Herpes simplex virus infection

HerpesSimplex Virus I fection ANDrt

J. NAHMIAS

M. OUSAMA TOMEH

HERPES SIMPLEX VIRUSES (HSVs) are among the most common infectious agents affecting man. These viruses can involve almost every organ in the body, and since they possess the capacity to persist, infected individuals can experience recurrent infections throughout their lives. Although many infections are asymptomatic, there is a wide spectrum of clinical disease, varying from mild to severe and fatal. The severity of the clinical effects of HSV depends on the organ involved--e.g., central nervous system (CNS)--and on the age and immune status of.the infected person (Table 1). HSV infections are of particular import to physicians caring for newborns, children and adolescents. Because of the high prevalence of nonvenereal (HSV-1) infections in children, such cases will be encountered frequently in practice. In adolescents with early sexual experience, the ven6real (HSV-2) infections also will be encountered quite commonly. With both nonvenereal and venereal herpetic infections there are patients who have a high frequency of recurrences, particularly those in whom the eyes or genitalia are affected. Although HSV infections are relatively uncommon in newborns and compromised individuals, and the CNS is not often involved, the usual severity o[ the infection when it does occur in such patients and their frequent long-term ill effects emphasize the need to consider possible preventive and therapeutic approaches. There are various such approaches currently under study, making an accurate diagnosis of HSV infection mandatory. We will present here current information regarding HSV infections as they affect the newborn, child and adolescent. Emphasis is given to the clinical, diagnostic, preventive and therapeutic aspects of interest to physicians caring for these age groups. Contributions to

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these aspects of current virologic, epidemiologic, pathogenetic and immunologic information are also stressed. ETIOLOGY Herpes simplex viruses belong to a large group of DNA viruses that comprises, besides the other human viruses (cytomegalovirus, varicella-zoster and Epstein-Barr viruses), over 50 herpesviruses in more than 30 other species. 1 An overview of these various viruses reveals many striking similarities in the clinicopathologic manifestations of the animal viruses in their own hosts as compared to the human viruses, z For instance, the disease produced by the canine herpesvirus in newborn pups cannot be differentiated clinically or histopathologically from the human HSV infection in newborns. The ability of several of the animal herpesviruses to cause abortions, stillbirths and cancer lends support to the possible association of the human herpesviruses with these ill effects in man. Herpesviruses consist of several structural elements arranged in concentric layers. 3 The innermost is a double-stranded DNA core measuring about 100 nm in diameter that is surrounded by an icosahedral protein capsid made up of 162 capsomeres or subunits. The capsid is surrounded in turn by two more layers, the tegument and the envelope, conferring to the complete virus particle (virion) a diameter of 150-200 nm. The DNA-containing nonenveloped particle is formed in the nucleus (Fig. 1), whereas the viral envelope is acquired from cell membranes, primarily nuclear membranes. The basic information on the structure and composition of HSVs and their effect on cells has provided us with improved understanding of pathogenesis and of host-immune responses, as well as offering newer approaches to diagnosis, prevention and therapy. Such information hffs been particularly relevant in indicating that all cells FIG. 1.--Electron microscopic appearance of herpes simplex virus in the nonenveloped form in the cell nucleus.

infected by herpesviruses do not invariably die, so that the survival of virus-containing cells may explain persistent infection and the oncogenic potential of herpesviruses. Basic knowledge of the nucleic acids of HSV has been exploited to explore a variety of drugs that inhibit DNA synthesis, in current use or under clinical trials, for the treatment of ocular herpes or severe HSV infections (see later section on therapy). Furthermore, it now has become possible to investigate by nucleic acid hybridization methods the presence of the HSV genome in cancer cells4 or in cells suspected of harboring persistent virus. The molecular size of the HSV D N A of approximately 100 million daltons indicates that the viral genome could code for about 60 proteins. One of these proteins, for instance, is a specific viralinduced thymidine kinase; thus, the finding of this enzyme in certain clinical specimens (e.g., cerebrospinal fluid [CSF]) might offer a diagnostic test for suspected HSV encephalitis. Furthermore, the presence of so many viral proteins (at least 12 in the viral envelope and 15 in the viral capsid) suggests that a complexity of immune responses to HSV antigens would be expected in man. Such information also provides the necessary infrastructure for the development of protein subunit vaccines containing no viral DNA for possible prevention of HS'V infections. The fact that the cell membranes of

TABLE 2.--DIFFERENCESBETWEENHERPESSIMPLEXVIRUSES(HSV) TYPES I AND 2* C~tA~C'rERxS'rXc HSV-I HSV-2 I. Clinical Infects primarily Infects primarily nongeniral sites genital sites II. Epidemiologic Transmission Transmission primarily primarily via via genital route nongenital route (venereal or motherto-newborn) IlL Biochemical: DNA guanine + 67 69 cytosine (moles %) Homology of viral Approx. 50% DNAs IV. Biologic: A. Chick embryo Small pocks Large pocks (chorioallantoic membrane) B. Mice--genital or Less neurotropie More neurotropic intramuscular inoculation C. Tissue culture Differences between 2 virus types in their ability cells to propagate, their cytopathic characteristics or plaque size in certain cell cultures *Modifiedfrom Nahmias& Roizman3.

HSV-infected cells contain viral-specific antigenss has suggested also that host-immune factors might operate directly on viral-infected cells rather than on the extracellular virus alone. Indeed, the fusion of membranes of HSV-infected cells to form multinucleated giant cells has been exploited for close to a century as a diagnostic test for herpesvirus infections (HSV and varicella-zoster virus). Of particular clinical and epidemiologic import has been the discovery of at least two types of HSVs (HSV-1 and HSV-2) that can be differentiated serologically, possess about 50% of their genetic material in common and demonsirate a variety of biologic differences (Table 2). The observation that HSV-2 is transmitted primarily venereally or genitally from mother to newborn and that HSV-1 most commonly is transmitted nonvenereally6 has provided important clues regarding the clinicopathologic manifestations and other epidemiologic features of HSV infections. EPIDEMIOLOGY Human beings with either primary or recurrent infections represent the only natural source of HSVs. No animal source has been recognized to date, but it should be kept in mind that individuals exposed to macaque monkeys may acquire a Simian-B herpesvirus infection of the CNS, similar clinically to HSV encephalitis.7 Individuals with clinical or subclinical HSV infections can transmit the virus directly to others by close personal contact--kissing, wrestling or sexual intercourse.. (genital, anal or oral). Spread of virus by saliva is exemplified by the incidence of herpetic paronychia in medical or dental personnel who handle the infected oral cavity of patients or contaminated catheters, s Such aomode of viral transmission thus makes HSV a potential nosocomial infection and may account for the occasional outbreaks of HSV infection in families, orphanages and other closed populations.9. lO Airborne (air droplets or skin squames) transmission also can be inferred from some clinical and epidemiologic observations. Genital HSV-2 and, less commonly, genital HSV-1 infection in pregnant women have been found to be the major source of virus to the newborn. The genital infection in the mother may have been acquired from sexual contact prior to pregnancy. However, the acquisition of the virus by a woman late in pregnancy from a man with penile herpes, with subsequent genital transmission to the infant at delivery, has been well documented. Most infants will acquire the herpesvirus at about the time of delivery on passage through the infected birth canal or if membranes have been ruptured for over 4 hours, xl Transplacental transmission, well-documented with HSV experimental infection of animals,z has been suggested by a few cases of infants with chronic CNS or ocular manifestations detected 7

