Viral diseases of the skin

Herpetic gingivostomatitis

Herpetic gingivostomatitis most commonly occurs in children between the ages of 10 months and 5 years, although it may occur at any age. It presents with small vesicles on an erythematous base that evolve into painful, shallow gray erosions and ulcerations ( Fig. 15.1 ). The lesions most often involve the palate, tongue, and gingivae. Gingival swelling and easy bleeding may occur. Perioral lesions involving the lips, cheeks, and chin ( Fig. 15.2 ) occur in up to three-quarters of patients. Other common features include fever, drooling, eating and drinking difficulties, foul breath odor, and irritability. Cervical and submandibular lymphadenopathy is also quite common. Secondary bacteremia with group A β-hemolytic streptococci, Staphylococcus aureus, or other organisms may occasionally be a complication. Associated hepatitis has been observed, most often in neonates and immunosuppressed patients with acute primary HSV-1 infection, but also rarely in immunocompetent children.

The differential diagnosis of herpetic gingivostomatitis in a child includes herpangina, hand-foot-and-mouth disease, aphthous stomatitis, Behçet syndrome, pemphigus vulgaris, and Stevens–Johnson syndrome. The diagnosis can be confirmed by viral culture, direct fluorescent antibody studies, or PCR-based testing, when necessary. Although gingivostomatitis is usually caused by HSV-1, HSV-2 may cause a similar syndrome that usually occurs in adolescents and young adults who engage in oral–genital contact. Such primary HSV-2 infection results in similar symptoms of gingivostomatitis and pharyngitis, which in some patients may be difficult to differentiate from bacterial pharyngitis. Adolescents and young adults may also have primary HSV-1 gingivostomatitis. ^,

Although herpetic gingivostomatitis tends to be self-limited over 10 days to 2 weeks, dehydration may result from poor oral intake and excessive fluid losses, especially in younger children. In some patients, hospitalization may be required for intravenous hydration and pain control. Ambulatory treatment measures include supportive therapy with fluids and use of topical analgesics, anesthetics, or coating agents, including viscous lidocaine, diphenhydramine, milk of magnesia (“magic mouthwash”), Maalox, or Kaopectate. Specific antiviral therapy with acyclovir is advocated by some; seems most effective when started within 3 days of disease onset; and may reduce the number of oral lesions, prevent the development of new lesions, diminish difficulties with eating and drinking, and reduce the rates of hospitalization in young children.

Ocular herpes infection

Primary HSV infection of the eye can result in a severe purulent conjunctivitis with edema, erythema, and vesiculation, with superficial erosion or ulceration of the cornea (epithelial keratitis). Ocular HSV infection is a leading cause of recurrent keratoconjunctivitis with associated corneal opacification and is one of the chief causes of corneal blindness in the United States. ^, This infection results from recurrent viral shedding from the trigeminal nerve reactivation and is more often caused by HSV-1. Patients with keratoconjunctivitis present with pain, photophobia, lacrimation, and eye discharge. Fluorescein testing may reveal dendritic lesions. There may also be involvement of the eyelid (blepharitis). Deeper involvement of the cornea (stromal keratitis) or anterior uvea (iritis) may occur, and both are more serious and associated with a greater risk of visual loss. Children with HSV keratitis may have poorer visual outcomes than adults, are more often misdiagnosed, and are susceptible to amblyopia. Ocular HSV infections may be unilateral or bilateral; patients with bilateral involvement tend to have a more protracted clinical course, and recurrences are more common. Bacterial superinfection of herpetic keratoconjunctivitis is common. Acute retinal necrosis has rarely been reported in children.

The diagnosis of herpetic keratoconjunctivitis can be confirmed with viral culture. Nested PCR studies, where available, seem to be superior to culture and can be performed on tear film or corneal scrapings. The immunochromatographic assay (ICGA) kit utilizes a monoclonal antibody against HSV glycoprotein D and has high specificity (but lower sensitivity) when applied to corneal scrapings. Ophthalmology referral is indicated, and treatment includes topical antiviral ophthalmic ointments or solutions and oral antiviral agents. Topical antiviral agents include trifluridine, vidarabine, and idoxuridine. In a series of 53 pediatric patients with HSV eye infections, 79% of those with keratitis had corneal scarring and 26% experienced vision impairment, highlighting the importance of prompt referral and therapy. Recurrence of anterior-segment HSV is common in children, occurring in nearly 40% of 103 children in one series. Penetrating keratoplasty (full-thickness cornea transplant) has been reported for pediatric HSV keratitis and was shown to improve the best-corrected visual acuity when not complicated by amblyopia.

