SEMINARS I N NEUROLOGY-VOLUME
12, NO. 4 DECEMBER 1992
Herpes Simplex Mitra Mofid, B.S., Jeffrey S. Dover, M.D., F.R.C.P.(C), Mihnel Skerlev, M.D., and Ivan Dobric, M.D., Ph.D.
HISTORICAL ASPECTS The term "herpes" derives from the ancient Greek herpein, to creep, signifying the tendency of the skin lesions to spread. Richard Morton first used this term in 1694 to describe herpes facialis associated with fever,2 although herpetic eruptions had been previously and niuch earlier described under different name^.^ In the 18th and 19th centuries, herpetic infections were mostly described according to anatomic location (herpes labialis, preputialis, and vulvaris, for example), a classification system that endured until the virus was identified. Lowenstein and Gruter first isolated the agent from vesicles of patients with herpes facialis in 1919;9 their finding was confirmed 1 year later from the brain of a patient dying with encephalitis."
ETIOLOGY T h e etiologic agent of herpes simplex, H. hominis (herpes simplex virus [HSV]), belongs to the Herpetoviridae group. Apart from H. hominis, the other medically important members of' the Herpesviridae group are varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6. In spite of serologic cross-reactivity in some patients, H. hominis and varicella zoster virus are two antigenically distinct viruses causing specific nosologic entities. H. homiriis is a large virus containing a double-stranded DNA genome. Its nucleocapsid, which is about 100 nm in diameter, is surrounded by a protein coat and lipid envelope measuring nearly 150 nm across. There are two niajor antigenic types of H. hominis, HSV-1 and HSV-2, which have genomes encoding approximately 50% of' their nucleotide sequences in common. Although the most readily apparent distinctions between HSV-1 and HSV-2 are in their clinical and epidemiologic patterns, they can be separated by a variety of biologic and biochemical characteristics, such as genetic analysis and sensitivity to heparin or temperature change in cell culture. In general, HSV-1 is associated nlainly with oral-facial herpetic lesions and HSV-2 with genital HSV infections.
EPIDEMIOLOGY HSV is ubiquitous. Humans are the only known reservoirs of disease, although animals can
Department of Dermatology, IIarvard Medical School, and Division of Dermatology, New Englatlcl Deacoriess Hospital, Boston, Massachusetts Departrnent of llermatology and Vcncreology, Zagreb University School ot'hledici~leand Ur~iversi~y Clinical Center, Zagreb, Croatia Copyright O 1992 by Thierne Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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Herpes simplex may be defined as an inf'ection caused by Herpesvirus hominis, characterized clinically by mostly mucocutaneous and sometimes systemic involvement. After the primary infection, typically presenting as grouped vesicles on an erythematous base, virus usually persists in an individual for life,' creating the possibility of additional infections. T h e recurrence of infections is one of the main characteristics of the disease. Publicized as one of the most common human diseases in the world, herpes has become a popular, although feared, household word.
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be infected experimentally; patients with active lesions of primary or recurrent disease as well as healthy carriers constitute stores of infectious virus. Rates of infection among populations are inversely related to socioeconomic status, with adults in lower socioeconomic groups testing antibody positive to HSV at frequencies almost twice those found in higher socioeconomic groups5 Distinctive age-related patterns of infection characterize the two types of viral infections. Antibodies to HSV-1 rise rapidly during childhood, whereas those to HSV-2 increase following puberty.
ROUTES OF TRANSMISSION Primary infection with HSV occurs after direct contact with another infected individual through infected secretions. Passage of infection can occur from both overtly infected individuals and asymptomatic excretors, although virus titers are higher among those with active lesions. There is no reliable evidence that HSV infection can be acquired by the respiratory route or through water transmission. Although it has not been easy to define the incubation period because of the possibility of transmission from asymptomatic carriers, according to some studies the range for oral infection is 2 to 12 days with a peak at 5 days and the incubation period for genital herpes is 2 to 7 days with a peak at 5 days."
LATENCY Aside from similar ultrastructure and some similarities in replication cycle, the only major feature shared by the herpesviruses that infect humans is the capacity to establish l a t e n ~ y a, ~phenomenon long appreciated, although the basic mechanisms involved still have not been well delineated. Primary infection by HSV principally involves tissue derived from ectoderm, with any associated lesions often at the site of infection. After the initial infection and several rounds of viral replication at the body surface, viral material, probably as a nucleocapsid,~ravelsby retrograde axonal transport in neurons to cell bodies within sensory ganglia. Inside the soma, the virus either replicates and destroys its nerve cell host or establishes latent . ~ humans, infection within a preserved n e ~ r o nIn latency has been demonstrated within trigeminal, sacral, and vagal ganglia. Only about 1% of cells within a latently infected sensory ganglion are latently infected neu-
rons. Neurons constitute only a minor fraction of the cells within neural tissues and, of these, not all are infected even under the best experimental conditions. In situ nucleic acid hybridization has not allowed detection of the presumed viral DNA, perhaps because the DNA is present as part of a complex that is not accessible to detection by the methods used,7 although viral genetic expression in the form of a unique transcript termed "latency-associated transcript" has been detected in latently inCected sensory neurons of humans as well as experimental a n i m a l s . ~ e s p i t elack of identification of a protein encoded by the discovered ~ e q u e n c e , ~ the transcript has been shown to enhance the efficiency of reactivation greatly, although it is not absolutely required for the process.'0 Primary and recurrent HSV infections provoke an immune response, enlisting a variety of humoral and cell-mediated mechanisms. The production of various antibodies and interferon, the activation of macrophages, the induction of T cells, and the development of natural killer cell and antibody-dependent lymphocyte cytotoxicity have all been observed, although their specific rdes in the overall response are not well known. Through unclear mechanisms, possibly related to breakdown of immunologic protection, reactivation of latent virus within intact host neurons occurs, and the genome passes anterograde in neural axons before passing to epithelial cells. There, productive infection may result in characteristic lesions. In all model systems studied, including in vitro arid in vivo models, reactivation of latent infection producing mature infectious virus results in cell death.] In human hosts, however, multiple reactivations involving the same anatomic site without the development in time of anesthesia over the involved area are incompatible with destruction of neurons. It has been hypothesized, instead, that in vivo reactivation results in expression of a subset of viral genes and replication of' viral DNA without resulting in neuronal destruction. The DNA may pass intra-axonally to the epithelium where it transfects cells through intraepithelial nerve endings to initiate recurrent infection, which is then spread cell to celL7 An observation made repeatedly is that all areas supplied by a latently infected nerve are not equally involved; recurrences usually arise at the site of the primary infection. In experimental systems, persistence of infection has been demonstrated in mouse footpads and rabbit and mouse corneas for extended periods of time.'2-'4 Virus isolation did not constitute proof of the presence of latent infection because it was impossible to establish whether the systems were true models of
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CLINICAL MANIFESTATIONS OROFACZAL HERPES
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Herpetic gingivostomatitis, the most common manifestation of primary infection by HSV, is caused by HSV-1 in 80 to 90% of cases. Most cases occur in early childhood, between 1 and 5 years of age, but the disease may begin later. T h e course is variable; it may be asymptomatic or severe. T h e disease usually begins with fever (up to 40°C), malaise, restlessness, and other constitutiorial symptoms. Small vesicles are present on the tongue, palate, gingiva, pharynx, inner lip, and buccal mucous membranes. T h e vesicles usually coalesce to form white plaques, which are very often followed by ulcers. 'The oral lesions are exquisitely tender, rendering drinking and eating painful and sometimes impossible so that dehydration often becomes a concern. Gums are red and swollen and bleed easily, and the breath is usually fetid. Regional lymph nodes are enlarged. T h e prognosis is usually good, with the fever subsiding after 2 to 5 days and recovery usually complete in 10 to 14 days. In the differential diagnosis many diseases, especially those with ulcerative oral lesions, come into consideration; these include aphthous stomatitis, streptococcal and diphtheritic pharyngitis, Behcet's disease, Coxsackievirus infections, severe candidiasis, erythema multiforme, and infectious mononucleosis. Recurrent herpes labialis (cold sore) is the most typical clinical manifestation of recurrent HSV infection. About one-third of the United States population have recurrences of facial-oral herpes simplex, with the usual rate being three to . ~ . ~ ~ oral-labial lesions four ~ u t b r e a k s l ~ e a rHSV-2 recur less frequently than do those caused by HSV-1.16 Precipitating factors vary widely among individuals yet can be fairly stereotyped for a given individual. Various provocative factors include sunlight, fever, chronic infections, local trauma, menstruation, trigeminal nerve manipulation, and emotional stress. T h e onset of recurrent disease is characteristically preceded by a sensation of burning, pain, tingling, or itching a few hours before the development of lesions. T h e lesions are typically located on the vermilion border of the lip, more frequently at the skin-lip junction of the lower rather than the upper lip, but they can be situated anywhere on the body. Rarely, vesicles recur inside the mouth o r on the nose, chin, o r
cheek. Recurrences commonly appear in the same region but are not always located at the identical site.I7T h e lesions usually consist of small, clustered vesicles grouped on an erythematous base. 'The vesicles often ulcerate and progress to crusts within 4 days. Complete recovery, without scarring, occurs in 7 to 10 days. Kegional lymphadenopathy, fever, and other systemic complaints are rare in recurrent disease.IWerpes zoster, impetigo, and erythema multiforme should be considered in the differential diagnosis. GENITAL HERPES
Genital herpes represents the clinical manifestation of both primary and recurrent infection by HSV. It is overwhelmingly (80%) caused by HSV-2, although both HSV-1 and HSV-2 produce identical clinical features. Overall, approximately 60 to 90% of' those with primary infections develop recurrences. Occasional subsequent episodes are herpetic recurcaused by reinfection.l%enital rences are governed by a number of factors, including gender, HSV type, and presence and titer of neutralizing antibody." HSV-1 genital lesions recur less frequently than those caused by HSV-2, and men experience more recurrences than do women. The average rate of recurrence is 3 to 4 per year, although the rate in some patients may be much higher.*' It is estimated that about 30 million people in the United States are affected by this disease." In industrial countries, genital herpes is now the most frequent type of genital ulcerative lesion seen in sexually transmitted disease clinics. T h e lesions consist of small, grouped vesicles that rapidly progress to ulcers and are usually situated on the glans, prepuce, and shaft of the penis (Fig. 1) in males and on the vulva, vagina, and cervix in females. Primary genital herpetic lesions are usually multiple, whereas a single ulcer is characteristic of recurrent infection. In general, herpetic vesicles are small and fragile, so that patients are much more often seen during the ulcerative stage of disease. T h e ulcers are painful and, in women, dysuria is quite common. Inguinal lymph nodes are enlarged, tender on palpation, nonfixed, and slightly painful (especially in primary infections). T h e usual duration of disease is 2 to 3 weeks for primary infections and 1 to 2 weeks for recurrences. Aseptic meningitis may occur as a complication of primary genital herpes.*" T h e differential diagnosis of genital herpes includes genital candidiasis, mechanical ulceration secondary to local trauma, primary syphilis (syphilitic chancres may even coexist with genital herpes), chancroid, fixed drug reactions, erythema multiforme, and Behqet's disease.