soon after birth, lz Although HSV-2 has been detected recently in peripheral blood leukocytes of nonpregnant women, lz the transmission of virus from blood leukocytes of pregnant women to the fetus remains to be demonstrated. The transmission of HSV to the newborn postnatally from other infected newborns, infected persofinel or family contacts has not been well substantiated despite the fact that at least 1% of nursery personnel show evidence of clinical or subclinical HSV infection. HSV neonatal infections have been estimated to range from a minimum of 1 in 30,000 to as many as 1 in 3,500 deliveries. 1~ These infections are more common in premature than in full-term infants. Neonatal herpes also is noted most often in infants born to primigravidous mothers. Several sero-epidemiologic studies have demonstrated that the prevalence of HSV infection is closely related to socioeconomic conditions and to sexual mores. Thus, about 50% of children of lower socioeconomic groups have HSV-1 antibodies by the age of 5 years and at least two thirds of adolescents will have such antibodies in their serum. ~5 On the other hand, in higher socioeconomic groups, the frequency of HSV-1 antibodies is approximately half that found in lower socioeconomic populations. HSV-2 antibodies can be detected first at about the age of 14 years, and approximately 15% of adolescents who begin sexual activity at an early age will possess such antibodies in their serum. The antibodies transplacentally transmitted to the newborn, which usually disappear within 6 months, will thus depend on these epidemiologic variables as reflected in the mother. These sero-epidemiologic studies correlate well with the relative frequency of the various types of HSV-1 and HSV-2 infection according to age (Table 1). The incubation period for neonates with herpetic infection or for olde~ individuals with either primary HSV-1 or HSV-2 infections ranges from 2 - 2 0 days, with an average of 6 days. However, the incubation period for encephalitis, which is more difficult to assess, is probably longer. Seasonal differences in the different forms of HSV infection have been noted. Thus, infections of the skin are more common during warm months and those of the eyes and lips during cold months. No seasonal differences have been recorded for herpetic gingivostomatitis.

PATHOGENESIS As indicated earlier, and particularly cogent to discussion in this and subsequent sections, is the need to distinguish primary from recurrent HSV infections. This distinction is difficult to make on clinical grounds since both primary and recurrent infections can be clinically inapparent. The distinction has been rendered even more

difficult by the discovery of the two HSV types. In the final analysis, only laboratory methods, still incompletely developed, can differen- " tiate among (1) a primary HSV-1 or HSV-2 in individuals with no prior history of either HSV, (2) a recurrent infection with HSV-1 only, (3) a recurrent infection with HSV-2 only, (4) initial or recurrent HSV-2 infection in an individual with prior HSV-1 infection and (5) an initial or recurrent HSV-1 infection in an individual with prior HSV-2 infection. A similar problem arises in the need to differentiate the newboEn with no transplacental antibodies from the newborn with transplacental antibodies to (1) HSV-1 only, (2) HSV-2 only and (3) both HSV-1 and HSV-2. PRIMARY INFECTIONS Primary HSV-1 or HSV-2 infections in children and adolescents are often clinically inapparent, partly because most of the primary sites of infection do not occur on external areas and are not readily visible, at least to the patient, e.g., the mouth or cervix. Primary HSV-1 or HSV-2 infections, when clinically manifest, tend to be more severe (fever, constitutional signs, more extensive lesions and local adenopathy) than those in individuals with prior antibodies to either or both HSV-1 or HSV-2. Primary HSV infections are particularly severe in certain types of patients including severely malnourished children and those with associated measles; patients with severe burns or chronic skin disorders such as eczema; individuals receiving immunosuppressive therapy; those with certain cancers, particularly lymphomas; and children with certain forms of immune deficiency such as the Wiskott-Aldrich syndrome,a The pathogenesis of primary HSV infection has been defined most thoroughly in severely malnourished children. 16 In such cases, as a result of the initial replication of virus at the portal of entry, there is a primary viremia resulting in involvement of certain susceptible organ sites. A secondary viremia then ensues with further dissemination to visceral organs and more extensive damage. Thus, the clinical spectrum may differ, depending on which organ sites are involved and the amount of cellular damage in these organs. In the noncompromised host, recovery of virus from the blood or peripheral leukocytes has been infrequent. It is therefore not clear at present whether virus affects areas other than the local site and draining lymph nodes. However, the recovery of HSV-2 from peripheral blood leukocytes and from the CSF of patients with meningitis suggests that blood spread occurs more commonly than appreciated to date. Several human and experimental animal observations suggest that HSV may spread neurogenically when encephalitis occurs in otherwise normal individuals.13 Viral spread from superficial

areas of skin to deeper layers may be prevented by the meshwork of connective tissue fibers, because of size factors and by the possible effects of the negative electric charge on the virus of acid mucopolysaccharides in connective tissue. The pathogenesis of the deeper ocular manifestations associated with HSV has been attributed either to direct viral involvement or to a hypersensitivity reaction. The pathogenesis of the disseminated forms of neonatal herpes occurring in infants without transplacental antibodies appears to be similar to that of primary herpes in the severely malnourished child, although the brain is involved much more often in the newborn. Direct neurogenie spread to the brain, and possibly to the retina, appears to occur also in newborns. RECURRENT INFECTIONS The mechanisms of persistence of HSVs in individuals with prior experience of homologous virus, although still not completely defined, are beginning to be understood. Thus, studies in experimental animals and in man have demonstrated that HSV remains latent in sensory ganglia. 17, 18 Still unanswered, however, is the question of whether the virus persists in the ganglia in a complete or incom= plete form, and what may be the virus-cell interactions that permit fever, menstruation and other triggers to allow the infectious virus to manifest itself. Similarly, it is not clear whether nerve ceils or supporting ceils are involved, how and in what form the virus travels peripherally to the external sites and why the virus does not travel internally in the brain. There is little doubt that, on occasion, autoinfection from one site to another in the same individual can occur. Exogenous rein= fectjon with the heterologous HSV type is also well documented, but information is at present only suggestive regarding exogenous reinfection with the homologous virus type. The possibility of a chronic infection with low-grade virus multiplication also cannot be ruled out definitely at present. As noted earlier, recurrent infections tend to be less severe than primary infections. Nevertheless, in compromised individuals recurrent infections can be severe, tending to be more extensive and chronic, infrequently being associated with dissemination to the lungs and other interual organs. Although it was assumed originally that herpetic encephalitis would occur only in association with a primary infection, several reports have now documented this diagnosis in individuals with prior HSV infection. Similarly, although newborns with transplacental HSV antibodies originally were be= lieved to be protected from acquiring HSV infections, several cases of neonatal herpetic disease, including fatalities, have been recorded in such infants. 10

IMMUNOLOGY Because recurrent HSV infections occur in individuals with preexisting high titers of neutralizing HSV antibodies, a rather negative attitude has been assumed until recently regarding the role of immune factors in protecting the host from recurrent HSV infections and the possibilities of developing vaccines that might boost immune responses. This attitude is changing as it is becoming appreciated that (1) immune factors other than antibodies must be operative to explain the greater severity of HSV infection in individuals who are immunologically compromised, particularly those with T-cell deficiencies; (2) there is a large variability in responses to HSV infection in newborns and in the frequency of recurrences in older individuals; (3) newer assays to test for humoral and cellular immunity in vitro and in vivo are demonstrating the complexity of these responses in both~man and experimentally infected animals and have suggested that both nonspecific and specific factors may operate in the host's resistance to HSV infection.19 In individuals with a primary HSV infection, humoral antibodies usually can be detected within 1-3 weeks with use-of a variety of neutralization, complement-fixation, complement-mediated cytolysis or passive hemagglutination tests. With special serologic methods it is also possible to demonstrate an early rise of IgM antibodies to HSV, followed by IgA and IgG antibodies. In the newborn, IgM antibodies to HSV can be detected within 1--4 weeks after birth and are present for 6 or more months; such an assay is particularly helpful in diagnosing neonatal HSV infection. In addition to the humoral responses, various assays of cellular immunity in vitro have demonstrated a cell-mediated response within 1-2 weeks after onset of infection in both man and experimental animals. Such individuals also usually will demonstrate a delayed hypersensitivity skin test response to HSV antigens. It is as yet unclear as to which of these humoral or cellular factors operate in curtailing the virus in a primary infection or in a newborn without transplacental antibodies. In experimental animals it has been demonstrated that a depression of either T-lymphocytes or of macrophages leads to increased mortality. It has been noted that HSV multiplies in phytohemagglutinin-stimulated lymphocytes and that the virus also multiplies better in the macrophages of newborn mice than in those of adult mice. Since any virus circulating in the blood would be affected greatly bY the ability of reticuloendothelial cells in the liver or other organs to inactivate the virus or allow its multiplication and further spread, it is likely that macrophages play a central role in neonatal HSV infection and probably also in primary HSV infections of older individuals. It also may be relevant that with canine herpesvirus infection of the newborn, hyper11

