PRIMARY HERPETIC STOMATITIS

Primary infection is caused by Herpes simplex virus, usually type 1, which, in the non-immune, can cause an acute vesiculating stomatitis. However, most primary infections are subclinical. Thereafter, recurrent (reactivation) infections usually ta e the form of herpes labialis (cold sores or fever blisters). Transmission of herpes is by close contact and up to !"# of inhabitants of large, poor, urban communities, develop antibodies to herpes virus during early childhood. $n many %ritish and &' cities, by contrast, appro(imately )"# of *"-year-olds may be non-immune, because of lac of e(posure to the virus. $n more affluent countries the incidence of herpetic stomatitis has declined and it is seen in adolescents or adults, rather than children. $t is more common in the immunocompromised, such as H$+ infection, when it can be persistent or recurrent.

Clinical features
The early lesions are vesicles which can affect any part of the oral mucosa, but the hard palate and dorsum of the tongue are favoured sites (,igs 1*.1 and 1*.*). The vesicles are domeshaped and usually *-- mm in diameter. .upture of vesicles leaves circular, sharply defined, shallow ulcers with yellowish or greyish floors and red margins. The ulcers are painful and may interfere with eating. The gingival margins are fre/uently swollen and red, particularly in children, and the regional lymph nodes are enlarged and tender. There is often fever and systemic upset, sometimes severe, particularly in adults. 0ral lesions usually resolve within a wee to ten days, but malaise can persist so long that an adult may not recover fully for several wee s.

Pathology
+esicles are sharply defined and form in the upper epithelium (,ig. 1*.-). +irus-damaged epithelial cells with swollen nuclei and marginated chromatin (ballooning degeneration) are seen in the floor of the vesicle and in direct smears from early lesions (,ig. 1*.1). $ncomplete division leads to formation of multinucleated cells. 2ater, the full thic ness of the epithelium is destroyed to produce a sharply defined ulcer (,ig. 1*.3).

Diagnosis
The clinical picture is usually distinctive (Table 1*.*). 4 smear showing virus-damaged cells is additional diagnostic evidence. 4 rising litre of antibodies reaching a pea after *-- wee s provides absolute but retrospective confirmation of the diagnosis.

Treatment
4ciclovir is a potent antiherpetic drug and is life-saving for potentially lethal herpetic encephalitis or disseminated infection. 4ciclovir suspension used as a rinse and then swallowed should accelerate healing of severe herpetic stomatitis if used sufficiently early. %ed rest, fluids and a soft diet may sometimes be re/uired. $n mild cases, topical tetracycline suspension, rinsed round the mouth several times a day, relieves soreness and may hasten healing by controlling secondary infection. &nusually prolonged or severe infections or failure to respond to aciclovir (*""-1"" mg5day by mouth for seven days) suggest immunodeficiency, and herpetic ulceration persisting for more than a month is an 4$6'-defining illness.
Table 12.2 Typical features of herpetic stomatitis &sually caused by H. simplex virus type $ Transmitted by close contact +esicles, followed by ulcers, affect any part of the oral mucosa 7ingivitis sometimes associated 2ymphadenopathy and fever of variable severity 'mears from vesicles show ballooning degeneration of viraldamaged

cells .ising titre of antibodies to H'+ confirms the diagnosis 4ciclovir is the treatment of choice

