Viral Infections

CLINICAL FEATURES: Acute herpetic gingivostomatitis (primary herpes) is the most common pattern of symptomatic primary HSV infection, and more than 90% are the result of HSV-1. In a study of more than 4000 children with antibodies to HSV-1, Jureti found that only 12% of those infected had clinical symptoms and signs severe enough to be remembered by the affected children or their parents. Some health care practitioners suspect that the percentage of primary infections that exhibit clinical symptoms is much higher, whereas others believe the prevalence is lower. Many primary infections may manifest as pharyngitis that mimics the pattern seen in common colds. Further studies are needed to fully answer this question.

Most cases of acute herpetic gingivostomatitis arise between the ages of 6 months and 5 years, with the peak prevalence occurring between 2 and 3 years of age. In spite of these statistics, occasional cases have been reported in patients over 60 years of age. Development before 6 months of age is rare because of protection by maternal anti-HSV antibodies. The onset is abrupt and often accompanied by anterior cervical lymphadenopathy, chills, fever (103° to 105° F), nausea, anorexia, irritability, and sore mouth lesions. The manifestations vary from mild to severely debilitating.

Initially the affected mucosa develops numerous pinhead vesicles, which rapidly collapse to form numerous small, red lesions. These initial lesions enlarge slightly and develop central areas of ulceration, which are covered by yellow fibrin (Fig. 7-1). Adjacent ulcerations may coalesce to form larger, shallow, irregular ulcerations (Fig. 7-2). Both the movable and attached oral mucosa can be affected, and the number of lesions is highly variable. In all cases the gingiva is enlarged, painful, and extremely erythematous (Fig. 7-3). In addition, the affected gingiva often exhibits distinctive punched-out erosions along the midfacial free gingival margins (Fig. 7-4). It is not unusual for the involvement of the labial mucosa to extend past the wet line to include the adjacent vermilion border of the lips. Satellite vesicles of the perioral skin are fairly common. Self-inoculation of the fingers, eyes, and genital areas can occur. Mild cases usually resolve within 5 to 7 days; severe cases may extend to 2 weeks. Rare complications include keratoconjunctivitis, esophagitis, pneumonitis, meningitis, and encephalitis.

As mentioned previously, when the primary infection occurs in adults, some symptomatic cases exhibit pharyngotonsillitis. Sore throat, fever, malaise, and headache are the initial symptoms. Numerous small vesicles develop on the tonsils and posterior pharynx. The vesicles rapidly rupture to form numerous shallow ulcerations, which often coalesce with one another. A diffuse, gray-yellow exudate forms over the ulcers in many cases. Involvement of the oral mucosa anterior to Waldeyer’s ring occurs in less than 10% of these cases. HSV appears to be a significant cause of pharyngotonsillitis in young adults who are from the higher socioeconomic groups with previously negative test findings for HSV antibodies. Most of these infections are HSV-1, but increasing proportions are HSV-2. The clinical presentation closely resembles pharyngitis secondary to streptococci or infectious mononucleosis, making the true frequency difficult to determine.

Recurrent herpes simplex infections (secondary herpes, recrudescent herpes) may occur either at the site of primary inoculation or in adjacent areas of surface epithelium supplied by the involved ganglion. The most common site of recurrence for HSV-1 is the vermilion border and adjacent skin of the lips. This is known as herpes labialis (“cold sore” or “fever blister”). Prevalence studies suggest that from 15% to 45% of the United States population have a history of herpes labialis. In some patients, ultraviolet light or trauma can trigger recurrences. Prodromal signs and symptoms (e.g., pain, burning, itching, tingling, localized warmth, erythema of the involved epithelium) arise 6 to 24 hours before the lesions develop. Multiple small, erythematous papules develop and form clusters of fluid-filled vesicles (Fig. 7-5). The vesicles rupture and crust within 2 days. Healing usually occurs within 7 to 10 days. Symptoms are most severe in the first 8 hours, and most active viral replication is complete within 48 hours. Mechanical rupture of intact vesicles and the release of the virus-filled fluid may result in the spreading of the lesions on lips previously cracked from sun exposure (Fig. 7-6). Recurrences are observed less commonly on the skin of the nose, chin, or cheek. The majority of those affected experience approximately 2 recurrences annually, but a small percentage may experience outbreaks that occur monthly or even more frequently.

On occasion, some lesions arise almost immediately after a known trigger and appear without any preceding prodromal symptoms. These rapidly developing recurrences tend to respond less favorably to treatment.

Recurrences also can affect the oral mucosa. In the immunocompetent patient, involvement is limited almost always to keratinized mucosa that is bound to bone (attached gingiva and hard palate). These sites often exhibit subtle changes, and the symptoms are less intense. The lesions begin as 1- to 3-mm vesicles that rapidly collapse to form a cluster of erythematous macules that may coalesce or slightly enlarge (Figs. 7-7 and 7-8). The damaged epithelium is lost, and a central yellowish area of ulceration develops. Healing takes place within 7 to 10 days.

Less common presentations of HSV-1 do occur. Infection of the thumbs or fingers is known as herpetic whitlow (herpetic paronychia), which may occur as a result of self-inoculation in children with orofacial herpes (Fig. 7-9). Before the uniform use of gloves, medical and dental personnel could infect their digits from contact with infected patients, and they were the most likely group affected by this form of HSV-I infection. Recurrences on the digits are not unusual and may result in paresthesia and permanent scarring.

Cutaneous herpetic infections also can arise in areas of previous epithelial damage. Parents kissing areas of dermatologic injury in children represent one vector. Wrestlers and rugby players also may contaminate areas of abrasion, a lesion called herpes gladiatorum or scrumpox. On occasion, herpes simplex has been spread over the bearded region of the face into the minor injuries created by daily shaving, leading to a condition known as herpes barbae (barbae is Latin for “of the beard”). Ocular involvement may occur in children, often resulting from self-inoculation. Patients with diffuse chronic skin diseases, such as eczema, pemphigus, and Darier’s disease, may develop diffuse life-threatening HSV infection, known as eczema herpeticum (Kaposi’s varicelliform eruption). Newborns may become infected after delivery through a birth canal contaminated with HSV, usually HSV-2. Without treatment, there is greater than a 50% mortality rate.

HSV recurrence in immunocompromised hosts can be significant. Without proper immune function, recurrent herpes can persist and spread until the infection is treated with antiviral drugs, until immune status returns, or until the patient dies. On the skin, the lesions continue to enlarge peripherally, with the formation of an increasing zone of superficial cutaneous erosion. Oral mucosa also can be affected and usually is present in conjunction with herpes labialis. Although most oral mucosal involvement begins on the bound mucosa, it often is not confined to these areas. The involved sites begin as areas of necrotic epithelium that are brownish and raised above the surface of the adjacent intact epithelium. Typically, these areas are much larger than the usual pinhead lesions found in immunocompetent patients. With time, the area of involvement spreads laterally. The enlarging lesion is a zone of superficial necrosis or erosion, often with a distinctive circinate, raised, yellow border (Figs. 7-10 and 7-11). This border represents the advancing margin of active viral destruction. Microscopic demonstration of HSV infection in a chronic ulceration on the movable oral mucosa is ominous, and all such patients should be evaluated thoroughly for possible immune dysfunction or underlying occult disease processes.

Although a yellow curvilinear border often is present in many chronic herpetic ulcerations noted in immunocompromised patients, this distinctive feature might be missing. Several authors have reported persistent oral ulcerations in patients with acquired immunodeficiency syndrome (AIDS) that lack the distinctive periphery, often are nonspecific clinically, and may mimic aphthous ulcerations, necrotizing stomatitis, or ulcerative periodontal disease. Biopsy of persistent ulcerations in patients with AIDS is mandatory and may reveal any one of a number of infectious or neoplastic processes. These ulcers may reveal histopathologic evidence of herpesvirus, often combined with diagnostic features of CMV (HHV-5) coinfection (see page 255).

HISTOPATHOLOGIC FEATURES: The virus exerts its main effects on the epithelial cells. Infected epithelial cells exhibit acantholysis, nuclear clearing, and nuclear enlargement, which has been termed ballooning degeneration (Fig. 7-12). The acantholytic epithelial cells are termed Tzanck cells (not specific for herpes; refers to a free-floating epithelial cell in any intraepithelial vesicle). Nucleolar fragmentation occurs with a condensation of chromatin around the periphery of the nucleus. Multinucleated, infected epithelial cells are formed when fusion occurs between adjacent cells (see Fig. 7-12). Intercellular edema develops and leads to the formation of an intraepithelial vesicle (Fig. 7-13). Mucosal vesicles rupture rapidly; those on the skin persist and develop secondary infiltration by inflammatory cells. Once they have ruptured, the mucosal lesions demonstrate a surface fibrinopurulent membrane. Often at the edge of the ulceration or mixed within the fibrinous exudate are the scattered Tzanck or multinucleated epithelial cells.