thermia has been capable of preventing fatal viral dissemination in newborn pups, which have vacillating low body temperatilres until they reach the age of 2-3 weeks. In this regard, it is of some interest that very few human newborns with HSV infection demonstrate a sustained febrile response. In recurrent HSV infections all individuals appear to possess neutralizing antibodies in varying titers, and usually these do not rise after a recurrence. It appears, however, that such clinically apparent or inapparent recurrences might benecessary to maintain the neutralizing titer to constant levels in the serum. There are also individuals with frequent herpetic recurrences who possess persistent levels of IgG, IgA and IgM antibodies to HSV in their serum and who may demonstrate a significant boost in titers to antibodies in the various classes after a recurrence. Individuals with recurrences also demonstrate positive responses with a variety of in vitro cell-mediated assays. It is not clear at present whether depression in certain lymphokinins, e.g., macrophage inhibitory factor or interferon produced by the lymphocytes, is responsible for the onset of HSV recurrences. In vitro studies ~9 suggest that both nonspecific and specific mechanisms may explain how immune responses stop cell-to-cell spread of HSV, since neutralizing antibodies cannot prevent this type of cellular spread of virus. In addition, in vitro observations indicate that neutralizing antibodies are unable to inactivate large amounts of extracellular virus. A clearer understanding of the host resistance factor in HSV infection is needed for various pressing reasons: (1) the possible use of specific HSV vaccines for the prevention of primary infections or for amelioration of the problem of recurrent infections; (2) the possible use of specific antibodies or of transfer factors from immune lymphocytes for the prevention or treatment of neonatal herpes; (3) the possible use of nonspecifie factors such as BCG, macrophage activators, interferon or interferon stimulants or of hyperthermia in the prevention or treatment of herpetic infections.

CLINICAL MANIFESTATIONS The clinical spectrum of HSV-I and HSV-2 infection varies in several important respects according to whether the host is a newborn or a normal or compromised child or adolescent. Thus, whereas asymptomatic HSV infections in the newborn appear to be infrequent, they are common in older individuals. Although neonatal herpes is very often serious, with a high fatality rate or with sequelae in survivors, the large majority of HSV infections, other than those of the brain, in normal children and adolescents are of mild to moderate severity. Only in the compromised older individual does 12

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the severity of the infection occasionally approach that found in the newborn. A third point of difference is that the majority of neonatal infections are caused by HSV-2, whereas, except for venereally transmitted infections in children and adolescents, all other infections are caused primarily by HSV-1. Table 3 presents results of the serotyping of close to 1,000 strains isolated from individuals of varying ages. This table shows the approximate percentage of strains that were isolated from patients in the pediatric age groups. The sites of infection are listed also according to age and severity of infection. Thus, HSV-1 and HSV-2 infections in normal and compromised children or adolescents will be discussed according to site of infection. Since HSV infects so many body sites, the differential diagnosis is included in the discussion of the affected sites. The special problem of herpetic infection in the fetus and newborn will end this clinical section. CHILD AND ADOLESCENT 1. MOUTH AND RESPIRATORY AND GASTROINTESTINALTRACTS.-The oral cavity is by far the most common site of HSV infection in children, the peak incidence occurring in children 1-5 years of age. Although the majority of such infections are stated to be subclinical, careful clinical observations may detect a few oral ulcers. The severity of the clinically apparent infection varies, as do the sites of the oral lesions. Thus, one or more of the following sites may be affected: buccal mucosa, tongue, palate and fauces. The gums also may be inflamed and bleed readily. Cervical adenopathy is often present and the temperature varies, .ranging up to 106 ~ F, but more usually is about 102 ~ F. Excessive salivation may result from pain on swallowing, and feeding and even fluid intake may be painful. Hospitalization for fluid and electrolyte therapy may be indicated in severe cases. The oral lesions and clinical symptoms usually resolve within 10 days. Occasionally, herpetic infection of other sites such as the face or eyes may accompany the oral lesions, and finger suckers or cuticle biters in particular may develop concomitant infections of the fingers (Fig. 2). Encephalitis is a very infrequently associated complication. In normal children no significant sequelae occur except in those destined to have recurrent infections, which are infrequent as a cause of lesions in the mouth itself; however, virus is cultured not infrequently from the oral cavity of individuals with no apparent clinical lesions. In the compromised host (and in the newborn), oral infections may extend to involve the esophagus or lungs and may disseminate to the liver and other visceral organs. Oral infections are caused almost always by HSV-1 (Table 3); however, in the case of oral-genital sexual practices, HSV-2 some14

FI~. 2.--Gingivostomatitis in a thumb-sucking child, with ulcers on tongue and vesicles on thumb. (From Nahmias, A. J.: Infections Caused by Herpes Simplex Hominis, in Hoebrich, B. D. [ed.]: Infectious Diseases lNew York: Harper Row, Publishers, 1972].)

times can affect the oral cavity, causing asymptomatic or clinically apparent lesions. Although oral herpetic infections usually are readily diagnosed clinically, if the lesions are present only on the fauces, they may be confused with herpangina and, less commonly, with group A streptococcal infection, infectious mononucleosis and diphtheria. When the herpetic oral lesions are more widespread, they may be misdiagnosed as hand-foot-and-mouth syndrome (Coxsackie A viruses), Vincent's angina, moniliasis and the stomatitis associated with trauma or allergies (Stevens-Johnson syndrome). In some patients, particularly those receiving immunosuppressive therapy, oral herpes very often is confused with the stomatitis associated with drugs. One of the most common misdiagnoses we have encountered is in cases with recurrent oral ulcers that were presumed to be of herpetic origin. The large majority of such patients, however, have "canker sores" or "aphthous stomatitis" that are nonherpetic in etiology. 2. LIPs.--The lips are the most common site of herpetic recurrences due to HSV-1 (cold sores, fever blisters) and infrequently are the sites of primary infection. It is of some interest that, although most HSV oral infections occur in early childhood, recurrent labial herpes is not as frequent in children as in adults and that the frequency of recurrences varies greatly from patient to patient. It is 15

not uncommon for meningitis and other febrile illnesses to trigger the recurrences, which tend to extend beyond the lips to the face and neck. The labial recurrences usually involve the same or very close sites (Fig. 3), but on occasion involve the contralateral side of the lips. Labial herpes begins with a burning sensation or itching for 1-2 days prior to appearance of lesions. Despite the prodromal symptoms, some individuals occasionally may not develop any herpetic lesion or the lesion may be "aborted," i.e., not develop into a typical vesicle. In the compromised host the lips and adjacent facial areas may be involvecl for prolonged periods. Labial herpes is unlikely to be misdiagnosed, although occasionally the lip lesions may be mistaken for herpes zoster, aberrant vaccinia or even staphylococcal pustules. 3. SxIN.--Primary and recurrent HSV infections can cause skin vesicles and ulcers on almost any part of the body, including face, hands and feet. Obvious trauma to the skin is found occasionally, e.g., a laboratory-acquired infection in a finger with an open cut. Primary skin infections may be accompanied by deep burning pain, edema, lymphangitis, lymphadenopathy and fever. The vesicles in primary or recurrent infections may appear singly or in clusters, tend to become qgustular and crust over and heal within 1 week, usually leaving no scars. The skin lesions occasionally can assume a zosteriform distribution and may be severe and of prolonged duration in individuals compromised by certain cancers and/or immunosuppressive therapy. Four new forms of skin involvement associated with HSV infection have been described in recent years. The first, herpetic paronychia of the fingers, occurring in medical or dental personnel, s has been alluded to earlier. Such finger lesions are often very painful and are confused easily with bacterial infections; however, herpeFIG. 3.--Labial herpes involving right side of face also.

