VIRAL INFECTIONS IN THE IMMUNOCOMPETENT PATIENT

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DISORDERS AFFECTING THE ORAL CAVITY

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VIRAL INFECTIONS IN THE IMMUNOCOMPETENT PATIENT Craig S. Miller, DMD, MS

The purpose of this article is to provide an update of viral infections that affect children and adults who have normal immunosurveillance. Emphasis has been placed on new advances and knowledge regarding the herpesviruses and human papillomaviruses.

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HERPESVIRUSES

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There are now seven members of the viral family Herpesviridae. Herpes Virus-associated Diseases in Immunocompetent Persons

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1. Herpes simplex virus type 1 (HSV-1) Primary herpetic gingivostomatitis Herpetic whitlow Cutaneous lesions Eczema herpeticum Herpetic keratoconjunctivitis Herpes labialis (fever blister) Herpetic encephalitis 2. Herpes simplex virus type 2 (HSV-2) Genital herpes Neonatal herpes 3. Varicella-zoster virus (VZV) Varicella, chicken pox Reye's syndrome Zoster, shingles Postherpetic neuralgia 4. Cytomegalovirus (CMV) Infection of the newborn

Heterophile antibody negative mononucleosis Epstein-Barr virus (EBV) Infectious mononucleosis B-cell lymphomas Chronic fatigue syndrome? Burkitt lymphoma Nasopharyngeal carcinoma Human herpesvirus-6 (HHV-6) Exanthema subitum Human herpesvirus-7 (HHV-7) B virus (monkey) severe neurologic disease in humans

Classification has been determined by differences in virion architecture and the composition of the genome. All the human herpesviruses are ubiquitous, transmitted by close personal contact, and are known to cause a primary lytic infection, establish a latent infection following the primary infection, and can reactivate to cause localized recurrent disease in individuals with intact cellular immunity. The herpesviruses are acquired predominantly during childhood and to a smaller extent during early adolescence. Seropositivity is correlated with increasing age and low socioeconomic status. Transmission is enhanced by crowded living conditions and enrollment in preschool nurseries. All herpesviruses have been detected in the saliva at some 164, 197 The clinical manistage of infe~ti0n.l~~. festations of herpesvirus infections are di-

From the Oral Medicine Section, Department of Oral Health Science, University of Kentucky College of Dentistry, Lexington, Kentucky

DERMATOLOGIC CLINICS VOLUME 14 NUMBER 2 * APRIL 1996

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Figure 1. Oral involvement of primary herpetic gingivostomatitis.

verse, as is the site of latency. HSV and VZV establish latency in sensory nerve ganglia. EBV, HHV-6, and HHV-7 infect and persist in lymphocytes (EBV B-lymphocytes), and CMV has an affinity for peripheral blood mononuclear cells (PBMC), endothelial cells, and minor (labial) salivary gland tissue.17,l8 Cell-mediated (T-cell) immunity plays a critical role in the recovery from herpesvirus infections and may play a role in the development of recurrent disease. HERPES SIMPLEX VIRUS INFECTIONS

There are two types of HSV. HSV type 1 is the pathogen primarily responsible for cases of oral herpes. HSV-2 generally infects the skin below the waist. Transmission of HSV is by direct mucocutaneous contact with infected secretions. Dental manipulation, fomites (eating and drinking utensils), and selfinoculation are documented methods of Iz4 Primary infections aptransmi~sion.~~, pear to be slowly acquired throughout childhood. Kangro et a193report that antibodies to HSV are present in 37% of children of the United Kingdom under 12 years of age and 57% of children under 12 years of age living in Hong Kong. Approximately 70% to 90% of adults have been infected with HSV.4,47, 93 The majority of HSV infections are subclini~"~ cal and go unrecognized or are f l ~ - l i k e .The oral cavity is the most frequent site of primary HSV-1 infection. Other sites of entry include the nose, eye, and skin. Oral manifestations develop in about 10% of those infected. HSV replication in oral epithelial cells (primary herpetic gingivostomatitis) is char-

acterized by enlarged, erythematous, and tender gingiva and multiple vesicles of the buccal mucosa, labial mucosa, gingiva, palate, tongue, anklips (Figs. 1 and 2). The vesicles rupture, forming punctate ulcers with erythematous borders. Fever, chills, malaise, headache, sore throat, irritability, and regional lymphadenopathy are concurrent. Coalescence of lesions can result in large mucosal erosions that extend onto perioral skin. Dysphagia can result in dehydration and elevation of temperature. Scarring is not a feature of the disease, and complications involving multiorgan systems are rare. Most patients recover spontaneously in 10 to 20 days. Significant morbidity and mortality are seen in patients who have inadequate immune function.200A discussion of herpes lesions in immunoincompetent individuals appears elsewhere in this issue. Shedding of Herpes Simplex Virus

Reactivation of virus can occur with or without symptoms. Asymptomatic shedding of HSV in expectorated saliva has been detected in 0.19'0 to 9% of isolates of 1%to 10% of adults and 5% to 8% of children.27, 42, 92, 146, lB7 Intermittent shedding of a low amount of virus appears to be the pattern, with up to 80% of adults shedding HSV in oral secretions at least once when determined thrice weekly for 5 months.42 Kameyama et a192 found that healthy seropositive persons shed virus for an average of 1.2 days, whereas oral surgery patients showed continuous HSV-1 shedding over 2 to 10 days (5.8 days mean). Although HSV has been detected in whole saliva, the virus has not been found in the parotid gland.