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latency or merely examples of low-level virus replication. T h e possibility, then, of HSV latency in non-neuronal sites exists.
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The skin is indurated at the site of inoculation and erythematous, with vesicles or bullae usually located at the margin of infected skin. Regional lymph nodes are usually enlarged. If the inoculation occurs on a fingertip, the term "herpetic whitlow" is applied. This condition is an occupational risk for health workers, especially those in the dental profession. An example of the combined effect of trauma and salivary inoculation occurs in wrestlers, who can develop multiple herpetic skin lesions, a phenomenon traditionally termed herpes gladiatorum.24 HERPETIC OCULAR DISEASE
Perianal and anal HSV-2 infection is being recognized increasingly, particularly in male hom o s e x u a l ~ .T~h~e primary complaint is pain, although itching, tenesmus, dysuria, sacral paresthesia, and discharge are also often present. Constitutional symptoms such as fever, chills, malaise, and headache may also be noted. T h e perianal and anal vesicles and ulcerations may become confluent and result in a grayish ulcerating cryptitis surrounded by erythematous, edematous mucosa. Bilateral inguinal adenopathy often develops. T h e course is usually self-limited; signs resolve in 1 to 3 weeks unless bacterial superinfection occurs or the patient is also immunosuppressed, in which case the proctitis may be prolonged and progressive.
INOCULATION HERPES SIMPLEX Inoculation herpes simplex is the result of direct inoculation of HSV onto previously abraded skin. T h e infection may be primary or recurrent.
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Figure 1. Grouped vesicles on an erythematous base on the penis of a patient with primaty herpes simplex.
HSV keratitis, which is found in approximately 5% of those attending eye clinics, recurs within 2 years in 25 to 50% of patientsz5HSV infection of the eye can recur as erosive and ulcerative lesions of the cornea and conjunctiva as well as blepharitis. Eyelids become severely edematous and herpetic vesicles may be seen on the surrounding skin. Recurrent keratitis is usually unilateral. Two main types may develop. In the first, dendritic ulcers that stain with fluorescein are pathognomonic. Corneal sensation is often decreased, and visual acuity may be lessened by involvement of the pupillary portion of the cornea. When topical steroids are used, there is danger of evolution to extensive, ameboid corneal ulcers, but superficial keratitis usually heals spontaneously. 'I'he second type of recurrent keratitis is characterized by deep stromal involvement and uveitis, which lead to a gradual diminution in visual acuity and may result in permanent visual loss. HERPES SIMPLEX ENCEPHALITIS
Herpes simplex encephalitis (encephalitis herpetica; acute inclusion body encephalitis; necrotizing hemorrhagic encephalitis) is the most serious manifestation of HSV infection. Although a rare complication of herpetic infection, it is the most common cause of fatal sporadic encephalitis in the Western Estimates of its frequency range from several hundred to several thousand cases per year in the United States27and nearly one and ,~~ one-half million individuals w o r l d ~ i d enumbers that, many authors believe, significantly underestimate true adverse effects of the virus. Herpes encephalitis affects both sexes and all races equally. It appears sporadically throughout the year, in all areas of the world, without regard to season." Although it occurs in persons of all ages, there may be a relative sparing of those in the middle decades of life.'Qeyond the neonatal period, HSV-1 is the primary causative agent; oral lesions, however, are
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rarely associated with the en~ephalitis.'~HSV-2 may also cause an acute encephalitis, but the cases are almost exclusively neonatal and in relation to maternal genital herpetic infection.28 T h e clinical course, which evolves over several days, may begin suddenly o r follow a brief influenza-like p r o d r ~ m e .T~h~e symptoms of fever, headache, seizures, confusion, stupor, and coma are similar to those found in encephalitis of any other cause. Premonitory olfactory or gustatory h;illucinations, anosmia, temporal lobe seizures, a brief period of personality change, bizarre or psychotic behavior, aphasia, and hemiparesis may reveal inferomedial frontal and temporal lobe involvement, which is highly characteristic of HSV infection. Deep coma and respiratory arrest arising during the first 24 to 72 hours may occur as a result of' swelling of one or both temporal lobes and herniation through the t e n t ~ r i u m . ' ~ T h e distribution of lesions, so characteristic that post-mortem diagnosis can be made by inspection of gross brain specimens, is an intense hemorrhagic necrosis of the inferior and medial aspects of the temporal lobes and orbital sections of' the frontal lobes.28Such a unique pattern can be explained by one of t ~ suggested ~ o theories regarding routes of virus entry into the central nervous system (CNS).2"n the first, reactivation of latent infection in the trigeminal ganglia may allow virus to infect the nose and olfactory tract. Absence of olfactory bulb lesions in about 40% of' fatal cases,3o however, lends support to the second hypothesis, namely, that, with reactivation in the trigeminal ganglia, infection spreads along fibers innervating the leptomeninges of the anterior and middle fossae. Although either of' these routes might explain primary infection, they do not indicate a mechanism for recurrent encephalitis, which occurs in nearly two thirds of patients with encephaliti~.~" Because there are no pathognomonic clinical findings, diagnosis is often difficult. 'I'he differential diagnosis is broad: it irlcludes other viral encephalitides, tuberculous and fungal meningitis, acute hemorrhagic leukoencephalitis, subdural empyema, cerebral abscess, brain tumor, thrornbophlebitis, arld septic embolism. Because of the selective character of the infection, localizirlg studies are often helpful, although they are not diagnostic. Electroencephalographic changes such as periodic high-voltage sharp waves in the temporal regions and slow wave complexes are suggestive, although not specific.28 Computed axial tomography and magnetic resonance imaging may provide early evidence of locali~ation.'~~~' A lumbar puncture often reveals a cerebrospinal fluid (CSF) under increased pressure. Pleocytosis, usually with less than 200 cells/mrn4,is alrriost
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invariably present; lymphocytosis is usual, but there is occasionally a significant number of neutrophils. Red cells and xanthochromia, reflecting the hemorrhagic nature of the lesions, are sometimes evident. A slightly elevated protein level and normal glucose characterize the CSF. HSV can rarely be isolated from the CSF; and, although adjunctive antigen and antibody assays are available," they are not sensitive enough to provide a sufficiently early diagnosis. T h e current gold standard for laboratory confirmation of the diagnosis is brain biopsy followed by fluorescent antibody study and viral culture of cerebral tissue. Clearly, less invasive tests are needed. Outcome of the disease is governed to a large extent by three factors: (1) patient age; (2) level of consciousness; and (3) duration of the disease.33 'The course in untreated patients is usually a rapid deterioration over several days that progresses to coma arid death in 60 to 80% of patients. With antiviral therapy (vidarabine or acyclovir), prospects are significantly improved. Overall assessment of acyclovir-treated patients is that by 6 months after treatment, about 40% survive, many with mild levels of impairment." That is, more than half of treated patients die or have moderate to severe impairments (for example, Korsakoff amnesic defect or global dementia, seizures, dysphasia) in spite of receiving therapy. HERPES SIMPLEX IN THE IMMUNOCOMPROMISED PATIENT
HSV infections represent one of the most serious problems in the immunocon~promised.Patients with AIDS, those requiring cytotoxic therapy, or organ transplant recipients may experience frequent recurrences of very severe herpetic infections. T h e herpetic lesions nlay become deep, disseminated, progressive, and painful. -They may coalesce and become very large. For example, perianal HSV ulcers that do not heal are an early clue t o HIV infection and an AIDS-defining illness. Untreated, nlucocutaneous ulcers may become confluent, forming lesions up to 20 cm in diameter that involve half the face o r the circumferential anal ~kin.~"erpes viremia, hepatitis, and encephalitis may be common complications of recurrent genital or facial-oral herpes in the immunocompromised patier~t.~" HERPES SIMPLEX ASSOCIATED WITH OTHER SKIN DISORDERS
Eczema Herpeticum (Kaposi's Varicelliform Eruption) Eczema herpeticunl represents pririlary HSV infection superimposed on a preexisting skin dis-
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order, such as atopic dermatitis. It is usually transmitted by kissing from a mother with active herpes labialis; thus, the disease occurs mostly in infancy. It begins as clustered vesicles on an erythematous base which spread very rapidly over the face, head, and neck. T h e lesions are often secondarily infected, and the clinical picture is usually impressive. Fever, malaise, and lymphadenopathy are present in many cases. T h e disease heals in 2 to 6 weeks arid responds well to systemic antiviral therapy.
Erythema Multiforme Acute HSV infections may be complicated by recurrent localized cutaneous and mucous membrane disorders. Almost three quarters of all cases of erythema multiforme (EM) are preceded regularly by an attack of herpes simplex, and, in predisposed patients, each recurrence of HSV infection may be followed by typical EM lesions. Both HSV-1 and HSV-2 seem to be antigenic stimuli, but the mechanism is not completely understood. HSV antigen has been recovered from lesions," and inactivated HSV antigens injected intradermally into affected patients reproduce characteristic EM att a c k ~ Also, . ~ ~ HSV DNA has been extracted from recurrent EM blister^."^^' T h e cutaneous manifestations range from mild to severe and may be recurrent.
DIAGNOSIS The diagnosis of herpes simplex infection is made clir~icallyin the majority of patients.-" When the lesions are not characteristic, or if the patient requests proof, a Tzanck smear should be done. A negative smear that does not agree with clinical impression or a positive smear that requires distinction of herpes simplex from varicella zoster infection can be followed by culture or immunofluorescence or immunoperoxidase studies. A description of the rnost common as well as other available tests follows. TZANCK PREPARATION
The Tzanck technique is an easy one with low morbidity, requiring for equipment only a light microscope and appropriate stains, both available in most physicians' offices. Cells are scraped from the base of a herpetic vesicle and spread on a glass slide before being stained with any of a number of reagents, according to personal preference; these include methylene blue, hematoxylin and eosin, the
Papanicolaou, and the Romanovsky stains, such as Giemsa and Wright. T h e low technical difficulty of the Tzanck smear should not be confused with the highly variable nature of' test interpretation, which is very much dependent on the interpreter. Findings range from easily identified multinucleated giant cells with molded nuclei, which are most nearly pathognomonic, to a ground-glass or homogenized appearance of nuclear chromatin that occurs in infected epidermal and mononuclear cells. Cowdry type A intranuclear inclusions are best seen with the Papanicolaou stain, which clarifies nuclear morphology but is a more difficult and time-consuming, multistep technique with higher cost that yields sensitivity and specificity about the same as other stains.42'The percent positivity of the test varies with the stage of' the lesion: more than 70% in vesicles, only slightly greater than half in pustules, and only occasionally in crusted le~ions.~' The specificity is fairly high, with experienced interpreters achieving a rate of false-positive results in the range of about 3%. 111 sum, the Tzanck preparation is a fairly easy, inexpensive, few-minUte test with sensitivity and specificity favorably comparable with cultures and immunofluorescence. Its only true drawback is an inability to differentiate among HSV-1, HSV-2, and VZV infections.