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FIo. 4.--Herpes gladiatorumin a college wrestler. tic paronychia does not require surgical drainage, which actually may prolong the healing time to more than the usual 2-3 weeks. A second type of newly described HSV skin infection is herpes gladiatorum, i.e., HSV infection occurring in wrestlers, most often reported in college wrestlers (Fig. 4). Such infections develop in skin areas abrased during the course of a wrestling match after contact with an individual with an inapparent or clinically apparent HSV infection. The third type of HSV infection, first noted only 4 years ago, occurs in patients with severe bums. In such individuals the disease may be particularly severe since it may be associated with herpetic pneumonia and disseminated infection. The fourth type of skin involvement, associated with either primary or recurrent HSV infection, is erythema multiforme. This entity has been noted with gingivostomatitis, genital herpetic infection and labial herpes. The lesions of erythema multiforme may recur with every recrudescence 17

Fro. 5.---Severe generalized skin HSV infection in child with Wiskott-Aldrich syndrome. (From Nahmias, A. J.: Infections Caused by Herpes Simplex Hominis, in Hoebrich, B. D. [ed.]: In]ectious Diseases [New York: Harper & Row, Publishers, 1972].) of the herpetic infection. They also can be induced by inactivated herpesvirus preparations, which suggests that they are caused by a hypersensitivity reaction to viral antigens. Another severe form of skin HSV infection, recognized 3 decades ago, is eczema herpeticum, which Occurs in individuals with preexisting chronic skin conditions. This entity, a form of Kaposi's varicelliform eruption, is encountered particularly in children in assodiation with atopic eczema and occasionally diaper rash. It also can be observed in children with the Wiskott-Aldrich syndrome (Fig. 5). Eczema herpeticum is usually a result of a primary HSV infection, but it may occur as a recurrent form in either eczematous skin areas or in intact skin after the eczema has cleared. There is usually prodromal fever followed by the appearance of crops of vesicles; the vesicles may then umbilicate and become pustular, confluent and hemorrhagic. In severe cases large areas of skin are affected, leading to marked losses in proteins and fluids. The virus usually remains localized to the skin, but on occasion may disseminate to the visceral organs or to the brain. Mortality (about 5 % ) is due either to such viral dissemination or to bacterial superinfection. The HSV type isolated from various parts of the skin (Table 3) is dependent on mode of acquisition of the virus. In general, skin lesions above the waist, and those found in children with eczema 18

herpeticum, are caused by HSV-1. Viruses isolated from lesions below the waist have been most commonly HSV-2, and those recovered from lesions on the hands or arms have been about equally divided between HSV-1 and HSV-2. HSV infections of the skin are sometimes difficult to diagnose, particularly when the physician does not see the patient when he has fresh vesicles, but only when the lesions have crusted or are pustular or when the affected skin area is denuded. In such cases the herpetic infection may be confused with bacterial or fungal infections or with an allergic dermatitis or skin insect bites. Accuracy of diagnosis of recurrent herpes on the face appears to be related directly to how far the lesions are from the lips, and herpetic paronychia often is confused with bacterial infection of the finger. When HSV skin lesions assume a zosteriform distribution, they are readily mistaken for herpes zoster, although recurrent herpes zoster always should raise the question of HSV. Eczema herpeticum is most difficult to differentiate from eczema vaccinatum or eczema coxsackium (associated with hand-foot-and-mouth syndrome) and may be misinterpreted as increased severity of the underlying skin disorder or as a bacterial or fungal infection. 4. EYE.---Herpetic involvement of the eye is of particular medical concern because of the occasional loss of vision that might ensue. Primary infections may be accompanied by conjunctivitis and tender preauricular nodes, with or without associated keratitis. Conjunctivitis also is noted occasionally with recurrent infection, but the most common recurrent form 'is herpetic keratitis. Clinically, this entity is diagnosed readily because of the characteristic dendritic, branched, fluorescent-staining corneal ulcers. Herpetic vesicles are occasionally present concomitantly on the eyelid (Fig. 6), on other parts of the face or in the mouth. A history of trauma to the eye occasionally may be elicited. Recurrent keratitis is usually unilateral, Fro. 6.--HSV infection of r

in child with associated herpetic keratitis.

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Fro. 7.----Severe herpes keratitis. but in about 5% of cases there may be bilateral involvement; recurrences occur within 2 years in at least one quarter of the patients. Deeper ocular involvement may occur occasionally, including stromal keratitis (Fig. 7) and iridocyclitis. Corticosteroids should be avoided in ocular herpes since they have been implicated in contributing to deeper ocular involvement, including perforation of the globe. Ocular infections occurring in individuals beyond the newborn age are caused primarily by HSV-1 (Table 3"). 5. UROGENITAL TRACT.--Infection of these sites by HSV is of particular interest to the pediatrician for several reasons. It is now apparent that genital herpetic infection is a common venereal disease and that at least one third of these infections occur in individuals 18 years old or younger. It has been observed in girls below the age of 12 years (Fig. 8) who had been molested sexually. However, it should be appreciated that occasional genital infections, e.g., in a 3-year-old boy (Fig. 9), are autoinfections from concomitantly infected sites such as the mouth. A second concern is the possible involvement of the fetus and newborn secondary to genital HSV during pregnancy. A third possible cause for concern is the relationship demonstrated between genital herpetic infection and cervical c a n c e r . 20

About 90% of urogenital infections are caused by HSV-2 (Table 3). Some HSV-1 infections may result from oral-genital contact. Although herpetic infections originally were considered to involve 20

only the external genital sites in both male and female patients. (hence the term, which should be abandoned, of herpes progenitalis), it is now appreciated that the most common site of involvement in female patients is the cervix, with the vagina being infected less commonly, and that infections of the prostate or seminal vesicles can occur in males. In addition, the virus may infect the urethra, bladder and anorectal area in both sexes. Approximately one quarter to one third of genital infections are primary, in which case symptomatolow tends to be more severe, with fever, constitutional signs, pelvic or sciatic pain, regional adenopathy and dysuria. The vulvar, penile or perineal lesions demonstrate characteristic vesicles, which are usually multiple (Fig. 8). However, herpetic infections of the cervix are more difficult to diagnose clinically, since the large majority do not demonstrate any lesions suggestive of herpes. Urogenital infections in individuals with prior experience of either HSV-1 or HSV-2 usually will be less severe than primary infections. However, recurrent infections also may be accompanied by pain and dysuria and, if these recurrences are frequent, they may be psychologically incapacitating. The complications of genital herpetic infections include meningitis, Fro. 8.--Genital herpetic infection in an 8-year-old girl. (From Nahmias, A. Genital infections with Herpesvirus hominis types 1 and 2 in children, Pediatrics 42:659, Oct., 1968.)