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Figure 2. Palatal involvement of primary herpetic gingivostomatitis.

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Recurrent Herpes Simplex Virus Type 1 Infections (Herpes Labialis and Recurrent Oral Herpes)

About 20% to 40% of HSV-infected immunocompetent persons experience recurrent HSV infections, a repeated infection of mucocutaneous structures by HSV despite normal cell-mediated and humoral response.47,lM 171, Several stimulating factors including physical and emotional stress and trauma are known to initiate the disease. For example, section or decompression of the trigeminal nerve root has been reported to induce recurrent oral herpes in 60% to 90% of patients undergoing 152, these p r o c e d ~ r e s .46,~ ~ , 193 Oral surgery has provoked HSV recurrences in 20% of patients.92,l M Reactivated virus after tooth extraction has been shown to delay subsequent healing of the socket.144A direct association with alveolar osteitis (dry socket) has not been shown, however. HSV can infect and recur at any skin or mucous membrane site including the face and eye. Prodromal symptoms (i.e., tingling, throbbing, itching, and burning at the infected site) precede the eruption of lesions by 12 to 24 hours in 65% to 85% of patients. The initial lesion consists of a small cluster of vesicles, 1 to 3 mm in diameter. The vesicles rupture within 6 to 12 hours, resulting in punctate ulcers bordered by distinct red halos. Coalescence of adjacent ulcers and spread to perioral skin are common, especially if greasy lip ointments are used that permit horizontal weeping of vesicular fluid. Intraoral recurrent infections of HSV occur mostly over periosteum, that is, attached gingiva and the hard palate (Fig. 3). Extraoral recurrent infections are most common on the vermilion of the lip (Fig. 4). In relatively healthy persons,

Figure 3. Recurrent herpes of the attached gingiva.

Figure 4. Herpes labialis.

recurrent herpetic infections are of lesser intensity and shorter duration than the primary infection. Healing usually occurs in 5 to 10 days. Clinical findings are often pathognomonic; however, confirmation can be gained by viral culture or antigen detection using immunofluorescence or immunoperoxidase staining. Treatment of Primary Infection

Treatment of primary HSV-1 disease in normal patients requires the use of topical and systemic analgesics and antiviral agents. Dyclonine, viscous lidocaine, diphenhydramine (Benadryl) elixir, and Benadryl with Kaopectate are effective topical anesthetics when used as a rinse every 2 hours for 2 minutes. Salicylates, nonsteroidal anti-inflammatory agents, and acetaminophen also can be used to manage the pain. The former two drug categories are advantageous in that they provide anti-inflammatory properties. Salicylates should be avoided in children to minimize the risk of developing Reye’s syndrome in those who have febrile viral illness. HSV-1 is more suseptible to the antiviral drug acycloguanosine (acyclovir) than any other human herpesvirus. Acyclovir has low host cell toxicity and is preferentially incorporated into the growing viral DNA chain of infected cells via thymidine kinase phosphorylation, resulting in chain termination of HSV DNA repli~ation.’~~ Acyclovir, 200 mg five times daily, shortens the duration of viral shedding and ameliorates many of the symp160 Adverse effects are toms of infection.140* infrequent and antiviral resistance to HSV-1 has not been documented from isolates of saliva or lesions of immunocompetent persons who took acyclovir.187Penciclovir (9-(4-

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hydroxy-3-hydroxymethylbut-l-yl) guanine is a new antiviral agent currently undergoing testing. Neither agent has been shown to prevent the establishment of latency. Treatment of Recurrent Infection Prophylactic measures and avoidance of triggering stimuli are effective methods for reducing the risk of HSV recurrence. Sunscreens with 15 or greater skin protection factor minimize exposure to harmful ultraviolet rays and are effective in preventing recurrent disease.162A diet low in arginine and high in lysine and bioflavonoid-ascorbic acid complex reduces HSV-1 replication and aids in wound healing.143, lS8,lS9,192 When prophylaxis is unsuccessful, systemic acyclovir is the treatment of choice for recurrent 174 Oral acyclovir (200 mg), used 5 times a day, hastens lesion resolution and reduces HSV-1 shedding and duration of pain, when treatment begins in the prodrome or early ery174 Continuous systemic adthema ministration of acyclovir also helps to prevent recurrences.'" Intravenous acyclovir (5 mg/ kg every 8 hours) is reserved for severe oral disease in the immunocompromised patient. Topical 5% acyclovir has limited virostatic properties for orolabial lesions owing to its presence in a polyethylene-glycol base that does not penetrate oral epithelium well.158

