Chapter 11: Viral Infections of the Skin

Despite all the advances in antiviral therapy and the body's efficient immune system, the viruses that cause common skin infections continue to evade complete destruction. The herpes simplex and herpes zoster virus can persist in a dormant state in the ganglia. The viruses that cause verrucae vulgaris (common warts) and molluscum contagiosum can persist for months to several years in the epidermis.

Herpes simplex and herpes zoster infections can cause significant illness and death, especially in immunocompromised patients if the infection spreads to other organs. Common nongenital warts and molluscum contagiosum rarely cause significant problems in immunocompetent patients, but for various reasons most patients want treatment for these conditions. Genital warts are often asymptomatic and may be clinically undetectable; however, patients with oncogenic wart virus infections are at increased risk for anogenital and oropharyngeal cancers.

Introduction

Herpes simplex viruses (HSV) cause primary, latent, and recurrent infections. Human herpes virus-1 (HSV-1) primarily infects the oral cavity, lips, and perioral skin. Human herpes virus-2 (HSV-2) primarily infects the genital area. However, HSV-1 is becoming a common cause of genital herpes infections in young women. HSV has a worldwide distribution and is more common in less developed countries. Antibodies to HSV-1 are present in up to 85% of adults, and antibodies to HSV-2 are present in 20% to 25% of adults.¹ However, many patients who have antibodies to HSV do not recall having an infection.

Pathophysiology

HSV-1 and HSV-2 are human herpesviruses (HHV) that have double-stranded DNA and replicate within the nuclei of infected cells. HSV infects mucocutaneous tissue after direct contact or by way of secretions, mainly saliva in the case of HSV-1. The virus is transmitted via sensory nerves to the ganglia, where it may reside in a latent stage. Recurrent infections are caused by reactivation of the virus which travels back to the skin or mucous membranes resulting in an active infection. Immune mechanisms suppress the virus with clearing of the lesions in 1 to 2 weeks, but latency in the ganglia persists. Recurrent mucocutaneous infection may occur every few weeks to months to years. Viral shedding may continue after the infection has clinically resolved.

Clinical Presentation

History

Patients with orolabial HSV may complain of "fever blisters" or "cold sores" on the lips or perioral area or sores within the oral cavity. Patients with genital herpes may complain of pain or tingling in the genital area in the prodromal and active phase of the infection. Primary infection occurs 3 to 7 days following exposure. Localized pain, tenderness, and burning may be accompanied by fever, malaise, and tender lymphadenopathy. Vesicles develop, progressing to pustules and/or erosions. The eruption resolves in 1 to 2 weeks. Recurrent infection tends to be milder, with fewer vesicles and absent, or minimal systemic symptoms. Fever, sun exposure, and possibly stress may trigger recurrence of infection. Many individuals harboring HSV are asymptomatic.

Physical Examination

HSV infections present with vesicles that tend to be grouped in clusters with underlying and surrounding erythema.

There are several presentations of HSV infections:

• HSV-1 most frequently affects the lip area (Figure 11-1), but may involve the buccal mucosa, gingiva, and oropharyngeal membranes. Primary infection may present as a gingivostomatitis in children, with fever, sore throat, and painful vesicles and ulcerative erosions on the tongue, palate, gingiva, buccal mucosa, and lips. Patients may develop lymphadenopathy and an inability to eat. Recurrent eruptions are less severe, mostly affecting the vermilion border of the lip, and, less frequently, the perioral skin, nose, and cheeks. Patients may develop concomitant impetigo.

• HSV-2 usually affects the genital area and is the most common cause of genital ulcerations. The primary infection may be extremely painful with erosive vulvitis or vaginitis. The cervix, perineum, and buttocks may be involved with accompanying inguinal lymphadenopathy and dysuria. Affected men may develop an erosive balanitis. Recurrent genital infections can be subclinical or mild with few vesicles (Figure 11-2), clearing in 1 to 2 weeks. Most individuals found to be seropositive for HSV-2 have no reported history of genital herpes symptoms, yet shed the virus and can transmit the virus to a partner.

