Introduction
Viral infections of skin and mucosa produce a wide spectrum of local and systemic manifestations.
Human papillomavirus (HPV) and molluscum contagiosum virus (MCV) colonize the epidermis of most individuals without causing any clinical lesions. Benign epithelial proliferations such as warts and molluscum occur in some colonized persons, are transient, and eventually resolve without therapy. In immunocompromised individuals, however, these lesions may become extensive, persistent, and refractory to therapy.
Primary infections with many viruses cause acute systemic febrile illnesses and exanthems, are usually self-limited, and convey lifetime immunity. Smallpox caused severe morbidity and mortality, but no longer occurs because of worldwide immunization.
Eight human herpesviruses (HHV) often have asymptomatic primary infection but lifelong latent infection. With host defense defects, herpesviruses can become active and cause disease with significant morbidity and mortality.
Poxvirus Diseases
Poxvirus family is a diverse group of epitheliotropic viruses that infect humans and animals. Only smallpox virus and MCV cause natural disease in humans. Smallpox virus causes systemic infection with exanthema, i.e., smallpox or variola. MCV causes localized skin lesions. Human orf and milker’s nodules are zoonoses that can occur in humans, given exposure to infected sheep or cattle. Other poxviruses zoonoses occurring in monkeys, cows, buffalo, sheep, and goats can also infect humans.
Molluscum Contagiosum ICD-9: 078.0 
ICD-10: B08.1 
Molluscum contagiosum is a self-limited epidermal viral infection.
Clinical Manifestation. Skin-colored papules; often umbilicated. Few to myriads of lesions. Host defense defects: large nodules with confluence.
Course. In healthy persons, resolves spontaneously.
Etiology and Epidemiology
Etiology. MCV with four discrete viral subtypes, I, II, III, IV. 30% homology with smallpox virus. The virus has not been cultured. Not distinguishable from other poxviruses by electron microscopy. MCV colonizes the epidermis and infundibulum of hair follicle. Transmitted by skin-to-skin contact.
Demography. More common in children and sexually active adults; males >females. In advanced human immunodeficiency virus (HIV) disease, hundreds of small mollusca or giant mollusca occur on the face and other sites. Pathogenesis. A subclinical carrier state of MCV probably exists in many healthy adults. Unique among poxviruses, MCV infection results in epidermal tumor formation; other human poxviruses cause a necrotic “pox” lesion. Rupture and discharge of the infectious viruspacked cells occur in the umbilication/crater of the lesion.
Clinical Manifestation
Papules, nodules, tumors with central umbilication or depression (Figs. 27-1–27-4). Skin-colored. Round, oval, hemispherical. Isolated single lesion; multiple, scattered discrete lesions; or confluent mosaic plaques. Larger mollusca may have a central keratotic plug, which gives the lesion a central dimple or umbilication. Gentle pressure on a molluscum extrudes the central plug.
Figure 27-1. Molluscum contagiosum Typical umbilicated papules. Discrete, solid, skincolored papules 3–5 mm on the chest of an adolescent female. The lesion with red halo is regressing spontaneously.
Autoinoculation is apparent in that mollusca are clustered at a site such as the axilla (Fig. 27-2).
Host immune response to viral antigen results in an inflammatory halo around mollusca (Fig. 27-2) and heralds spontaneous regression.
Figure 27-2. Molluscum contagiosum: axilla Multiple, small pink papules in the axilla of a healthy child. The erythema surrounding the lesions represents an inflammatory response to MC and usually indicates the lesions are regressing.
Host defense defects MC can be extensive with immunosuppressive therapy and HIV disease (Figs. 27-3 and 27-4).
Figure 27-3. Molluscum contagiosum: penis Multiple, small shiny papules on penile shaft.
Figure 27-4. Molluscum contagiosum: face A 52-year-old male with HIV disease. Discrete and confluent umbilicated papules on the face.
In individuals with darker skin, significant postinflammatory hyperpigmentation may occur after treatment or spontaneous regression. Distribution. Any site may be infected, especially naturally occluded sites, i.e., axillae, antecubital, popliteal fossae, anogenital folds. Autoinoculation spreads lesions. Mollusca may be widespread in areas of atopic dermatitis. In adults with sexually transmitted mollusca: groins, genitalia, thighs, and lower abdomen. Multiple facial mollusca (Fig. 27-4) suggest host defense defect. Mollusca can occur in the conjunctiva, causing a unilateral conjunctivitis.
Differential Diagnosis
Multiple Small Papules. Flat warts, condylomata acuminata, syringoma, sebaceous hyperplasia.
Large Solitary Molluscum. Keratoacanthoma, squamous cell carcinoma (SCC), basal cell carcinoma, epidermal inclusion cyst.
Multiple Facial Mollusca in HIV Disease. Disseminated invasive fungal infection, i.e., cryptococcosis, histoplasmosis, coccidioidomycosis, and penicilliosis (see Appendix C).
Laboratory Findings
Dermatopathology. Epidermal cells contain large intracytoplasmic inclusion bodies, i.e., molluscum bodies that appear as single, ovoid eosinophilic structures in lower cells of stratum malpighii. Infection also occurs in epidermis and superficial hair follicle. Molluscum bodies can also be seen on smears of keratin extruded from the center of a lesion.
Diagnosis
Usually made on clinical findings. Biopsy lesion in HIV disease if disseminated invasive fungal infection is in the differential diagnosis.
Course
In the normal host, mollusca often persist up to 6 months and then undergo spontaneous regression without scarring. In HIV disease, mollusca persist and proliferate even after aggressive local therapy. Mollusca are usually symptomatic, and can cause cosmetic disfigurement and concern about transmission of mollusca to a sexual partner.