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HERPES SIMPIJEX-Mo~rn
VIRAL CULTURE
Despite a lack of 100% sensitivity or specificity, isolation of virus in tissue culture is the current gold standard fbr HSV identification and diagnois.^^ Explanations for imperfect sensitivity include lack of virus survival during inappropriate transport, improper sampling of the lesion, insufficient virus (for instance, at crusted sites), and successful antiviral therapy.42Tissues currently used to support the replication of HSV include primary human embryonic kidney, rabbit kidney, and human amnion cells, all which have replaced hosts such as experimental animals and embryonated eggs. Although cell lines also support HSV replication, infection is to a lesser degree. Cytopathic effects of HSV, which are nonspecific, usually appear within 24 to 48 hours but may take as long as 7 days to develop. Infection of the cellular monolayer causes affected cells to become rounded, to clump together, and to display characteristic intranuclear inclusions. Ballooning degeneration and rnultirlucleated syncytial giant cells are observed, especially with HSV-2. Varicella zoster virus produces similar effects at a slower rate, usually requiring 1 to 3 weeks before manifesting characteristic changes. Newer techniques make possible even more rapid detection. For example,
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tination, indirect immunofluorescence, radioimmunoassay, complement-mediated cytolysis, and antibody-dependent cytolysis. Enzyme-linked immunosorbent assay (ELISA), which can distinguish antibody immunoglobulin subtypes, and Western blot analysis, which is capable of determining antibody levels to specific HSV polypeptide antigens, are techniques that hold potential for future use. For a diagnosis of primary infection, a fourfold or greater rise in antibody titer is observed between acutc and convalescent sera. Less than 5% of those with recurrent infections show a similar increa~e.'~ However, serologic techniques can be useful in presumed recurrent infections: because virtually HISTOPATHOLOGY all of these patients have detectable serum antibodIn cases in which morphology of the gross leies, a negative test result strongly argues against sion fails to be diagnostic, as is the case in immusuch a diagnosis. In newborns, immunoglobulin M nocornpromised individuals who present with herHSV antibodies usually appear within the first 4 petic lesions that are far from characteristic, a weeks of life in infected infants and persist for biopsy may help by adding histologic informamany months; they may therefore be used in the tion to cytologic findings. Diagnostic lindings indiagnosis of neonatal infe~tion.~"n many of the clude ballooning degeneration of infected epitheserologic testing techniques, an important caveat is lial cells, giant cells containing multiple nuclei, and the cross-reactivity of antibodies to HSV-1, HSV-2, typical intranuclear inclusions. Sensitivity and speciand VZV, which results in decreases specificity of ficity are comparable to results obtained with positive test results. smears, but there is the disadvantage that biopsy results usually take several days for interpretation. DNA HYBRIDIZATION (POLYMERASE CHAIN REACTION) IMMUNOMORPHOLOGIC TESTS
Both smears and histologic sections can be used with these techniques, which have the added ability to distinguish among infections caused by HSV-1, HSV-2, and VZV. With the peroxidase-antiperoxidase and avidin-biotin methods, which are the techniques used by most laboratories, commercially available antibodies are employed on fixed tissues and smears. Technical difficulties are high but interpretational problems are low, as easily visualized chrornogens are activated by immunologic reactants. Results are returned within 4 to 5 hours. The tests are relatively inexpensive and are positive in approximately two-thirds of infected specimens, with a high degree of specificity. Immunofluorescence, which has the additional requirements of a fluorescence microscope, frozen or specially fixed biopsy materials, and considerable interpreter experience, can be used with direct o r indirect methods to yield similar results.42 SEROLOGY
Serologic techniques are used infrequently in diagnosis to document primary HSV infections. T h e various assays in use include complement fixation (the standard and most often employed despite low sensitivity relative to the other available tests), neutralization, direct and passive hemagglu318
l'he recently developed polymerase chain reaction ( Y C X ) technique is a very sensitive and rapid diagnostic method. PCK is a more sensitive measure of HSV infection than routine viral culture and detects the presence of HSV at times when the culture is negative.*' 'I'his technique will likely become more routinely available in the near future.
MANAGEMENT TOPICAL TREATMENT
Although handfuls of topical remedies have been used over the years to treat herpes simplex, few have been well studied in a controlled fashion. Nucleoside derivatives have been found to interfere with the synthesis of HSV DNA and some, such as idoxuridine, trifluorothymidine, acyclovir, and vidarabine, are licensed for topical treatment of herpes keratitk4' Many studies regarding the use of topical acyclovir for mucocutaneous lesions have been published. Several investigators claim a significant reduction in viral shedding, new lesion formation, time to healing, and the duration of symptoms with treatment;4s-5' however, disappointing results have been obtained by other^.^^,^^ Since the availability of oral treatment, there has been little if any need for topical therapy.
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the addition of tagged antibody to cultures can result in detection of viral antigen significantly before cytopathic effects are e~ident.~"ntiviral drugs, such as E-5 (2-brornovinyl)-2' deoxyuridine, which selectively inhibits HSV-1 more than HSV-2, can also aid in diagnosis. Subsequent typing of isolates can be accomplished by a variety of techniques that contribute to greater sensitivity and specificity. These include immunofluorescence and microneutralization. Biologic properties, such as temperature or heparin sensitivity, are also used in diagnosis."
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SYSTEMIC TREATMENT
darabine has not proved to be clinically useful against TK-negative mutants, treatment with foscarnet has been enc~uragin~.~"."' In one study, all patients receiving foscarnet had lesions that healed completely; however, acyclovir-resistant infection recurred in all individuals after therapy was dis~ o n t i n u e d .Avoiding ~' the use of acyclovir for viral suppression may decrease the selection of acyclovir-resistant mutants, but the morbidity associated with recurrent HSV infections must also be considered. Vaccines against HSV have shown some success in animal models and are currently undergoing human trial^.^' Problems such as HSV latency and vaccination with a vaccinia virus-HSV recombinant of a human population of which a significant segment has already been immunized with vaccinia virus are only two of the many complications that must be considered before an acceptable vaccine can become available for general use.
The development of acyclovir, or 9-(2-hydroxyethoxy methyl) guanine, represents the major breakthrough in antiherpetic therapy in the past 20 years. HSV-infected cells produce a viral thymidine kinase, which phosphorylates acyclovir to a monophosphate form that is subsequently converted to acyclovir triphosphate by cellular enzymes. The nucleoside triphosphate then potently inhibits HSV DNA polymerase without causing much cellular toxicity.54 For the treatment of primary oral and genital herpes, oral acyclovir 200 mg five times daily for 7 to 10 days is the recorrlrnerlded dosage.55In patients with frequent and severe recurrences or in those in whom recurrences are associated with EM, recurrent aseptic meningitis, o r eczema herpeticum, suppression or prophylaxis with oral acyclovir is often helpful. Recurrent oral and genital herpes can be treated with several regimens when recurrences are frequent enough to be disruptive. PREVENTION With the onset of tingling, 200 mg orally three to Given the problems with treatment of a latent five times per day is given for 7 to 10 days for each new episode. Alternatively, in patients who cannot virus, prevention should be a strong focus of attenrecognize the onset of the eruption, acyclovir 200 tion. Members of the health care industry should mg orally is given three to five times per day as be strongly encouraged to wear gloves in order to long-term prophylaxis. A daily suppressive regi- avoid direct contact with potentially infectious lemen of 200 mg orally three to four times daily has sions. Those patients who have extensive, active been shown to be safe and effective when used con- herpetic lesions, as can be found in eczema herpetinuously for up to 1 year, although it does not al- ticum, should be isolated. Abstinence or the use of condoms is recommended to prevent genital ter the natural history of di~ease.~" Disseminated or CNS HSV infections warrant spread between sexual partners who have active leparenteral therapy. In a study of patients with bi- sions, a history of recurrent genital infections, or opsy-proved HSV encephalitis, acyclovir at a dose both. For the prevention of neonatal disease, cesarof 10 mglkg intravenously three times daily was ean section is currently recommended if clinically found to reduce mortality by 54% and to be supe- apparent cervical infection is detected at parturition before membrane rupture.63Once membrane rior in efficacy to ~ i d a r a b i n e . ~ ~ In immunocompromised hosts, acyclovir is rupture has occurred, however, rapid delivery by successful for treatment and suppression of recur- any route is indicated to lessen exposure of the inrent HSV lesions. Intravenous therapy or oral reg- fant to HSV. Vaginal delivery appears to be safe imens of 400 mg five times daily have been shown when there is a negative clinical examination at the to prevent recurrences, reduce viral shedding, de- time of parturition, but close monitoring and early crease local symptoms such as pain, and accelerate intervention if illness develops during the first few weeks of life is advised for infants born to seropostime to healing during acute episode^.^' A concern about chronic acyclovir therapy is itive mothers. the possible development of resistant HSV mutants. Although the selective pressure of acyclovir therapy may result in a mutant having altered subREFERENCES strate specificity of thymidine kinase (TK), lacking TK, or coding for DNA polymerase with altered 1 . McNair Scott TF. Historical aspects of herpes simplex infection. Int J Dern~atol1986;25:63-9 substrate specificity, resistance is usually associated 2. Beswick TSL. The origin and the use of the word herpes. with loss of viral thymidine kinase a ~ t i v i t y . ~ ~ , ~ ~Med Hist 1962;6:214-32 Pathogenic acyclovir-resistant isolates are becom3. Kaplan AS. Herpes simplex and pseudorabies viruses. Berlin: Springer, 1969 ing increasingly associated with progressive dis4. Levaditi C, Harvier P. Le virus de l'encephalite letharease, whereas most of these were not associated gique (encephalite epidemique) CR Soc Biol 1920;83: with significant disease in the past. Although vi354-5