DIAGNOSIS: With a thorough knowledge of the clinical presentations, the clinician can make a strong presumptive diagnosis of HSV infection. On occasion, HSV infections can be confused with other diseases, and laboratory confirmation is desirable. Viral isolation from tissue culture inoculated with the fluid of intact vesi-cles is the most definitive diagnostic procedure. The problem with this technique in primary infections is that up to 2 weeks can be required for a definitive result. Laboratory tests to detect HSV antigens by direct fluorescent assay or viral DNA by polymerase chain reaction (PCR) of specimens of active lesions also are available. Serologic tests for HSV antibodies are positive 4 to 8 days after the initial exposure. Confirmation of primary infection by serology requires a specimen obtained within 3 days of the presentation and a second sample approximately 4 weeks later. In such cases the initial specimen should be negative, with antibodies discovered only in the convalescent sample. These antibody titers are useful in documenting past exposure and are used primarily in epidemiologic studies.

Intact vesicles are rare intraorally. Therefore, using intraoral viral culture as the sole means of diagnostic confirmation of HSV infection is inappropriate. Research has shown that asymptomatic oral HSV shedding occurs in up to 9% of the general population. During periods of mental or physical stress, asymptomatic viral shedding rises to approximately one third of those previously exposed to the virus. In immunocompromised patients, the prevalence rises to 38%; this percentage is low and most likely would double if the investigation were restricted to those previously exposed to the virus. Therefore, culture of lesions contaminated with saliva that might contain coincidentally released HSV is meaningless unless supplemented by additional diagnostic procedures.

Two of the most commonly used diagnostic procedures are the cytologic smear and tissue biopsy, with cytologic study being the least invasive and most cost-effective. The virus produces distinctive histopathologic alterations within the infected epithelium. Only VZV produces similar changes, but these two infections usually can be differentiated on a clinical basis. Fluorescent monoclonal antibody typing can be performed on the direct smears or on infected cells obtained from tissue culture.

If diagnostic features of herpesvirus are discovered in a biopsy of a persistent ulceration in an immunocompromised patient, immunocytochemical studies for CMV also should be performed to rule out coinfection. The histopathologic features of CMV can be missed easily, resulting in patients not receiving the most appropriate therapy.

TREATMENT AND PROGNOSIS: In the past, primary herpetic gingivostomatitis was treated best symptomatically; however, if the infection is diagnosed early, antiviral medications can have a significant influence. Patients should be instructed to restrict contact with active lesions to prevent the spread to other sites and people. As mentioned previously, autoinoculation of the eyes can result in ocular involvement with the possibility of recurrence. Repeated ocular reinfection can produce permanent damage and blindness. HSV is the leading infectious cause of blindness in the United States.

When acyclovir suspension is initiated during the first 3 symptomatic days in a rinse-and-swallow technique five times daily for 5 days (children: 15 mg/kg up to the adult dose of 200 mg), significant acceleration in clinical resolution is seen. Once therapy is initiated, development of new lesions ceases. In addition, the associated eating and drinking difficulties, pain, healing time, duration of fever, and viral shedding are shortened dramatically. The use of a topical spray with 0.5% or 1.0% dyclonine hydrochloride also dramatically, but temporarily, decreases the mucosal discomfort. Compounding pharmacists also can provide tetracaine lollipops that can be used for rapid and profound numbing of the affected mucosa. Viscous lidocaine and topical benzocaine should be avoided in pediatric patients because of reports of lidocaine-induced seizures in children and an association between topical benzocaine and methemoglobinemia. Nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen, also help alleviate the discomfort. Use of antiviral medications in capsule or tablet form is much less effective because of the increased time these formulations require to exert a significant effect.

Recurrent herpes labialis has been treated with everything from ether to voodoo; nothing has solved the problem for all patients. Of the antiherpetic medications, acyclovir ointment in polyethylene glycol was the initial formulation available for topical therapy. Acyclovir ointment has been of limited benefit for herpes labialis in immunocompetent patients, because its base is thought to prevent significant absorption. Subsequently, penciclovir cream became available in a base that allows increased absorption through the vermilion border. Use of this formulation has resulted in a statistically significant, although clinically minimal, reduction in healing time and pain (duration decreased approximately 1 day). Although the best results are obtained if use of penciclovir cream is initiated during the prodrome, late application has produced a measurable clinical benefit. Other current choices are acyclovir cream and an over-the-counter formulation of 10% n-docosanol cream. Although acyclovir cream does appear more effective than n-docosanol, both of these therapeutic choices are associated with statistically significant, but clinically minimal, reduction in healing time and pain, but at a lesser degree than that associated with penciclovir cream.

Systemic acyclovir and the two newer related medications, valacyclovir and famciclovir, appear to demonstrate similar effectiveness against HSV. However, valacyclovir and famciclovir exhibit improved bioavailability and more convenient oral dosing schedules. Of the three medications, a dosing schedule with valacyclovir, consisting of an initial 2 g taken on recognition of prodromal symptoms followed by another 2 g 12 hours later, has been most successful in minimizing the recurrences. The effects of this treatment are reduced significantly if it is not initiated during the prodrome. Although much less convenient, 400 mg of acyclovir taken five times daily for 5 days appears to produce similar results. For patients whose recurrences appear to be associated with dental procedures, a regimen of 2 g of valacyclovir taken twice on the day of the procedure and 1 g taken twice the next day may suppress or minimize any associated attack. In individuals with a known trigger that extends over a period of time (e.g., skiing, beach vacation), prophylactic short-term use of one of the antivirals (acyclovir, 400 mg twice a day [b.i.d.]; valacyclovir 1 g daily; or famciclovir 250 mg b.i.d.) has been shown to reduce the prevalence and severity of any associated recurrence.

Most cases of recurrent herpes labialis are infrequent; therefore, rarely can regular use of systemic antiviral medications be justified in immunocompetent individuals. Long-term suppression of recurrences with an antiviral medication is reserved by many for patients with more than six recurrences per year, those suffering from HSV-triggered erythema multiforme, and the immunocompromised. In recent years the emergence of acyclovir-resistant HSV has been seen with increasing frequency. Such resistance has arisen almost exclusively in immunocompromised patients receiving intermittent therapy, and the use of prophylactic therapy does not appear to be associated with emergence of resistant strains. In immunocompromised patients, the viral load tends to be high and replication is not suppressed completely by antiviral therapy, creating the environment for generating drug-resistant mutants. Although resistance is seen primarily in immunocompromised patients, cavalier use of antiviral medications for mild cases of recurrent herpes infection probably is inappropriate.

The pain associated with intraoral secondary herpes usually is not intense, and many patients do not require treatment. Some studies have shown chlorhexidine to exert antiviral effects in vivo and in vitro. In addi-tion, acyclovir appears to function synergistically with chlorhexidine. Extensive clinical trials have not been performed, but chlorhexidine alone or in combination with acyclovir suspension may be beneficial in patients who desire or require therapy of intraoral lesions.

Immunocompromised hosts with HSV infections often require intravenous (IV) antiviral medications to control the problem. Furthermore, severely immunosuppressed individuals, such as bone marrow transplant patients and those with AIDS, often need prophylactic doses of oral acyclovir, valacyclovir, or famciclovir. On occasion, viral resistance develops, resulting in the onset of significant herpetic lesions. Any herpes lesions that do not respond to appropriate therapy within 5 to 10 days most likely are the result of resistant strains. At this point the initial antiviral therapy should be repeated at an elevated dose. If this intervention fails, IV trisodium phosphonoformate hexahydrate (foscarnet) is administered. If the infection persists, IV cidofovir is recommended. Another antiviral, adenine arabinoside (vidarabine), is reserved for patients in whom all of the previously described medications have failed. In resistant cases that have been treated successfully, it appears that only the peripheral virus mutates, because future recurrences often are once again sensitive to the first-line antivirals. Ulcerations that reveal coinfection with HSV and CMV respond well to ganciclovir, with foscarnet used in refractory cases.

Although a successful live-virus vaccine has been available for the closely related varicella virus for over 25 years, similar approaches against HSV have produced less satisfactory results. Significant research for a potential vaccine is ongoing and offers hope for the future.