Treatment
Office-based treatments include curettage, cryosurgery, and electrodessication. Imiquimod 5% cream may be effective.
Human Orf ICD-9: 059.9 ICD-10: B08.02 
Zoonosis. Caused by a dermatotropic parapoxvirus that commonly infects ungulates (sheep, goats, deer, etc.); it is transmitted to humans through contact with an infected animal or fomites. Most common in farmers, veterinarians, and sheep shearers. Only newborn animals lacking viral immunity are susceptible. Manifested as erythematous, exudative nodules around mouth that heal spontaneously, resulting in permanent immunity.
Transmission to Humans. Humans are infected by inoculation of virus by direct contact with lambs and indirectly by fomites. Human-to-human infection does not occur. Exposure occurs at the time of slaughter of lambs for Easter or the Muslim holiday Eid al-Adha.
Clinical Manifestation
Macules, Papules, Nodules at Site of Inoculation. Most commonly occur on hands, arms, legs, and face (Figs. 27-5 and 27-6). Lesions may appear edematous or bullous. Immune reconstitution inflammatory syndrome (IRIS) or target lesions occur. Color is pink to red to blanched. Lesions evolve to crusted erosions or ulcers. Healing occurs spontaneously in 4–6 weeks without scarring.
Figure 27-5. Human orf: multiple lesions on hands Multiple blisters with target/IRIS patterns in lesions on the hands of a sheep herder.
Figure 27-6. Human orf: finger A 19-year-old male of Greek heritage; lesions appeared 10 days after Greek Easter and was associated with slaughter of a lamb for the Easter feast.
Other Findings. Ascending lymphangitis and lymphadenopathy. More extensive infection may occur with host defense defects.
Differential Diagnosis
Impetigo, furuncles, milker’s nodules.
Diagnosis
Clinical findings with the appropriate history. Can be confirmed by detection of orf virus DNA by quantitative polymerase chain reaction (qPCR).
Course
Resolves spontaneously in 4–6 weeks, healing without scar formation. Erythema multiformelike eruptions (see Section 14) have been reported in human orf. Widespread lesions spread by autoinoculation may occur in atopic dermatitis. In humans, lasting immunity is conferred by infection.
Treatment
No effective antiviral treatment. Treat bacterial secondary infection.
Milkers’ Nodules ICD-9: 051.1 ICD-10: B08.03 
Zoonosis parapoxvirus infection. Papular lesions occur on muzzles and oral cavity of calves and on teats of cows. Virus transmitted to humans by contact with bovine lesions or teat cups of milking machines; most common in dairy farmers. Clinical findings and course are similar to human orf.
Clinical Manifestation
Solitary or multiple red-purple nodules (Fig. 27-7) occur at site of inoculation. Usually on exposed sites such as hands; may occur in burn wounds.
Figure 27-7. Milker’s nodule: finger A single beefy eroded nodule on the finger of a dairy farmer at the site of inoculation.
Other Findings. Lymphadenopathy.
Differential Diagnosis
Orf, furuncle, herpes simplex virus (HSV) infection, pyogenic granuloma.
Diagnosis
Usually made on history of bovine exposure and clinical findings.
Course
Resolves spontaneously.
Treatment
No effective antiviral treatment. Treat bacterial secondary infection.
Smallpox ICD-9: 050.9 ICD-10: B03 
Smallpox is a viral infection unique to humans. The disease has been eradicated due to a global immunization program, last case having been reported in 1977.
http://www.bt.cdc.gov/agent/smallpox/overview/disease-facts.asp
http://www.who.int/csr/disease/smallpox/en/
Etiology and Epidemiology
The last cases of endemic smallpox occurred in 1977. Eradication declared in 1980. Smallpox estimated to have killed 300–500 persons during the 20th century. Persons in the general population in the United States under age 30 have not been vaccinated.
Etiology. Variola major and Variola Minor. Humans are the only host of variola. DNA virus that replicates in cell cytoplasm. Transmitted by respiratory-droplets or fomites.
Classification. Variola Major. 90% of cases. 30% mortality.
Variola Minor or Alastrim. 2% of cases in unvaccinated persons and 25% of vaccinated persons. Variola Sine Eruptione. Occurs in vaccinated persons and infants with maternal antibodies. Smallpox with Flat Lesions. Case fatality 97% among unvaccinated persons.
Hemorrhagic smallpox. Near 100% case fatality rate.
Pathogenesis. Enters the respiratory tract, seeding mucous membranes, passing rapidly into local lymph nodes. Mouth/pharynx is infected during viremia. Virus invades capillary endothelium of dermis, resulting in skin lesions. Virus is abundant in skin and oropharyngeal lesions in early illness. Death ascribed to toxemia, associated with immune complexes, and to hypotension. Infection with smallpox confers lifelong immunity.
Clinical Manifestation
Small red macules evolve to papules over 1–2 days. Initial lesions on face and extremities, then gradually become disseminated. In 1–2 more days, papules become vesicles. Vesicles evolve to pustules 4–7 days after onset of rash (Figs. 27-8), and last for 5–8 days. Followed by umbilication and crusting (Fig. 27-8C). Lesions are generally all at the same stage of development. Pockmarks/pitted scars occur in 65–85% of severe cases, especially on the face (Fig. 27-9). Secondary Staphylococcus aureus infection with abscesses and cellulitis may occur in smallpox lesions.
Figure 27-8. Smallpox: variola major Multiple pustules becoming confluent on the face.
Figure 27-9. Smallpox: scarring on face A 50-year-old Indian male with a history of smallpox as a child has multiple depressed scars on face 40 years after smallpox infection. (Courtesy of Atul Taneja, MD.)