Herpes labialis

Herpes labialis refers to herpetic infections occurring on the lips, most often the vermilion border. This is the most common type of recurrent herpes infection and represents the classic “cold sore.” As with other types of recurrent infection, it occurs after reactivation of latent HSV in the cells of the trigeminal ganglia. Herpes labialis often presents initially with prodromal symptoms such as tingling, burning, or itching. After 1 to 2 days the cutaneous eruption appears as a localized cluster of small vesicles or erosions on an erythematous base ( Figs. 15.3 and 15.4 ). Occasionally other areas of the face may be involved, and in immunocompromised individuals oral mucosal and/or severe involvement ( Fig. 15.5 ) may be noted (see later). Topical and oral antiviral agents are useful in treating herpes labialis, especially when initiated within 1 to 2 days of the disease onset. Prophylaxis with oral agents is advocated by many for patients with a history of multiple recurrences of herpes labialis.

Genital herpes

Genital herpes (herpetic vulvovaginitis, herpes progenitalis) is one of the most widespread sexually transmitted diseases (STDs) in the developed world. ^, HSV-2 is primarily responsible for genital tract herpetic infections, and seroprevalence studies reveal rates as high as 60% to 90% in developing countries and 20% to 22% of the general population in developed countries. ^, The proportion of HSV-1 isolates in genital herpes is also increasing, especially in young adults and college students. A large prospective study in young women demonstrated a primary HSV-1 infection rate of over twice that of HSV-2 and that it presented more often as genital rather than oral disease. Given that the overall seroprevalence of HSV-1 in teenagers has decreased over the last few decades, an increasing number of adolescents lack protective HSV-1 antibodies when they become sexually active, which may be one factor leading to an increase in the frequency of HSV-1 genital herpes from oral–genital sex practices. Risk factors that directly correlate with HSV-2 infection include race (higher risk in Blacks and Hispanics), age, years of sexual experience, lower family income, lower education level, number of sexual partners, and other STDs. The diagnosis of genital HSV in a child should raise the suspicion of sexual abuse. Maternal–fetal transmission of HSV may result in neonatal herpes, which is discussed in Chapter 2 .

The majority of genital HSV infections are subclinical and go unrecognized by the host. Symptomatic primary genital herpes presents with lesions 2 to 8 days after contact with an infected individual. In contrast, first-episode, nonprimary genital herpes (the initial episode of genital herpes in a host with a past history of nongenital herpes) may not present with signs or symptoms for several months. The lesions of primary genital HSV are painful vesicles clustered on an erythematous base ( Fig. 15.6 ) and distributed on the vulva, labia, vagina, perineum, penile shaft, glans penis, urethra, and, less often, the scrotum. In females, cervical involvement, intense soft-tissue swelling, and severe pain may be present. The vesicles rupture rapidly, leaving behind painful erosions or ulcers that may be associated with pruritus, dysuria, vaginal and urethral discharge, and tender inguinal lymphadenopathy. Pustules may occasionally be present. Systemic signs and symptoms may include fever, malaise, headache, and myalgias. Herpetic sacral radiculomyelitis with urinary or fecal retention and neuralgias may occur, as may aseptic meningitis. ^, Less common features of HSV infection include endometritis and salpingitis in women and prostatitis in men. The symptoms of genital HSV usually improve over 5 to 7 days, and the cutaneous lesions crust over and gradually heal over 2 to 4 weeks without therapy. HSV replicates locally and spreads to adjacent cells and is then transported to the neuronal cell bodies of the dorsal root ganglion, where it establishes latent infection or is transported back to mucocutaneous sites, where it again replicates and leads to clinical findings.

Genital herpes may show a heterogeneous clinical spectrum. Extragenital involvement may be seen, with lesions most commonly involving the buttocks, anal region, thighs, mouth, and fingers (see later). ^, Atypical morphologies may also be present, including deep and tender ulcers, single erosions, erosive urethritis, vulvar fissure, and penile edema. A high index of suspicion must be maintained, especially in the immunocompromised host or in patients with features of other STDs. The differential diagnosis for genital herpes includes syphilis, chancroid, lymphogranuloma venereum, condylomata acuminate, Behçet syndrome, HZ, erosive candidiasis, and lichen sclerosis. Acute infection with EBV may also present with acute genital ulceration (see Chapter 16 ).

Recurrent genital HSV infection is characterized by less severe cutaneous lesions that are usually preceded by a prodrome of pain, tenderness, itching, tingling, or paresthesia. The vesicles are fewer in number, the duration of clinical findings is less than with primary disease, and recurrent disease may be less common with HSV-1 versus HSV-2 infection. Triggering factors for recurrent disease may include physical or emotional stress, febrile illness, and menstruation. Recurrence rates tend to be highest for the first years after the initial infection. Asymptomatic (subclinical) HSV shedding is another feature of genital herpes and among individuals with genital HSV-2 infection, occurs on 10% to 20% of days. ^, The risk of subclinical shedding increases with the rate of symptomatic recurrences.