CLINICAL FEATURES: The symptomatic phase of VZV infection usually begins with malaise, pharyngitis, and rhinitis. In older children and adults, additional symptoms (e.g., headache, myalgia, nausea, anorexia, vomiting) occasionally are seen. This is followed by a characteristic, intensely pruritic exanthem. The rash begins on the face and trunk, followed by involvement of the extremities. Each lesion rapidly progresses through stages of erythema, vesicle, pustule, and hardened crust (Figs. 7-14 and 7-15). The early vesicular stage is the classic presentation. The centrally located vesicle is surrounded by a zone of erythema and has been described as “a dewdrop on a rose petal.” In contrast to herpes simplex, the lesions typically continue to erupt for 4 days; in some cases the exanthem’s arrival may extend to 7 or more days. Old crusted lesions intermixed with newly formed and intact vesicles are commonplace. Affected individuals are contagious from 2 days before the exanthem until all the lesions crust. Fever usually is present during the active phase of the exanthem. The severity of the cutaneous involvement is variable and often more severe in adults and in household members secondarily infected by the initial patient.

Perioral and oral manifestations are fairly common and may precede the skin lesions. The vermilion border of the lips and the palate are the most common sites of involvement, followed by the buccal mucosa. Occasionally, gingival lesions resemble those noted in primary HSV infections, but distinguishing between the two is not difficult because the lesions of varicella tend to be relatively painless. The lesions begin as 3- to 4-mm, white, opaque vesicles that rupture to form 1- to 3-mm ulcerations (Fig. 7-16). The prevalence and number of the oral lesions correlate with the severity of the extraoral infection. In mild cases, oral lesions are present in about one third of affected individuals. Often only 1 or 2 oral ulcers are evident, and typically these heal within 1 to 3 days. In contrast, patients with severe infections almost always have oral ulcerations, often numbering up to 30 lesions and persisting for 5 to 10 days. In severe cases of chickenpox, old ruptured lesions will often become intermixed with fresh vesicles.

Complications can occur, with the need for hospitalization in children approximating 1 in 600 in the prevaccine era. Possible complications include Reye’s syndrome, secondary skin infections, encephalitis, cerebellar ataxia, pneumonia, gastrointestinal dis-turbances (e.g., vomiting, diarrhea, associated dehydration), and hematologic events (i.e., thrombocytopenia, pancytopenia, hemolytic anemia, sickle cell crisis).

In childhood the most frequent complications are secondary skin infections, followed by encephalitis and pneumonia. With enhanced public education and decreased use of aspirin in children, the prevalence of Reye’s syndrome is decreasing. Although associated bacterial infections had decreased after the introduction of antibiotics, an increased prevalence of significant complications related to secondary infections caused by group A, b-hemolytic streptococci was seen during the 1990s. These organisms have created life-threatening infections and areas of highly destructive necrotizing fasciitis.

The prevalence of complications in adults exceeds that noted in children. The most common and serious complication is varicella pneumonitis, which features dry cough, tachypnea, dyspnea, hemoptysis, chest pain, and cyanosis. Encephalitis and clinically significant pneumonia are diagnosed in 1 in 375 affected adults older than 20 years of age. The central nervous system (CNS) involvement typically produces ataxia but may result in headaches, drowsiness, convulsions, or coma. The risk of death is reported to be 15 times greater in adults compared with children, mostly because of an increased prevalence of encephalitis.

Infection during pregnancy can produce congenital or neonatal chickenpox. Involvement early in the pregnancy can result in spontaneous abortion or congenital defects. Although complications can occur in newborns, the effects of maternal varicella infection appear minimal. A multicenter prospective study of live births associated with maternal varicella infection revealed only a 1.2% prevalence of embryopathy. However, infection of the mother close to delivery can result in a severe fetal infection caused by a lack of maternal antibodies.

Infection in immunocompromised patients also can be most severe. The cutaneous involvement typically is extensive and may be associated with high fever, hepatitis, pneumonitis, pancreatitis, gastrointestinal obstruction, and encephalitis. Before effective antiviral therapy, the mortality rate in immunocompromised individuals was approximately 7%. Secondary bacterial infections often complicate the process.

HISTOPATHOLOGIC FEATURES: The cytologic alterations are virtually identical to those described for HSV. The virus causes acantholysis, with formation of numerous free-floating Tzanck cells, which exhibit nuclear margination of chromatin and occasional multinucleation.

DIAGNOSIS: The diagnosis of chickenpox usually can be made from a history of exposure to VZV within the last 3 weeks and the presence of the typical exanthem. Confirmation can be obtained through a demonstration of viral cytopathologic effects present within the epithelial cells harvested from the vesicular fluid. These cytologic changes are identical to those found in herpes simplex, and further confirmation sometimes is desired. Viral isolation in cell culture or rapid diagnosis from fluorescein-conjugated VZV monoclonal antibodies can be performed. Finally, serum samples can be obtained during the acute stage and 14 to 28 days later. The later sample should demonstrate a significant (fourfold) increase in antibody titers to VZV.

TREATMENT AND PROGNOSIS: Before the current antiviral medications became available, the treatment of varicella primarily was symptomatic. Warm baths with soap or baking soda, application of calamine lotion, and systemic diphenhydramine still are used to relieve pruritus. VZV has a lipid envelope that is destroyed rapidly by soap and other detergents. Lotions with diphenhydramine are not recommended because of reports of toxicity secondary to percutaneous absorption of the medication. Antipyretics other than aspirin should be given to reduce fever.

Use of peroral antiviral medications such as acyclovir, valacyclovir, and famciclovir has been shown to reduce the duration and severity of the infection if it is administered within the first 24 hours of the rash. Routine use of these antiviral medications is not recommended in immunocompetent children with uncomplicated chickenpox. Typically, such therapy is reserved for patients at risk for more severe disease, such as those over 13 years of age and individuals who contract the disease from a family member. Intravenous formulations are used in immunosuppressed patients or those exhibiting a progressive, severe infection. Treatment with one of the available antiviral medications does not alter the antibody response to VZV or reduce immunity later in life.

In patients without evidence of immunity who become exposed to VZV and are at high risk for severe disease or complications, purified varicella-zoster immune globulin can be given to modify the clinical manifestations of the infection. Individuals at risk include immunocompromised patients, pregnant women, premature infants, and neonates whose mothers do not have evidence of immunity. The U.S.-licensed manufacturer of the immune globulin marketed the material under the name VZIG but discontinued production in October 2004. At the time of this writing, the immune globulin is being made by a Canadian company and is known as VariZIG. This product has not completed full U.S. Food and Drug Administration (FDA) approval and is currently classified as an investigational new drug (IND). In an attempt to improve access during this critical period of transition, an expanded access protocol has been approved by a central institutional review board (IRB), with the FDA not requiring additional local IRB approval at the treatment site. VariZIG is most effective if administered within 96 hours of initial exposure. In most instances the material can be delivered from the distributor to the treatment site within 24 hours.

A live attenuated varicella vaccine has been available since 1974 and has been used extensively outside the United States, especially in Japan. In 1995 the vaccine was approved for use in the United States. Before that time, the annual incidence of infection in the United States was approximately 4 million, with an associated 11,000 hospitalizations and 100 deaths. Vaccination is recommended for children between 12 and 18 months of age, as well as for all susceptible individuals over the age of 13. Although the vaccination rates vary by state, the national coverage is approximately 85% and has led to a reduction of reported infection rates that also is around 85%.

During the first year after vaccination, the efficacy appears to be 100% but drops to 95% after 7 years. When breakthrough infections do occur, they usually are very mild. Because of continued exposure to wild virus, previously vaccinated patients have not required boosters to maintain immunity. As the prevalence of the wild virus diminishes, booster vaccines may be required to maintain lifelong immunity. Extensive follow-up of vaccinated groups is ongoing; if antibody levels wane with time, booster immunizations will be recommended. It should be remembered that the vaccine is a live virus that can be spread to individuals in close contact. Vaccine recipients who develop a rash should avoid contact with those at risk, such as immunocompromised or pregnant individuals.

The national health objectives for 2010 included a goal to obtain and maintain ≥95% vaccination coverage among first graders for hepatitis B, diphtheria, tetanus, pertussis, poliovirus, measles, mumps, rubella, and varicella. The measles, mumps, and rubella (MMR) vaccine currently has achieved a 93% vaccination rate, whereas the frequency for the varicella vaccine remains below 90%. Use of a combined measles, mumps, rubella, and varicella (MMRV) vaccine has demonstrated comparable effectiveness and safety. This approach would provide protection via a single injection and have the potential to increase the vaccination rate for varicella more rapidly.

CLINICAL FEATURES: The clinical features of herpes zoster can be grouped into three phases: (1) prodrome, (2) acute, and (3) chronic. During initial viral replication, active ganglionitis develops with resultant neuronal necrosis and severe neuralgia. This inflammatory reaction is responsible for the prodromal symptoms of intense pain that precedes the rash in more than 90% of the cases. As the virus travels down the nerve, the pain intensifies and has been described as burning, tingling, itching, boring, prickly, or knifelike. The pain develops in the area of epithelium innervated by the affected sensory nerve (dermatome). Typically, one dermatome is affected, but involvement of two or more can occur. The tho racic dermatomes are affected in about two thirds of cases. This prodromal pain, which may be accompanied by fever, malaise, and headache, normally is present 1 to 4 days before the development of the cutaneous or mucosal lesions. During this period (before the exanthem) the pain may masquerade as sensitive teeth, otitis media, migraine headache, myocardial infarction, or appendicitis, depending on which dermatome is affected.