Mucous Membranes. Enanthema (tongue, mouth, oropharynx) precedes exanthem by a day.
General Findings. Variants: Panophthalmitis, keratitis, secondary infection of eye (1%). Arthritis in children (2%). Encephalitis (<1%)
Differential Diagnosis
Severe chicken pox (varicella lesions are in different stages of development), measles, secondary syphilis (great pox), hand-foot-and-mouth disease (HFMD) (coxsackievirus A-16), cowpox, monkeypox, tanapox.
Diagnosis
A febrile illness with acute onset of fever >38.3°C (101°F) followed by exanthem characterized by firm, deep-seated vesicles or pustules in the same stage of development without other apparent cause (see http://www.bt.cdc.gov/agent/smallpox/diagnosis/casedefinition.asp).
Treatment
Report possible smallpox to public health officials; diagnosis confirmed in a Biological Safety Level 4 laboratory where staff members have been vaccinated. Cidofovir may be effective.
Smallpox Vaccination ICD-9: V04.1 ICD-10: B03
Vaccinia virus is related to cowpox virus and is used for smallpox immunization (vaccination). Origin of the strains of vaccinia virus currently used for vaccination is unknown. Natural infection with cowpox virus confers immunity to smallpox. Prior vaccine (Dryvax) was made from vaccine virus cultured in the skin of calved. The current vaccine (ACAM2000) is made from vaccinia virus cultured in vitro on kidney epithelial cells.
Clinical Manifestation
Normal Vaccination Reaction. (Fig. 27-10)
Figure 27-10. Primary smallpox vaccination site reaction Expected vaccine site reaction and progression following primary smallpox vaccination or revaccination after a prolonged period between vaccinations. Multiple pressure vaccination technique used.
• 6-8 days after vaccination, loculated pustule (Jennerian pustule) 1-2 cm in diameter develops at site.
• Central crusting begins and spreads peripherally over 3–5 days.
• Local edema and a dark crust remain until the third week.
• Other reactions are classified as equivocal, and another vaccination is required. Local “satellite” pustules may occur.
Reactions and Complications
Noninfectious Rashes. Erythema multiformelike.
Macular (“Toxic Eruption”). Maculopapular; vesicular. Urticarial. Most common 7–14 days after primary vaccination or earlier after revaccination.
Noninfectious. Immune-mediated encephalitis, pericarditis, myocarditis.
Bacterial Infection. S. aureus and group A streptococcus can cause enlarging crusted inoculation site (impetigo or soft tissue infection). Tetanus.
Accidental inoculation to normal or abnormal skin such as atopic dermatitis (eczema vaccinatum).
Congenital Vaccinia. Vaccination during pregnancy may result in dissemination of infection to fetus.
Generalized Vaccinia. Generalized vesicular/pustular reaction. Self-limited, usually occurring in one crop. Usually occurs in a healthy individual whose antivaccinal antibody response is delayed but adequate. Almost always benign, with normal-healing primary vaccination. May become malignant with progression (see below).
Progressive Vaccinia. Vaccination site fails to heal and continues to enlarge forming an ulcer with raised edges. Relentless outward spread of infection from vaccination site and eventual dissemination to other areas of the body.
Diagnosis
Clinical history, physical examination, and clinical course. Persistence of virus can be confirmed by culturing vaccinia virus from the skin lesions.
Human Papillomavirus Infections
ICD-9: 079.4 ICD-10: B97.7
HPV are ubiquitous in humans, causing:
Subclinical infection
Wide variety of benign clinical lesions on skin and mucous membranes.
Cutaneous and mucosal premalignancies (Table 27-1): Squamous cell carcinoma in situ (SCCIS); invasive SCC
More than 150 types of HPV have been identified and are associated with various clinical lesions and diseases. Papillomaviruses infect all mammalian species as well as birds, reptiles, and others.
Cutaneous HPV infections occur commonly in the general population:
Common warts: Represent approximately 70% of all cutaneous warts, occurring in up to 20% of all school-age children.
Butcher’s warts: Common in butchers, meat packers, fish handlers.
Plantar warts: Common in older children and young adults, accounting for 30% of cutaneous warts.
Flat warts: Occur in children and adults, accounting for 4% of cutaneous warts.
Oncogenic HPV can cause SCCIS and invasive SCC with host defense defects.
Epidermodysplasia verruciformis (EDV). Anogenital HPV infections.
External genital wart: most prevalent sexually transmitted infection (see Section 30).
Squamous Cell Carcinoma. Some HPV types have a major etiologic role in the pathogenesis of in situ as well as invasive SCC of the anogenital epithelium.
During delivery, maternal genital HPV infection can be transmitted to the neonate, resulting in anogenital warts and respiratory papillomatosis after aspiration of the virus into the upper respiratory tract.
TABLE 27-1 CORRELATION OF HUMAN PAPILLOMAVIRUS TYPE WITH DISEASE
Etiology
Papillomaviruses are double-stranded DNA viruses of the papovavirus class, which infect most vertebrate species with exclusive host and tissue specificity. Infections are restricted squamous epithelia of skin and mucous membranes. Clinical lesions induced by HPV and their natural history are largely determined by HPV type. HPV are normally grouped according to their pathologic associations and tissue specificity—either cutaneous or mucosal. Mucosal-associated HPV can be further subgrouped according to their risk of malignant transformation. New types of HPV are defined as possessing <90% homology to known types in six specified early and late genes.
Human Papillomavirus: Cutaneous Diseases 
Certain human HPV types commonly infect keratinized skin.
Cutaneous warts are:
Discrete benign epithelial hyperplasia with varying degrees of surface hyperkeratosis.
Manifested as minute papules to large plaques.