Herpetic Stomatitis: Primary

Etiology Herpes simplex virus (HSV) Over 95% of oral primary herpes due to HSV ! Physical co"tact is mode of tra"smissio" Clinical Presentation ##% of populatio" experie"ce su$cli"ical i"fectio" or mild tra"sie"t symptoms %ost cases occur i" those $et&ee" '(5 a"d 5 years of a)e( *"cu$atio" period of up to + &ee,s -$rupt o"set i" those &ith lo& or a$se"t a"ti$ody to HSV ! .ever/ a"orexia/ lymphade"opathy/ headache/ i" additio" to oral ulcers 0oalesci")/ )rouped/ pi"head si1ed vesicles that ulcerate 2lcers sho& a yello&/ fi$ri"ous $ase &ith a" erythematous halo 3oth ,erati"i1ed a"d "o",erati"i1ed mucosa affected 4i")ival tissue &ith edema/ i"te"se erythema/ pai"/ a"d te"der"ess 5ips/ perioral s,i" may $e i"volved 6 to !7 day course Diagnosis 2sually $y cli"ical prese"tatio" a"d patter" of i"volveme"t 0ytolo)y preparatio" to demo"strate multi"ucleate virusi"fected )ia"t epithelial cells 3iopsy results of i"tact macular area sho& i"traepithelial vesicles or early virus i"duced epithelial (cytopathic) cha")es Viral culture or polymerase chai" reactio" (P08) exami"atio" of $lister fluid or scrapi") from $ase of erosio" Differential Diagnosis Herpa")i"a Ha"d foot a"d mouth disease Varicella Herpes 1oster (shi")les) 9rythema multiforme (typically "o )i")ival lesio"s)
Vesiculo$ullous :iseases 65

Treatment Soft diet a"d hydratio" -"tipyretics (avoid aspiri") 0hlorhexidi"e ri"ses Systemic a"tiviral a)e"ts (acyclovir/ valacyclovir) if early i" course or i" immu"ocompromised patie"ts 0ompou"ded mouth ri"se Prognosis 9xcelle"t i" immu"ocompete"t host 8emissio";late"t phase i" "early all those affected &ho have ade<uate a"ti$ody titers

Herpes simplex infections Primary herpetic Multiple painful oral ulcers preceded by vesicles; Herpes simplex virus type 1 Self-limited; heals in about 2 weeks; in ivostomatitis may have similar perioral and skin lesions; fever !occasionally type 2" reactivation of latent virus results in and in ivitis usually present; usually affects secondary infections; circulatin children under # years of a e antibodies provide only partial immunity Secondary herpes Multiple small ulcers preceded by vesicles; Herpes simplex virus- Self-limited; heals in about 2 weeks simplex infection prodromal symptoms of tin lin $ burnin $ or represents reactivation of without scar; lesions infectious durin pain; most common on lip$ intraorally on palate latent virus and not vesicular sta e; patient must be cautioned and attached in iva; adults and youn adults reinfection; commonly a ainst autoinoculation; herpes type 1

usually affected; very common; called herpetic precipitated by stress$ infections have not been convincin ly whitlow when occurs around fin ernail sunli ht$ cold temperature$ linked to oral cancer; any site affected in low resistance$ and %&'S patients immunodeficiency (aricella Painful pruritic vesicles and ulcers in all sta es (aricella-)oster virus Self-limited; recovery uneventful in on trunk and face; few oral lesions; common several weeks childhood disease Herpes )oster *nilateral multiple ulcers preceded by vesicles +eactivation of varicella- Self-limited$ but may have a prolon ed$ distributed alon a sensory nerve course; very )oster virus painful course; seen in debilitation$ painful; usually on trunk$ head$ and neck; rare trauma$ neoplasia$ and immunodeficiency intraorally; adults Hand-foot-and- Painful ulcers preceded by vesicles on hands$ ,oxsackie viruses Self-limited; recovery uneventful in about mouth disease feet$ and oral mucosa; usually children; rare 2 weeks Herpan ina Multiple painful ulcers in posterior oral cavity ,oxsackie viruses Self-limited; recovery uneventful in less and pharynx; lesions preceded by vesicles; than a week children most commonly affected; seasonal occurrence; rare