Approximately 10% of affected individuals will exhibit no prodromal pain. Conversely, on occasion there may be recurrence in the absence of vesiculation of the skin or mucosa. This pattern is called zoster sine herpete (zoster without rash), and affected patients have severe pain of abrupt onset and hyperesthesia over a specific dermatome. Fever, headache, myalgia, and lymphadenopathy may or may not accompany the recurrence.

The acute phase begins as the involved skin develops clusters of vesicles set on an erythematous base (Fig. 7-17). Within 3 to 4 days, the vesicles become pustular and ulcerate, with crusts developing after 7 to 10 days. The lesions tend to follow the path of the affected nerve and terminate at the midline (Fig. 7-18). The exanthem typically resolves within 2 to 3 weeks in otherwise healthy individuals. On healing, scarring with hypopigmentation or hyperpigmentation is not unusual.

Oral lesions occur with trigeminal nerve involvement and may be present on the movable or bound mucosa. The lesions often extend to the midline and frequently are present in conjunction with involvement of the skin overlying the affected quadrant. Like varicella, the individual lesions manifest as 1- to 4-mm, white, opaque vesicles that rupture to form shallow ulcerations (Fig. 7-19). Involvement of the maxilla may be associated with devitalization of the teeth in the affected area.

Several reports have documented significant bone necrosis with loss of teeth in areas involved with herpes zoster. Because of the close anatomic relationship between nerves and blood vessels within neurovascular bundles, inflammatory processes within nerves have the potential to extend to adjacent vessels. It is postulated that the gnathic osteonecrosis may be secondary to damage of the blood vessels supplying the alveolar ridges and teeth, leading to focal ischemic necrosis. Of the reported cases, there is almost an equal distribution between the maxilla and mandible, with both sexes affected similarly. Although the average patient age is approximately 55, a wide range has been seen from the second to late eighth decade. The average interval between the appearance of the exanthem and the osteonecrosis is 21 days, but it has been reported as late as 42 days.

Ocular involvement is not unusual and can be the source of significant morbidity, including permanent blindness. The ocular manifestations are highly variable and may arise from direct viral-mediated epithelial damage, neuropathy, immune-mediated damage, or secondary vasculopathy. If the tip of the nose is involved, this is a sign that the nasociliary branch of the fifth cranial nerve is involved, suggesting the potential for ocular infection. In these cases, referral to an ophthalmologist is mandatory.

Facial paralysis has been seen in association with herpes zoster of the face or external auditory canal. Ramsay Hunt syndrome is the combination of cutaneous lesions of the external auditory canal and involvement of the ipsilateral facial and auditory nerves. The syndrome causes facial paralysis, hearing deficits, vertigo, and a number of other auditory and vestibular symptoms. In multiple studies of patients thought to have Bell’s palsy (see page 859), evidenced of active VZV infection was detected in approximately 30% of patients by polymerase chain reaction (PCR) or via demonstration of appropriate antibody titers, suggesting an underlying viral cause for many cases of “idiopathic” facial paralysis. Similar associations also have been demonstrated with HSV and EBV.

Approximately 15% of affected patients progress to the chronic phase of herpes zoster, which is characterized by pain (postherpetic neuralgia) that persists longer than 3 months after the initial presentation of the acute rash. Postherpetic neuralgia is uncommon in individuals under the age of 50 but affects at least 50% of patients older than 60 years of age. The pain is described as burning, throbbing, aching, itching, or stabbing, often with flares caused by light stroking of the area or from contact with adjacent clothing. Most of these neuralgias resolve within 1 year, with half of the patients experiencing resolution after 2 months. Rare cases may last up to 20 years, and patients have been known to commit suicide as a result of the severe, lancinating quality of the pain. Although the cause is unknown, some investigators believe chronic VZV ganglionitis is responsible. Clearance of the pain has been reported within days after initiation of long-term famciclovir, with recurrence of the pain if the medication is stopped. Additional double-blind, placebo-controlled studies will need to be performed to confirm this observation.

HISTOPATHOLOGIC FEATURES: The active vesicles of herpes zoster are identical microscopically to those seen in the primary infection, varicella. For more information, refer to the previous portions of the chapter on the histopathologic presentation of varicella and herpes simplex.

DIAGNOSIS: The diagnosis of herpes zoster often can be made from the clinical presentation, but other procedures may be necessary in atypical cases. Viral culture can confirm the clinical impression but takes at least 24 hours. Cytologic smears demonstrate viral cytopathologic effects, as seen in varicella and HSV. In most cases the clinical presentation allows the clinician to differentiate zoster from HSV, but cases of zosteriform recurrent HSV infection, although uncommon, do exist. A rapid diagnosis can be obtained through the use of direct staining of cytologic smears with fluorescent monoclonal antibodies for VZV. This technique gives positive results in almost 80% of the cases. Molecular techniques such as dot-blot hybridization and PCR also can be used to detect VZV.

TREATMENT AND PROGNOSIS: Before the development of the current antiviral medications, therapy for herpes zoster was directed toward supportive and symptomatic measures. Fever should be treated with antipyretics that do not contain aspirin. Antipruritics, such as diphenhydramine, can be administered to decrease itching. Skin lesions should be kept dry and clean to prevent secondary infection; antibiotics may be administered to treat such secondary infections.

Early therapy with appropriate antiviral medications such as acyclovir, valacyclovir, and famciclovir has been found to accelerate healing of the cutaneous and mucosal lesions, reduce the duration of the acute pain, and decrease the duration of postherpetic neuralgia. These medications are most effective if initiated within 72 hours after development of the first vesicle. The newer generation of antiviral drugs, famciclovir and valacyclovir, may be more successful than acyclovir in reducing the prevalence of postherpetic neuralgia.

Once the skin lesions have healed, the neuralgia may become the worst aspect of the disease and often is the most difficult to resolve successfully. This intense pain has been treated with variable results by a variety of methods, including analgesics, narcotics, tricyclic antidepressants, anticonvulsants, gabapentin, percutaneous electric nerve stimulation, biofeedback, nerve blocks, and topical anesthetics. As mentioned previously, postherpetic neuralgia may be related to chronic VZV ganglionitis and respond to long-term famciclovir. In those who do not respond to famciclovir, IV acyclovir often leads to clinical improvement.

One topical treatment, capsaicin, has had significant success, with almost 80% of patients experiencing some pain relief; however, the medication’s effect often does not occur until 2 weeks or more of therapy. Capsaicin is derived from red peppers and is not recommended for placement on mucosa or open cutaneous lesions. Capsaicin has been associated with significant burning, stinging, and redness in 40% to 70% of patients, with up to 30% discontinuing therapy because of this side effect. After use, patients must be warned to wash their hands and avoid contact with mucosal surfaces.

Corticosteroid therapy has been used in the hope it might decrease the neural inflammation and associated chronic pain. Although conflicting research has been published, studies have shown no long-term benefit when corticosteroids are added to an acyclovir regimen. In addition, an increased prevalence of side effects was noted in groups treated with corticosteroids.

A live attenuated VZV vaccine has been approved for use in adults 60 years of age or older. The vaccine, Zostavax, is 14 times more potent than Varivax, the vaccine for chickenpox. In a study of more than 38,000 adults, Zostavax markedly decreased the prevalence of herpes zoster, as well as the morbidity and frequency of postherpetic neuralgia in those who did develop the infection. In an October 2006 press release, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention (CDC) recommended that the vaccine be given to all people 60 years of age and older. This recommendation is being reviewed and becomes official only when published in the CDC’s Morbidity and Mortality Weekly Report.

CLINICAL FEATURES: Most EBV infections in children are asymptomatic. In children younger than 4 years of age with symptoms, most have fever, lymphadenopathy, pharyngitis, hepatosplenomegaly, and rhinitis or cough. Children older than 4 years of age are affected similarly but exhibit a much lower prevalence of hepatosplenomegaly, rhinitis, and cough.

Most young adults experience fever, lymphadenopathy, pharyngitis, and tonsillitis. Hepatosplenomegaly and rash are seen less frequently. In adults older than 40 years of age, fever and pharyngitis are the predominant findings, with less than 30% demonstrating lymphadenopathy. Less frequent signs and symptoms in this group include hepatosplenomegaly, rash, and rhinitis or cough. Possible significant complications include splenic rupture, thrombocytopenia, autoimmune hemolytic anemia, aplastic anemia, and neurologic problems with seizures. These complications are uncommon at any age but more frequently develop in children.