Lesions may become confluent, forming a mosaic.
The extent of lesions is determined by the immune status of the host.
Epidemiology
Transmission. Skin-to-skin contact. Minor trauma with breaks in stratum corneum facilitates epidermal infection.
Demography. Host defense defects are associated with an increased incidence of and more widespread cutaneous warts: HIV disease, iatrogenic immunosuppression with solid organ transplantation.
Epidermodysplasia Verruciformis. Autosomal-recessive hereditary disorder. Acquired EDV-like lesions seen in HIV disease.
Clinical Manifestation
Common Wart or Verruca Vulgaris
Firm papules, 1–10 mm or larger (Figs. 27-11–27-15), hyperkeratotic, clefted surface, with vegetations. Isolated lesion, scattered discrete lesions. Occur at sites of trauma: hands, fingers, and knees. Palmar lesions disrupt the normal line of fingerprints. Return of fingerprints is a sign of resolution of the wart. Characteristic “red or brown dots,” best visualized with dermatoscope, are pathognomonic, representing thrombosed dermal papilla capillary loops.
Figure 27-11. Verruca vulgaris on face A 3-year-old boy with common wart on the moustache area.
Figure 27-12. Verruca vulgaris: thumb A 25-year-old male with hyperkeratotic, verrucous papules on the dorsal thumb. The dark points represent thrombosed capillaries. The lesion resolved with electrodessication, having failed to respond to cryosurgery.
Figure 27-13. Verruca vulgaris: hands A 20-year-old immunosuppressed male with nephrotic syndrome. Multiple verrucae on the (A) dorsum and (B) palm of the hand.
Figure 27-14. Periungual warts A 77-year-old male with extensive periungual warts. He was depressed and picked at periungual skin folds created portal of entry for HPV. Lesions resolved with hyperthermia.
Figure 27-15. Giant warts on hand and forearm. A 51-year-old female with recalcitrant warts on hands for 2 years. Immunodeficiency was suspected but not detected.
Linear arrangement: inoculation by scratching.
Annular warts: at sites of prior therapy.
Butcher’s warts: large cauliflower-like lesions on hands of meat handlers.
Filiform warts have relatively small bases, extending out with elongated cap (Fig. 27-11).
Plantar Warts (Verruca Plantaris)
Early small, shiny, sharply marginated papule (Fig. 27-16) → plaque with rough hyper-keratotic surface, studded with brown-black dots (thrombosed capillaries). As with palmar warts, normal dermatoglyphics are disrupted. Return of dermatoglyphics is a sign of resolution of the wart. Warts heal without scarring. Therapies such as cryosurgery and electrosurgery can result in scarring at treatment sites. Tenderness may be marked, especially in certain acute types and in lesions over sites of pressure (metatarsal head).
Figure 27-16. Verruca plantaris: plantar feet A 71-year-old male with chronic lymphatic leukemia. Large and painful on pressure, warts are seen on the plantar feet and toes. Multiple warts were also present on the fingers. After many failed therapeutic modalities, he was successfully treated with electron beam radiation.
Mosaic warts: Confluence of many small warts. “Kissing” warts: lesion may occur on opposing surface of two toes (Fig. 27-17). Plantar foot, often solitary but may be three to six or more. Pressure points, heads of metatarsal, heels, toes.
Figure 27-17. Extensive verrucae A 49-year-old male with HIV disease has confluent warts on the hands and feet. The large warts on opposing toes are referred to as “kissing warts.”
Flat Warts (Verruca Plana)
Sharply defined, flat papules (1–5 mm); “flat” surface; the thickness of the lesion is 1–2 mm (Fig. 27-18). Skin-colored or light brown. Round, oval, polygonal, linear lesions (inoculation of virus by scratching). Occur on face, beard area (Fig. 27-19), dorsa of hands, and shins.
Figure 27-18. Verruca plana A 12-year-old male kidney transplant recipient. Multiple brown keratotic papules are seen on the forehead and scalp.
Figure 27-19. Filiform and flat warts A 38-year-old male with HIV disease has a confluence of lesions on face and beard area. Lesions resolved after successful antiretroviral therapy.
Epidermodysplasia Verruciformis
Autosomal-recessive condition. Flat-topped papules. Tinea versicolor-like lesions, particularly on the trunk. Color: skin-colored, light brown, pink, hypopigmented. Lesions may be numerous, large, and confluent. Seborrheic keratosis-like and actinic keratosis-like lesions. Linear arrangement after traumatic inoculation. Distribution: face, dorsa of hands, arms, legs, anterior trunk (Fig. 27-20). Premalignant and malignant lesions arise most commonly on face. SCC: in situ and invasive.
Figure 27-20. EDV-like flat warts on chest A 44-year-old male with HIV disease had extensive flat wart-like lesions on face, neck, trunk, abdomen.
Host Defense Defects
(HIV disease, iatrogenic immunosuppression). HPV-induced warts are common (Fig. 27-21) and may be difficult to treat successfully. Some have atypical histologic features and may progress to in situ and invasive SCC.
Figure 27-21. Multiple oral condylomata in HIV disease. Lesions resolved with antiretroviral therapy.
Human Papillomavirus: Oropharyngeal Diseases
HPV infects mucosal epithelial cells of the mouth, nose, and airways (Fig. 27-21). Oral infections may be subclinical or cause benign or malignant oral neoplasms. In respiratory or laryngeal papillomatosis, HPV 6 and 11 are acquired during vaginal delivery and cause warts of the oropharynx and upper airways. Laryngeal lesions cause major morbidity. SCC occurs in some persons.
Human Papillomavirus: Anogenital Infections
See Section 30, “Sexually Transmitted Diseases.”