ERYTHEMA MULTIFORME

Figure 5. Erythema multiforme limited to tongue involvement. (from Langlais RP, Miller CS: Color Atlas of Common Oral Diseases. Baltimore, Williams and Wilkins, p 91; with permission.)

ties, face, neck, oral cavity, and eyes of varied appearance (erythematous macules, papules, vesicles, and ulcerative lesions) but bilateral involvement. Lesions limited to the oral cavity occur in about 40% of patients.53,113,114 Oral and skin involvement occur in about 25% of patient^."^ Intraorally, lesions begin as red macules with irregular and erythematous borders. Predominant sites of occurrence include the buccal mucosa, labial mucosa, tongue, and lips (Fig. 5). The gingiva is rarely involved. Epithelial sloughing commonly results in map-like ulcers and hemorrhagic crusts, particularly of the lips. Lymphadenopathy usually is not present. Low-grade fever, malaise, and headache typically precede the emergence of lesions by several days and may persist during the illness. Pain is the most common symptom. Hemorrhage, sialorrhea, dysphagia, and arthralgia also have been associated with the condition. Without complications, healing requires 2 to 4 weeks. Recurrent and chronic forms exist, as well as a severe form, Stevens-Johnson syndrome, which disseminates to involve the eyes and

Erythema multiforme is an acute ulcerative condition of skin and mucous membranes caused by an immunologic response to foods, drugs (especially sulfa- and barbiturate-containing drugs), radiation, and microbial infections.8, 86, 113, 114, 131 Th'is abnormal response genitals.28,104.113.114. 177 leads to circulating immune complexes that provoke complement-mediated cytopathic effects, combined with lymphocytic and neutrophilic-stimulated vascular injury. Young Treatment adults, particularly men, are most commonly affected.165Rare cases have been associated Although there is some debate as to the with underlying internal ma1ignan~ies.l~~necessity to treat erythema multiforme leHSV has recently been established as the etiosions, oral disease is more persistent without logic agent responsible for many of the cases, treatment and severe cases can progress to primarily based on studies that identified Stevens-Johnson syndrome. In the past, good HSV DNA in 35% and 72% of skin lesions of clinical response has been demonstrated erythema multiforme.", 25, 37 when treatment with corticosteroids (i.e., Erythema multiforme, as the name sug0.1% dexamethasone elixir four times a day) gests, produces clinical lesions of the extremibegins early.l13 Moderate doses of systemic

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corticosteroids (1 to 2 mg/kg/d) also have been successful in patients with diffuse dermatologic and oral involvement. The use of corticosteroids with the recent implication of HSV has been questioned by Dhar and others.4' It is likely that clinical studies shortly will identify the value of antiviral agents in the course of this disease. Already, recurrent erythema multiforme can be suppressed with oral acyclovir, 400 to 800 mg three times a day, and prednisolone with levamisole has been reported to be useful.112 Figure 6.

Chickenpox involvement of the soft palate.

ORAL CANCER

HSV is synergistic with nitrosamines in oral carcinogenesis in animals, and certain HSV proteins may be associated with an increased risk of carcinoma in heavy smokers.'OZ,149 Nevertheless, the majority of viral evidence today associates human papillomavirus with the development of oral cancer.

VARICELLA ZOSTER VIRUS

palate (Fig. 6). Healing occurs slowly over 2 to 3 weeks. Common complications include secondary bacterial skin infection and otitis media. Pneumonia, arthritis, orchitis, uveitis, nephritis, encephalitis, Reye's syndrome, and Ramsay Hunt syndrome are rare developments. Second cases of varicella have been reported infreq~ent1y.I~~ Herpes Zoster

Recurrent VZV infection is referred to as Chickenpox is the most common skin rash shingles or zoster. The disease results when disease of childhood, with antibodies to VZV VZV is released from its dormant state and present in more than 90% of the p ~ p u l a t i o n . ' ~ ~spreads along peripheral nerves of the senIt occurs in all parts of the world, but is sory dermatome. Reactivation often is trigparticularly endemic to large cities. The disgered by underlying trauma, neoplasia, deease is highly contagious and is spread by pressed immune system, and stress. The respiratory aerosol and direct contact with incidence increases with age from 1.4 per lesions. Coughing precedes the infection and 1000 per year in 10- to 19-year-old subjects, helps spread the disease. All persons are susto 5.1 per 1000 per year among 50- to 59-yearold patients, to 10.1 per 1000 per month in ceptible; there is no race or sex predilection. 80- to 89-year-old patients.64 Attack rates are highest among children durThe disease is characterized by abrupt oning temperate climates, with peak incidence set and multiple vesicles that are distributed occurring during late winter months and unilaterally along a dermatome. Lesions classpring. Chickenpox is usually a self-limiting, morsically stop at the midline. Like chickenpox, the cutaneous lesions begin as erythematous billiform disease in children, but more severe in adults.26*179 The red macular rash is most macules that develop into vesicles, ulcers, and pustules. The truncal dermatome between prevalent on the head, trunk, and neck. Spread to the face, scalp, extremities, and muvertebrae T3 and L2, and the face along the cous membranes is common. All stages of ophthalmic division of the trigeminal nerve are affected most commonly. Oral lesions are the disease (i.e., macules, papules, vesicles, unilateral and segmentally distributed. Infedrying vesicles, and scabs) present at the rior alveolar nerve involvement typically afsame time and are characteristic. Fever, chills, fects the lips, tongue, and buccal mucosa. myalgia, malaise, and anorexia usually acInvolvement of the second division usually company the disease. Pruritus that is intense, produces unilateral palatal ulcerations. Red constant, and annoying is the main complaint. Intraoral lesions develop most often as inflammatory borders of the ulcers are promivesicles on the lips, hard palate, and soft nent and may resemble aphthae, but the ul-