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5. Rawls WE, Campione-Piccardo J. Epidemiology of herpes simplex virus type 1 and type 2 infections. In Nahmias AJ, Dowdle WR, Schinazi RF, eds: T h e human herpesviruses: an interdisciplinary approach. New York: Elsevier Science Publishing, 198 1: 137 6. Bader C. T h e natural history of recurrent facial-oral infection with herpes simplex virus. J Infect Dis 1978; 138:897-905 7. Stevens, JG Hurrran herpesviruses: a consideration of the latcnt state. Microbial Rev 1989;53:318-32 8. Lycke E, Kristensson K, Svennerholm B, et al. Uptake and transport of herpes sinlplex virus in neurites of rat dorsal root ganglia cells in culture. J Gen Virol 1984;65:55-64 9. Wagner EK, Devi-Rao G , Feldman KT, et al. Physical characterization of the hcrpcs simplex virus latency-associated transcript in neurons. J Virol 1988;62:ll94202 10. Hill JM, Sedarati F,Javiar KT, et al. Herpes simplex virus latent phase transcription facilitates in vivo reactivation. Virology 1990; 174: 117-25 11. Stevens J G . Latent characteristics of selected herpesviruses. Adv Cancer Res 1978;26:227-56 12. Clements GB, Subak-Sharpc J . Herpes simplex virus type 2 establishes latency in the rnouse footpad. J Gen Virol 1988;69:375-83 IS. Cook SD, Batia SK, Brown SM. Recovery of herpes simplex virus from the corneas of experimentally infected rabbits. J Gen Virol lY87;68:2013-7 14. Abgharis SZ, Stulting RD. Recovery of herpes simplex virus from ocular tissues of latently infected inbred mice. Invcst Ophthalmol Visual Sci 1988;29:239-43 15 Young SK, Rowe NH, Buchanan RA. A clinical study for the control of facial mucocutaneous herpes virus infections. 1. Characteristics of natural history in a professional school population. Oral Surg 1976;41:498-507 16 Lafferty WE, Coombs RW, Bcnedetti J, et al. Recurrences after oral and genital herpes infection and viral type. N Engl J Med 1987;316: 1444-9 17. Nagington J, Rook A, Highet A. Virus a n d related infections. In Rook A, Wilkir~sorlDS, Ebling FJG, et al, eds: Textbook of dermatology. Blackwell Scientific Publications, 1988:685-90 18 Gaffey MJ, Ben-Ezra JM, Weiss LM. Herpes simplex lymphadenitis. Am J Clin Pathol 1991;95:709-14 19. Buchman T G , Roizman B, a n d Nah~niasAJ. Demonstration of exogenous genital reinfection with hcrpes simplex virus type 2 by restriction endonuclease fingerprinting of viral DNA. J Infect Dis 1979;140:295-304 20. Corcy I., Adams H , Brown Z, et al. Genital herpes simplex virus infections: clinical manifestations, course and complications. Ann Intern Med 1983;98:95872 21. Jeansson SS, Molin L. O n the occurrence of genital herpes simplex virus infection: clinical and virological findings and relation to gonorrhea. Acta Derrr~Venereol (Stockh) 1974;54:79 22. Crun~packerCS. Herpes simplex. I n Fitzpatr-ick 'I'B, Eisen AZ, Wolff K , et al, eds: Dermatology in general medicine. New York: McGraw-Hill, 1987:2302-14 23. Goodell SE, Quinn T C , Mkrttichian et al. Herpes simplex virus proctitis in homosexual men. Clinical, sigmoidoscopic, and histopathological fcaturcs. N Engl J Med 1983;308:868-71 24. Belongia EA, Goodman, JL, Holland EJ, et al. An outbreak of herpes gladiatorum at a high-school carnp. N Engl J Med l991;325:906-10 25. Kaufman HE, Brown DC, Ellison ED. Hcrpes virus in the lacrimal gland, conjunctiva, and cornea of man: a chronic infection. Am J Ophthalmol 1968;65:32-5 26. Whitley q.Antiviral treatment of a serious herpes sinrplex infection: encephalitis. J Am Acad Dermatol 1988; 18:209-11 27. Straus SE. Introduction to h e r ~ e s v i r i d a eIn . Marldell GL. Dougas RG Jr, Bennett JE, eds: Principles and practice
28. 29. 30. 31. 32.
33. 34. 35. 36.
37. 38. 39.
40.
41. 42. 43.
44. 45. 46.
c,
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47. 48.
49. 50.
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of infectious diseases, 3rd ed. New York: Churchill I.ivingstone, 1990: 1139-44 Adanrs RD, Victor M. Principles of neurology, 4th ed. New York: McGraw-Hill, 1989, p p 598-616 David I>E,Johnson RT. An explanation for the localization of herpes simplex encephalitis. Ann Neurol 1979; 5:2-5 Esiri MM. Herpes simplex encephalitis: an immunohistological study of the distribution of viral antigen within the brain. J Neurol Sci 1982;54:209-26 Schroth G, Gawchn J , T h r o n A, et al. Early diagnosis of herpes simplex encephalitis by MRI. Neurology 1987; 37: 179-83 Lakeman FD, Koga J , Whitley RJ. Detection of antigen to herpes sinrplex virus in cerebrospinal fluid from patients with herpes simplex encephalitis. J Infect Dis 1987; 155: 1172 Whitley KJ, Soong SJ, Linneman C Jr, et al: Herpes simplex encephalitis. Clinical assessment. JAMA 1982; 247:s 17-320 Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 1986; 3 14: 144-9 Dover JS, Arndt KA. Dermatology, Contempo 1991. JAMA 1991;265:3111-3 Hall WW, Farmer PM, Takahashi H , et al. Pathological features of virus infections of the central nervous system (CNS) in the acquired immunodeficiency syndrome (AIDS). Acta Pathol J p n 1991;4 1: 172-81 Orton PW, Huff JC, Tonncsen MG, ct al. Detection of a herpes viral antigen in skin lesions of erythema multiforme. Ann Intern Med 1984;101:48 Shelley WB. Herpes simplex virus as a cause of erythema multiforme. JAMA 1967;201: 153-6 Darragh T M , Egbert BM, Berger T G , et al. Identification of herpes simplex virus DNA in lesions of erythema multiforme by the polymerase chain reaction. J Am Acad Dermatol 1991;24:23-6 Miura S, Smith CC, Burnett JW et al. Detection of viral DNA within skin of healed recurrent herpes simplex infection and erythema multiforme lesions. J Invest Dermatol 1992;98:68-72 Weston WL, Brice SL, Jester JD, et al. Herpes simplex virus in childhood erythema multiforme. Pediatrics 1992;89:32-4 Solomon AR. New diagnostic tests for herpes simplex and varicella zoster infections. J Am Acad Ilermatol 1988;18:218-21 Meyer MP, Anrortegui HJ. Rapid detection of herpes simplex virus using a combination of human fibroblast cell culture and peroxidase-antiperoxidase staining. Am J Clin Pathol 1984;81:43-7 Coleman RM, Nahmias A.1, Williams SC, e t al. IgG subclass antibodies to herpes simplex virus. J Infect Dis 1985; 15 1:929-35 Nahrnias AJ, Dowdle WR, Josey WE, et al. Newborn infection with herpesvirus hominis types 1 and 2. J Pediatr 1970; 17: 185 Conc RW, Hobson AC, Palmer J , et al. Extended duration of herpes simplex virus DNA in genital lesions detected by the polymerase chain reaction. J Infect Dis 1991;164:757-60 Pavan-Langston D. Herpetic diseases. I n Smolin G, 'l'hoft R, eds: T h e cornea-scientific foundations and clinical practice. Boston: Little, Brown, 1983: 178 Fiddian AP, Kinghorn GR, Goldrneier D, et al. Topical acyclovir in the treatment of genital herpes: a comparison with systemic therapy. J Antimicrob Chemother 1983; 12(Suppl B):67-77 Gibson JR, Klaber MR, Harvey SG, et al. Prophylaxis against herpes labialis with acyclovir cream-a placebocontrolled study. Dermatologica 1986;172: 104-7 Kinghorn GR, Turner ER, Barton IG, et al. Efficacy of topical acyclovir cream in first and recurrent episodes of genital herpes. Antiviral Res 1983;3:291-301
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51. Whitley RJ, Levin M, Barton N, et al. lnfcctions caused by herpes simplex virus in the i~nmunocompromised host: natural history a n d topical acyclovir therapy. J Infect Dis 1984; 150:329-9 52. Shaw M, King M, Best JM, et al. Failure of acyclovir cream in treatment of recurrent herpes labialis. Br Med J (Clin Res Ed) 1985;291:7-9 53. Spruance SL, Crumpacker CS, Schnipper LE, et al. Early, patient-initiated treatment of herpes lahialis with topical 1 0 1 acyclovir. Antimicrob Agents Chemother 1984; 25:553-5 54. Clive D, Corey L, Keichman RC, et al. A double-blind, placebo-controlled cytogenetic study of oral acyclovir in patients with recurrent genital herpes. J Infect Dis 1991;4:753-7 55. Brysorl YJ, Dillon M, Lovett M , et al. Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. A randomized double-blind controlled trial in normal subjects. N Engl J Med 1983;308:91621 56. Gold L), Corey I,. Acyclovir prophylaxis for herpes simplex virus infection. Antimicrob Agents Chenlother 1987;31:361-7 57. Conant MA. Prophylactic and suppressive treatment with acyclovir and the management of herpes in patients
58.
59.
60. 61.
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63.
with acquired immunodeficiency syndrome. J Am Acad Dermatol 1988; 18: 186-8 Crumpacker CS, Chartrand P, Subak-Sharpe J H , et al. Resistance of herpes simplex virus to acycloguanosine-genetic and physical analysis. Virology 1980;105: 171-84 Erlich KS, Mills J , Chatis P, et al. Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 1980;320:293-6 Mirsch MS, Schooley RT. Resistance to antiviral drugs: the end of innocence. N Engl J Med 1989;320:313-4 Saf'rin S, Crumpacker C, Chatis P, et al. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant rrlucocutaneous herpes simplex in the acquired immunodeficiency syndrome. T h e AIDS Clinical Trials Group. N Engl J Med 1991;325:551-5 Kooney JF, Wohlenherg C, Cremer KJ, et al. Immunization with a vaccinia virus recombinant expressing herpes simplex virus type 1 glycoprotein D: long-term protection and effect of revaccination. J Virol 1988;62: 1530-4 Brown ZA, Vontver LA, Aenedetti J , et al. Effects o n infants of first episode of genital herpes during pregnancy. N Engl J Med 1987;s 17: 1246-51
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HERPES SIMPLEX-MOFID
12, NO. 4 DECEMBER 1992
Herpes Simplex Mitra Mofid, B.S., Jeffrey S. Dover, M.D., F.R.C.P.(C), Mihnel Skerlev, M.D., and Ivan Dobric, M.D., Ph.D.