The diagnosis of genital herpes can be confirmed by viral culture, Tzanck preparation (cannot distinguish between HSV-1 and HSV-2), direct fluorescent antibody testing, Western blot serologic testing, or PCR. PCR assays for HSV are rapid and type-specific, highly sensitive, and competitive from a cost perspective. Serologic screening for genital HSV infection in asymptomatic adolescents and adults is not recommended and is associated with a high rate of false-positive results and potential psychosocial harms. ^, Treatments for genital herpes include supportive care and antiviral therapy (see Table 15.1 ). Supportive measures include warm sitz baths, topical anesthetics, topical antibacterial ointments to prevent secondary infection, and oral analgesics. Education regarding the nature and risks of HSV infection and safe sex practices should be offered, and evaluation for other STDs should be considered when appropriate. An effective vaccine against HSV is highly desirable, and research toward this end is ongoing. Experimental vaccines contain recombinant glycoprotein subunits, attenuated or replication-defective virus vaccines, and those composed of plasmids expressing glycoprotein subunits. Vaccine development has been challenging, given the poor understanding of the mechanisms by which host immune responses fail to control HSV.

The choice of antiviral therapy depends on the host immune status and the nature of the infection (primary or recurrent). Oral acyclovir, famciclovir, and valacyclovir may all help to speed healing, decrease symptoms, and decrease viral shedding. Long-term suppressive therapy in patients with frequent recurrences is useful in reducing both the rate and duration of flares. Although topical acyclovir ointment may offer some benefit for initial genital herpes infections, it offers little in the way of recurrent infections. Tenofovir, a nucleoside reverse transcriptase inhibitor used orally for the treatment of HIV in adults and children >2 years of age, was shown with topical pericoital application to reduce HSV-2 acquisition in women in one study, and in another study of vaginal application, decreased the quantity of vaginal HSV shed by 60%. ^,

Cutaneous herpes and eczema herpeticum

Cutaneous HSV infection can occur on any body surface area. Involvement of the finger (herpetic whitlow) is discussed in the next section. Nonorolabial, nongenital involvement presents in a similar fashion, with clustered vesicles or erosions on an erythematous base ( Figs. 15.7 and 15.8 ). The lesions may be misdiagnosed as impetigo or HZ. Occasionally, recurrent cutaneous HSV may present only with prodromal symptoms followed by skin erythema and edema but without the characteristic vesiculation. In some instances, patients with recurrent cutaneous HSV may develop associated secondary bacterial infection or lymphangitis.

Eczema herpeticum (EH, or Kaposi varicelliform eruption; see Chapter 3 ) is a severe, disseminated HSV infection that occurs in individuals with atopic dermatitis or other chronic skin disease, including pemphigus, Darier disease, burns, and others. Although the etiology of EH has not been clearly established, the impaired skin barrier associated with these diseases is believed to create a more permissive environment for viral invasion and binding to cellular receptors, leading to a higher prevalence of EH with greater dermatitis severity. Despite the high prevalence of atopic dermatitis (AD) in the general population and frequent exposure to HSV, EH is quite rare, possibly relating to a requirement for multiple additional host and environmental factors. Single-nucleotide polymorphisms in the interferon regulatory factor 2 ( IRF2 ) gene have been demonstrated to confer a greater risk of EH, possibly reflecting an abnormal immune response to HSV. A type 2 immune response by virus-specific T cells has been suggested by analysis of cellular immune responses (specifically, measurement of interleukin 4 [IL-4] and interferon gamma [IFN-γ] expression and characterization of T-cell markers) in AD patients both with and without a history of EH.

Patients with EH usually experience an abrupt onset of fever, malaise, and a widespread eruption of monomorphous vesicles and erosions ( Figs. 15.9 and 15.10 ; see Chapter 3 , Figs. 3.30 , 3.31 and 3.32 ). The lesions are most prominent in areas of active dermatitis but especially tend to involve the head, neck, and trunk. Complications of EH include keratoconjunctivitis, secondary bacterial superinfection, fluid loss, and viremia. The mainstay of treatment for EH is systemic antiviral therapy, which for the majority of patients is most appropriately administered via intravenous delivery in the hospital. Early initiation of therapy is preferable, and delays in starting acyclovir therapy appear to be associated with increased length of hospital stay. Other treatment considerations include hydration with attention to electrolyte balance, antibiotic therapy for secondary bacterial infection, and pain control. Meticulous skin care should be performed, with bland emollients applied during the early phase of barrier recovery, as well as the application of antiinflammatory agents for the underlying dermatitis. The timing of the latter remains controversial; although some have suggested that use of topical corticosteroids during active EH may adversely affect prognosis, a review of more than 1300 children admitted for treatment revealed no increase in length of stay when these agents were started at the time of admission. Ophthalmologic evaluation is indicated when facial involvement is present. More extensive EH at presentation may be an indicator of an increased rate of repeated episodes.