In classic infectious mononucleosis in a young adult, prodromal fatigue, malaise, and anorexia occur up to 2 weeks before the development of pyrexia. The body temperature may reach 104° F and lasts from 2 to 14 days. Prominent lymphadenopathy is noted in more than 90% of the cases and typically appears as enlarged, symmetrical, and tender nodes, frequently with involvement of the posterior and anterior cervical chains. Enlargement of parotid lymphoid tissue rarely has been reported and can be associated with facial nerve palsy. More than 80% of affected young adults have oropharyngeal tonsillar enlargement, sometimes with diffuse surface exudates and secondary tonsillar abscesses (Fig. 7-20). The lingual tonsils, which are located on the base of the tongue and extend from the circumvallate papilla to the epiglottis, can become hyperplastic and compromise the airway. Rare fatalities have been reported from respiratory difficulties secondary to the combined effects of hyperplasia of the lingual and palatine tonsils, arytenoid hypertrophy, pharyngeal edema, uvular edema, and epiglottal swelling.

Oral lesions other than lymphoid enlargement also may be seen. Petechiae on the hard or soft palate are present in about 25% of patients (Fig. 7-21). The petechiae are transient and usually disappear within 24 to 48 hours. Necrotizing ulcerative gingivitis (NUG) (see page 157) also is fairly common. NUG-like pericoronitis (see page 171) and necrotizing ulcerative mucositis (see page 158) occur less frequently. Cases of NUG that are refractory to normal therapy should be evaluated to rule out the possibility of EBV.

A controversial symptom complex called chronic fatigue syndrome has been described, and several investigators have tried to associate EBV with this problem. Patients complain of rather nonspecific symptoms of chronic fatigue, fever, pharyngitis, myalgias, headaches, arthralgias, paresthesias, depression, and cognitive defects. These patients often demonstrate elevations in EBV antibody titers, but this finding alone is insufficient to prove a definite cause-and-effect relationship. Several studies have cast serious doubt on a relationship between EBV and the chronic fatigue syndrome.

DIAGNOSIS: The diagnosis of infectious mononucleosis is suggested by the clinical presentation and should be confirmed through laboratory procedures. The white blood cell (WBC) count is increased, with the differential count showing relative lymphocytosis that can become as high as 70% to 90% during the second week. Atypical lymphocytes usually are present in the peripheral blood. The classic serologic finding in mononucleosis is the presence of Paul-Bunnell heterophil antibodies (immunoglobulins that agglutinate sheep erythrocytes). A rapid test for these antibodies is available and in-expensive. More than 90% of infected young adults have positive findings for the heterophil antibody, but infected children younger than age 4 frequently have negative results. Indirect immunofluorescent testing to detect EBV-specific antibodies should be used in those suspected of having an EBV infection but whose findings were negative on the Paul-Bunnell test. Enzyme-linked immunosorbent assays (ELISA) and recombinant DNA-derived antigens also may be used in place of the indirect immunofluorescent test.

TREATMENT AND PROGNOSIS: In most cases, infectious mononucleosis resolves within 4 to 6 weeks. Non–aspirin-containing antipyretics and NSAIDs can be used to minimize the most common symptoms. Infrequent complications include splenic rupture, EBV-related hepatitis, and Bell’s palsy. Patients with significant enlargement of the spleen should avoid contact sports to prevent the rare possibility of splenic rupture. On occasion, the fatigue may become chronic. In immunocompromised patients, a polyclonal B-lymphocyte proliferation may occur and possibly lead to death.

The tonsillar involvement may, on occasion, resemble streptococcal pharyngitis or tonsillitis (see page 183). However, treatment with ampicillin and penicillin should be avoided because the use of these antibiotics in infectious mononucleosis has been associated with a higher than normal prevalence of allergic morbilliform skin rashes.

Corticosteroid use is the recommended therapy in many textbooks. Such drugs, however, should not be used indiscriminately because the person’s immune response appears to be the most important factor in fighting the infection and preventing a potentially fatal polyclonal B-lymphocyte proliferation. In addition, an increased prevalence of encephalitis and myocarditis has been noted in patients who have infectious mononucleosis and are treated with steroids. Corticosteroid use produces a shortened duration of fever and shrinkage of enlarged lymphoid tissues, but its use should be restricted to life-threatening cases (e.g., those with upper-airway obstruction because of massive lymphadenopathy, tonsillar hyperplasia, and oropharyngeal edema). If corticosteroid therapy fails to resolve the airway obstruction, acute tonsillectomy and tracheostomy may be necessary.

Although antiviral medications such as acyclovir, valacyclovir, and famciclovir have been used successfully for temporary resolution of oral hairy leukoplakia, these medications do not demonstrate clinically obvious benefit for patients with infectious mononucleosis. Although the medications most likely have an effect on viral replication, the main clinical manifestations appear to be secondary to the immune response to EBV-infected activated B lymphocytes and are not altered by the medical intervention.

CLINICAL FEATURES: At any age, almost 90% of CMV infections are asymptomatic. In clinically evident neonatal infection, the infant appears ill within a few days. Typical features include hepatosplenomegaly, extramedullary cutaneous erythropoiesis, and thrombocytopenia (often with associated petechial hemorrhages). Significant encephalitis frequently leads to severe mental and motor retardation.

Although the majority of acute CMV infections are asymptomatic, less than 10% may include a nonspecific pattern of symptoms that ranges from an influenza-like presentation to lethal multiorgan involvement. In a review of 115 hospitalized immunocompetent adults with CMV infection, the most common symptoms (in order) include fever, joint and muscle pain, shivering, abdominal pain, nonproductive cough, cutane-ous eruption (maculopapular rash), and diarrhea. Associated signs include hepatomegaly, splenomegaly, adenopathy, pharyngitis, jaundice, and evidence of meningeal irritation. The authors stress that symptomatic CMV infection should not be dismissed in immunocompetent patients and should be considered in any patient with unexplained persistent fever.

In contrast to patients with infectious mononucleosis, only about one third of patients with CMV infection demonstrate pharyngitis and lymphadenopathy. Rarely, immunocompetent patients may show signs of an acute sialadenitis that diffusely involves all of the major and minor salivary glands. In such cases, xerostomia often is noted and the affected glands are painful. Involvement of the major glands usually results in clinically obvious enlargements of the parotid and submandibular glands. Unusual complications of primary CMV infection include myocarditis, pneumonitis, and septic meningitis.

Evident CMV involvement is not unusual in immunocompromised transplant patients. In some cases a temporary mild fever is the only evidence; in others, the infection becomes aggressive and is characterized by significant hepatitis, leukopenia, pneumonitis, gastroenteritis, and, more rarely, a progressive wasting syndrome.

CMV disease is common in patients with AIDS (see page 264). CMV chorioretinitis affects almost one third of patients with AIDS and tends to progress rapidly, often resulting in blindness. Bloody diarrhea from CMV colitis is fairly common but may respond to appropriate antiviral medications.

Although oral lesions from CMV infection have been documented in a number of immunosuppressive conditions, reports of oral involvement by CMV have been increasing since the advent of the AIDS epidemic. Most affected patients have chronic mucosal ulcerations, and CMV changes are found on biopsy. Occasionally, chronic oral ulcerations in immunocompromised patients will demonstrate coinfection (usually CMV combined with HSV).

Neonatal CMV infection also can produce developmental tooth defects. Examination of 118 people with a history of neonatal CMV infection revealed tooth defects in 40% of those with symptomatic infections and slightly more than 5% of those with asymptomatic infections. The teeth exhibited diffuse enamel hypoplasia, significant attrition, areas of enamel hypomaturation, and yellow coloration from the underlying dentin.

HISTOPATHOLOGIC FEATURES: Biopsy specimens of intraoral CMV lesions usually demonstrate changes within the vascular endothelial cells. Scattered infected cells are extremely swollen, showing both intracytoplasmic and intranuclear inclusions and prominent nucleoli. This enlarged cell has been called an “owl eye” cell. Gomori’s methenamine silver and periodic acid-Schiff (PAS) stains demonstrate the cytoplasmic inclusions but not the intranuclear changes. Salivary ductal epithelium also may be affected and form “owl eye” cells (Fig. 7-22).

DIAGNOSIS: The diagnosis of CMV infection is made by considering a combination of the clinical features and by conducting other examinations. Biopsy material can demonstrate cellular changes that suggest infection. Because effective therapies exist for CMV infections in immunocompromised patients, biopsies are recommended for chronic ulcerations that are not responsive to conservative therapy. More specific verification can be made by electron microscopy, detection of viral antigens by immunohistochemistry, in situ hybridization, polymerase chain reaction (PCR), demonstration of rising viral antibody titers, or viral culture. Enzyme-linked immunosorbent assay (ELISA) serologic testing for CMV is inexpensive, demonstrates good specificity, and should be considered in any patient with an unexplained fever or signs of CMV infection.