• Fingers (herpetic whitlow) may be affected in children who suck their fingers or in healthcare workers from exposure to secretions.

• Herpes simplex keratitis is the second most common cause of corneal blindness in the United States. It presents with pain, redness, blurred vision, and photophobia.

• Primary neonatal infection usually develops after exposure to HSV in a mother's vaginal secretions during delivery, less commonly the virus is transmitted in utero. This is much more likely to occur when the mother has a primary infection. Infected healthcare workers can also transmit the virus to the neonate. Vesicles, if present, appear 4 to 7 days after birth and may be localized or widespread. The central nervous system and visceral organs can be affected, sometimes in the absence of skin lesions. Infected neonates may have significant morbidity and mortality.

• Patients with atopic dermatitis are at risk of developing eczema herpeticum, which is disseminated cutaneous HSV infection (Figure 8-10). This may begin as an orolabial HSV infection, which rapidly spreads, or may develop after exposure to an individual with HSV infection.

Laboratory Findings

Tzanck smears can be done by scraping the base of a lesion with a number 15 scalpel blade and spreading the contents on a glass slide (Table 4-2). Microscopic examination after staining with the Wright or Giemsa stain reveals multinucleated epithelial giant cells (Figure 4-4). A skin biopsy will show changes in the nuclei of keratinocytes characteristic of a viral infection. Viral cultures and polymerase chain reaction (PCR) are sensitive and specific tests and can differentiate HSV-1 from HSV-2. The Western blot is a 99% sensitive and specific test for serologic status.

Diagnosis

The key diagnostic clinical features of herpes simplex are painful, grouped vesicles, or erosions on the face or genital area.

Differential Diagnosis

For orolabial herpes

• ✓ Impetigo: Presents with flaccid vesicles with a honey-colored crust, usually not recurrent in the same area.

• ✓ Aphthous stomatitis: Presents with painful 4 to 8 mm oral ulcers with white centers and sharp red borders.

• ✓ Other: Behcet's disease, diphtheria, herpangina (coxsackie virus infection), Epstein–Barr Virus (EBV) infection, oral candidiasis, and drug-induced mucositis.

For genital herpes

• ✓ Syphilitic chancre: Presents most commonly with a single, nontender, indurated ulcer.

• ✓ Other: Trauma, aphthae, chancroid, and granuloma inguinale.

Management

Mild and limited orolabial HSV in immunocompetent patients does not require therapy; however, moderate to severe disease can be treated with topical or oral medications as listed in Tables 11-1 and 11-2. Treatment should be initiated quickly after onset of symptoms, as these medications may not be helpful if started 72 hours after onset of symptoms.

The Centers for Disease Control and Prevention (CDC) has updated information for clinicians on the treatment of immunocompromised patients and for chronic suppressive treatment for genital herpes.² Immunocompromised individuals require higher doses of oral antiviral medications or may require intravenous therapy. Recurrent episodes of HSV-1 are less common after age 35. Recurrent episodes of genital herpes can have a major psychosocial impact on an affected individual. The American Social Health Association (www.ashastd.org) and the CDC have patient-oriented information on these issues.

Indications for Consultation

Patients with ocular or systemic involvement and immunocompromised patients with widespread disease should be referred to the appropriate specialist.