Erythema multiforme (see Chapter 20 ), an acute, self-limited reactive skin disease, has been associated with HSV infection in both children and adults. In prepubertal children with erythema multiforme, especially the recurrent type, HSV DNA was detected by PCR studies on skin biopsy specimens taken from the target lesions. ^, This finding was noted both in patients with a known history of HSV and in those without any such history. Prophylactic acyclovir may thus be useful in abrogating recurrences of erythema multiforme in children.

Herpetic whitlow

Herpetic whitlow is a unique form of HSV infection involving the pulp of the distal phalanx (or multiple phalanges). It is seen most often in physicians, dentists, dental hygienists, and nurses who have contact with the mouth or genital regions of patients with herpetic lesions. It may also occur as a result of autoinoculation in patients with herpes labialis, herpes stomatitis, or genital herpes. The virus is inoculated onto the skin of one or more fingers, resulting in a deep-seated, painful vesicular or bullous eruption with erythema ( Fig. 15.11 ). Spontaneous resolution usually occurs over 3 weeks if the condition is left untreated. The differential diagnosis of herpetic whitlow may include blistering dactylitis, burns, and impetigo. The diagnosis is confirmed by viral culture or direct fluorescent antibody testing, and treatment with oral acyclovir or other antiviral agents may result in alleviation of pain and more rapid healing.

Herpes gladiatorum

Herpes gladiatorum is a term used to describe a widespread primary inoculation HSV infection occurring in contact sports enthusiasts such as wrestlers or rugby players. It may occur at some time in up to one-third of wrestlers and is characterized by grouped vesicles on an erythematous base. It has also been observed after shared use of boxing gloves believed to be contaminated by HSV-1, with lesions occurring over the knuckles. The most common locations for herpes gladiatorum are the head ( Fig. 15.12 ), neck, and upper extremities. ^, In addition to widespread cutaneous lesions, affected individuals may have fever, malaise, sore throat, anorexia, headache, weight loss, and regional lymphadenopathy. The cutaneous lesions of herpes gladiatorum may occasionally lack classic vesicles, in which case the differential diagnosis may include tinea corporis gladiatorum, impetigo, and atopic dermatitis. EH may also occur with increased frequency in wrestlers.

Herpes gladiatorum can be effectively treated with oral acyclovir, famciclovir, or valacyclovir. The duration of therapy necessary before allowing the athlete to return to competition is controversial, and evidence-based recommendations do not exist. Sharing of equipment and towels should be discouraged and appropriate cleaning of wrestling mats encouraged. Expert organizations recommend that wrestlers with visible, uncovered lesions be excluded from competition and that wrestling mats be disinfected between each match with an Environmental Protection Agency (EPA)–approved disinfectant active against both S. aureus and HSV-1. Seasonal antiviral prophylaxis has been advocated by some in an effort to suppress recurrent outbreaks and reduce the risk of spread to susceptible teammates or opponents. ^, In one 10-year observational study of a 28-day high school wrestling camp, valacyclovir 1 gram taken once daily for the duration of the camp resulted in an 84% decrease in the probability of an HSV outbreak.

Herpes in the immunocompromised host

Severe, chronic, and recalcitrant HSV infections may be seen in the setting of immunodeficiency. These settings include individuals with hematologic malignancy, those with a history of bone marrow or solid-organ transplantation, and those with HIV infection. Although these patients may develop common forms of HSV infection, their lesions may be more widespread and extensive. Persistent or recurrent ulcers are a common manifestation of HSV infection in patients with AIDS. Large, persistent ulcers in patients infected with HIV should arouse suspicion for HSV, although the differential diagnosis may include syphilis and chancroid. Less common locations such as the buttocks and back are also more likely to be involved in these patients. HSV lesions in immunocompromised hosts may also be verrucous, pustular, markedly crusted ( Fig. 15.13 ), necrotic ( Fig. 15.14 ), or exophytic.

In addition to cutaneous lesions, disseminated HSV may be noted in this patient population. Oropharyngeal involvement, esophagitis, tracheobronchitis, pneumonitis, hepatitis, pancreatitis, adrenal necrosis, and gastrointestinal tract and bone marrow involvement may occur. These severe and/or disseminated infections may be caused by either HSV-1 or HSV-2.