Differential Diagnosis
Verruca vulgaris molluscum contagiosum, seborrheic keratosis, actinic keratosis, keratoacanthoma, SCCIS, invasive SCC.
• Verruca plantaris callus, corn or keratosis, exostosis.
• Verruca plana, syringoma (facial), molluscum contagiosum.
• Epidermodysplasia verruciformis pityriasis versicolor, actinic keratoses, seborrheic keratoses, SCCIS, basal cell carcinoma.
Laboratory Findings
Dermatopathology. Acanthosis, papillomatosis, hyperkeratosis. Characteristic feature is foci of vacuolated cells (koilocytosis), vertical tiers of parakeratotic cells, and foci of clumped keratohyaline granules.
Diagnosis. Usually made on clinical findings. With host defense defects, HPV-induced SCC at periungual sites or anogenital region should be ruled out by lesional biopsy.
Course
In immunocompetent individuals, cutaneous HPV infections usually resolve spontaneously, without therapeutic intervention. With host defense defects, cutaneous HPV infections may be very resistant to all modalities of therapy. With EDV, lesions first occur at 5–7 years of age and increase in numbers progressively, becoming widespread in some. About 30–50% of individuals with EDV develop malignant cutaneous lesions on areas of skin exposed to sunlight.
Treatment
Goal. Aggressive therapies, which are often quite painful and may be followed by scarring, are usually to be avoided because the natural history of cutaneous HPV infections is for spontaneous resolution in months or a few years. Plantar warts that are painful because of their location warrant more aggressive therapies. Patient-Initiated Therapy. Minimal cost; no/minimal pain.
For Small Lesions. 10–20% salicylic acid and lactic acid in collodion.
For Large Lesions. 40% salicylic acid plaster for 1 week, then application of salicylic acid–lactic acid in collodion.
Imiquimod Cream. At sites that are not thickly keratinized, apply half-strength three times per week. Persistent warts may require occlusion. Hyperkeratotic lesions on palms/soles should be debrided frequently; Imiquimod used alternately with a topical retinoid such as tazarotene topical gel may be effective.
Hyperthermia for Verruca Plantaris. Hyperthermia with hot water [45°C (113°F)] immersion for 20 minutes or three times weekly for up to 16 treatments is effective in some patients.
Clinician-Initiated Therapy. Costly, painful.
Cryosurgery. If patients have tried home therapies and liquid nitrogen is available, light cryo-surgery using a cotton-tipped applicator or cryospray, freezing the wart and 1–2 mm of surrounding normal tissue for approximately 30 seconds, is quite effective. Freezing kills the infected tissue but not HPV.
Cryosurgery is usually repeated about every 4 weeks until the warts have disappeared. Painful.
Electrosurgery. More effective than cryosurgery, but also associated with a greater chance of scarring. EMLA cream can be used for anesthesia for flat warts. Lidocaine injection is usually required for thicker warts, especially palmar/plantar lesions.
CO2 Laser Surgery. May be effective for recalcitrant warts, but no better than cryosurgery or electrosurgery in the hands of an experienced clinician.
Surgery. Single, nonplantar verruca vulgaris: curettage after freon freezing; surgical excision of cutaneous HPV infections is not indicated in that these lesions are epidermal infections.
Systemic Viral Infections with Exanthems 
Primary systemic infections often present with characteristic mucocutaneous rashes: exanthems and enanthems.
Exanthem and enanthem. An exanthem is eruptive rash associated with a systemic disorder; enanthem, mucosal lesions, associated with systemic disorder often associated with an exanthem. Often caused by viral agents but can also be associated with other infections: (bacterial, parasitic infections, sexually transmitted disease), adverse cutaneous reactions to drugs or toxin, and autoimmune disease.
Etiology and Epidemiology
RNA Viruses. Picornaviridae: Poliovirus, coxsackieviruses, echovirus, enterovirus, hepatitis A virus, rhinovirus. Togaviridae: Rubella virus, attenuated rubella virus in vaccine. Flaviviridae: Dengue, hepatitis C virus. Paramyxoviridae: measles, mumps. Orthomyxoviridae: influenza A, B, and C viruses. Retroviridae: Human T-lymphotrophic virus types I and II, HIV types 1 and 2 (acute HIV syndrome). DNA Viruses. Parvoviridae: Parvovirus B19 (erythema infectiosum). Hepadnaviridae hepatitis B virus. Adenoviridae. Herpesviridae: HSV types 1 and 2, varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein–Barr virus (EBV), HHV 6 and 7 (exanthem subitum, roseola infantum), Kaposi sarcoma (KS)-associated virus (HHV-8). Poxviridae: Variola (smallpox) virus, orf virus, and MCV. Bacteria. Group A streptococcus: scarlet fever, toxic shock syndrome. S. aureus: toxic shock syndrome. Legionella, Leptospira, Listeria, Meningococci, Treponema pallidum. Mycoplasmal Mycoplasma pneumoniae
Rickettsiae Rocky Mountain spotted fever. Tick-borne spotted fevers. Rickettsialpox. Murine typhus. Epidemic typhus
Miscellaneous Strongyloides, Toxoplasma.
Pathogenesis. Skin lesions may be produced by the following:
• Direct effect of microbial replication in infected cells.
• Host response to the microbe.
• Interaction of these two phenomena.
Clinical Manifestation
Prodrome. Acute infection syndrome: Fever, malaise, coryza, sore throat, nausea, vomiting, diarrhea, abdominal pain, and headache. Exanthematous Eruption. Resembles the exanthem occurring with measles or morbilli, i.e., measles-like or “morbilliform.” Also referred to as maculopapular. Characterized by initially discrete, often becoming confluent pink macules and papules (Fig. 27-22). Usually central, i.e., head, neck, trunk, and proximal extremities. Most often progresses centrifugally. Lesions can become hemorrhagic with petechiae, hemorrhagic measles.