In immunocompromised patients with chronic ulcerations, the typical “owl eye” cells may be few and difficult to discover on routine light microscopy. When biopsy is performed on a chronic oral ulceration in these patients, in situ hybridization or immunohistochemical evaluation for CMV should be performed, even in the absence of “owl eye” cells. In addition, close examination to rule out coinfection by HSV also should be performed.

TREATMENT AND PROGNOSIS: Although most CMV infections resolve spontaneously, therapy often is required in the immunosuppressed patient. Ganciclovir has resolved clinical symptoms in more than 75% of treated immunocompromised patients. However, the medication must be continued to prevent a relapse if the immune dysfunction persists. In patients with oral ulcerations coinfected with CMV and HSV, intravenous (IV) ganciclovir will produce resolution in most instances. The development of resistance to ganciclovir has been reported; other effective medications include foscarnet, cidofovir, and valganciclovir. In spite of these antiviral medications, the best therapy in immunocompromised patients remains improvement of their immune status, such as that achieved with highly active anti-retroviral therapy (HAART) therapy in many patients with AIDS (see page 280).

Immunocompetent patients with clinically evident CMV infection usually are treated symptomatically with antipyretic medications and NSAIDs. Corticosteroids or IV gammaglobulins have been used in patients with hemolytic anemia or severe thrombocytopenia. There is no consensus related to the use of antiviral agents in immunocompetent patients.

CLINICAL FEATURES: In many countries, epidemics occur every 2 to 3 years and primarily affect children aged 1 to 4 years. The timing of the epidemics appears to be correlated to the accumulation of a new population of susceptible young children. In all three clinical patterns, the severity and significant complications are variable and appear associated with the particular strain that is responsible. In general, most strains produce a self-limiting disease that requires no therapy, but occasional strains can produce epidemics with an increased number of significant complications and occasional mortalities. Systemic complications include pneumonia, pulmonary edema and hemorrhage, acute flaccid paralysis, encephalitis, meningitis, and carditis. Infection with coxsackie B virus during pregnancy occasionally has been associated with fetal and neonatal death, whereas cardiac anomalies have been noted in infants who survive the initial infection.

In 1998 a massive epidemic spread over Taiwan (population 21,178,000), and it is estimated that approximately 1.5 million people developed clinical evidence of the infection. A group of sentinel physicians (8.7% of primary physicians) documented 129,106 infected patients. Of these patients, the vast majority were infected with enterovirus 71; a much lesser number were infected with one of a number of coxsackieviruses (predominantly A16). When patients infected with the same strain were examined, clinical patterns diagnostic of both herpangina and hand-foot-and-mouth disease were detected. In this epidemic, more than 75% had symptoms of hand-foot-and-mouth disease, but it is clear these two clinical patterns represent variations of the same disorder.

In the surveillance document by the Centers for Disease Control and Prevention (CDC) of the reported enterovirus infections between 1970 and 2005, 44.2% occurred in infants younger than 1 year of age, 15% in children aged 1 to 4 years, 11.6% in children aged 5 to 9 years, 11.9% in those aged 10 to 19 years, and 17.3% in patients older than 20 years. During this period, 131 deaths were reported secondary to complications such as aseptic meningitis, encephalitis, paralysis, myocarditis, and neonatal enteroviral sepsis. The most common viruses to produce herpangina or hand-foot-and-mouth disease were, in order, coxsackieviruses B5, A9, B3, B1, and A16, followed by enterovirus 71. In patients younger than the age of 20, there was a male predominance. In those older than 20, females were infected more frequently, most likely because of exposure as the primary caregivers to infected young children.

HISTOPATHOLOGIC FEATURES: In patients with herpangina and hand-foot-and-mouth disease, the areas of affected epithelium exhibit intracellular and intercellular edema, which leads to extensive spongiosis and the formation of an intraepithelial vesicle. The vesicle enlarges and ruptures through the epithelial basal cell layer, with the resultant formation of a subepithelial vesicle. Epithelial necrosis and ulceration soon follow. Inclusion bodies and multinucleated epithelial cells are absent.

DIAGNOSIS: The diagnoses of herpangina, hand-foot-and-mouth disease, and acute lymphonodular pharyngitis usually are made from the distinctive clinical manifestations. In patients with atypical presentations, laboratory confirmation appears prudent. Viral isolation from culture can be performed, and analysis of stool specimens is the best technique in patients with only mucosal lesions. Throat culture findings tend to be positive predominantly during the early acute stage. The culture of cutaneous lesions is best for the diagnosis of hand-foot-and-mouth disease. A serologic demonstration of rising enteroviral antibody titers between the acute and convalescent stages can be used to confirm the diagnosis in questionable cases. Polymerase chain reaction (PCR) assay is increasingly available and replacing viral culture in many diagnostic laboratories.

TREATMENT AND PROGNOSIS: In most instances, the infection is self-limiting and without significant complications. Therapy for patients with an enterovirus infection is directed toward symptomatic relief. Nonaspirin antipyretics and topical anesthetics, such as dyclonine hydrochloride, often are beneficial.

Occasionally, certain strains produce infections with a more aggressive clinical course. During the 1998 epidemic in Taiwan, a large group of physicians reported 405 patients with severe disease and 78 deaths. Patients with more significant complications demonstrated higher body temperature (>102° F), fever for longer than 3 days, more serious vomiting, and greater lethargy. When these findings are present, the physician must monitor the patient more closely for the development of more serious complications.

CLINICAL FEATURES: Most cases of measles arise in the winter and are spread through respiratory droplets. The incubation period is from 10 to 12 days, and affected individuals are infectious from 2 days before becoming symptomatic until 4 days after appearance of the associated rash. The virus is associated with significant lymphoid hyperplasia that often involves sites such as the lymph nodes, tonsils, adenoids, and Peyer’s patches. Giant cell infiltration is noted in various tissues along with a vasculitis that is responsible for the characteristic skin rash.

There are three stages of the infection, with each stage lasting 3 days and justifying the designation nine-day measles. The first 3 days are dominated by the three Cs: Coryza (runny nose), Cough (typically brassy and uncomfortable), and Conjunctivitis (red, watery, and photophobic eyes). Fever typically accompanies these symptoms. During this initial stage, the most distinctive oral manifestation, Koplik’s spots, is seen. Multiple areas of mucosal erythema are visible on the buccal and labial mucosa, and less often on the soft palate; within these areas are numerous small, blue-white macules (Fig. 7-28). In addition, similar spots rarely are noted on the inner conjunctival folds of the eye or the vaginal mucosa. These pathognomonic spots represent foci of epithelial necrosis and have been described as “grains of salt” on a red background.

As the second stage begins, the fever continues, the Koplik’s spots fade, and a maculopapular and erythematous (morbilliform) rash begins. The face is involved first, with eventual downward spread to the trunk and extremities. Ultimately, a diffuse erythematous maculopapular eruption is formed, which tends to blanch on pressure (Fig. 7-29). Abdominal pain secondary to lymphatic involvement is not rare.

In the third stage, the fever ends. The rash begins to fade and demonstrates a similar downward progression with replacement by a brown pigmentary staining. Ultimately, desquamation of the skin is noted in the areas previously affected by the rash.

Common complications in young children are otitis media, pneumonia, persistent bronchitis, and diarrhea. Acute appendicitis occasionally is seen secondary to vascular obstruction created by the swelling of Peyer’s patches. Encephalitis develops in approximately 1 in 1000 cases, often resulting in death or permanent brain damage and mental retardation. In about 1 in 100,000 cases, a delayed complication termed subacute sclerosing panencephalitis (SSPE) arises as late as 11 years after the initial infection. This degenerative disorder of the CNS leads to personality changes, seizures, coma, and death. Widespread vaccine use has virtually eliminated SSPE in developed nations. In the United States, one to two deaths occur for every 1000 reported cases of measles. In developing countries, the infection often is more severe, and the case-to-fatality rate can be as high as 25%. The most common causes of death are pneumonia and acute encephalitis.

Measles in immunocompromised patients can be serious, with a high risk of complications and death. Most of these patients exhibit either an atypical rash or no exanthem. Pneumonitis is the primary complication. The fatality rate of measles in patients with a malignancy is greater than 50%; AIDS-associated measles results in the death of more than one third of affected patients.

Koplik’s spots are not the only oral manifestation that may be associated with measles. Candidiasis, necrotizing ulcerative gingivitis (NUG), and necrotizing stomatitis may occur if significant malnutrition also is present. Severe measles in early childhood can affect odontogenesis and result in pitted enamel hypoplasia of the developing permanent teeth. Enlargement of accessory lymphoid tissues such as the lingual and pharyngeal tonsils also may be noted.