J., et al.:

21

Fxo. 9.--Penile herpes in a 3-year-old boy with associatedoral herpes. (From Nahmias, A. J., et al.: Genital infectionswith Herpesvirus hominis types 1 and 2 in children, Pediatrics42:659, Oct., 1968.) radiculitis, myelitis, urethral stricture, labial fusion and bacterial or mycotic superinfection. The herpetic lesions may be confused with the lesions associated with other venereal diseases, particularly chancroid disease and, less Often, syphilis and lymphogranuloma venereum. (It should be appreciated that at least 10% of cases of genital herpes occur in individuals with some othel" venereal disease, e.g., gonorrhea.) Other less common problems in differential diagnosis are genit.al involvement by varicella-zoster, diphtheria, Vincent's angina, impetigo and the recurrent ulcers associated with canker sores in the mouth. 6. NERVOUSSYSTEM.---HSV infections have been associated with a variety of neurologic manifestations including encephalitis, meningitis, radiculitis and myelitis. Evidence of the role of the viruses in Bell's palsy and in chronic neurologic and psychiatric disorders is much more tenuous. It is of interest that almost all of the isolates from the brains of individuals beyond the newborn age group have been HSV-1 (Table 3). This virus has been isolated very infrequently from the CSF of patients with HSV encephalitis. On the other hand, HSV-2 has been associated frequently with CSF pleocytosis and often with meningitis, and the virus is more readily recoverable from the CSF than HSV-1. Herpes simplex encephalitis, the most common cause of nonepi22

demic encephalitis in the United States, has a higher fatality rate than almost any other encephalitis of known or unknown etiology. About 4,000 cases each year are believed to occur in the United States, of which at least one quarter are in children or adolescents. This entity occurs most often in individuals with no prior HSV infection, but it also has been noted less frequently in patients with a documented prior HSV infection. All areas of the brain may be affected, but the inferior and mesial portions of the temporal lobe and the orbital region of the frontal lobe are especially vulnerable. The onset of HSV encephalitis is usually acute but occasionally can be subacute. The presentation is that of an encephalitic picture or of a focal mass lesion in the brain, particularly of the temporal lobe. Headaches, fever, vomiting, meningismus, chills and myalgia may occur over a period of a few days. The patient then may show confusion, disorientation, irrational behavior, coma, recent memory loss and focal or generalized seizures. Examination also may reveal papilledema, signs of unilateral pyramidal tract involvement and sensory deficits, although bilateral involvement may be present occasionally. A few patients also may demonstrate concomitant skin, lip or oral lesions before or after onset of the encephalitic signs. CSF values are variabl~, but there is usually evidence of increased intracranial pressure and lymphocytic pleocytosis, most often less than 1,000 cells mm 3. Polymorphonuclear leukocytes may predominate early, with a later increase in the number of lymphocytes and occasionally also of erythrocytes. The protein concentration in the CSF is usually elevated and the CSF sugar level is normal, except in rare cases when it may be decreased. Many patients demonstrate changes on EEG examination a n d / o r brain scan, usually consistent with a diffuse brain process but occasionally denoting a localized process, most frequently involving the temporal lobe. Death occurs in at least one third of untreated patients within 2 weeks. The prognosis is worse if the patient has been comatose or has experienced seizures at any time during his illness. Many of the survivors are left with severe or mild neurologic deficits, some of which can be detected only by detailed neuropsychologie testing. The prognosis in HSV meningitis appears to be excellent, although recurrent meningitis has been described. The diagnosis of HSV involvement of the nervous system is very difficult to make on clinical grounds alone. Unlike those in the newborn, in whom the concomitant findings of visible herpetic lesions and encephalitis make the diagnosis of HSV encephalitis almost certain, similar findings in older individuals are not diagnostic. The reason is that herpetic recurrences may be triggered by febrile illnesses or diseases of the CNS of nonherpetic etiology. Encephalitis associated with the disease must be differentiated from the many other causes of this entity, whether infectious or noninfectious, 23

as well as from other causes of localized brain masses such as .tumors or brain abscesses. Brain biopsy (as discussed later) is at present the only certain way to diagnose this entity. HSV meningitis also cannot be differentiated from the multitude of other causes of the "aseptic meningitis" syndrome. The association of a clinically evident genital herpetic infection would suggest this diagnosis stron#y. Since HSV meningitis is caused primarily by HSV-2, this disease would be unlikely to occur in children but might be encountered in adolescents. THE IMMUNOLOGICALLY COMPROMISED HOST Besides that occurring in the newborn, HSV infection can cause severe localized disease or disseminated infection in immunologically impaired persons, including those with certain cancers (e.g., Hodgkin's disease and other lymphomas), patients undergoing immunosuppressive therapy (e.g., for renal transplants) and children with certain immunologic deficiencies. As mentioned earlier, severe herpetic disease also occurs in patients with chronic skin conditions and severe burns. The basic defect common to all of these conditions has not been ascertained although a common denominator could be a defect in cellular immunity. The disseminated disease, which occurs in severely malnourished children in developing countries, has not been reported in this country, although it has been described occasionally here in association with measles or pertussis. Clinical signs of disseminated infection may be nonspecific, e.g., poor feeding and poor weight gain, and may include jaundice, hepatosplenomegaly, pneumonitis and abnormal CNS findings. Hypotension may ensue and there is usually rapid deterioration with a fatal outcome. The diagnosis is usually difficult to make in such cases, but it should be suspected in compromised individuals, particularly if clinically visible herpetic lesions are noted. THE FETUS AND NEWBORN The clinical spectrum and outcome of neonatal herpetic infection as noted in close to 200 published or personally studied cases are presented in Table 4. Since about one third of the cases were diagnosed post mortem, it is probable that the fatality rate of 63% does not reflect the true mortality incurred from this neonatal infection. Although it might have been assumed that neonatal HSV infection might resemble cytomegalovirus infection in being most often asymptomatie, intensive virologic studies to detect subclinical HSV have been generally unrewarding. On the other hand, it is well appreciated that many infants with clinical manifestations of HSV infections within the first month of life can be missed or misdiagnosed. 2a

TABLE

4 . - - C L I N I C A L SPECTRUM AND OUTCOME OF 198 CASES OF NEONATAL HERPETIC INFECTION OLrI'COMEIN INFANT Survived

CLINICALGROUPS

Disseminated Without CNS involvement With CNS involvement Localized* CNS Eye Skin Oral cavity Asymptomatic TOTAL

Without Apparent Sequelae

No. Cases

Died

With Sequelae

90 85

82 62

1 12

7 11

15 5 8 0 0 4-i (16%)

8 5 20 3 2 5"-6(22%)

40 I0 28 3 2 25"--'-8t

17 0 0 0 0 16""~(62%)

*Classified according to major site of involvement when more than one site infected. t A n additional 12 cases could not be classified due to insufficient data.

