

18 14 16 14 28

(4-49)t (1-14)t (7-49)t (6-49)t (10-49)t

P*

Acyclovir

Placebo

P

.00005 .05 .03 .01 .03

2 3 6 6 8

> 9 16 16 11 21

.0008 .04 .05 .01 .01

*Compared by Kaplan-Meier plots and analyzed by Mantel-Cox test. tPatient removed from study and given open-label acyclovir.

sea, vomiting, dysphagia, and the need for IV administration. Frequent and rapid recurrence of HSV infection has been reported after completion of successful acyclovir treatment, especially among bone marrow transplant recipients. HSV reactivation has also been reported after discontinuation of prophylactic therapy. However, the occurrence of severe infection has been dramatically limited, and only one third of individuals receiving prophylactic therapy experience future recurrence requiring acyclovir treatment. This suggests that the ability to delay the reactivation of infection until there is some stabilization of the patient's underlying immune status will not eliminate further reactivation, but may allow such infection to be associated with significantly less morbidity. Topical acyclovir has also been shown to be effective in the treatment of immunocompromised patients with cutaneous lesions confined to the lips, face, or external genitalia. However, the use of topical acyclovir is not generally recommended; the oral and IV formulations are preferred. Acyclovir Resistance Isolates of HSV resistant to acyclovir have been reported.758- To date, the majority of these clinical isolates have lacked the viral-specific thymidine kinase necessary for the initial monophosphorylation of acyclovir to its active triphosphorylated form. Two trials conducted with oncology and other immunocompromised patients have analyzed the frequency of recovery-resistant isolates. Acyclovir-resistant isolates were recovered from one of 52 (1.9%) marrow transplant recipients at the completion of the first treatment course. 74 Two of 22 patients (9.1%) receiving a second treatment course and none of six patients receiving a third and fourth treatment course developed resistance. A more recent evaluation of HSV resistance to

acyclovir was performed by investigators at the University of Minnesota.80 While duration of therapy, dosage, and course of acyclovir were not standardized, seven viral isolates from 148 immunocompromised patients collected during a 1-year period were found to be resistant to acyclovir. This contrasted with a lack of acyclovir-resistant isolates recovered from 59 immunocompromised patients during the same time period. Acyclovirresistant HSV clinical isolates have been presumed to be less virulent, and murine inoculation of thymidine kinase-negative mutants have suggested that they may be unable to establish latency. Yet, the Seattle Marrow Transplant Group recently reported three bone marrow transplant patients who developed pneumonia due to acyclovirresistant HSV-1 isolates. The clinical and virologic significance of acyclovir-resistant strains remains to be determined. However, the prophylactic utilization of acyclovir in patients with cancer has not been associated with the development of acyclovir resistance. Acyclovir is a virustatic drug, and because patients with malignancies are often profoundly immunodeficient, the lack of immediate infection resolution does not necessarily mean that the treatment failure is due to drug resistance. A more prolonged course of acyclovir at higher doses or continuous infusion dosing has been clinically successful for many patients with recalcitrant infections. For those patients with true acyclovirresistant isolates, two approaches have been recommended. One alternative is to discontinue acyclovir therapy and await spontaneous resolution. The second approach, for particularly severe infections, would be to use a newly investigated antiviral agent, phosphonoformic acid (foscarnet). Preliminary experience with foscarnet for the treatment of acyclovir-resistant mucocutaneous HSV infection in patients with acquired immune


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deficiency syndrome has been encouraging. One must remember that the other commercially available nucleoside analogue, ganciclovir, is not helpful for patients with acyclovir-resistant strains because both agents continue to require the viralencoded thymidine kinase for drug activation. SUMMARY

Viral infection has increasingly been recognized as a frequent cause of morbidity and mortality in immunosuppressed patients with cancer. The herpesviruses are the pathogens most frequently encountered because of their ubiquitousness and the high prevalence of seropositivity in the general population. HSV frequently infects humans early in life, causing specific clinical syndromes. Mucocutaneous, oropharyngeal, esophageal, and respiratory tract infections with HSV are distinct clinical syndromes that are frequently associated with underlying cell-mediated immunosuppression and neutropenia. These infections are most prominent in patients with hematologic malignancies, particularly those with acute myelogenous leukemia who are receiving induction chemother-

apy, and in bone marrow transplant recipients. These infections are frequently associated with significant patient discomfort and the potential for bacterial and fungal superinfection as well as viral dissemination. The diagnosis of HSV infection is usually made on clinical grounds, but serologic evaluation of patients who are about to undergo immunosuppression is important to identify those who are at risk for clinical reactivation. Acyclovir, an acyclic purine nucleoside analogue, is a potent and specific inhibitor of HSV-1, HSV-2, and VZV. Acyclovir has been shown to be effective in preventing HSV infection in patients at risk and in treating immunocompromised patients with cancer who have severe HSV infection, including HSV encephalitis. Acyclovir is also effective in treating and halting the progression of dermatomic and disseminated VZV infection. Although acyclovir-resistant strains of HSV have been encountered, this has occurred relatively infrequently, and, apparently, they have not been associated with increased virulence. If the problem of resistance becomes more prevalent, however, the development and introduction of new antiviral agents will become necessary.

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Neonatal herpes simplex virus infection.

Herpes simplex virus infection in pregnancy.

Primary herpes simplex virus infection mimicking cervical cancer.

Tinea incognito simulating herpes simplex virus infection.

Prostatodynia and herpes simplex virus infection.

Atypical presentations of herpes simplex virus infection.

Recurrent lumbosacral herpes simplex virus infection.

Symposium: oral herpes simplex virus infection.

The "Knife-Cut Sign" Revisited: A Distinctive Presentation of Linear Erosive Herpes Simplex Virus Infection in Immunocompromised Patients.

Neonatal herpes simplex virus infection and asymptomatic maternal infection.

The role of antiviral therapy in immunocompromised patients with herpes simplex virus meningitis.

West Nile Virus Infection in the Immunocompromised Patient.

Tranylcypromine reduces herpes simplex virus 1 infection in mice.

Role of Fc receptors in herpes simplex virus infection.

Disseminated Herpes simplex virus infection in ataxia-telangiectasia.

Antiviral drug sensitivity in ocular herpes simplex virus infection.

Herpes simplex induced necrotizing tonsillitis in an immunocompromised patient with ulcerative colitis.

Herpes simplex virus and intraoral ulcers in immunocompromised patients with haematologic malignancies.

Quantitative herpes simplex virus concentrations in neonatal infection.

Concurrent meningococcal and herpes simplex infection in a non-immunocompromised child.

Herpes simplex virus blepharitis in a patient with Crohn's colitis.

Herpes simplex virus.

Ulcerating Herpes Simplex Infection.

Fungal metabolite myriocin promotes human herpes simplex virus-2 infection.