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cers tend to be more numerous and confluent. Healing is slow and generally takes 2 to 3 weeks. Extreme pain accompanied by paresthesia, tenderness, malaise, fever, and distress is usual. The course of the infection is worse for patients with immune suppression and can result in tooth exfoliation, bony necrosis, severe periodontitis, scarring of the skin, root resorption, or mucocutaneous disseminat i ~ n . ' ~ ~A , ' "variant form of shingles, zoster sine herpete, exists in which symptoms are present but vesicular eruptions are absent.I6 Severe infections can cause skeletal muscle paralysis, disseminating pneumonia, meningoencephalitis, and hepatitis. Recurrent zoster heralds a poor prognosis.

immunogenic, and efficacious after a single dose in healthy and high-risk children.68,77, 88,184 Its use is anticipated to reduce the number of uncomplicated cases of chickenpox substantially, as well as decrease the number of complicated cases requiring hospitalizat i ~ nBreakthrough .~~ varicella after immunization has been documented in about 5% to 30% of the vaccinated population.20,loo Cases of breakthrough varicella are similar to natural varicella except breakthrough varicella is less severe, with up to one sixth fewer total and vesicular lesions, minimal fever, and shorter duration of illness by 1 day. Current data indicate that the cellular and humoral immune responses persist for at least 6 years after irnm~nization.'~~

Treatment Other Varicella-Zoster Virus Related Diseases

The treatment of mild chickenpox is debatable, but if needed, acyclovir is currently the drug of choice. Oral acyclovir (Zovirax) has been shown to shorten the course of the disease and significantly reduce fever when given within 48 hours of onset of rash.14,l5 The drug is also beneficial for those infected who have increased risk for severe illness (i.e., adults and immunocompromised patients). The recommended dosage for chickenpox is 20 mg/kg of body weight, with a maximum of 800 mg per dose four times daily for 5 days. Antiviral therapy is unlikely to reduce VZV transmission. There are three antiviral drugs available for shingles, famciclovir (Famvir), valacyclovir (Valtrex), and acyclovir. These agents should be used as early as possible to minimize the pain and morbidity associated with the disease. The recommended oral dosage of acyclovir for shingles in an adult is 800 mg five times daily for 7 to 10 days.57Famvir, 500 mg, is dosed three times per day for 7 days.45 Valtrex is dosed 1000 mg three times daily for 7 days. Antibiotics and interferon-a are second-line agents used to manage secondary infection and m~e1itis.I~~

Recurrent aphthous ulceration (RAU), also known as a canker sore, is a common oral mucosal disease affecting approximately 20% of the population.'2 The condition is characterized by recurring painful ulcers of the nonkeratinized mucosa. Young adult women are affected most often. An unknown antigen may initiate the disease. The role of VZV in the etiology of RAU has been proposed based on evidence that VZV antibody titers increase during the ulcerative phase of RAU, and VZV DNA has been detected by polymerase chain Whereas the reaction in 10 of 10 cases.153-155 recurrent nature of the disease and the immunologic response make viral agents suspect, the exact involvement of VZV remains to be determined. VZV has been shown to infect synovial membranes, but its association with arthritogenic conditions has not been e~tablished.~~ Likewise, VZV has transformation capacity of mammalian cells in vitro and has been shown to be oncogenic in vivo for the mouse cervix, but no human neoplastic condition has yet 78 been associated with the infection.6R,

Vaccination

CYTOMEGALOVIRUS

The Oka/Merck live-attenuated vaccine (Varivax)has been studied extensively for the past 20 years. It is licensed for use in Japan and Korea for healthy children and became available in the United States in 1995. This vaccine has been shown to be well tolerated,

CMV, although ubiquitous, is one of the least prevalent herpesvirus infections. It is spread by blood transfusions, saliva, sexual contact, and respiratory secretions. In the United Kingdom only 19% of adolescents and 34% of maternal adults had antibody to the