Patient Information

• Centers for Disease Control and Prevention: www.cdc.gov/std/Herpes/STDFact-Herpes.htm

• American Academy of Dermatology: www.aad.org/skin-conditions/dermatology-a-to-z/herpes-simplex

Introduction

Herpes zoster (shingles) represents reactivation of latent varicella (chicken pox) infection. Persons with a history of primary varicella have a 20% to 30% lifetime risk of developing herpes zoster. Herpes zoster seldom affects children or adolescents. Incidence and severity increase after age 60 and in immunocompromised individuals.³

Pathophysiology

The varicella-zoster virus is a double-stranded DNA virus. Following a varicella infection, varicella-zoster virus may be retained in dorsal root ganglia in a latent form. Reactivation of the virus, leading to the cutaneous eruption in the distribution of the affected sensory nerve(s), may be induced by trauma, stress, fever, radiation therapy, or immunosuppression. Direct contact with vesicular fluid can result in varicella in a susceptible person.

Clinical Presentation

History

Herpes zoster often begins with intense pain, which may precede the eruption by one or a few days. Pruritus, tingling, tenderness, or hyperesthesia may also develop.

Physical Examination

The eruption presents as grouped vesicles within the dermatome of the affected nerves, usually within a single unilateral dermatome. Any area of the body may be affected, but it is seen most frequently on the trunk (Figure 11-3).

Involvement of the trigeminal nerve, particularly the 1st (ophthalmic) division (Figure 11-4), occurs in 10% to 15% of patients. When vesicles develop on the tip or side of the nose, indicating involvement of the nasociliary branch (Hutchinson's sign), the eye is more likely to be affected, sometimes resulting in blindness. Herpes zoster affecting the 2nd and 3rd division of the trigeminal nerve may cause symptoms, vesicles, and erosions in the mouth, ears, pharynx, or larynx. Facial palsy may develop with involvement of the ear and/or tympanic membrane with or without tinnitus, vertigo, and deafness (Ramsay Hunt Syndrome). Herpes zoster may involve adjacent dermatomes or become disseminated in immunocompromised patients.

The rash associated with herpes zoster usually resolves in 3 to 5 weeks, but symptoms may persist for a longer time, sometimes for many months or years (postherpetic neuralgia). This may occur in 5% to 20% of patients, but is rarely seen in those less than 40 years of age. Incidence increases with age.³ Symptoms resolve in 3 months in 50% of patients and in 1 year in 75% of patients.

Laboratory Findings

A Tzanck smear (Table 4-2) or skin biopsy may reveal characteristic multinucleated giant cells (Figure 4-4), which cannot be differentiated from those seen in herpes simplex infection. Viral cultures and PCR testing are more specific and sensitive tests for herpes zoster.

Diagnosis

The key diagnostic clinical features of herpes zoster are grouped painful vesicles within a dermatome.

Differential Diagnosis

• ✓ Herpes simplex: Presents with vesicles that are similar, but the lesions are not as painful and they do not extend over an entire dermatome.

• ✓ The prodromal pain of herpes zoster can mimic headaches, myocardial infarction, pleuritic chest pain, or an acute abdomen.

Management

Oral antiviral medications, if given early, may reduce the duration of the eruption and may reduce the risk and severity of acute pain and perhaps postherpetic neuralgia. The treatments should be started within 72 hours of onset of symptoms. Recommended dosing for immunocompetent adults is as follows:

• Acyclovir (Zovirax) 800 mg 5 times a day for 7 days.

• Famciclovir (Famvir) 500 mg 3 times a day for 7 days.

• Valacyclovir 1000 mg (Valtrex) 3 times a day for 7 days.

Appropriate treatment for acute pain may be needed. Persistent postherpetic neuralgia can have a negative impact on a patient's health and quality of life. It is associated with insomnia, anorexia, and depression especially in the elderly.³ Treatments may include topical lidocaine or capsaicin, antidepressants (such as amitriptyline, desipramine, and nortryptyline), and anticonvulsants (such as carbamazepine and gabapentin). Acupuncture and biofeedback may also be helpful.^4,5

Vaccination with live zoster vaccine (Zostavax) may reduce the risk of development of herpes zoster.⁶ It is recommended for persons 60 years of age or older. It is not indicated in patients with active herpes zoster infection or postherpetic neuralgia. The vaccine has been shown to reduce the risk of developing herpes zoster by 51% and the risk of postherpetic neuralgia by 67%. The vaccine is effective for at least 6 years, but may last much longer. It is not yet determined whether booster shots may be needed. Recurrence of herpes zoster is rare, but is more common in immunocompromised patients.