Figure 27-22. Measles-like exanthema Disseminated erythematous macules and papules, typical of the cutaneous changes with many viral infections. Differential diagnosis of an exanthematous or morbilliform adverse cutaneous drug eruption. (A) Typical distribution of lesions on the trunk and extremities. (B) Closeup of pink macules and papules becoming confluent in some areas.
Scarlatiniform Eruption. Diffuse erythema.
Vesicular Eruptions. Initially, vesicles with clear fluid. May evolve to pustules. In a few days to a week, roof of vesicle sloughs, resulting in erosions. In varicella, lesions are disseminated and may involve oropharynx. In hand foot and mouth disease, vesicles/erosion occur in oropharynx; painful linear vesicles on palms/soles.
Oropharyngeal Lesions. Enanthem. Koplik spots in measles. Petechiae on soft palate (Forchheimer sign). Microulcerative lesions in herpangina due to coxsackievirus A (Fig. 27-27). Palatal petechiae in mononucleosis syndrome of primary EBV or CMV infection. Aphthous ulcer-like lesions occur with primary HIV infection.
Conjunctivitis. Occurs with measles.
Genitalia. External aphthous ulcer-like lesion with primary HIV infection.
Systemic Findings. Lymphadenopathy. Hepatomegaly. Splenomegaly.
Differential Diagnosis
Adverse cutaneous drug eruption (ACDE), systemic lupus erythematosus, Kawasaki syndrome.
Diagnosis
Usually made on history and clinical findings. Serology: Acute and convalescent titers most helpful in specific diagnosis. Cultures: If practical.
Rubella ICD-9: 056 ICD-10: B06 
Etiologic Agent. Rubella virus, an RNA togavirus.
Clinical Manifestation. Characteristic exanthem and lymphadenopathy. Many infections are subclinical.
Congenital Rubella Syndrome. Rubella virus infecting a pregnant female, while causing a benign illness in the mother, may result in serious chronic fetal infection and malformation.
Prophylaxis. Childhood immunization is highly effective at preventing infection.
Synonyms: German measles, “3-day measles.”
Etiology and Epidemiology
Etiology. Rubella virus, an RNA togavirus, member of Rubivirus genus. Attenuated rubella virus used in immunization can cause an illness with rubella-like rash, lymphadenopathy, and arthritis.
Demography. Before widespread immunization, most commonly occurred in children <15 years. Currently young adults. Risk factors: Lack of active immunization and lack of natural infection. After immunization began in 1969, incidence decreased by 99% in industrialized countries.
Transmission. Inhalation of aerosolized respiratory droplets. Moderately contagious. 10–40% of cases asymptomatic. Period of infectivity from end of incubation period to disappearance of rash.
Clinical Manifestation
Prodrome. Prodrome usually absent, especially in young children. In adolescents and young adults: anorexia, malaise, conjunctivitis, headache, low-grade fever, and mild upper respiratory tract symptoms. In women, rubella-like illness frequently follows administration of attenuated live rubella virus with arthralgias.
Exanthem. Pink macules, papules (Fig. 27-23). Initially on forehead, spreading inferiorly to face, trunk, and extremities during first day. By second day, facial exanthem fades. By third day, exanthem fades completely without residual pigmentary change or scaling. Truncal lesions may become confluent, creating a scarlatiniform eruption.
Figure 27-23. Rubella A 21-year-old male. Erythematous macules and papules appearing initially on the face and spreading inferiorly and centrifugally to the trunk and extremities, usually within the first 24 hours. Postauricular and posterior cervical lymph nodes were enlarged. Lesions becoming confluent on the cheeks while clearing on the forehead. Truncal lesions appear 24 hours after onset of facial lesions.
Mucous Membranes. Petechiae on soft palate (Forchheimer sign) during prodrome (also seen in infectious mononucleosis).
Lymph Nodes. Enlarged during prodrome. Postauricular, suboccipital, and posterior cervical lymph nodes enlarged and possibly tender. Mild generalized lymphadenopathy may occur. Enlargement usually persists for 1 week but may last for months.
Spleen. May be enlarged.
Joints. Arthritis in adults; possible effusion. Arthralgia, especially in adult women after immunization.
Congenital Rubella Syndrome. Congenital heart defects; cataracts; microphthalmia, microcephaly, hydrocephaly, deafness.
Differential Diagnosis
Exanthem. Other viral exanthems, ACDE, and scarlet fever.
Exanthem with Arthritis. Acute rheumatic fever, rheumatoid arthritis, erythema infectiosum.
Diagnosis
Clinical diagnosis; can be confirmed by serology. Virus can be isolated from throat, joint fluid aspirate.
Course
In most persons, rubella is a mild, inconsequential illness. However, when rubella occurs in a pregnant woman during the first trimester, the infection can be passed transplacentally to the developing fetus. Approximately half of infants who acquire rubella during the first trimester of intrauterine life will show clinical signs of damage from the virus.
Treatment
Rubella is preventable by immunization. Previous rubella should be documented in young women: if antirubella antibody titers are negative, rubella immunization should be given.
Measles ICD-9: 055 ICD-10: B05 
A highly contagious childhood viral disease characterized by fever, coryza, cough; an exanthema; conjunctivitis; pathognomonic enanthem (Koplik spots).
Significant morbidity and mortality occur in acute and chronic course.
Childhood immunization is highly effective at preventing infection.
Synonyms: Morbilli, rubeola.