0ral mucous membranes may be infected by one of several different viruses, each producing a relatively distinct clinical pathologic picture (Table 1-1). The herpesviruses are a large family of viruses characteri8ed by a 694 core surrounded by a capsid and an envelope. 'even types of herpesviruses are nown to be pathogenic for humans, with si( of these lin ed to diseases in the head and nec area. Herpes simple( virus (H'+) infections are common vesicular eruptions of the s in and mucosa. They occur in two forms:systemic or primary:and may be locali8ed or secondary in nature. %oth forms are self-limited, but recurrences of the secondary form arc common because the virus can be se/uestered within ganglionic tissue in a latent state. ;ontrol rather than cure is the usual goal of treatment. Pathogenesis. Physical contact with an infected individual is the typical route of H'+ inoculation for a seronegative individual who has not been previously e(posed to the virus or possibly for someone with a low liter of protective antibody to H'+ (,igure 1-1). The virus binds to the cell surface epithelium via heparan sulfate, followed by the se/uential activation of specific genes during the lytic phase of infection. These genes include immediate early ($<) and early (<) genes coding for regulatory proteins and for 694 replication, and late (2) genes coding for structural proteins. 6ocumentation of the spread of infection through airborne droplets, contaminated water, or contact with inanimate ob=ects is generally lac ing. 6uring the primary infection, only a small percentage of individuals show clinical signs and symptoms of infectious systemic disease, whereas a vast ma=ority e(perience only subclinical disease. This latter group, now seropositive, can be identified through the laboratory detection of circulating antibodies to H'+. The incubation period after e(posure ranges from several days to * wee s. $n overt primary disease a vesiculoulcerative eruption (primary gingivostomatitis) typically occurs in the oral and perioral tissues. The focus of eruption is e(pected at the original site of contact. 4fter resolution of primary herpetic gingivostomatitis, the virus is believed to migrate, through some un nown mechanism, along the peria(on sheath of the trigeminal nerve to the trigeminal ganglion, where it is capable of remaining in a latent or

se/uestered state. 6uring latency no infectious virus is produced> there is e(pression of early, but not late, genes> and there is no free virus. 9o ma=or histocompatibility (?H;) antigens are e(pressed, so there is no T-cell response during latency. .eactivation of virus may follow e(posure to sunlight (@fever blisters@), e(posure to cold (@cold sores@), trauma, stress, or immunosuppression causing a secondary or recurrent infection. 4n immunocompromised host may develop severe secondary disease. H'+-seropositive patients being prepared for bone marrow transplants with chemotherapeutic drugs such as cyclophosphamide (with or without total-body radiation) are at ris for a secondary herpes infection that is particularly severe. Posttransplant chemotherapy also predisposes seropositive patients to severe recurrent oral infections. H'+-seropositive patients infected with human immunodeficiency virus (H$+) may also e(hibit intense secondary disease. &ncommonly, H$+-positive patients may have lesions that are coinfected by both H'+ and cytomegalovirus. The pathogenesis of dually infected ulcers is unclear. 'eronegative patients may rarely be affected with herpetic disease during immunosuppressive transplant states. The reactivated virus travels by way of the trigeminal nerve to the originally infected epithelial surface, where replication occurs, resulting in a focal vesiculoulcerative eruption. Presumably because the humoral and cell-mediated arms of the immune system have been sensiti8ed to H'+ antigens, the lesion is limited in e(tent, and systemic symptoms usually do not occur. 4s the secondary lesion resolves, the virus returns to the trigeminal ganglion and evidence of viral particles can no longer be found within the epithelium. $t is believed that nearly all secondary lesions develop from reactivated latent virus, although reinfection by different strains of the same subtype is considered a remote possibility. ?ost oral-facial herpetic lesions are due to H'+ type 1 (H'+1), although a small percentage may be caused by H'+ type * (H'+*) secondary to oralgenital contact. 2esions caused by either virus are clinically indistinguishable. H'+* has a predilection for genital mucosa, with infections having a pathogenesis similar to that of H'+1 infections of the head and nec . 2atent virus, however, is se/uestered in the lumbosacral ganglion. Previous H'+1 infections may provide some protection against H'+* infection because of antibody cross-reactivity. 4symptomatic shedding of intact H'+ virus particles in saliva can be identified in appro(imately 2% to 1"# of healthy adults in the absence of clinical disease. The level of ris of infection from @shedders@ to others has not been measured, although it is probably low and dependent on the /uantity of shed viral particles. There is an association between H'+* and carcinoma of the cervi(. However, the lin between H'+1 and oral cancer is less compelling. $n e(perimental studies of oral tissues there is evidence that H'+1 is