Indications for Consultation

Patients with severe disease or systemic involvement and patients with postherpetic neuralgia who are not responding to treatment should be referred to the appropriate specialist. Patients with eye involvement should be referred to ophthalmology.

Patient Information

• Centers for Disease Control and Prevention: www.cdc.gov/shingles/about/index.html

• American Academy of Dermatology: www.aad.org/skin-conditions/dermatology-a-to-z/herpes-zoster

Introduction

Molluscum contagiosum is a benign viral infection of the skin and mucous membranes. The infection has a worldwide distribution and occurs in all ethnicities. Children are most frequently affected. In adults, it is mostly seen in the genital area and represents a sexually transmitted disease. It is more common and severe in patients with HIV infection, especially in patients with low CD4 counts.

Pathophysiology

Molluscum contagiosum is caused by a member of the pox virus group that contain double-stranded DNA and replicate within the cytoplasm of epithelial cells. The virus is spread by direct skin-to-skin contact.

Clinical Presentation

History

Small papules develop on the skin and sometimes on the genital mucous membranes usually within 2 to 7 weeks after contact with an infected individual. The lesions are typically initially asymptomatic, but pruritus and inflammation can develop.

Physical Examination

The typical lesions present as pearly, 2 to 10 mm dome-shaped papules with a waxy surface (Figure 11-5), which often have a central umbilication and erythema around the rim. Papules may be larger and more extensively distributed in immunocompromised patients. The face, upper chest, and upper extremities are most frequently affected in children, whereas the anogenital, suprapubic, and thigh areas are the usual site of infection in adults.

Laboratory Findings

The diagnosis can be confirmed by incising a lesion with a needle and squeezing out the core with gloved fingers or with a small curette. The core should be squashed between two glass slides to flatten the specimen. The specimen can be stained with Giemsa stain and examined for the presence of large, purple, oval bodies that are the viral inclusion bodies within the cytoplasm of keratinocytes.⁷ These inclusion bodies can also be seen in skin biopsy specimens.

Diagnosis

The key diagnostic clinical features of molluscum are small skin-colored papules with central umbilication.

Differential Diagnosis

• ✓ Acne: Presents with papules and pustules and cysts that could appear similar to molluscum. But, comedones should be present and there is no central umblications of acne lesions.

• ✓ Folliculitis: Presents with small papules and/or pustules without umbilication.

• ✓ Other: Syringomas, flat warts, and cryptococcosis.

Management

A recent Cochrane review reported that no single treatment has been shown to be convincingly effective.⁸ However, several options for therapy are commonly used.

Molluscum papules can be removed surgically using a small skin curette. They can also be incised with a needle and the contents expressed with gloved fingers or with a comedone extractor. Liquid nitrogen cryotherapy can be used, in a single pulse. 17% salicylic acid nonprescription products that are normally used for common warts can also be used. Spontaneous resolution typically occurs in 6 to 9 months, but may take one to several years.

Public Health Issues

Because molluscum contagiosum is easily spread among children, the parents and the schools should be notified of the infectious nature of the virus and the potential for skin to skin transfer of the virus. There is also frequent spread in certain sports activities, particularly in wrestling. Therefore, coaches and participants should be educated about the infection. Individuals with involvement of the genital region should practice safe sex.

Indications for Consultation

Patients with symptomatic lesions that have not responded to treatment should be referred to dermatology.

Patient Information

American Academy of Dermatology: www.aad.org/skin-conditions/dermatology-a-to-z/molluscum-contagiosum

WARTS

Introduction

Warts (verrucae vulgaris) represent one of the most frequently seen viral mucocutaneous infections. All age groups can be affected; the incidence is higher in children and young adults. In immunocompromised individuals, warts are more common and widespread, more resistant to treatment and more frequently progress to intraepithelial neoplasms. Wart infections can be seen worldwide and affect all ethnicities.