HISTORICAL ASPECTS The term "herpes" derives from the ancient Greek herpein, to creep, signifying the tendency of the skin lesions to spread. Richard Morton first used this term in 1694 to describe herpes facialis associated with fever,2 although herpetic eruptions had been previously and niuch earlier described under different name^.^ In the 18th and 19th centuries, herpetic infections were mostly described according to anatomic location (herpes labialis, preputialis, and vulvaris, for example), a classification system that endured until the virus was identified. Lowenstein and Gruter first isolated the agent from vesicles of patients with herpes facialis in 1919;9 their finding was confirmed 1 year later from the brain of a patient dying with encephalitis."
ETIOLOGY T h e etiologic agent of herpes simplex, H. hominis (herpes simplex virus [HSV]), belongs to the Herpetoviridae group. Apart from H. hominis, the other medically important members of' the Herpesviridae group are varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6. In spite of serologic cross-reactivity in some patients, H. hominis and varicella zoster virus are two antigenically distinct viruses causing specific nosologic entities. H. homiriis is a large virus containing a double-stranded DNA genome. Its nucleocapsid, which is about 100 nm in diameter, is surrounded by a protein coat and lipid envelope measuring nearly 150 nm across. There are two niajor antigenic types of H. hominis, HSV-1 and HSV-2, which have genomes encoding approximately 50% of' their nucleotide sequences in common. Although the most readily apparent distinctions between HSV-1 and HSV-2 are in their clinical and epidemiologic patterns, they can be separated by a variety of biologic and biochemical characteristics, such as genetic analysis and sensitivity to heparin or temperature change in cell culture. In general, HSV-1 is associated nlainly with oral-facial herpetic lesions and HSV-2 with genital HSV infections.
EPIDEMIOLOGY HSV is ubiquitous. Humans are the only known reservoirs of disease, although animals can
Department of Dermatology, IIarvard Medical School, and Division of Dermatology, New Englatlcl Deacoriess Hospital, Boston, Massachusetts Departrnent of llermatology and Vcncreology, Zagreb University School ot'hledici~leand Ur~iversi~y Clinical Center, Zagreb, Croatia Copyright O 1992 by Thierne Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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Herpes simplex may be defined as an inf'ection caused by Herpesvirus hominis, characterized clinically by mostly mucocutaneous and sometimes systemic involvement. After the primary infection, typically presenting as grouped vesicles on an erythematous base, virus usually persists in an individual for life,' creating the possibility of additional infections. T h e recurrence of infections is one of the main characteristics of the disease. Publicized as one of the most common human diseases in the world, herpes has become a popular, although feared, household word.
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be infected experimentally; patients with active lesions of primary or recurrent disease as well as healthy carriers constitute stores of infectious virus. Rates of infection among populations are inversely related to socioeconomic status, with adults in lower socioeconomic groups testing antibody positive to HSV at frequencies almost twice those found in higher socioeconomic groups5 Distinctive age-related patterns of infection characterize the two types of viral infections. Antibodies to HSV-1 rise rapidly during childhood, whereas those to HSV-2 increase following puberty.
ROUTES OF TRANSMISSION Primary infection with HSV occurs after direct contact with another infected individual through infected secretions. Passage of infection can occur from both overtly infected individuals and asymptomatic excretors, although virus titers are higher among those with active lesions. There is no reliable evidence that HSV infection can be acquired by the respiratory route or through water transmission. Although it has not been easy to define the incubation period because of the possibility of transmission from asymptomatic carriers, according to some studies the range for oral infection is 2 to 12 days with a peak at 5 days and the incubation period for genital herpes is 2 to 7 days with a peak at 5 days."
LATENCY Aside from similar ultrastructure and some similarities in replication cycle, the only major feature shared by the herpesviruses that infect humans is the capacity to establish l a t e n ~ y a, ~phenomenon long appreciated, although the basic mechanisms involved still have not been well delineated. Primary infection by HSV principally involves tissue derived from ectoderm, with any associated lesions often at the site of infection. After the initial infection and several rounds of viral replication at the body surface, viral material, probably as a nucleocapsid,~ravelsby retrograde axonal transport in neurons to cell bodies within sensory ganglia. Inside the soma, the virus either replicates and destroys its nerve cell host or establishes latent . ~ humans, infection within a preserved n e ~ r o nIn latency has been demonstrated within trigeminal, sacral, and vagal ganglia. Only about 1% of cells within a latently infected sensory ganglion are latently infected neu-
rons. Neurons constitute only a minor fraction of the cells within neural tissues and, of these, not all are infected even under the best experimental conditions. In situ nucleic acid hybridization has not allowed detection of the presumed viral DNA, perhaps because the DNA is present as part of a complex that is not accessible to detection by the methods used,7 although viral genetic expression in the form of a unique transcript termed "latency-associated transcript" has been detected in latently inCected sensory neurons of humans as well as experimental a n i m a l s . ~ e s p i t elack of identification of a protein encoded by the discovered ~ e q u e n c e , ~ the transcript has been shown to enhance the efficiency of reactivation greatly, although it is not absolutely required for the process.'0 Primary and recurrent HSV infections provoke an immune response, enlisting a variety of humoral and cell-mediated mechanisms. The production of various antibodies and interferon, the activation of macrophages, the induction of T cells, and the development of natural killer cell and antibody-dependent lymphocyte cytotoxicity have all been observed, although their specific rdes in the overall response are not well known. Through unclear mechanisms, possibly related to breakdown of immunologic protection, reactivation of latent virus within intact host neurons occurs, and the genome passes anterograde in neural axons before passing to epithelial cells. There, productive infection may result in characteristic lesions. In all model systems studied, including in vitro arid in vivo models, reactivation of latent infection producing mature infectious virus results in cell death.] In human hosts, however, multiple reactivations involving the same anatomic site without the development in time of anesthesia over the involved area are incompatible with destruction of neurons. It has been hypothesized, instead, that in vivo reactivation results in expression of a subset of viral genes and replication of' viral DNA without resulting in neuronal destruction. The DNA may pass intra-axonally to the epithelium where it transfects cells through intraepithelial nerve endings to initiate recurrent infection, which is then spread cell to celL7 An observation made repeatedly is that all areas supplied by a latently infected nerve are not equally involved; recurrences usually arise at the site of the primary infection. In experimental systems, persistence of infection has been demonstrated in mouse footpads and rabbit and mouse corneas for extended periods of time.'2-'4 Virus isolation did not constitute proof of the presence of latent infection because it was impossible to establish whether the systems were true models of
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Herpetic gingivostomatitis, the most common manifestation of primary infection by HSV, is caused by HSV-1 in 80 to 90% of cases. Most cases occur in early childhood, between 1 and 5 years of age, but the disease may begin later. T h e course is variable; it may be asymptomatic or severe. T h e disease usually begins with fever (up to 40°C), malaise, restlessness, and other constitutiorial symptoms. Small vesicles are present on the tongue, palate, gingiva, pharynx, inner lip, and buccal mucous membranes. T h e vesicles usually coalesce to form white plaques, which are very often followed by ulcers. 'The oral lesions are exquisitely tender, rendering drinking and eating painful and sometimes impossible so that dehydration often becomes a concern. Gums are red and swollen and bleed easily, and the breath is usually fetid. Regional lymph nodes are enlarged. T h e prognosis is usually good, with the fever subsiding after 2 to 5 days and recovery usually complete in 10 to 14 days. In the differential diagnosis many diseases, especially those with ulcerative oral lesions, come into consideration; these include aphthous stomatitis, streptococcal and diphtheritic pharyngitis, Behcet's disease, Coxsackievirus infections, severe candidiasis, erythema multiforme, and infectious mononucleosis. Recurrent herpes labialis (cold sore) is the most typical clinical manifestation of recurrent HSV infection. About one-third of the United States population have recurrences of facial-oral herpes simplex, with the usual rate being three to . ~ . ~ ~ oral-labial lesions four ~ u t b r e a k s l ~ e a rHSV-2 recur less frequently than do those caused by HSV-1.16 Precipitating factors vary widely among individuals yet can be fairly stereotyped for a given individual. Various provocative factors include sunlight, fever, chronic infections, local trauma, menstruation, trigeminal nerve manipulation, and emotional stress. T h e onset of recurrent disease is characteristically preceded by a sensation of burning, pain, tingling, or itching a few hours before the development of lesions. T h e lesions are typically located on the vermilion border of the lip, more frequently at the skin-lip junction of the lower rather than the upper lip, but they can be situated anywhere on the body. Rarely, vesicles recur inside the mouth o r on the nose, chin, o r
cheek. Recurrences commonly appear in the same region but are not always located at the identical site.I7T h e lesions usually consist of small, clustered vesicles grouped on an erythematous base. 'The vesicles often ulcerate and progress to crusts within 4 days. Complete recovery, without scarring, occurs in 7 to 10 days. Kegional lymphadenopathy, fever, and other systemic complaints are rare in recurrent disease.IWerpes zoster, impetigo, and erythema multiforme should be considered in the differential diagnosis. GENITAL HERPES
Genital herpes represents the clinical manifestation of both primary and recurrent infection by HSV. It is overwhelmingly (80%) caused by HSV-2, although both HSV-1 and HSV-2 produce identical clinical features. Overall, approximately 60 to 90% of' those with primary infections develop recurrences. Occasional subsequent episodes are herpetic recurcaused by reinfection.l%enital rences are governed by a number of factors, including gender, HSV type, and presence and titer of neutralizing antibody." HSV-1 genital lesions recur less frequently than those caused by HSV-2, and men experience more recurrences than do women. The average rate of recurrence is 3 to 4 per year, although the rate in some patients may be much higher.*' It is estimated that about 30 million people in the United States are affected by this disease." In industrial countries, genital herpes is now the most frequent type of genital ulcerative lesion seen in sexually transmitted disease clinics. T h e lesions consist of small, grouped vesicles that rapidly progress to ulcers and are usually situated on the glans, prepuce, and shaft of the penis (Fig. 1) in males and on the vulva, vagina, and cervix in females. Primary genital herpetic lesions are usually multiple, whereas a single ulcer is characteristic of recurrent infection. In general, herpetic vesicles are small and fragile, so that patients are much more often seen during the ulcerative stage of disease. T h e ulcers are painful and, in women, dysuria is quite common. Inguinal lymph nodes are enlarged, tender on palpation, nonfixed, and slightly painful (especially in primary infections). T h e usual duration of disease is 2 to 3 weeks for primary infections and 1 to 2 weeks for recurrences. Aseptic meningitis may occur as a complication of primary genital herpes.*" T h e differential diagnosis of genital herpes includes genital candidiasis, mechanical ulceration secondary to local trauma, primary syphilis (syphilitic chancres may even coexist with genital herpes), chancroid, fixed drug reactions, erythema multiforme, and Behqet's disease.