oncogenic in vitro, provided that cytolysis is inhibited by ultraviolet (&+) light or chemicals. $n the hamster chee pouch model, H'+ can induce genetic changes, including chromosome translocations, mutations, and gene amplifications, and in other animal models H'+ acts as a cocarcinogen with tobacco and other chemical carcinogens. $n patients with oral cancers there is a high prevalence of H'+ antibodies and antibodies to the immediate early proteins, but the significance is unclear.

Primary Herpetic Gingivostomatitis . Primary disease is usually seen in children, although adults who have not been previously exposed to HSV or who fail to mount an appropriate response to a previous infection may be affected. By age 15 about half the population is infected. The vesicular eruption may appear on the skin, vermilion, and oral mucous membranes (Box 1-1; Figure 1-2). Intraorally, lesions may appear on any mucosal surface. This is in contradistinction to the recurrent form of the disease, in which lesions are confined to the hard palate and gingiva. The primary lesions are accompanied by fever, artbralgia, malaise, anorexia, headache, and cervical lymphadenopathy. After the systemic primary infection runs its course of about 1 week to 10 days, the lesions heal without scar formation. By this time the virus may have migrated to the trigeminal ganglion to reside in a latent form. The number of individuals with primary clinical or subclinical infections in which virus assumes dormancy in nerve tissue is unknown. Secondary, or Recurrent, Herpes Simplex Infections . Secondary herpes represents the reactivation of latent virus. It is believed that only rarely does reinfection from an exogenous source occur in seropositive individuals. Alarge majority of the population (up to 90%) have antibodies to HSV, and up to 4 0 % of this group may develop secondary herpes. The pathophysiology of recurrence has been related to either a breakdown in focal immunosurveillance or an alteration in local inflammatory mediators that allows the virus to replicate. Patients usually have prodromal symptoms of tingling, burning, or pain in the site in which lesions will appear. Within a matter of hours, multiple fragile and short-lived vesicles appear. These become unroofed and coalesce to form maplike superficial ulcers. The lesions heal without scarring in 1 to 2 weeks and rarely become secondarily infected (Box 1-2; Figures 1-3 to 1-6). The number of recurrences is variable and ranges from one per year to as many as one per month. The recurrence rate appears to decline with age with each individual. The secondary lesions typically occur at or near the same site with each recurrence. Regionally, most secondary lesions appear on the vermilion and surrounding skin. This type of disease is usually referred to as herpes labialis. Intraoral recurrences are almost always restricted to the hard palate or gingiva.