Pathophysiology

Warts are caused by the human papillomavirus (HPV), a double-stranded DNA virus with over 100 genotypes. Some HPV genotypes are found on normal skin and mucous membranes, sometimes inducing wart development when patients become immunocompromised. Other HPV genotypes, such as 16, 18, 31 and 33, may be oncogenic, inducing malignant transformation to squamous cell carcinoma in the anogenital and oralpharengeal areas.⁹ The virus infects keratinocytes in skin and mucous membranes by direct skin-to-skin contact or less commonly via fomites such as floors. Autoinoculation frequently occurs. Warts can spontaneously resolve after months to a few years. In two-thirds of infected individuals, warts regress within 2 years.

Clinical Presentation

History

Warts may develop on any skin or mucous membrane surface, most frequently affecting the hands, feet, and genitalia. Trauma to the skin may encourage inoculation of the virus. Widespread infection can be seen in immunocompromised individuals. There may be an inherited susceptibility to wart infections.

Physical Examination

There are several clinical presentations for warts, which depend on location and genotype.

• Verrucae vulgaris (common warts): Skin-colored, hyperkeratotic, exophytic dome-shaped papules ranging in size from 1 to 10 mm. Mild erythema may be seen around the borders (Figure 11-6). The papules can be in a linear configuration, due to inoculation of the virus in an excoriation. Warts are most frequently seen on the hands, but may involve other skin areas.

• Verrucae plantaris (plantar warts): Verrucous or endophytic papules, 1 to 10 mm, affecting the plantar surface of the foot. Black or brown dots created by thrombosed capillaries may be seen on the surface or after paring the wart (Figure 11-7).

• Mosaic warts: Localized confluent collection of small warts, usually seen on the palms and soles (Figure 11-7). Brown dots are commonly seen.

• Verrucae planae (flat warts): Small, 1 to 3 mm, slightly elevated, flat-topped papules with minimal scale, frequently seen on the face and hands (Figure 11-8).

• Filiform/digitate warts: Pedunculated papules with finger-like projections arising from the skin's surface, frequently seen on the face and neck.

• Condylomata accuminata (genital or venereal warts): Sessile, smooth-surfaced exophytic papillomas that may be skin-colored, brown, or whitish (Figure 11-9). The papillomas may be pedunculated or broad-based, sometimes coalescing to form confluent plaques. There may be extension into the vagina, urethra, or anal canal.

Laboratory Findings

A skin biopsy may be done, especially if a carcinoma is suspected, or if the diagnosis is unclear. Histopathologic examination of a skin biopsy of an active wart infection is usually diagnostic.

Diagnosis

The key diagnostic clinical features of warts are 2 to 10 mm verrucous or smooth papules, usually present on the hands, feet, or genitals.

Differential Diagnosis

• ✓ Squamous cell carcinoma: Typically presents as an isolated papule or plaque that may ulcerate or appear inflamed. It usually occurs on sun-exposed areas of older patients. It can also occur on the genitals.

• ✓ Seborrheic keratoses: Presents with verrucous tan to dark brown papules or plaques and is commonly seen in older adults. Skin-colored lesions on the dorsum of the hand may closely resemble warts.

• ✓ Corns and calluses: These lesions have no red or brown dots (thrombosed capillary loops) when pared.

• ✓ Pearly penile papules: These are often confused with HPV warts on the penis. They present with numerous 1- to 3-mm smooth papules (angiokeratomas), in a linear arrangement, on the corona and are seen in up to 10% of males.