HISTOPATHOLOGIC FEATURES: Because of the reduced prevalence of measles and the transient nature of Koplik’s spots, few oral and maxillofacial pathologists have had the opportunity to view these lesions microscopically. Initially, Koplik’s spots represent areas of focal hyperparakeratosis in which the underlying epithelium exhibits spongiosis, intercellular edema, dyskeratosis, and epithelial syncytial giant cells. The number of nuclei within these giant cells ranges from three to more than 25. Close examination of the epithelial cells often reveals pink-staining inclusions in the nuclei or, less commonly, in the cytoplasm. On electron microscopy, the inclusions have been shown to represent microtubular aggregates characteristic of the causative paramyxovirus. As the spot ages, the epithelium exhibits heavy exocytosis by neutrophils leading to microabscess formation, epithelial necrosis, and, ultimately, ulceration. Frequently, examination of the epithelium adjacent to the ulceration will reveal the suggestive syncytial giant cells.

Examination of hyperplastic lymphoid tissue during the prodromal stage of measles often reveals a similar alteration. In 1931, Warthin and Finkeldey, in two separate publications, reported an unusual finding in patients who had their tonsils removed within 1 to 5 days of the clinical appearance of measles. Within the hyperplastic lymphoid tissue, there were numerous multinucleated giant lymphocytes (Fig. 7-30). These multinucleated cells subsequently have been termed Warthin-Finkeldey giant cells and were thought for a time to be specific for measles. Since that time, however, similar-appearing cells have been noted in a variety of lymphoproliferative conditions such as lymphoma, Kimura’s disease, AIDS-related lymphoproliferative disease, and lupus erythematosus.

DIAGNOSIS: The diagnosis of typical measles in an epidemic setting usually is straightforward and based on the clinical features and history. Laboratory confirmation can be of value in isolated or atypical cases. Viral isolation or rapid detection of viral antigens is possible, but confirmation usually is established through a demonstration of rising serologic antibody titers. The antibodies appear within 1 to 3 days after the beginning of the exanthem and peak in about 3 to 4 weeks.

TREATMENT AND PROGNOSIS: With a complication rate of 21%, the best treatment for measles is a good vaccination program; rubeola is part of the widely used MMR vaccine. In an attempt to stop the resurgence of measles that began in 1989, the vaccination schedule was altered and the pockets of young, unvaccinated children were targeted. This action brought the transmission of indigenous measles to record lows. Although the number is variable from year to year, since 1993 the annual incidence of reported cases in the United States typically is well below 500. Total eradication of the infection is technically feasible with existing vaccines but will require universal cooperation and enthusiasm from across the globe. Renewed emphasis in the noncompliant sections of society must be stressed. In addition, a new two-dose vaccination schedule has been adopted in an attempt to decrease the vaccine failures. Currently, routine vaccination is recommended for all children between the ages of 12 and 15 months, with a second dose administered between the ages of 4 and 6 years.

In otherwise healthy patients with measles, fluids and nonaspirin antipyretics are recommended for symptomatic relief. Immunocompromised patients also may be treated with one of a number of medications that have shown promise but definitively have not been proven to be efficacious. The most promising is ribavirin; however, immunoglobulin, interferon, and vitamin A also are being used.

CLINICAL FEATURES: A large percentage of infections are asymptomatic; the frequency of symptoms is greater in adolescents and adults. Prodromal symptoms may be seen 1 to 5 days before the exanthem and include fever, headache, malaise, anorexia, myalgia, mild conjunctivitis, coryza, pharyngitis, cough, and lymphadenopathy. The lymphadenopathy may persist for weeks and is noted primarily in the suboccipital, postauricular, and cervical chains. The most common complication is arthritis, which increases in frequency with age and usually arises subsequent to the rash. Rare complications include encephalitis and thrombocytopenia.

The exanthematous rash is often the first sign of the infection and begins on the face and neck, with spread to the entire body within 1 to 3 days. The rash forms discrete pink macules, then papules, and finally fades with flaky desquamation. The rash fades as it spreads and often exhibits facial clearing before the completion of its spread into the lower body areas. Generally, the rash is resolved completely by day 3, giving rise to the designation three-day measles.

Oral lesions, known as Forchheimer’s sign, have been reported to be present in about 20% of the cases. These consist of small, discrete, dark-red papules that develop on the soft palate and may extend onto the hard palate. This enanthem arises simultaneously with the rash, becoming evident in about 6 hours after the first symptoms and not lasting longer than 12 to 14 hours. Palatal petechiae also may occur.

The risk of CRS correlates with the time of infection. The frequency of transmission from an infected mother is greater than 80% during the first 12 weeks of pregnancy, with the risk of fetal damage decreasing dramatically at 8 weeks and becoming rare after 20 weeks of gestation. The classic triad of CRS consists of deafness, heart disease, and cataracts. Deafness is the most common manifestation, affecting more than 80% of patients. This hearing loss may not become evident until 2 years of age and usually is bilateral. Less common, late emerging complications include encephalopathy, mental retardation, diabetes mellitus, and thyroid disorders.

DIAGNOSIS: The diagnosis of rubella is contingent on laboratory tests because the clinical presentation of the acquired infection is typically subclinical, mild, or nonspecific. Although viral culture is possible, serologic analysis is the mainstay of diagnosis.

TREATMENT AND PROGNOSIS: Rubella is mild, and therapy usually is not required. Nonaspirin antipyretics and antipruritics may be useful in patients with significant fever or symptomatic cutaneous involvement. Passive immunity may be provided by the administration of human rubella immunoglobulin. If immunoglobulin is given within a few days of exposure, it decreases the severity of the infection. This therapy typically is reserved for pregnant patients who decline abortion.

During the 1962 to 1965 worldwide rubella epidemic, the estimated number of infections in the United States was 12.5 million. These infections were associated with 20,000 infants born with CRS, 11,250 fetal deaths, and 2100 neonatal deaths. Because of the two-dose vaccination schedule with the MMR and at least 95% vaccination coverage among school-aged children, in 2004, rubella was declared no longer to be endemic in the United States. The annual reported incidence of rubella was 23 in 2001, 18 in 2002, 7 in 2003, and 9 in 2004. Approximately half of these infections occurred in individuals born outside the United States. Likewise, from 2001 to 2004, only four cases of CRS were reported, and three of the mothers of these infants were not born in the United States.

CLINICAL FEATURES: Approximately 30% of mumps infections are subclinical. In symptomatic cases, prodromal symptoms of low-grade fever, headache, malaise, anorexia, and myalgia arrive first. Most frequently, these nonspecific findings are followed within 1 day by significant salivary gland changes. The parotid gland is involved most frequently, but the sublingual and submandibular glands also can be affected. Discomfort and swelling develop in the tissues surrounding the lower half of the external ear and extending down along the posterior inferior border of the adjacent mandible (Fig. 7-31). The enlargement typically peaks within 2 to 3 days, and the pain is most intense during this period of maximal enlargement. Chewing movements of the jaw or eating saliva-stimulating foods tends to increase the pain. Enlargement of the glands usually begins on one side and is followed by contralateral glandular changes within a few days. Unilateral involvement is seen in about 25% of patients.

The second most common finding is epididymo-orchitis, which occurs in about 25% of postpubertal males. In those affected the testicle exhibits rapid swelling, with significant pain and tenderness. The enlargement can range from a minimal swelling to a fourfold increase in size. Unilateral involvement is most common. On resolution of the swelling, atrophy occurs in the affected testicle. Permanent sterility from testicular changes is rare. Less commonly, oophoritis and mastitis can be seen in postpubertal females. In addition, spontaneous abortion occurs in approximately 25% of women who contract mumps during the first trimester of pregnancy.

Less commonly, meningoencephalitis (from involvement of the choroid plexus), cerebellar ataxia, hearing loss, pancreatitis, arthritis, carditis, and decreased renal function may occur. The most common symptom associated with CNS involvement is headache, whereas involvement of the pancreas can lead to nausea and vomiting. Isolated changes, such as orchitis or meningitis, may occur in the absence of salivary gland involvement, thereby making diagnosis difficult in nonepidemic settings. Mumps-related mortality is exceedingly rare and most frequently associated with mumps encephalitis.

The most frequently reported oral manifestation is redness and enlargement of Wharton’s and Stensen’s salivary gland duct openings. In addition, involvement of the sublingual gland may produce bilateral enlargements of the floor of the mouth.

DIAGNOSIS: The diagnosis of mumps can be made easily from the clinical presentation when the infection is occurring in an epidemic fashion; however, isolated cases must be differentiated from other causes. The most frequently used confirmatory measures are demonstration of mumps-specific IgM or a fourfold rise of mumps-specific IgG titers when measured during the acute phase and about 2 weeks later. In addition, a swab of secretions obtained from parotid or other affected salivary gland ducts can be used for viral isolation or reverse-transcriptase–polymerase chain reaction testing.