Etiology and Epidemiology
Etiology. Measles virus, member of RNA genus Morbillivirus and family Paramyxoviridae.
Demography. Measles is no longer endemic in United States, Europe, Canada, and Japan; cases result from importation of measles. Hyperendemic in many developing nations, resulting in 164,000 deaths in 2008.
Risk Factors. Current outbreaks in the United States occur in inner city unimmunized preschool-age children, school-age persons immunized at an early age, and imported cases.
Transmission spread by respiratory droplet aerosols produced by sneezing and coughing. Infected persons contagious from several days before onset of rash up to 5 days after lesions appear. Attack rate for susceptible contacts >90–100%. Asymptomatic infection uncommon.
Pathogenesis. Virus enters cells of respiratory tract, replicates locally, spreads to regional lymph nodes, and disseminates hematogenously to skin and mucous membranes, where it replicated. Modified measles, a milder form of the illness, may occur in individuals with preexisting partial immunity induced by active or passive immunization. Persons deficient in cellular immunity are at high risk for severe measles.
Clinical Manifestation
Incubation Period. 10–15 days.
Prodrome. Fever. Malaise. Upper respiratory symptoms (coryza, hacking bark-like cough). Photophobia, conjunctivitis with lacrimation. Periorbital edema. As exanthem progresses, systemic symptoms subside.
Exanthem. On the fourth febrile day, erythematous macules and papules appear on forehead at hairline, behind ears; spread centrifugally and inferiorly to involve the face, trunk (Fig. 27-24), extremities, palms/soles, reaching the feet by third day. Initial discrete lesions may become confluent, especially on face, neck, and shoulders. Lesions gradually fade in order of appearance, with subsequent residual yellowtan stain or faint desquamation. Exanthem resolves in 4–6 days.
Figure 27-24. Measles with exanthem (A) Erythematous macule, first appearing on the face and neck where they become confluent, spreading to the trunk and arms in 2–3 days where they remain discrete. In contrast, rubella also first appears initially on the face but spreads to the trunk in 1 day. Koplik spots on the buccal mucosa were also present. Erythematous papules have become confluent on the face on the fourth day.
Measles with Koplik spots (B) Red papules on buccal mucosa opposite premolars prior of appearance of exanthema. (From the CDC.)
Enanthem. Cluster of tiny bluish-white spots on red background, appearing on or after second day of febrile illness, are seen on buccal mucosa opposite premolar teeth, i.e., Koplik spots that are pathognomonic of measles. Appear before exanthem. Also: entire buccal/inner labial mucosa may be inflamed.
Bulbar Conjunctivae. Conjunctivitis, injected, red.
General Examination. Generalized lymphadenopathy. Diarrhea, vomiting. Splenomegaly
Modified Measles. Milder clinical findings with preexisting partial immunity.
Atypical Measles. Occurs in individuals immunized with formalin-inactivated measles vaccine, subsequently exposed to measles virus. Exanthem begins peripherally and moves centrally; can be urticarial, maculopapular, hemorrhagic, and/or vesicular. Systemic symptoms can be severe.
Measles in Host With Defense Defects. Rash may not occur. Pneumonitis and encephalitis more common.
Differential Diagnosis
Disseminated Maculopapular Eruption. Morbilliform drug eruption, scarlet fever. Kawasaki syndrome.
Diagnosis
Clinical diagnosis confirmed by serology. Multinucleated giant cells in secretions. Isolate virus from blood, urine, and pharyngeal secretions. Detect measles antigen in respiratory secretions by immunofluorescent staining. Detects genomic sequences of measles virus RNA in serum, throat swabs, and cerebrospinal fluid (CSF).
Course
Self-limited infection in most patients. Mortality rate in developing countries up to 10%. Age-specific rates of complications highest among children <5 years old and adults >20 years. Sites of complications: respiratory tract, central nervous system (CNS), tract. Complications more common in malnourished children, the unimmunized, and those with congenital immunodeficiency and leukemia. Acute complications (10% of cases): otitis media, pneumonia (bacterial or measles), diarrhea, measles encephalitis, and thrombocytopenia. Chronic complication: subacute sclerosing panencephalitis (Dawson encephalitis).
Treatment
Prophylactic immunization. Supportive care.
Enteroviral Infections ICD-9: 047 ICD-10: B34.1 
Etiologic Agents. Intestinal viruses echovirus 9 and 16, coxsackie A 16 virus, and enterovirus 71 (EV71).
Enteroviral Infections with Rash:
Echovirus 9 (E9): Discrete pink macules and papules resembling rubella ± fever.
Echovirus 16: exanthem, roseola-like (confluent pink papules) ± fever.
Coxsackievirus A16, EV71: hand foot and mouth disease.
A1–10, 16, 22, CB1–5; EV6, 9, 11, 16, 17, 25; EV71: Herpangina.
Other enteroviruses reported to cause erythema multiforme: vesicular, urticarial, petechial, and purpuric rashes.
Hand-Foot-and-Mouth Disease
ICD-9: 074.3 ICD-10: 074.3 
Systemic viral infection characterized by ulcerative enanthem; vesicular exanthem on the distal extremities; mild constitutional symptoms.
Etiology. Enterovirus (picornavirus group, single-stranded RNA, nonenveloped). Commonly: coxsackievirus A16 and EV71.
Demography. Most common in first decade. Outbreaks during warmer months (late summer, early fall) in temperate climes. Highly contagious, spread from person to person by oral–oral and fecal–oral routes.
Pathogenesis. Enteroviral implantation in the GI tract (buccal mucosa and ileum) with extension into regional lymph nodes. Seventy-two hours later viremia occurs with seeding of the oral mucosa and skin of the hands and feet.