VIRAL INFECTIONS IN THE IMMUNOCOMPETENT PATIENT

virus.y3Forty percent to 80% of adults in developed countries are infected.lY, 176 A higher incidence is found in homosexual men, the economically disadvantaged, and daycare lY, 21, 43, 44, 123, 151 In one report, trans~ersonnel.~, mission from infected children of daycare centers to parent occurred in 30% of families.15oNo particular syndrome has been attributed to the several strains of CMV that exist. Almost all primary infections in immunocompetent patients are asymptomatic or flu-like, and rarely do serious consequences develop. CMV has a predilection for infecting endothelial or ductal epithelial cells. During the initial infection, the virus infects neutrophils and monocytes and spreads throughout the blood and vital organs. Incubation is 4 to 8 weeks. The most common manifestation is heterophile, antibody-negative mononucleosis. CMV mononucleosis is seen more frequently in adults producing self-limiting manifestations that include mild hepatitis, fever, malaise, and swollen lymph nodes (glandular fever-type syndrome), respiratory disease (but rarely pneumonia), and blood dyscrasia (usually thrombocytopenia or hemolytic anemia). The pharyngitis and cervical lymphadenopathy are generally less severe than EBV-associated disease.132Oral lesions associated with CMV (i.e., gingival hyperplasia, sialadenitis, oral ulcerations, Kaposi’s sarcoma) have been described thus far only in immunocompromised patients, and significant morbidity (i.e., progressive oropharyngeal ulcerations, hepatitis, pneumonia, graftversus-host disease, or chorioretinitis) can result from reactivation of CMV during peri74, 8y Diagnosis ods of immunosuppression.43~ generally is made by the detection of IgM antibodies against CMV using enzyme-linked immunosorbent assay. Immunohistochemistry and polymerase chain reaction are used increasingly when samples of tissue are obtainable. Reactivated virus can appear in all bodily secretions and has been shown to be shed in saliva and urine for 2 or more years.5oPersistent CMV infections have been detected in lymphocytes, monocytes, and minor (labial) salivary gland tissues from patients with Sjogren’s syndrome and nonspecific sialadenitis.121,lYy The role of CMV in Sjogren’s syndrome has not been established, however. Intrauterine Infection

Intrauterine infection with CMV is a serious congenital disease in the newborn that

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affects 0.5% to 2% of live births (cytomegalic inclusion disease).24Previous exposure is not associated with congenital transmission. Primary maternal infection results when pregnant women have a primary infection, or when the virus reactivates during the first two trimesters of pregnancy. Cytomegalic inclusion disease is associated with several birth defects including microcephaly, mental retardation, deafness, motor disability, liver abnormalities, and enamel hypoplasia of the primary dentition. Treatment

Antiviral therapy for CMV infections generally is reserved for immunosuppressed patients and as prophylaxis in bone marrow transplant patients. Ganciclovir (2-hydroxyl-hydroxymethyl) ethoxymethyl) guanine; DHPG), a nucleoside analogue similar to acyclovir, is the current drug of choice, with foscarnet, a phosphonoformate, the alterna147 Longtive in cases of drug re~istance.’~~, term use of ganciclovir has been associated with granulocytopenia. A live-attenuated vaccine prepared from the Towne strain of CMV has been tested in renal transplant patients with encouraging results.’57 EPSTEIN-BARR VIRUS INFECTION

EBV is the causative agent of infectious mononucleosis and has been associated with chronic (fatigue) mono syndrome and other lymphoproliferative disorders (i.e., Burkitt lymphoma), nasopharyngeal carcinoma, and thymic carcinoma.84EBV is transmitted orally. Acquisition of virus occurs in 50% of preschool children and 80% to 100% of the population of developing countries by age 21 years.13,23 The majority of primary infections are symptomless and occur early in life. The incubation period is generally 15 to 30 days. Most children are infected by 18 months, with a second peak of prevalence in adoles54 ~ence.*~, EBV can infect B and T lymphocytes and certain types of squamous epithelial cells that express a cellular membrane receptor corres137 ponding to the complement C3d receptor.5y, After penetrating the superficial layers of the nasopharynx, the virus replicates and produces pharyngitis in a small percentage of persons or latently can infect basal and inter-

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mediate layers and certain B-cell clones. EBV has been found in minor (labial) salivary gland, major (parotid) salivary gland, and in clinically normal mucosa of the tongue, gingiva, buccal mucosa, floor of mouth, and uterine cervix.'09,120, 12', lZ5,133, 168 Salivary EBV secretion has been detected in 20% of healthy antibody-positive persons and 50% of seropositive immunosuppressed patients.'67, 178 These findings suggest that latent infection may persist at multiple sites, and occasional periods of reactivation, associated with immunosuppression, lead to asymptomatic salivary secretion of virus and a continual source of infection of B cells and orpharyngeal epitheli~m.~~ Infectious Mononucleosis