TREATMENT AND PROGNOSIS: The treatment of mumps is palliative in nature. Frequently, nonaspirin analgesics and antipyretics are administered. In an attempt to minimize orchitis, bed rest is recommended for males until the fever breaks. Avoidance of sour foods and drinks helps to decrease the salivary gland discomfort. As with measles and rubella, the best results come from prior vaccination, thereby preventing the infection.

CLINICAL FEATURES: HIV infection initially may be asymptomatic, or an acute response may be seen. The acute viral syndrome that occurs typically develops within 1 to 6 weeks after exposure in 50% to 70% of infected patients. The symptoms bear some resemblance to those of infectious mononucleosis (e.g., generalized lymphadenopathy, sore throat, fever, maculopapular rash, headache, myalgia, arthralgia, diarrhea, photophobia, peripheral neuropathies). Oral changes may include mucosal erythema and focal ulcerations.

The acute viral syndrome clears within a few weeks; during this period, HIV infection usually is not considered or investigated. A variable asymptomatic period follows. Some patients have persistent generalized lymphadenopathy (PGL), which may later resolve. In some patients (before development of overt AIDS), there is a period of chronic fever, weight loss, diarrhea, oral candidiasis, herpes zoster, and/or oral hairy leukoplakia (OHL). This has been termed AIDS-related complex (ARC).

The presentation of symptomatic, overt AIDS is highly variable and often is affected by a person’s prior exposure to a number of chronic infections. The signs and symptoms described under ARC are often present, along with an increasing number of opportunistic infections or neoplastic processes. In 50% of the cases, pneumonia caused by the protozoan Pneumocystis carinii is the presenting feature leading to the diagnosis. Other infections of diagnostic significance include disseminated cytomegalovirus (CMV) infection, severe herpes simplex virus (HSV) infection, atypical mycobacterial infection, cryptococcal meningitis, and cen-tral nervous system (CNS) toxoplasmosis. Persistent diarrhea is commonplace and may be bacterial or protozoal in origin. Clinically significant neurologic dysfunction is present in 30% to 50% of patients, and the most common manifestation is a progressive encephalopathy known as AIDS-dementia complex.

The most widely accepted classification of the oral manifestations of AIDS was compiled by the EC-Clearinghouse on Problems Related to HIV Infection and the WHO Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus. This classification divided the manifestations into three groups: (1) strongly associated, (2) less commonly associated, and (3) seen in patients HIV infection (Box 7-1). The discussion here concentrates primarily on the clinical presentations. (For detailed information on the histopathology, diagnosis, and treatment of each condition, see the text covering the individual disease.) When the infections are treated differently in HIV-infected patients, these variations are presented here. The most common manifestations are presented first, followed by a selection of the less frequently encountered disorders.

The prevalence and mixture of oral manifestations noted in HIV-infected patients has been altered dramatically by the current antiretroviral therapies. Numerous investigations of patients receiving HAART (see Treatment and Prognosis section) have demonstrated an increase in CD4+ count and a reduction in viral load that appear to be correlated with a reduced prevalence of many oral manifestations. Other factors that appear to affect the frequency of oral manifestations include xerostomia, poor oral hygiene, and smoking. Subsequent to HAART, the overall prevalence of oral manifestations decreased, including significant reductions in the frequency of oral candidiasis, OHL, HIV-associated periodontal disease, and Kaposi’s sarcoma. Although the prevalence of certain lymphomas has decreased because of HAART, the frequency of all HIV-related lymphomas has not demonstrated significant change. In contrast, many researchers have reported an increased prevalence of benign human papillomavirus (HPV)-induced pathoses. A similar increased frequency of HIV-related salivary gland disease has been noted by some, but disputed by others.

The detection of oral manifestations can be critical, because it may suggest possible HIV infection in an unaware individual. The discovery in a patient with known HIV infection who is not yet on active therapy may signal progression of HIV disease. Finally, if new oral manifestations surface in a patient receiving antiretroviral therapy, it may lead to reevaluation and possible adjustment of the therapeutic regimen

ORAL AND MAXILLOFACIAL LESIONS STRONGLY ASSOCIATED WITH HIV INFECTION:

LESS COMMON ORAL AND MAXILLOFACIAL MANIFESTATIONS OF HIV INFECTION:

OTHER ORAL AND MAXILLOFACIAL LESIONS SEEN IN HIV INFECTION:

DIAGNOSIS: Confirmation of HIV infection can be made by viral culture or by detection of HIV antibodies or antigens. The standard screening tool is the enzyme immunoassay (EIA) for antibodies to HIV. This test can have false-positive results or cross-reactions; therefore, it should be repeated and followed by the more accurate Western blot antibody assay. Other alternatives include radioimmunoprecipitation (RIPA), rapid latex agglutination assay, and dot-blot immunobinding assay. All of these evaluations are used to detect antibodies to HIV.

In an attempt to improve the safety of the blood supply, a few assays have been approved by the FDA to detect viral antigens before development of anti-HIV antibodies. These tests are not used widely and include the p24 antigen capture assay and polymerase chain reaction (PCR) for detection of HIV DNA that may be integrated into the host DNA. This latter method may be used to identify someone who was infected recently or HIV carriers who otherwise have negative antigen or antibody findings.

The diagnosis of AIDS is indicated if the patient has laboratory evidence of HIV infection combined with documentation of less than 200 CD4+ T lymphocytes per microliter or a CD4+ T-lymphocyte percentage of total lymphocytes that is less than 14. In addition, the diagnosis of AIDS can be made in an HIV-infected person if one of the indicator diseases listed in Box 7-2 has been documented.

TREATMENT AND PROGNOSIS: As mentioned previously, HIV infection initially was considered fatal; however, the introduction of HAART has altered the course of the epidemic. A wide variety of antiretroviral agents is available and continues to expand (Box 7-3), increasing the effectiveness of medical therapy. Although numerous drug combinations are possible, HAART often consists of two nucleoside analogue reverse-transcriptase inhibitors, at least one protease inhibitor, and/or one nonnucleoside analogue reverse-transcriptase inhibitor. Alternatively, one nucleoside analogue reverse-transcriptase inhibitor can be combined with one nonnucleoside ana-logue reverse-transcriptase inhibitor and one protease inhibitor.

The current therapeutic approaches have driven HIV to undetectable levels in many patients, with a resultant clinically significant reconstitution of the immune system. With the current antiretroviral medications, total HIV eradication would take at least a decade and presently is not a realistic goal. Although no cure exists, survival times are increasing as a result of earlier diagnosis and improved therapy.

Although antiretroviral therapy is effective for many patients, it is expensive. In addition, this treatment often is associated with significant adverse reactions, may not be effective in all patients, or may fail after a period of initial success. Work is proceeding toward the development of a safe and effective vaccine against HIV infection, but complex issues slow the progress. Advances in therapy and prevention of HIV infection occur daily; however, the best defense against the disease is prevention of the initial infection.

Despite the continuing advances in medical therapy and the ongoing work toward a successful vaccine, many of the positive gains against the epidemic have been achieved through epidemiologically directed public health interventions. The ever-changing data continue to be important and highlight increasingly important areas (e.g., increasing prevalence in heterosexuals and blacks) for present and future interventions. Routine HIV testing is critical, because it represents the best avenue toward life-saving early therapy and prevention of HIV transmission to others. It is estimated that more than 300,000 individuals in the United States are unaware that they are infected with HIV. To appropriately emphasize early diagnosis and prevention, the CDC recommends HIV testing as a part of routine clinical care in all health care settings.

Some health professionals have been concerned about the risk of occupational transmission of HIV. The average risk of seroconversion after a percutaneous exposure to HIV-infected blood is estimated to be approximately 0.3%. Mucous membrane exposure to HIV-infected blood results in seroconversion in only 0.09% of cases, and the rate is even lower after a nonintact skin exposure. The risk of transmission after exposure to fluids or tissues other than blood has not been quantified but most likely is considerably lower. On exposure to HIV-contaminated material, the risk of seroconversion can be reduced by greater than 75% through postexposure prophylaxis (PEP) with antiretroviral medications if initiated within hours of the event. Four weeks of therapy is recommended; however, this often is difficult to complete because of adverse reactions; therefore, the regimen probably should not be used for exposures that pose a negligible risk for transmission. The basic PEP consists of a two-drug regimen that may be expanded to a three-drug combination for more severe exposures. Because of the complexity of choosing and administering the regimen, involvement of an infectious disease specialist or a physician experienced in antiretroviral therapy is strongly recommended. Regardless, promptness in the initiation of the therapy is paramount.