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latency or merely examples of low-level virus replication. T h e possibility, then, of HSV latency in non-neuronal sites exists.
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The skin is indurated at the site of inoculation and erythematous, with vesicles or bullae usually located at the margin of infected skin. Regional lymph nodes are usually enlarged. If the inoculation occurs on a fingertip, the term "herpetic whitlow" is applied. This condition is an occupational risk for health workers, especially those in the dental profession. An example of the combined effect of trauma and salivary inoculation occurs in wrestlers, who can develop multiple herpetic skin lesions, a phenomenon traditionally termed herpes gladiatorum.24 HERPETIC OCULAR DISEASE
Perianal and anal HSV-2 infection is being recognized increasingly, particularly in male hom o s e x u a l ~ .T~h~e primary complaint is pain, although itching, tenesmus, dysuria, sacral paresthesia, and discharge are also often present. Constitutional symptoms such as fever, chills, malaise, and headache may also be noted. T h e perianal and anal vesicles and ulcerations may become confluent and result in a grayish ulcerating cryptitis surrounded by erythematous, edematous mucosa. Bilateral inguinal adenopathy often develops. T h e course is usually self-limited; signs resolve in 1 to 3 weeks unless bacterial superinfection occurs or the patient is also immunosuppressed, in which case the proctitis may be prolonged and progressive.
INOCULATION HERPES SIMPLEX Inoculation herpes simplex is the result of direct inoculation of HSV onto previously abraded skin. T h e infection may be primary or recurrent.
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Figure 1. Grouped vesicles on an erythematous base on the penis of a patient with primaty herpes simplex.
HSV keratitis, which is found in approximately 5% of those attending eye clinics, recurs within 2 years in 25 to 50% of patientsz5HSV infection of the eye can recur as erosive and ulcerative lesions of the cornea and conjunctiva as well as blepharitis. Eyelids become severely edematous and herpetic vesicles may be seen on the surrounding skin. Recurrent keratitis is usually unilateral. Two main types may develop. In the first, dendritic ulcers that stain with fluorescein are pathognomonic. Corneal sensation is often decreased, and visual acuity may be lessened by involvement of the pupillary portion of the cornea. When topical steroids are used, there is danger of evolution to extensive, ameboid corneal ulcers, but superficial keratitis usually heals spontaneously. 'I'he second type of recurrent keratitis is characterized by deep stromal involvement and uveitis, which lead to a gradual diminution in visual acuity and may result in permanent visual loss. HERPES SIMPLEX ENCEPHALITIS
Herpes simplex encephalitis (encephalitis herpetica; acute inclusion body encephalitis; necrotizing hemorrhagic encephalitis) is the most serious manifestation of HSV infection. Although a rare complication of herpetic infection, it is the most common cause of fatal sporadic encephalitis in the Western Estimates of its frequency range from several hundred to several thousand cases per year in the United States27and nearly one and ,~~ one-half million individuals w o r l d ~ i d enumbers that, many authors believe, significantly underestimate true adverse effects of the virus. Herpes encephalitis affects both sexes and all races equally. It appears sporadically throughout the year, in all areas of the world, without regard to season." Although it occurs in persons of all ages, there may be a relative sparing of those in the middle decades of life.'Qeyond the neonatal period, HSV-1 is the primary causative agent; oral lesions, however, are
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rarely associated with the en~ephalitis.'~HSV-2 may also cause an acute encephalitis, but the cases are almost exclusively neonatal and in relation to maternal genital herpetic infection.28 T h e clinical course, which evolves over several days, may begin suddenly o r follow a brief influenza-like p r o d r ~ m e .T~h~e symptoms of fever, headache, seizures, confusion, stupor, and coma are similar to those found in encephalitis of any other cause. Premonitory olfactory or gustatory h;illucinations, anosmia, temporal lobe seizures, a brief period of personality change, bizarre or psychotic behavior, aphasia, and hemiparesis may reveal inferomedial frontal and temporal lobe involvement, which is highly characteristic of HSV infection. Deep coma and respiratory arrest arising during the first 24 to 72 hours may occur as a result of' swelling of one or both temporal lobes and herniation through the t e n t ~ r i u m . ' ~ T h e distribution of lesions, so characteristic that post-mortem diagnosis can be made by inspection of gross brain specimens, is an intense hemorrhagic necrosis of the inferior and medial aspects of the temporal lobes and orbital sections of' the frontal lobes.28Such a unique pattern can be explained by one of t ~ suggested ~ o theories regarding routes of virus entry into the central nervous system (CNS).2"n the first, reactivation of latent infection in the trigeminal ganglia may allow virus to infect the nose and olfactory tract. Absence of olfactory bulb lesions in about 40% of' fatal cases,3o however, lends support to the second hypothesis, namely, that, with reactivation in the trigeminal ganglia, infection spreads along fibers innervating the leptomeninges of the anterior and middle fossae. Although either of' these routes might explain primary infection, they do not indicate a mechanism for recurrent encephalitis, which occurs in nearly two thirds of patients with encephaliti~.~" Because there are no pathognomonic clinical findings, diagnosis is often difficult. 'I'he differential diagnosis is broad: it irlcludes other viral encephalitides, tuberculous and fungal meningitis, acute hemorrhagic leukoencephalitis, subdural empyema, cerebral abscess, brain tumor, thrornbophlebitis, arld septic embolism. Because of the selective character of the infection, localizirlg studies are often helpful, although they are not diagnostic. Electroencephalographic changes such as periodic high-voltage sharp waves in the temporal regions and slow wave complexes are suggestive, although not specific.28 Computed axial tomography and magnetic resonance imaging may provide early evidence of locali~ation.'~~~' A lumbar puncture often reveals a cerebrospinal fluid (CSF) under increased pressure. Pleocytosis, usually with less than 200 cells/mrn4,is alrriost
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invariably present; lymphocytosis is usual, but there is occasionally a significant number of neutrophils. Red cells and xanthochromia, reflecting the hemorrhagic nature of the lesions, are sometimes evident. A slightly elevated protein level and normal glucose characterize the CSF. HSV can rarely be isolated from the CSF; and, although adjunctive antigen and antibody assays are available," they are not sensitive enough to provide a sufficiently early diagnosis. T h e current gold standard for laboratory confirmation of the diagnosis is brain biopsy followed by fluorescent antibody study and viral culture of cerebral tissue. Clearly, less invasive tests are needed. Outcome of the disease is governed to a large extent by three factors: (1) patient age; (2) level of consciousness; and (3) duration of the disease.33 'The course in untreated patients is usually a rapid deterioration over several days that progresses to coma arid death in 60 to 80% of patients. With antiviral therapy (vidarabine or acyclovir), prospects are significantly improved. Overall assessment of acyclovir-treated patients is that by 6 months after treatment, about 40% survive, many with mild levels of impairment." That is, more than half of treated patients die or have moderate to severe impairments (for example, Korsakoff amnesic defect or global dementia, seizures, dysphasia) in spite of receiving therapy. HERPES SIMPLEX IN THE IMMUNOCOMPROMISED PATIENT
HSV infections represent one of the most serious problems in the immunocon~promised.Patients with AIDS, those requiring cytotoxic therapy, or organ transplant recipients may experience frequent recurrences of very severe herpetic infections. T h e herpetic lesions nlay become deep, disseminated, progressive, and painful. -They may coalesce and become very large. For example, perianal HSV ulcers that do not heal are an early clue t o HIV infection and an AIDS-defining illness. Untreated, nlucocutaneous ulcers may become confluent, forming lesions up to 20 cm in diameter that involve half the face o r the circumferential anal ~kin.~"erpes viremia, hepatitis, and encephalitis may be common complications of recurrent genital or facial-oral herpes in the immunocompromised patier~t.~" HERPES SIMPLEX ASSOCIATED WITH OTHER SKIN DISORDERS
Eczema Herpeticum (Kaposi's Varicelliform Eruption) Eczema herpeticunl represents pririlary HSV infection superimposed on a preexisting skin dis-
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order, such as atopic dermatitis. It is usually transmitted by kissing from a mother with active herpes labialis; thus, the disease occurs mostly in infancy. It begins as clustered vesicles on an erythematous base which spread very rapidly over the face, head, and neck. T h e lesions are often secondarily infected, and the clinical picture is usually impressive. Fever, malaise, and lymphadenopathy are present in many cases. T h e disease heals in 2 to 6 weeks arid responds well to systemic antiviral therapy.
Erythema Multiforme Acute HSV infections may be complicated by recurrent localized cutaneous and mucous membrane disorders. Almost three quarters of all cases of erythema multiforme (EM) are preceded regularly by an attack of herpes simplex, and, in predisposed patients, each recurrence of HSV infection may be followed by typical EM lesions. Both HSV-1 and HSV-2 seem to be antigenic stimuli, but the mechanism is not completely understood. HSV antigen has been recovered from lesions," and inactivated HSV antigens injected intradermally into affected patients reproduce characteristic EM att a c k ~ Also, . ~ ~ HSV DNA has been extracted from recurrent EM blister^."^^' T h e cutaneous manifestations range from mild to severe and may be recurrent.
DIAGNOSIS The diagnosis of herpes simplex infection is made clir~icallyin the majority of patients.-" When the lesions are not characteristic, or if the patient requests proof, a Tzanck smear should be done. A negative smear that does not agree with clinical impression or a positive smear that requires distinction of herpes simplex from varicella zoster infection can be followed by culture or immunofluorescence or immunoperoxidase studies. A description of the rnost common as well as other available tests follows. TZANCK PREPARATION
The Tzanck technique is an easy one with low morbidity, requiring for equipment only a light microscope and appropriate stains, both available in most physicians' offices. Cells are scraped from the base of a herpetic vesicle and spread on a glass slide before being stained with any of a number of reagents, according to personal preference; these include methylene blue, hematoxylin and eosin, the
Papanicolaou, and the Romanovsky stains, such as Giemsa and Wright. T h e low technical difficulty of the Tzanck smear should not be confused with the highly variable nature of' test interpretation, which is very much dependent on the interpreter. Findings range from easily identified multinucleated giant cells with molded nuclei, which are most nearly pathognomonic, to a ground-glass or homogenized appearance of nuclear chromatin that occurs in infected epidermal and mononuclear cells. Cowdry type A intranuclear inclusions are best seen with the Papanicolaou stain, which clarifies nuclear morphology but is a more difficult and time-consuming, multistep technique with higher cost that yields sensitivity and specificity about the same as other stains.42'The percent positivity of the test varies with the stage of' the lesion: more than 70% in vesicles, only slightly greater than half in pustules, and only occasionally in crusted le~ions.~' The specificity is fairly high, with experienced interpreters achieving a rate of false-positive results in the range of about 3%. 111 sum, the Tzanck preparation is a fairly easy, inexpensive, few-minUte test with sensitivity and specificity favorably comparable with cultures and immunofluorescence. Its only true drawback is an inability to differentiate among HSV-1, HSV-2, and VZV infections.