Management of Nongenital Warts

There are multiple treatments for warts, none showing consistent efficacy in controlled studies, with the exception of topical salicylic acid products.¹⁰ Existing modalities mostly aim at destruction or removal of visible lesions or induction of an immune response to the virus. Choice of treatment depends on the location, size, number, and type of wart, as well as the age and cooperation of the patient. Induction of pain and the risk of scarring need to be considered. The patient and the treating clinician need to be persistent with therapy as it may take up to 4 to 6 months for the warts to resolve.

• Topical Therapies: Salicylic acid preparations are available as nonprescription solutions, gels, plasters, or patches. Compound W wart remover, Dr. Scholl's Clear Away, Duofilm, Mediplast, Occlusal, Trans-Ver-Sal, and Wart-Off are examples of some available products with salicylic acid. The patients should follow the package instructions. Most preparations are applied at bedtime, after the wart(s) has been soaked in warm water. Surface thick layers of keratin should be removed with an emory board. The induced irritation causes an inflammatory immune response, which speeds resolution of the wart. Treatment may take up to 4 to 12 weeks to be effective.

• Cryotherapy: Liquid nitrogen is applied to the wart by a healthcare provider using a Q-tip or a spray canister for 10 to 20 seconds or until a 2-mm rim of white frost appears beyond the border of the wart. The treatment can be repeated 2 or 3 times during a visit (see Chapter 7 for instructions). Repeat treatments can be done every 2 to 3 weeks if improvement is noted. Over-the-counter cryotherapy kits are available. Although the agent is not as cold as liquid nitrogen, these home kits can sometimes be successful in destroying warts. Patients must carefully follow the package insert directions for use, to avoid injury.

• Procedures: Surgical excision, electrosurgery, and laser surgery may be used to remove or destroy warts, but these may result in significant scarring and recurrence of the wart within or adjacent to the scar.

Management of Genital Warts

• Imiquimod 5% cream (Aldara cream) is an immune response modifier, used primarily for genital warts.⁹ A thin layer of the cream is applied by the patient 3 times a week (eg, Monday, Wednesday, and Friday) sparingly to warts at bedtime and washed off in 6 to 10 hours for a maximum of 16 weeks. The cream may induce an inflammatory response prior to clearing of the warts.

• 25% podophyllin in tincture of benzoin is an antimitotic agent applied every 1 to 3 weeks to external genital warts by a healthcare provider. It should be washed off in 20 minutes to 2 hours. It is should not be used in pregnant or lactating women.

• 0.5% podophyllotoxin (Condylox gel or solution) is a prescription medication that can be used at home by the patient. It is applied to external genital warts twice a day for 3 consecutive days per week, for up to 4 weeks. It should not be used in pregnant or lactating women.

• 15% sinecatechins (Veregen) ointment, a green tea extract, is applied 3 times a day to external genital warts until the warts are clear. It should not be used longer than 16 weeks. It should not be used in pregnant or lactating women or in children.

• HPV vaccine: Two HPV vaccines are currently available, Gardasil and Cervarix. Both protect against the two HPV genotypes (HPV-16 and 18) that cause 70% of cervical cancers. Garadisil also protects against the 2 HPV genotypes (HPV 6 and 11) that cause 90% of genital warts. Vaccination is recommended for young women to prevent cervical intraepithelial neoplasia and cervical carcinoma. Gardasil has also been shown to be effective in preventing genital warts in males. The CDC has up to date information on these vaccines.

Prevention

Patients with anogenital warts need to use safe-sex practices. Sexual partners should be examined and treated, if necessary. Infected women should undergo evaluation of the uterine cervix to rule out neoplasia.

Indications for Consultation

Widespread warts that have not responded to therapy should be referred to dermatology or to gynecology, in cases of female genital warts.

Patient Information

For Nongenital Warts

American Academy of Dermatology: www.aad.org/skin-conditions/dermatology-a-to-z/warts

For Genital Warts

Centers for Disease Control and Prevention: www.cdc.gov/std/hpv/common-clinicians/InsertGW.pdf