The separation of cases into various groups of disseminated or localized infections is important for several reasons. One relates to the possible pathogenetic mode of viral spread. Thus, in disseminated cases with evidence of visceral organ involvement, the virus must have to reach these organs via the blood. The brain in such cases may demonstrate no histopathologic changes, the virus may not be recoverable or the virus can be recovered from the brain without demonstrable histopathologie findings. Furthermore, virus usually can be isolated from the CSF in cases of neonatal encephalitis with visceral organ involvement. The occasional absence of clinical or laboratory evidence of visceral organ involvement in neonatal herpetic encephalitis ahd the frequent inability to isolate virus from the CSF (as noted in older patients with encephalitis) suggest that the virus may be neurologically transmitted to the brain. Another important reason for the classification of cases of neonatal herpes into different groups is related to prognosis, which is much worse in disseminated than in localized disease. It must be emphasized that it is not possible to determine whether skin or throat infection will remain localized or be manifested later as disseminated disease a n d / o r encephalitis. It should be stressed also that the true prognosis may not be reflected in the figures given in Table 4 since follow-up of surviving infected infants was often performed inadequately or was only short-term in most reported cases. The disseminated form of HSV infection affects primarily the liver and the adrenals, but many other organs also are involved commonly; these include the spleen, brain, trachea, lungs, esophagus, stomach, kidneys, pancreas, heart and bone marrow. Initial indica25

tions of illness may appear at birth or only 21 days postnatally (average 6 days). Nonspecific constitutional signs are most frequent, e.g., hypoactivity, vomiting, respiratory difficulty and occasionally fever. External signs suggestive of herpetic infection (such as skin vesicles) are absent in more than half of the cases. The infants may demonstrate hepatosplenomegaly, jaundice with direct hyperbilirubinemia, bleeding diathesis and CNS abnormalities including convulsions. The course of disseminated infection is generally stormy with rapid deterioration. Shock and disseminated intravascular coagulation may occur terminally. A few survivors with no apparent sequelae have been recorded, but in general this form of herpetic disease has a very grave prognosis. The localized form of infection affecting the CNS also carries a relatively poor prognosis as regards mortality and sequelae. The onset of illness averages about 1 week longer than that noted for disseminated infections and most of these patients demonstrated visible stigmata of herpetic infection of the skin, eyes or oral cavity. Onset of herpetic illness is manifest in about half of the patients with convulsive phenomena. Other neurologie findings of opisthotonus, bulging fontanelle, aberrations in muscle tone and coma are frequently present. Abnormalities in the CSF similar to those found in older individuals with encephalitis (see above) are usually present. More infants survive this form of HSV infection than the disseminated form. However, disabling sequelae are very common. These include rnicrocephaly, hydrocephaly, porencephalic cysts and varying degrees of psychomotor retardation. Intracranial calcifications also have been observed in a few cases. The eye can be the primary and only site of HSV involvement or be associated with local CNS or disseminated infections. One or both eyes may be affected by conjunctivitis, keratitis and/or chorioretinitis (Fig. 10). The sequelae comprise residual corneal scars, chorioretinitis leading occasionally to blindness or cataracts, in which case HSV can be isolated from the lens. The newborn may demonstrate only skin lesions without evidence of associated ocular, CNS or disseminated involvement. The skin lesions are characteristically vesicular (Fig. 11), but rapid ulceration and skin denudation may confuse the diagnosis. The skin lesions can appear on any part of the body at varying times. Interestingly, they are more likely to be in the perianal region in the case of breech deliveries and are often found on the head in cephalic deliveries. The skin vesicles in localized cases or in survivors of disseminated infections can recur repeatedly over the following years, occurring not only at the site of original involvement but also in previously unaffected skin areas. Other skin manifestations of neonatal HSV infection have been described. These include an exanthem appearing as red patches on 26

Fro. 10.----Chorioretinitisassociatedwith neonatal HSV infection. the first day of life, a generalized erythematous macuIar exanthem noted early and petechiae that are noted later in infants with disseminated infection. Erythema multiforme also has been recorded in one case. Although most infants with local skin infections survive with no apparent sequelae, a few have been found later to demonstrate psychomotor retardation or chorioretinitis. These observations point to the need for careful neurologic and ophthalmologic examinations and follow-up'studies in all such cases. Very few cases have been reported so far of infections affecting the oral cavity only or of subclinical infections (Table 4). These infants appear to have survived without sequelae. A few cases of neonatal herpes have been suspected within the first 24 hours of life because of the appearance of visible lesions in that period. Although such cases provide evidence of an intrauterine infection, they do not prove a transplacental infection. Indeed, in most such cases, membranes were ruptured for prolonged periods, indicating an ascending infection. Reports of infants who demonstrated microcephaly or chorioretinitis within the first few days of life are more suggestive of a transplacentally transmitted infection. Such a pathway of viral transmission might explain the increased abortion rate in pregnant women with genital herpes during the first part of gestation. However, even though HSV has been isolated from abortus material, it is possible that the abortus was 27

Fro. 1I.--HSV vesicleson the foot of a newborn. contaminated on passage through the infected genital tract and that abortions may be an indirect result of the severity of the maternal herpetic infection. Neonatal herpes may be suspected if the mother had genital herpes during pregn~incy. The diagnosis is Considered particularly when visible lesions of the skin (Fig. 11 ) or oral cavity are present or when the characteristic herpetic_keratitis is visualized. The skin lesions not uncommonly are diagnosed erroneously as being due to bacterial infections and may be misdiagnosed also as herpes zoster or varicella. However, this entity i n newborns is most unusual in the absence of maternal infection with varicella-zoster virus during pregnancy. It is particularly difficult to diagnose HSV infection clinically in infants with conjunctivitis, chorioretinitis (Fig. 10) or cataracts, or those with CNS findings or disseminated disease. In such eases the differential diagnosis with infections caused by Toxoplasmosis, Rubella virus and Cytomegalovirus is very difficult without laboratory aids. For this reason we have grouped these infections into the TORCH complex of perinatal infections.

LABORATORY DIAGNOSIS Herpetic gingivostomatitis, labial herpes, herpetic keratitis and some forms of cutaneous and genital herpes usually can be readily diagnosed clinically, although, as noted earlier, these herpetic diseases may be mistaken for other infectious and noninfectious entities. The 28

diagnosis of the various forms of herpetic infection in the newborn and of the severe infections in the normal or compromised individual (e.g., encephalitis or disseminated disease) requires specific laboratory aids, particularly when therapy is contemplated. MORPHOLOGIC AIDS The intranuclear inclusions and multinucleated giant cells that are seen in Papanicolaou-stained smears of cells, fixed in 90% alcohol and obtained by scraping the base of herpetic vesicles or ulcers of the skin or mouth or by scraping the conjunctiva or cornea, are characteristic of herpesviruses, including HSV and varicella-zoster viruses (Fig. 12). The intranuclear inclusions are less readily apparent in Wright- or Giemsa-stained smears. In most instances there is little difficulty in differentiating clinically between HSV and varicellazoster infection. The inclusions in urinary cells may make it difficult, however, to distinguish HSV from cytomegalovirus infection. Papanicolaou smears of the cervix are particularly helpful in detecting subclinical herpetic cervicitis in adolescent girls. The morphologic findings in this genital site have been found to be specific for HSV and to be two thirds as sensitive as virologic methods. Biopsy or autopsy material preferably should be fixed in Bouin's fixative rather than formalin in order to enhance the demonstration FIO. 12.--Multinucleated giant cells and intranuclear inclusions characteristic of herpetic infections demonstrated by cytologic technics. (From Nahmias, A. J.: Infections Caused by Herpes Simplex Hominis, in Hoebrich, B. D. [ed.]: In#ctious Diseases [New York: Harper & Row, Publishers,d972].)

29

of the characteristic inclusions and giant cells. Such material obtained from the brain or various other organs has been particularly useful in the diagnosis of suspected neonatal herpes. It should be appreciated that multinucleated cells can be produced by nonherpetic diseases and that intranuclear inclusions in the brain may be observed with subacute sclerosing encephalitis or Simian herpes B and varicellazoster encephalitis. More specific virologic assays therefore are required for finite diagnosis. VIROLOGIC AIDS Clinical specimens for virus isolation should be processed as rapidly as possible or frozen at - 7 0 ~ C until processed. It is better to keep the specimen for a few hours at 4 ~ C icebox temperature than in the - 1 5 ~ C freezing compartment. The recent development of a transport medium (Leibovitz-Emory) has facilitated the shipment of clinical specimens at --70 ~ C (dry ice), since the swab with which the specimen is obtained, when placed in this medium, can be stored and shipped at ambient temperature, zx Virus can be isolated readily in a number of tissue culture systems, and an almost pathognomonic cytopathic effect can be detected as rapidly as in a bacterial culture (usually within 1-3 days). Specific identification of HSV and its antigenic types then can be obFI6. 13.---Specificimmunofluorescent staining of HSV-infected cells in a brain biopsy.