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VIRAL CULTURE
Despite a lack of 100% sensitivity or specificity, isolation of virus in tissue culture is the current gold standard fbr HSV identification and diagnois.^^ Explanations for imperfect sensitivity include lack of virus survival during inappropriate transport, improper sampling of the lesion, insufficient virus (for instance, at crusted sites), and successful antiviral therapy.42Tissues currently used to support the replication of HSV include primary human embryonic kidney, rabbit kidney, and human amnion cells, all which have replaced hosts such as experimental animals and embryonated eggs. Although cell lines also support HSV replication, infection is to a lesser degree. Cytopathic effects of HSV, which are nonspecific, usually appear within 24 to 48 hours but may take as long as 7 days to develop. Infection of the cellular monolayer causes affected cells to become rounded, to clump together, and to display characteristic intranuclear inclusions. Ballooning degeneration and rnultirlucleated syncytial giant cells are observed, especially with HSV-2. Varicella zoster virus produces similar effects at a slower rate, usually requiring 1 to 3 weeks before manifesting characteristic changes. Newer techniques make possible even more rapid detection. For example,
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tination, indirect immunofluorescence, radioimmunoassay, complement-mediated cytolysis, and antibody-dependent cytolysis. Enzyme-linked immunosorbent assay (ELISA), which can distinguish antibody immunoglobulin subtypes, and Western blot analysis, which is capable of determining antibody levels to specific HSV polypeptide antigens, are techniques that hold potential for future use. For a diagnosis of primary infection, a fourfold or greater rise in antibody titer is observed between acutc and convalescent sera. Less than 5% of those with recurrent infections show a similar increa~e.'~ However, serologic techniques can be useful in presumed recurrent infections: because virtually HISTOPATHOLOGY all of these patients have detectable serum antibodIn cases in which morphology of the gross leies, a negative test result strongly argues against sion fails to be diagnostic, as is the case in immusuch a diagnosis. In newborns, immunoglobulin M nocornpromised individuals who present with herHSV antibodies usually appear within the first 4 petic lesions that are far from characteristic, a weeks of life in infected infants and persist for biopsy may help by adding histologic informamany months; they may therefore be used in the tion to cytologic findings. Diagnostic lindings indiagnosis of neonatal infe~tion.~"n many of the clude ballooning degeneration of infected epitheserologic testing techniques, an important caveat is lial cells, giant cells containing multiple nuclei, and the cross-reactivity of antibodies to HSV-1, HSV-2, typical intranuclear inclusions. Sensitivity and speciand VZV, which results in decreases specificity of ficity are comparable to results obtained with positive test results. smears, but there is the disadvantage that biopsy results usually take several days for interpretation. DNA HYBRIDIZATION (POLYMERASE CHAIN REACTION) IMMUNOMORPHOLOGIC TESTS
Both smears and histologic sections can be used with these techniques, which have the added ability to distinguish among infections caused by HSV-1, HSV-2, and VZV. With the peroxidase-antiperoxidase and avidin-biotin methods, which are the techniques used by most laboratories, commercially available antibodies are employed on fixed tissues and smears. Technical difficulties are high but interpretational problems are low, as easily visualized chrornogens are activated by immunologic reactants. Results are returned within 4 to 5 hours. The tests are relatively inexpensive and are positive in approximately two-thirds of infected specimens, with a high degree of specificity. Immunofluorescence, which has the additional requirements of a fluorescence microscope, frozen or specially fixed biopsy materials, and considerable interpreter experience, can be used with direct o r indirect methods to yield similar results.42 SEROLOGY
Serologic techniques are used infrequently in diagnosis to document primary HSV infections. T h e various assays in use include complement fixation (the standard and most often employed despite low sensitivity relative to the other available tests), neutralization, direct and passive hemagglu318
l'he recently developed polymerase chain reaction ( Y C X ) technique is a very sensitive and rapid diagnostic method. PCK is a more sensitive measure of HSV infection than routine viral culture and detects the presence of HSV at times when the culture is negative.*' 'I'his technique will likely become more routinely available in the near future.
MANAGEMENT TOPICAL TREATMENT
Although handfuls of topical remedies have been used over the years to treat herpes simplex, few have been well studied in a controlled fashion. Nucleoside derivatives have been found to interfere with the synthesis of HSV DNA and some, such as idoxuridine, trifluorothymidine, acyclovir, and vidarabine, are licensed for topical treatment of herpes keratitk4' Many studies regarding the use of topical acyclovir for mucocutaneous lesions have been published. Several investigators claim a significant reduction in viral shedding, new lesion formation, time to healing, and the duration of symptoms with treatment;4s-5' however, disappointing results have been obtained by other^.^^,^^ Since the availability of oral treatment, there has been little if any need for topical therapy.
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the addition of tagged antibody to cultures can result in detection of viral antigen significantly before cytopathic effects are e~ident.~"ntiviral drugs, such as E-5 (2-brornovinyl)-2' deoxyuridine, which selectively inhibits HSV-1 more than HSV-2, can also aid in diagnosis. Subsequent typing of isolates can be accomplished by a variety of techniques that contribute to greater sensitivity and specificity. These include immunofluorescence and microneutralization. Biologic properties, such as temperature or heparin sensitivity, are also used in diagnosis."
EI. AL
SYSTEMIC TREATMENT
darabine has not proved to be clinically useful against TK-negative mutants, treatment with foscarnet has been enc~uragin~.~"."' In one study, all patients receiving foscarnet had lesions that healed completely; however, acyclovir-resistant infection recurred in all individuals after therapy was dis~ o n t i n u e d .Avoiding ~' the use of acyclovir for viral suppression may decrease the selection of acyclovir-resistant mutants, but the morbidity associated with recurrent HSV infections must also be considered. Vaccines against HSV have shown some success in animal models and are currently undergoing human trial^.^' Problems such as HSV latency and vaccination with a vaccinia virus-HSV recombinant of a human population of which a significant segment has already been immunized with vaccinia virus are only two of the many complications that must be considered before an acceptable vaccine can become available for general use.
The development of acyclovir, or 9-(2-hydroxyethoxy methyl) guanine, represents the major breakthrough in antiherpetic therapy in the past 20 years. HSV-infected cells produce a viral thymidine kinase, which phosphorylates acyclovir to a monophosphate form that is subsequently converted to acyclovir triphosphate by cellular enzymes. The nucleoside triphosphate then potently inhibits HSV DNA polymerase without causing much cellular toxicity.54 For the treatment of primary oral and genital herpes, oral acyclovir 200 mg five times daily for 7 to 10 days is the recorrlrnerlded dosage.55In patients with frequent and severe recurrences or in those in whom recurrences are associated with EM, recurrent aseptic meningitis, o r eczema herpeticum, suppression or prophylaxis with oral acyclovir is often helpful. Recurrent oral and genital herpes can be treated with several regimens when recurrences are frequent enough to be disruptive. PREVENTION With the onset of tingling, 200 mg orally three to Given the problems with treatment of a latent five times per day is given for 7 to 10 days for each new episode. Alternatively, in patients who cannot virus, prevention should be a strong focus of attenrecognize the onset of the eruption, acyclovir 200 tion. Members of the health care industry should mg orally is given three to five times per day as be strongly encouraged to wear gloves in order to long-term prophylaxis. A daily suppressive regi- avoid direct contact with potentially infectious lemen of 200 mg orally three to four times daily has sions. Those patients who have extensive, active been shown to be safe and effective when used con- herpetic lesions, as can be found in eczema herpetinuously for up to 1 year, although it does not al- ticum, should be isolated. Abstinence or the use of condoms is recommended to prevent genital ter the natural history of di~ease.~" Disseminated or CNS HSV infections warrant spread between sexual partners who have active leparenteral therapy. In a study of patients with bi- sions, a history of recurrent genital infections, or opsy-proved HSV encephalitis, acyclovir at a dose both. For the prevention of neonatal disease, cesarof 10 mglkg intravenously three times daily was ean section is currently recommended if clinically found to reduce mortality by 54% and to be supe- apparent cervical infection is detected at parturition before membrane rupture.63Once membrane rior in efficacy to ~ i d a r a b i n e . ~ ~ In immunocompromised hosts, acyclovir is rupture has occurred, however, rapid delivery by successful for treatment and suppression of recur- any route is indicated to lessen exposure of the inrent HSV lesions. Intravenous therapy or oral reg- fant to HSV. Vaginal delivery appears to be safe imens of 400 mg five times daily have been shown when there is a negative clinical examination at the to prevent recurrences, reduce viral shedding, de- time of parturition, but close monitoring and early crease local symptoms such as pain, and accelerate intervention if illness develops during the first few weeks of life is advised for infants born to seropostime to healing during acute episode^.^' A concern about chronic acyclovir therapy is itive mothers. the possible development of resistant HSV mutants. Although the selective pressure of acyclovir therapy may result in a mutant having altered subREFERENCES strate specificity of thymidine kinase (TK), lacking TK, or coding for DNA polymerase with altered 1 . McNair Scott TF. Historical aspects of herpes simplex infection. Int J Dern~atol1986;25:63-9 substrate specificity, resistance is usually associated 2. Beswick TSL. The origin and the use of the word herpes. with loss of viral thymidine kinase a ~ t i v i t y . ~ ~ , ~ ~Med Hist 1962;6:214-32 Pathogenic acyclovir-resistant isolates are becom3. Kaplan AS. Herpes simplex and pseudorabies viruses. Berlin: Springer, 1969 ing increasingly associated with progressive dis4. Levaditi C, Harvier P. Le virus de l'encephalite letharease, whereas most of these were not associated gique (encephalite epidemique) CR Soc Biol 1920;83: with significant disease in the past. Although vi354-5