EBV is the causative agent of the majority of cases of infectious mononucleosis (IM), with 12% of heterophile antibody-negative IM linked to other viral agents, particularly CMV and HHV-6.2,175 Lytic infection of B lymphocytes and some T lymphocytes with EBV results in activated and atypical (Downey cells) lymphocytes, a laboratory sign of IM. Orofacial manifestations of IM include multiple palatal petechiae, enlarged exudative tonsillitis, bilateral posterior cervical lymphadenopathy, and infrequently acute gingival ulcerations. Fatigue, malaise, lowgrade fever, and dysphagia usually accompany the condition. Liver involvement and splenomegaly occur in 25% to 40% of patients. For diagnosis the Monospot (Ortho Diagnostics) or Monosticon (Organon) test is performed to detect B cells, polyclonally activated by EBV, that produce multiple antibodies that react to several species (heterophile antibodies). Cytohybridization studies can be used to show the EBV genome within desquamated epithelial cells of saliva during IM. Treatment

Recovery requires bed rest, soft diet, analgesics, and antipyretics and usually takes 30 days. Corticosteroids have been used in select cases. Intravenous and oral acyclovir have been shown to reduce EBV oropharyngeal shedding in patients with IM, but do not affect the course of the infe~tion.'~ Acyclovir therapy for EBV-associated lymphoproliferative disorders generally has not been effec-

t i ~ ePatients . ~ ~ who receive ampicillin or other antibiotics may develop a rash or dermatographism. Rare complications include pharyngeal edema and airway compromise, meningitis, and serious liver disease. CHRONIC FATIGUE SYNDROME

Chronic fatigue syndrome (CFS) is an unexplained illness, most common in women, marked by unexplained chronic fatigue lasting 6 months or more that reduces normal activity to less than 50%. Common physical findings are low-grade fever, nonexudative pharyngitis, and palpable cervical or axillary lymph nodes. In addition to fatigue, symptoms include sore throat, painful lymphadenopathy, generalized muscle weakness and pain, headache, photophobia, and sleep disturbance. The immunologic abnormalities seen resemble those of the recovery phase from acute viral infection.'07 EBV has been the focus of many investigations because elevated titers of antibody to EBV characteristic of acute EBV infection have been detected in CFS patients.90,98, 180 Antiviral agents do not appear to control CFS, however, and several reports' indicate that more than one viral agent (i.e., enteroviruses and HHV-6, HHV7) may contribute to CFS. LYMPHOPROLIFERATIVE DISEASES

EBV has been detected in neoplastic cells of Burkitt's (approximately 70%) and nonBurkitt's lymphoma (17%-50%), nasopharyngeal carcinoma, and oropharyngeal lymphomata of immunocompromised patients and generally is considered causative of these ma52, =, 95 The ability of EBV to imlignancie~.~~, mortalize lymphocytes may be related to the expression of nuclear antigens (EBNA)-2A and latent membrane proteins (LMP-1) that can induce cell proliferation and activate certain oncogenes.49Of the two EBV strains identified, types A and B, the EBV-A variant is more efficient at transformation of B cells in vitro.161, 169 SJOGREN'S SYNDROME

EBV has been identified in parotid glands of patients with Sjogren's syndrome and nonspecific sialadenitis. The prevalence, how-

VIRAL INFECTIONS IN THE IMMUNOCOMPETENT PATIENT

ever, is similar to that found in persons without Sjogren's lZ6, 191 HUMAN HERPESVIRUS 6

Human herpesvirus 6 and 7 (HHV-6 and HHV-7) are newly recognized T-cell lymphotropic members of the herpesvirus family. HHV-6, a virus structurally similar to CMV, was first isolated in 1986 from peripheral blood mononuclear cells of patients suffering from lymphoproliferative disorders and AIDS."' More recently, it has been isolated from the saliva of those infected.Io6HHV-6 stimulates B cells in vitro and can induce Tcell division.'17 Two distinct classes of HHV6 (type A and B) exist, based on different molecular structure and immunologic properties; however, no distinction in pathogenesis has been determined.2 HHV-6 is acquired rapidly throughout the world. Transmission is most likely from mother to child by exchange of ~ a 1 i v a . lIt~ ~ infects more than 90% of children of the United States by age 2 and continues to infect those susceptible to about 8 years of age.93,lo6 Infection ranges from asymptomatic to severe disease.139When apparent, the virus causes roseola infantum (exanthema subitum), a generally benign disease characterized by spiking fever and truncal rash of 3 to 4 days' duration.z02Rare outcomes include diarrhea, bronchial pneumonia, convulsions, hepatocellular dysfunction, encephalitic complications, and fatal fulminant hepatitis. HHV-6 has been isolated at a high rate from submandibular and parotid gland biopsies, suggesting that these tissues may be sites of replication and persistence of the virus.61The virus frequently is reactivated in immunocompromised hosts and recently has emerged as a cause of rashes and febrile episodes in these patients.'42The virus may be a cofactor in the pathogenesis of HIV and human papillomavirus (HPV) infection via transactivation of HIV and HPV genes.48, Its role in the etiology of recurrent aphthous stomatitis has been proposed but not e~tab1ished.l~~ HUMAN HERPESVIRUS 7