30

rained by neutralization or immunofluorescent technics. The latter technic can be used for rapid identification and direct typing of herpes simplex in clinical specimens. Immunofluorescent tests are particularly helpful for the diagnosis of HSV in brain biopsies of patients with encephalitis (Fig. 13) and are currently under study for the detection of HSV antigens in CSF leukocytes. Embryonated eggs and laboratory animals, e.g., mice or rabbits, can be used for initial isolation of HSV; however, these assays are more laborious than tissue c]alture methods. HSV typing can be done also in embryonated eggs (HSV-2 produces larger pocks than HSV-1) or by differences in the ability of HSV-1 and HSV-2 to grow in certain tissue culture cells or to produce plaques of different size. However, serologic typing methods are more finite than these biologic assays, which could yield erroneous virus typing results, particularly if the virus first has been passaged many times in the laboratory. In addition, HSV can be demonstrated in vesicular fluid, biopsy or autopsy specimens by the use of electron microscopic technics, which would reveal enveloped or nonenveloped virus particles (Fig. 1). The morphologic appearance of HSV by this technic cannot be distinguished from that bbserved with other herpesviruses such as cytomegalovirus or varicella-zoster virus. The virus can be distinguished as HSV by the use of HSV antibodies labeled specifically with ferritin or horseradish peroxidase. SEROLOGIC AIDS Many serologic assays can be used to demonstrate HSV antibodies, e.g., neutralization, complement fixation, p~ssive hemagglutination, complement-mediated cytolytic and indirect immunofluorescent tests. A primary infection is suggested by the finding of a fourfold or greater rise in titer between the acute and the convalescent serum, obtained 1 week or more later. Since such a titer rise may be observed with recurrent infections, the distinction between primary and recurrent infection is occasionally difficult. For sero-epidemiologic surveys, neutralization assays have proved to be more sensitive than complement fixation tests. The HSV antibody type (type 1 and/or 2) can be determined by more specialized serologic procedures such as microneutralization, kinetic neutralization, multiplicity analysis and inhibition passive hemagglutination tests. Since there is partial crossing between the two HSV types, some sera, particularly those from individuals who have experienced both types of infections, may be difficult to characterize. This problem may be alleviated once type-specific antigens for each of the two virus types are purified. Indirect immunofluorescent tests have been developed recently 31

to detect HSV antibodies in the IgM, IgG, IgA class of immunoglobulins. Thus, IgM HSV antibodies can be used to diagnose neonatal herpes in patients with no characteristic findings in the eyes, throat or skin. Such IgM antibodies usually appear within 1--4 weeks after birth and persist for at least 6 months. The detection of IgM or IgA antibodies in the serum of older individuals unfortunately cannot be used to differentiate a primary from a recurrent HSV infection since such antibodies occasionally can be found in recurrent cases. The ~ppearance of IgM, IgA or IgG HSV antibodies in the CSF are also not diagnostic of HSV encephalitis since occasionally these antibodies may be transuded into the CSF from the blood in patients with CNS diseases of other etiology, e.g., tuberculous meningitis. A similar problem is encountered if passive hemagglutination tests are applied to the CSF of patients with suspected encephalitis. However, the major difficulty is that detectable CSF HSV antibodies may not appear for some time after onset of HSV encephalitis. In vitro assays for cell-mediated immunity to HSV are still in the research stage but may be potentially useful i n diagnosis or in the demonstration of individuals more prone to HSV recurrences. Positive skin tests o f delayed hypersensitivity can be elicited with inactivated HSV preparations that correlate well with the presence of serum neutralization antibodies. Such HSV skin test materials are not available clinically.

PREVENTION AND TREATMENT Preventive measures f o r the milder forms of herpetic disease in normal individuals are not feasible at present. They should be attempted in certain groups of compromised hosts--children with chronic skin diseases, severe burns or immunologic defects or. those on immunosuppressive therapy--in that contact with individuals with overt herpetic lesions should be avoided. Despite such precautions, patients may become infected with virus from persons with subclinical infections. Protective gloves should be worn by hospital personnel caring for patients with overt herpetic infections. This measure is particularly warranted for the prevention of herpetic paronychia in personnel using suction catheters. Men with penile herpetic lesions should be cautioned to avoid sexual intercourse with pregnant women, particularly during the third trimester, because of the risk of the mother acquiring an infection close to the time of delivery that could be transmitted to the newborn. Controlled studies have not been done as yet to evaluate finitely whether or not neonatal herpes can be prevented by performance of a cesarean section in women with genital herpes close to the time of delivery. Current information (Table 5) suggests 32

T A B L E 5.--RISK OF NEONATAL HERPETIC INFECTION FROM I~'[OTttER WITII GENITAL INFECTION* AT DELIVERY TYPE OF DELIVERY

Vaginal Abdominal > 6 hours after membrane rupture Before or within4 hours of membrane rupture

NO. INFANTS INFECTED/ No. OF CASES

10/21 (48%) 6/7

(86%)

1/16 (6%)

*Proved by virologic and/or cytologic examinations.

that about 50% of newborns delivered vaginally become infected and that the risk of infected infants being severely damaged or killed by their herpetic infection is quite high (Table 4). It appears that a cesarean section performed over 6 hours after rupture of membranes (Table 5) probably would be unsuccessful in protecting the newborn owing to increased opportunity for an ascending viral infection to occur. Amniocentesis in women with genital herpes at about the time of delivery also should be considered. If HSV is detected in the amniotic fl~id, it is doubtful that abdominal delivery would be helpful. Guidelines regarding approaches to this problem have been suggested, and the need for individualization of every case and for close communication between obstetrician and pediatrician has been emphasized,zz , Mild gingivostomatitis requires no therapy except the maintenance of proper oral hygiene and the application of a topical anesthetic for pain. In severe cases fluid and electrolyte therapy may be needed. Herpetic infections of the lips, skin and genitalia also will require no specific therapy usually. Analgesic ointments may relieve pruritus and burning, and antibacterial ointments may prevent secondary infection. Topical iododeoxyuridine (IDU) has been used for these conditions, but its effectiveness has been questioned in control studies. IDU in a higher concentration combined with dimethyl sulfoxide (DMSO) is reported to be more effective than IDU alone; however, DMSO is approved only for investigative studies in the United States. Consultation with an ophthalmologist is advisable for children with ocular herpes. For superficial corneal infections topical IDU, as a solution or an ointment, is applied to the eye at frequent intervals. Such treatment is usually effective but recurrences are not prevented. Because ocular herpes can be worsened by the use of corticosteroids, these drugs should be avoided except if combined with IDU for the treatment of stromal keratitis. The use of corticosteroids in HSV encephalitis has not been well evaluated. Systemic administration of IDU and several other antiviral drugs 33