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5. Rawls WE, Campione-Piccardo J. Epidemiology of herpes simplex virus type 1 and type 2 infections. In Nahmias AJ, Dowdle WR, Schinazi RF, eds: T h e human herpesviruses: an interdisciplinary approach. New York: Elsevier Science Publishing, 198 1: 137 6. Bader C. T h e natural history of recurrent facial-oral infection with herpes simplex virus. J Infect Dis 1978; 138:897-905 7. Stevens, JG Hurrran herpesviruses: a consideration of the latcnt state. Microbial Rev 1989;53:318-32 8. Lycke E, Kristensson K, Svennerholm B, et al. Uptake and transport of herpes sinlplex virus in neurites of rat dorsal root ganglia cells in culture. J Gen Virol 1984;65:55-64 9. Wagner EK, Devi-Rao G , Feldman KT, et al. Physical characterization of the hcrpcs simplex virus latency-associated transcript in neurons. J Virol 1988;62:ll94202 10. Hill JM, Sedarati F,Javiar KT, et al. Herpes simplex virus latent phase transcription facilitates in vivo reactivation. Virology 1990; 174: 117-25 11. Stevens J G . Latent characteristics of selected herpesviruses. Adv Cancer Res 1978;26:227-56 12. Clements GB, Subak-Sharpc J . Herpes simplex virus type 2 establishes latency in the rnouse footpad. J Gen Virol 1988;69:375-83 IS. Cook SD, Batia SK, Brown SM. Recovery of herpes simplex virus from the corneas of experimentally infected rabbits. J Gen Virol lY87;68:2013-7 14. Abgharis SZ, Stulting RD. Recovery of herpes simplex virus from ocular tissues of latently infected inbred mice. Invcst Ophthalmol Visual Sci 1988;29:239-43 15 Young SK, Rowe NH, Buchanan RA. A clinical study for the control of facial mucocutaneous herpes virus infections. 1. Characteristics of natural history in a professional school population. Oral Surg 1976;41:498-507 16 Lafferty WE, Coombs RW, Bcnedetti J, et al. Recurrences after oral and genital herpes infection and viral type. N Engl J Med 1987;316: 1444-9 17. Nagington J, Rook A, Highet A. Virus a n d related infections. In Rook A, Wilkir~sorlDS, Ebling FJG, et al, eds: Textbook of dermatology. Blackwell Scientific Publications, 1988:685-90 18 Gaffey MJ, Ben-Ezra JM, Weiss LM. Herpes simplex lymphadenitis. Am J Clin Pathol 1991;95:709-14 19. Buchman T G , Roizman B, a n d Nah~niasAJ. Demonstration of exogenous genital reinfection with hcrpes simplex virus type 2 by restriction endonuclease fingerprinting of viral DNA. J Infect Dis 1979;140:295-304 20. Corcy I., Adams H , Brown Z, et al. Genital herpes simplex virus infections: clinical manifestations, course and complications. Ann Intern Med 1983;98:95872 21. Jeansson SS, Molin L. O n the occurrence of genital herpes simplex virus infection: clinical and virological findings and relation to gonorrhea. Acta Derrr~Venereol (Stockh) 1974;54:79 22. Crun~packerCS. Herpes simplex. I n Fitzpatr-ick 'I'B, Eisen AZ, Wolff K , et al, eds: Dermatology in general medicine. New York: McGraw-Hill, 1987:2302-14 23. Goodell SE, Quinn T C , Mkrttichian et al. Herpes simplex virus proctitis in homosexual men. Clinical, sigmoidoscopic, and histopathological fcaturcs. N Engl J Med 1983;308:868-71 24. Belongia EA, Goodman, JL, Holland EJ, et al. An outbreak of herpes gladiatorum at a high-school carnp. N Engl J Med l991;325:906-10 25. Kaufman HE, Brown DC, Ellison ED. Hcrpes virus in the lacrimal gland, conjunctiva, and cornea of man: a chronic infection. Am J Ophthalmol 1968;65:32-5 26. Whitley q.Antiviral treatment of a serious herpes sinrplex infection: encephalitis. J Am Acad Dermatol 1988; 18:209-11 27. Straus SE. Introduction to h e r ~ e s v i r i d a eIn . Marldell GL. Dougas RG Jr, Bennett JE, eds: Principles and practice
28. 29. 30. 31. 32.
33. 34. 35. 36.
37. 38. 39.
40.
41. 42. 43.
44. 45. 46.
c,
320
47. 48.
49. 50.
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of infectious diseases, 3rd ed. New York: Churchill I.ivingstone, 1990: 1139-44 Adanrs RD, Victor M. Principles of neurology, 4th ed. New York: McGraw-Hill, 1989, p p 598-616 David I>E,Johnson RT. An explanation for the localization of herpes simplex encephalitis. Ann Neurol 1979; 5:2-5 Esiri MM. Herpes simplex encephalitis: an immunohistological study of the distribution of viral antigen within the brain. J Neurol Sci 1982;54:209-26 Schroth G, Gawchn J , T h r o n A, et al. Early diagnosis of herpes simplex encephalitis by MRI. Neurology 1987; 37: 179-83 Lakeman FD, Koga J , Whitley RJ. Detection of antigen to herpes sinrplex virus in cerebrospinal fluid from patients with herpes simplex encephalitis. J Infect Dis 1987; 155: 1172 Whitley KJ, Soong SJ, Linneman C Jr, et al: Herpes simplex encephalitis. Clinical assessment. JAMA 1982; 247:s 17-320 Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 1986; 3 14: 144-9 Dover JS, Arndt KA. Dermatology, Contempo 1991. JAMA 1991;265:3111-3 Hall WW, Farmer PM, Takahashi H , et al. Pathological features of virus infections of the central nervous system (CNS) in the acquired immunodeficiency syndrome (AIDS). Acta Pathol J p n 1991;4 1: 172-81 Orton PW, Huff JC, Tonncsen MG, ct al. Detection of a herpes viral antigen in skin lesions of erythema multiforme. Ann Intern Med 1984;101:48 Shelley WB. Herpes simplex virus as a cause of erythema multiforme. JAMA 1967;201: 153-6 Darragh T M , Egbert BM, Berger T G , et al. Identification of herpes simplex virus DNA in lesions of erythema multiforme by the polymerase chain reaction. J Am Acad Dermatol 1991;24:23-6 Miura S, Smith CC, Burnett JW et al. Detection of viral DNA within skin of healed recurrent herpes simplex infection and erythema multiforme lesions. J Invest Dermatol 1992;98:68-72 Weston WL, Brice SL, Jester JD, et al. Herpes simplex virus in childhood erythema multiforme. Pediatrics 1992;89:32-4 Solomon AR. New diagnostic tests for herpes simplex and varicella zoster infections. J Am Acad Ilermatol 1988;18:218-21 Meyer MP, Anrortegui HJ. Rapid detection of herpes simplex virus using a combination of human fibroblast cell culture and peroxidase-antiperoxidase staining. Am J Clin Pathol 1984;81:43-7 Coleman RM, Nahmias A.1, Williams SC, e t al. IgG subclass antibodies to herpes simplex virus. J Infect Dis 1985; 15 1:929-35 Nahrnias AJ, Dowdle WR, Josey WE, et al. Newborn infection with herpesvirus hominis types 1 and 2. J Pediatr 1970; 17: 185 Conc RW, Hobson AC, Palmer J , et al. Extended duration of herpes simplex virus DNA in genital lesions detected by the polymerase chain reaction. J Infect Dis 1991;164:757-60 Pavan-Langston D. Herpetic diseases. I n Smolin G, 'l'hoft R, eds: T h e cornea-scientific foundations and clinical practice. Boston: Little, Brown, 1983: 178 Fiddian AP, Kinghorn GR, Goldrneier D, et al. Topical acyclovir in the treatment of genital herpes: a comparison with systemic therapy. J Antimicrob Chemother 1983; 12(Suppl B):67-77 Gibson JR, Klaber MR, Harvey SG, et al. Prophylaxis against herpes labialis with acyclovir cream-a placebocontrolled study. Dermatologica 1986;172: 104-7 Kinghorn GR, Turner ER, Barton IG, et al. Efficacy of topical acyclovir cream in first and recurrent episodes of genital herpes. Antiviral Res 1983;3:291-301
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SEMINARS IN NEUROLOGY
ET AL
51. Whitley RJ, Levin M, Barton N, et al. lnfcctions caused by herpes simplex virus in the i~nmunocompromised host: natural history a n d topical acyclovir therapy. J Infect Dis 1984; 150:329-9 52. Shaw M, King M, Best JM, et al. Failure of acyclovir cream in treatment of recurrent herpes labialis. Br Med J (Clin Res Ed) 1985;291:7-9 53. Spruance SL, Crumpacker CS, Schnipper LE, et al. Early, patient-initiated treatment of herpes lahialis with topical 1 0 1 acyclovir. Antimicrob Agents Chemother 1984; 25:553-5 54. Clive D, Corey L, Keichman RC, et al. A double-blind, placebo-controlled cytogenetic study of oral acyclovir in patients with recurrent genital herpes. J Infect Dis 1991;4:753-7 55. Brysorl YJ, Dillon M, Lovett M , et al. Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. A randomized double-blind controlled trial in normal subjects. N Engl J Med 1983;308:91621 56. Gold L), Corey I,. Acyclovir prophylaxis for herpes simplex virus infection. Antimicrob Agents Chenlother 1987;31:361-7 57. Conant MA. Prophylactic and suppressive treatment with acyclovir and the management of herpes in patients
58.
59.
60. 61.
62.
63.
with acquired immunodeficiency syndrome. J Am Acad Dermatol 1988; 18: 186-8 Crumpacker CS, Chartrand P, Subak-Sharpe J H , et al. Resistance of herpes simplex virus to acycloguanosine-genetic and physical analysis. Virology 1980;105: 171-84 Erlich KS, Mills J , Chatis P, et al. Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 1980;320:293-6 Mirsch MS, Schooley RT. Resistance to antiviral drugs: the end of innocence. N Engl J Med 1989;320:313-4 Saf'rin S, Crumpacker C, Chatis P, et al. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant rrlucocutaneous herpes simplex in the acquired immunodeficiency syndrome. T h e AIDS Clinical Trials Group. N Engl J Med 1991;325:551-5 Kooney JF, Wohlenherg C, Cremer KJ, et al. Immunization with a vaccinia virus recombinant expressing herpes simplex virus type 1 glycoprotein D: long-term protection and effect of revaccination. J Virol 1988;62: 1530-4 Brown ZA, Vontver LA, Aenedetti J , et al. Effects o n infants of first episode of genital herpes during pregnancy. N Engl J Med 1987;s 17: 1246-51
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