HHV-7 was first recovered from CD4+ T (helper) cells of a healthy individual after activation of T cells with a m i t ~ g e n HHV-7 .~~ infection occurs later in childhood than HHV-

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6, with one study showing that antibodies to HHV-7 were present in 40% of newborns, 45% of children 1 to 4 years old, and 60% of HHV-7 has adolescents 11 to 13 years been isolated from the saliva of up to 81% of adults, and 70% of children older than 1 year.82,201, 203 Latency is probably established in T-helper cells and may be activated by Tcell a ~ t i v a t i o nThe . ~ ~pathogenic role of HHV7 is still undefined. HHV-7 can act as a helper virus for the reactivation of HHV-6 from latency, however, and the virus has been isolated from one 5-year-old boy suffering from repeated episodes of fever, hepatosplenomegaly, and pan~ytopenia.~~ HHV-7 has not been recovered from nonactivated T cells. HERPES B VIRUS INFECTION

Herpes B virus (Cercopithecine herpesvirus, herpesvirus simiae, simian herpesvirus, monkey B virus) infection is an enzootic infection of cynomolgus or long-tailed monkeys (Macaca fascicularis), rhesus monkeys (Macaca rnulatta), and other monkeys of the genus Macacu. Although the disease rarely affects humans, it is of concern to the medical and dental professions because of the increased contact of monkeys with humans involved in biomedical research and the severe outcome of infection. In the literature, 25 documented cases have been reported in which 22 cases (88%)progressed to encephalomyelitis and 16 resulted in death.*96 B virus is a herpesvirus that structurally resembles herpes simplex virus. Primary infection is often asymptomatic but may result in gingivostomatitis. Latency is established in sensory ganglia, and recurrent infection (localized lesions) result from stress. Transmission in monkeys is primarily by sexual contact. Less common modes of transmission are oral and dermal routes. Risk of B virus infection increases with age of the monkey, with serologic surveys revealing antibodies to B virus present in 51% of 97% of monkeys 138, 198 older than 2 years.97* Human infection by B virus has been reported to occur by direct inoculation of wounds from needle sticks, bites, scratches, and cage scratches with saliva, bodily fluids, and tissue cultures of infected monkey^.^, 148*196 There is one known case of human-tohuman transmis~ion.'~~ The incubation period ranges from 1 day to 10 years. Early manifestations are erythema, induration, and vesicu-

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lations at the site of infe~tion."~Constitutional symptoms include fever, malaise, myalgia, fatigue, lymphadenopathy, headache, and nausea and vomiting. Invariably, neurologic findings develop that include ataxia, agitation, diplopia, hyperesthesia, and ascending paralysis. Death as a result of encephalitis, encephalomyelitis, or respiratory failure usually results within 3 weeks, and human survivors often are left with moder196 Imate-to-severe neurologic impairment.148, mediate high-dose acyclovir, 800 mg five times daily or 10 to 15 mg/kg every 8 hours, is the recommended treatment for B-virus infection in humans. Ganciclovir may work in in vitro studies, but there are no human studies to date. HUMAN PAPILLOMAVIRUSES

HPVs are small DNA viruses that infect and replicate in squamous epithelia. Over 70 different HPV genotypes have been isolated and characterized. Each HPV subtype exhibits preferential anatomic sites of infection.l18 Although the majority of HPV subtypes have been associated with anogenital growths and uterine cancer, 13 genotypes have been identified and isolated in oral mucosal lesions.* The most common oral lesions associated 156 with HPV are benign exophytic Certain high-risk HPV subtypes (types 16 and 18) have been found in dysplastic epithelium and squamous cell carcinomas of the oral cavity.t Transmission is by direct contact with infected lesions from cutaneous and mucosal sites or by self-inoculation. SQUAMOUS PAPILLOMA

The squamous papilloma is the most common benign epithelial neoplasm of the oral cavity. The mean age of occurrence is 35 years and men are affected more frequently. Papillomas are asymptomatic small, slow-growing exophytic papules with a pedunculated base and pebbly surface (Fig. 7). Common locations are the uvulopalatal complex, tongue, frenum, lips, buccal mucosa, and gingiva. Intraoral lesions are soft, whereas those on the lips are generally rough and scaly. Solitary *References 6, 22, 30, 31, 39, 40, 56, 71, 73, 79, 99, 108, 110, 122, 128, 130, 156, 163, 181-183, 190, 206. tReferences 31, 42, 108, 110, 166, 181, 190, 195, 204.