has been used to a limited extent so far in the treatment of HSV encephalitis, neonatal herpes and severe HSV infection in compromised hosts. These drugs, which all interfere with viral DNA synthesis, include, in addition to IDU, cytosine arabinoside (Ara-C) and adenine arabinoside ( A r a - A ) . * All of these drugs have potential toxic effects, especially on the hematopoietic system, and may be immunosuppressive. Ara-A at present appears to have less of these ill-effects; in addition, unlike the other two drugs, Ara-A is metabolized to its hypoxanthine derivative, which retains significant antiviral activity. Close monitoring of hematopoietic, liver and kidney function is required when any of the drugs are used, and informed consent should be obtained. The effectiveness of these drugs has been difficult to evaluate since some untreated patients with severe forms of HSV infection have survived with no ill-effects, whereas other patients have died in spite of therapy. Controlled studies currently under way should allow a determination of the true efficacy and the toxic reactions of these agents. As indicated earlier, the mechanisms responsible for protection of the host f r o m severe HSV disease and for the frequency of recurrences still are understood incompletely. In addition, many specific and nonspecific measures such as hyperthermia, macrophage activators, interferon or interferon stimulants, transfer factor, or HSV antibodies await evaluation of their possible effectiveness. The efficacy of older approaches is still unestablished. Thus, many types of immunizing agents have been used for treatment of recurrent herpes. The oldest method was autoimmunization whereby the virus from a recurrent site was applied to ~nother site. Recurrences on the new site occurred on occasion, and this approach is no longer in use. Smallpox vaccination is still being administered by several clinicians; however, control studies have not demonstrated any real effectiveness. In addition, severe vaccinia reactions have been reported in some compromised hosts treated in this manner. Inactivated HSV-1 or HSV-2 vaccines also have been used for several years, but their efficacy has not been evaluated fully. A more recent approach involving the application of a vital dye such as neutral red or proflavine, followed by exposure to light, for the treatment and prevention of recurrent herpetic lesions also awaits *IDU: 75-100 mg/kg/day intravenously for 5 days. Contact Calbiochem (Dr. L. Freeman) in Los Angeles, Calif. Ara-C: 200 mg/m2/day intravenously in newborns for 5 days; 2-3 mg/kg/day intravenously for older individuals. Contact Dr. G. Royer, Upjohn Co., Kalamazoo, Mich. Ara-A: 15 mg/kg/day intravenously in newborns or patients with encephalitis for 10 days; l0 mg/kg/day intravenously in immunosuppressed hosts for 7 days. Contact Drs. L. Chien or C. Alford, Dept. of Pediatrics, Uni~;. of Alabama, Birmingham, Ala. 34

confirmation. T h e possible relation of H S V to h u m a n c a n c e r a n d the in v i t r o ability of inactivated H S V to cause neoplastic transf o r m a t i o n indicate c a u t i o n in the use o f e i t h e r inactivated H S V vaccines o r vital dye treatment. I t s h o u l d b e noted also that certain patients, such as those with e c z e m a h e r p e t i c u m a n d n e o n a t a l infection, are p r o n e to bacterial s e c o n d a r y infection requiring use of a n t i b a c t e r i a l therapy. Careful fluid, electrolyte and b l o o d m o n i t o r i n g also m a y be indicated, as well as m e a s u r e s to c o m b a t . s h o c k and d i s s e m i n a t e d i n t r a v a s c u l a r coagulation.

ACKNOWLEDGMENTS This w o r k was s u p p o r t e d b y a grant f r o m the N a t i o n a l F o u n d a tion. W e wish to thank Drs. S. K i b r i c k a n d H. K a u f m a n for s o m e p h o t o g r a p h s a n d Mrs. J a c q u e M u t h e r for h e r assistance. REFERENCES 1. Nahmias, A.: Evolution (evovirology) of herpesviruses, Comp. Virol. (in press). 2. Nahmias, A.: Herpesvirl2ses from Fish to M a n - - a Pathobiological Viewpoint, in Ioachim, J. (ed.): Pathobiology Annual (New York: AppletonCentury-Crofts, 1972), pp. 153-182. 3. Nahmias, A., and Roizman, B.: Herpes simplex viruses (Medical Progress article), N. Engl. J. Med. 289:667, 719, 781, 1973. 4. Frenkel, N., Roizman, B., Cassai, E., and Nahmias, A.: A DNA fragment of herpes simplex 2 and its transcription in human cervical cancer tissue, Proc. Natl. Acad. Sci. U.S.A. 69:3784, 1972. 5. Nahmias, A., Fritz, M., and Chang, G.: Herpesviruses as infectious and oncogenic agents in man and other vertebrates, i,n ]ilembranes, Viruses and Cancer (New York: Academic Press, 1972), pp. 293-318. 6. Nahmias, A., and Dowdle, W.: Antigenic and biologic differences in Herpesvirus hominis, Prog. Med. Virol. I0:110, 1968. 7. Davidson, W., and Hummeler, K.: B virus infection in man, Ann. N.Y. Acad. Sci. 85:970, 1960. 8. Stern, H., Elek, S. D., Millar, D. M., et al.: Herpetic whitlow, a form of cross-infection in hospitals, Lancet 2:871, 1959. 9. Hale, B. D., Rendtorff, R. C., Walker, L. C., et aL: Epidemic herpetic stomatitis in an orphanage nursery, J.A.M.A. 183:1068, 1963. 10. Juretie, M.: Natural history of herpetic infection. Helv. Paediatr. Acta 21:356, 1966. 11. Nahmias, A. J., Josey, W. E., Naib, Z. M., Freeman, M. G., Fernandez, R. J., and Wheeler, J. H.: Perinatal risk associated with maternal genital herpes simplex virus infection, Am. J. Obstet. Gynecol. 110:825, 1971. 12. Florman, A. L., Gershon, A. A., Blackett, P. R., and Nahmias, A. J.: Intrauterine infection with herpes simplex virus: resultant congenital malformations, J.A.M.A. 225:129, 1973. 13. Craig, C., and Nahmias, A.: Different patterns of central nervous system involvement with herpes simplex types 1 and 2, J. Infect. Dis. 127:365, 1973. 14. Nahmias, A., Alford, C., and Korones, S.: Infection of the Newborn with Herpesvirus Hominis, in Schulman, I. (ed.): .4dvances in Pediatrics, Voh 17 (Chicago: Year Book Medical Publishers, 1970), pp. 185-226. 35

15. Nahmias, A., Josey, W., Naib, Z., Luce, C., and Duffey, C.: Antibodies to Herpesvirtts hominls types I and 2 in humans. I. Patients with genital herpetic infections, Am. J. Epidemiol. 91:547, 1970. 16. Becker, W. B., Kipps, A., and McKenzie, D.: Disseminated herpes simplex virus infection. Am. J. Dis. Child. 115:1, 1968. 17. Stevens, J. G., and Cook, M. L.: Latent infections induced by herpes simplex viruses, Cancer Res. 33: 1399, 1973. 18. Baringer, J. R., and Swoveland, P.: Recovery of herpes simplex virus from human trigeminal ganglions, N. Engl. J. Med. 288:648, 1973. 19. Lodmell, D. L., Niwa, A., Hayashi, K., et al.: Prevention of cell-to-cell spread of herpes simplex virus by leukocytes, J. Exp. Med. 137:706, 1973. 20. Symposium: tlerpesvirus and cervical cancer, Cancer Res. 33:1345, 1973. 21. Nahmias, A., Wickliffe, C., Pipkin, J., Leibovitz, A., and Hutton, R.: Transport media for herpes simplex viruses types I and 2, Appt. Microbiol. 22:451, 1971. 22. Nahmias, A., Josey, W., and Naib, Z.: Significance of genital herpetic infection during pregnancy, Clin. Obstet. Gynecol. 15:929, 1973.

THE N E X T ISSUE DifJerential Diagnosis o] Childhood Asthma by Warren Richards, M.D., Head, Division of Allergy at the University of Southern California School of Mcdicine, is the March issue. The characteristics of asthma may be found to some degree in a wide variety of chest conditions :~nd general systemic diseases. Dr. Richards' purpose is to review the conditions that may be confused with asthma and to focus attention on the specific points of importance in the history, physical examination and laboratory test results that might provide clues to the final diagnosis. He then discusses methods of therapy available to reach the goal of a happy, healthy child.

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