Secondary herpes in the context of immunosupprcssion results in significant pain and discomfort, as well as a predisposition to secondary bacterial and fungal infections. In contrast to those occurring in nonimmunocompromised patients, lesions in the immunodeficient patient are atypical in that they can be chronic and destructive. They also are not site restricted orally. Herpetic Whitlow. Herpetic whitlow is either a primary or a secondary HSV infection involving the finger(s) (Figure 1-7). Before the universal use of examination gloves, this type of infection typically occurred in dental practitioners who had been in physical contact with infected individuals. In the case of a seronegative clinician, contact could result in a vesiculoulcerative eruption on the digit (rather than in the oral region), along with the signs and symptoms of primary systemic disease. Recurrent lesions, if they occur, would be expected on the finger(s). Herpetic whitlow in a seropositive clinician (e.g., one with a history of HSV infection) is believed to be possible, although less likely because of previous immune stimulation by herpes simplex antigens. Pain, redness, and swelling are prominent with herpetic whitlow and can be very pronounced. Vesicles or pustules eventually brea and become ulcers. 4(illary and5or epitrochlear lymphadenopathy may also be present. The duration of herpetic whitlow is protracted, and may be as long as 1 to A wee s. Histopathology. ?icroscopically, intraepithelial vesicles containing e(udate, inflammatory cells, and characteristic virus-infected epithelial cells are seen (,igure 1-B). The virus-infected eratinocytes contain one or more homogeneous, glassy nuclear inclusions. These cells are also readily found on cytologic preparations. H'+1 cannot be differentiated from H'+* histologically. 4fter several days, herpes-infected eratinocytcs cannot be demonstrated in either biopsy or cytologic preparations. Herpes simple( lesions in H$+-positive patients may be coinfected with cytomegalovirus. The pathogenesis and significance of this phenomenon are undetermined. Differential Diagnosis. Primary herpetic gingivostomatitis is usually apparent from clinical features. $t can be confirmed by a virus culture (which re/uires * to 1 days for positive identification). $mmunologic methods using monoclonal antibodies or 694 in situ hybridi8ation techni/ues have also become useful for specific virus identification in tissue sections. The systemic signs and symptoms coupled with the oral ulcers may re/uire differentiation from streptococcal pharyngitis, erythema multiforme, and acute necroti8ing ulcerative gingivitis (49&7, or +incentCs infection). ;linically, streptococcal pharyngitis does not involve the lips or perioral tissues, and vesicles do not precede the ulcers. 0ral ulcers of erythema multiforme are larger, usually without a vesicular stage, and are less li ely to affect the gingiva. 49&7 also commonly affects young adults> however, (he oral lesions are limited to the gingiva and are not preceded by vesicles. ?oreover, there is often considerable pain and

oral malodor in 49&7. 'econdary herpes is often confused with aphthous stomatitis but can usually be distinguished from it on the basis of clinical features. ?ultiple lesions, vesicles preceding ulcers, and palatal and gingival location are indicative of herpesvirus infection. $n addition, in contrast to herpetic lesions, aphthae usually only on non eratini8ed mucosa, such as the floor of the mouth, alveolar mucosa, and buccal mucosae. Treatment. 0ne of the most important factors in the treatment of H'+ infections is timing. ,or any drug to be effective, it must be used as soon as possible. 9o later than 1B hours from the onset of symptoms is generally regarded as the ideal time to start therapeutic measures. 4 number of virus-specific drugs have been developed. 4cyclovir and its analogs have shown the greatest efficacy in the treatment of mucocutaneous infections. The rationale for the use of topical agents resides in their ability to interrupt viral replication through inhibition of 694 polymeri8ation (acyclovir, penciclovir), or by interference with virus-epithelial interaction and prevention of intracellular access (docosanol). $n herpes-infected cells, acyclovir is converted by a virus-induced en8yme (thymidine inase) and other cellular en8ymes to a form that inhibits primarily viral 694 polymerase rather than host cell 694 polymerase. The end result is interruption of viral 694 synthesis and relative sparing of cellular 694 synthesis. 'ystemic acyclovir (*""- to 1""-mg tablets five times per day) is effective in the control of primary genital herpes and, to a lesser degree, primary oral herpes. 'upportive therapy (fluids, rest, oral lavage, analgesics, and antipyretics) is an essential component of any primary herpes simple( regimen. 'econdary herpes can be controlled to some degree with systemic acyclovir. .ecurrences are not prevented, but the course and severity of the disease are favorably affected. Prophylactic systemic acyclovir is effective in problematic cases and in immunosuppressed patients. $n H$+-positive patients with severe disease, aggressive therapy that may include intravenous acyclovir or ganciclovir may be necessary. Topical acyclovir, although it is only somewhat effective, has been advocated by some for the treatment of secondary herpes. 4 3# acyclovir (or analog) ointment applied five times per day when symptoms first appear slightly reduces the duration of herpes lesions and may abort some lesions. $t does not prevent recurrence, however, and may be ineffective in some patients.