Figure 7. A pedunculated squamous papilloma of the tongue.

lesions are the usual finding, but multiple lesions are seen occasionally. A viral etiology is probable, with recent studies implicating HPV types 6 and 11 in up to 100% of the papillomas examined.55,94, lS3 Another benign lesion with similar features is focal epithelial hyperplasia (Heck's disease). Clinically, the disease is characterized by multiple soft papules of the oral mucosa, particularly the lower lip. Native American Indians of North and South American are affected most frequently. HPV types 13 and 32 are the pathogens specifically found in 79,81 lesions of focal epithelial hyperpla~ia.~~, VERRUCA VULGARIS

Verruca vulgaris is a common skin growth caused by HPV that may occur intra~rally.'~~ The majority of oral warts are seen in children who have warts on their fingers. Transmission occurs by self-inoculation. HPV types 2 and 4 are implicated most often in the etiology of verruca vulgaris. Other subtypes (HPV 6, 11, and 16) also have been detected in verrucae.70,71. 119. 135. 145 Verrucae are found intraorally on the lips, tongue, labial mucosa, or gingiva (Fig. 8). They can be few or several in number. Clinically, they appear as firm, elevated papules that have a broad base and abrupt margins. The size is 0.2 to 1.5 cm in diameter. The surface is rough and white, pink, or slightly tan, depending on the degree of keratinization. Unlike skin warts, oral verrucae lack small, dark, surface discolorations. Onset of growth is sudden and rapid, whereas fully developed lesions often persist unchanged for months or years. Oral verrucae are usually

VIRAL INFECTIONS IN THE IMMUNOCOMPETENT PATIENT

235

mata acuminata have been described in immunosuppressed p a t i e n t ~ . ~ ~ Treatment

Figure 8. Multiple verrucae vulgaris of the labial commissure.

symptomless but may be tender at the base. A distinguishing feature of verrucae is that they are more likely to regress spontaneously than papillomas and c~ndylomata.'~~

The standard methods for eliminating benign HPV-induced oral lesions are surgical excision, cryotherapy, and laser ablation. Recurrences are rare when the entire lesion including the base is removed. Laser ablation requires the use of high-speed evacuation, because HPV DNA has been isolated from the laser plume and HPV pulmonary infections have resulted from inhalation of virus from the plume. The clinician is reminded that treatment of condylomata requires eradication of all lesions, even of infected partners. Chemical agents such as fluorouracil and formalin that are effective at extraoral sites generally are avoided in the oral cavity. Podophyllum requires careful application to min75 imize damage to adjacent normal mucosa.64,

CONDYLOMA ACUMINATUM OTHER HUMAN PAPILLOMAVIRUS-INDUCED LESIONS

Condyloma acuminatum is a venereal wart transmitted sexually to the oral cavity. Although its viral etiology has not been confirmed, HPV 6 and 11 have been isolated in more than 75% of lesions analyzed.56,182, ls3 Condylomata are seen in sexually active individuals in warm, moist, intertriginous areas, such as the anogenital skin and mouth. They appear as small, soft, pink to dirty-gray, papillomatous growths (Fig. 9). The surface is most often cauliflower-like, and the borders raised and rounded. Lesions are often multiple and recurrent and can coalesce to form large sessile, pebbly growths. Common sites include the ventral tongue, gingiva, labial mucosa, and palate. Recurrent oral condylo-

A discussion of all lesions associated with HPV is beyond the scope of this article (for additional reading see references 30 and 119). Nevertheless, it is important to mention that the presence of HPV does not always suggest a causal relationship. HPV has been detected in normal oral mucosa, benign leukoplakia, papillary hyperplasia, oral hairy leukoplakia, verrucous hyperplasia (Fig. lo), white sponge nevus, and an odontogenic keratocyst. The virus, however, does not appear to be related etiologically to the majority of these lesions.

Figure 9. Condyloma acuminatum of the lingual frenum. (From Miller CS: Semin Dermatol 13:114, 1994)

Figure 10. Verrucous hyperplasia in a patient with a 10pack-year history of smoking. (From Miller CS: Semin Dermatol 13:114, 1994)

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man infection with B virus following a needlestick injury. Rev Infect Dis 13:288-291, 1991 10. Asano Y , Nagai T, Miyata T, et al: Long-term protective immunity of recipients of the Oka strain of live varicella vaccine. Pediatrics 75:667-671, 1985 A recent review of the existing epidemio11. Aslanzadeh J, Helm KF, Espy MJ, et al: Detection of logic data derived from detection assays of HSV-specific DNA in biopsy tissue of patients with HPV in oral squamous cell carcinoma reerythema multiforme by polymerase chain reaction. vealed that HPV DNA was found 2 to 3.7 Br J Dermatol 12619-23, 1992 times more frequently in oral cancer speci12. Axel1 T, Henricsson V: The occurrence of recurrent mens compared with normal oral m ~ c o s a . ' ~ ~ aphthous ulcers in an adult Swedish population. Acta Odontol Scand 43:121-125, 1985 Virus also was detected in 75% of nodal me13. 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Address reprint requests to Craig S. Miller, DMD, MS MN 118 Oral Medicine Section Department of Oral Health Science University of Kentucky College of Dentistry Lexington, KY 40536-0084