Clinical Manifestation
Symptoms. Frequently 5–10 painful ulcerative oral lesions, leading to refusal to eat in children. Few to 100 cutaneous lesions appear together or shortly after the oral lesions and may be asymptomatic or painful and tender.
Macules and papules that quickly evolve to vesicles. Characteristically, lesions occur on palms and soles, especially on sides of fingers, toes, and buttocks. Vesicles may have characteristic “linear” shape; tender, painful; usually do not rupture (Fig. 27-25). At other cutaneous sites, vesicles can rupture, with formation of erosions and crusts. Lesions heal without scarring.
Figure 27-25. Hand-foot-and mouth disease A 21-year-old male with extensive blister formation on (A) palms and fingers, and (B) soles and toes.
Oral Lesions. Macules → grayish vesicles, arising on the hard palate, tongue, and buccal mucosa (Fig. 27-26). Vesicles quickly erode to 5- to 10-mm, small, punched out painful ulcers. General Findings.May be associated with high fever, severe malaise, diarrhea, and joint pains. EV17 infections may have associated CNS (aseptic meningitis, encephalitis, meningoencephalitis, flaccid paralysis), and lung involvement.
Figure 27-26. Hand-foot-and-mouth disease Multiple, superficial erosions with an erythematous halo on the lower labial mucosa; gingiva is normal. In primary herpetic gingivostomatitis, which presents with similar oral vesicular lesions, painful erosive gingivitis usually occurs as well.
Differential Diagnosis
A sudden outbreak of oral and distal extremity lesions is pathognomonic for hand foot and mouth disease. However, if only the oral lesions are present, the differential diagnosis would include HSV infection, aphthous stomatitis, herpangina, erythema multiforme, and adverse drug reaction.
Diagnosis
Usually made on clinical findings. Virus may be isolated from vesicles, throat washings, and stool specimens.
Course
Most commonly, hand foot and mouth disease is self-limited. Rise in serum antibodies eliminates the viremia in 7–10 days. Coxsackievirus has been implicated in cases of myocarditis, meningoencephalitis, aseptic meningitis, paralytic disease, and a systemic illness resembling measles. EV71 infections have higher morbidity/mortality rates due to CNS involvement and pulmonary edema.
Treatment
Symptomatic and supportive care.
Herpangina ICD-9: 074.0 ICD-10: B08.5
Etiologic Agent. Coxsackievirus A1–10; coxsackie B1–5; echoviruses; EV71.
Demography. It usually affects children <5 year, prevalent in late summer and early fall in temperate climes.
Clinical Manifestation. Sudden onset of fever, malaise, headache, anorexia, dysphagia, and sore throat.
Enanthem. 1- to 2-mm gray-white papules/vesicles that evolve to ulcers with red halos, and diffuse pharyngeal hyperemia (Fig. 27-27). Distributed on the anterior tonsillar pillars, soft palate, uvula, and tonsils. Usually lasts 4–6 days, and its course is self-limited.
Figure 27-27. Herpangina Multiple, small vesicles and erosions with erythematous halos on the soft palate; some taste buds on the posterior tongue are inflamed and prominent.
Erythema Infectiosum
ICD-9: 057.0 ICD-10: B08.3 
Childhood exanthem associated with primary human parvovirus b19 (HPVB19) infection.
Characterized by edematous erythematous plaques on the cheeks (“slapped cheeks”); erythematous lacy eruption on the trunk and extremities.
Etiology and Epidemiology
Etiology. HPVB19 is a small single-stranded, nonenveloped virus. It is present in respiratory tract during the viremic stage of primary infection. Transmission by droplet aerosol.
Demography. More common in young. Sixty percent of adolescents and adults are seropositive for antiparvovirus B19 IgG. Symptomatic rheumatic involvement is more common in adult women.
Pathogenesis. Viremia develops 6 days after intranasal inoculation of HPVB19 into volunteers who lack serum antibodies to the virus. IgM and then IgG antibodies develop after a week and clear viremia. Significant bone marrow depression can occur at this time. The exanthem begins 17–18 days after inoculation and may be accompanied by arthralgia and/or arthritis; these findings are mediated by immune complexes. In compromised hosts, PVB19 can destroy erythroid precursor cells, causing severe aplastic crisis in adults and hydrops fetalis in the fetus.
Clinical Manifestation
Constitutional symptoms more severe in adults, with fever, adenopathy. Arthritis/arthralgias involving small joints of hand, knees, wrists, ankles, feet. Numbness and tingling of fingers.
Cutaneous Lesions. Edematous, confluent plaques on malar face (“slapped cheeks”) (Fig. 27-28A) (nasal bridge, periorbital regions spared); lesions fade over 1–4 days. Usually absent in adults.
Nonfacial Lesions. Appear after facial lesions. Erythematous macules and papules that become confluent, giving a lacy or reticulated appearance (Fig. 27-28B). Best seen on extensor arms; also trunk and neck. Fade in 5–9 days.
Figure 27-28. A: Erythema infectiosum: slapped cheek A 10-year-old child. Diffuse erythema and edema of the cheeks with “slapped cheek” facies. B: Erythema infectiosum: reticulated erythema A 10-year-old child. Discrete, erythematous macules with ring formation on the arm.
Reticulated rash may recur. Adults: reticulated macules on extremities.
Less Commonly, morbilliform, confluent, circinate, annular exanthems. Rarely, purpura, vesicles, pustules, palmoplantar desquamation. PVB19 also reported to cause papular purpuric “gloves and socks” syndrome.
Mucosal Lesions. Uncommonly, enanthem with glossal and pharyngeal erythema; red macules on buccal and palatal mucosa.
Joints. Arthralgia and/or arthritis in 10% of children; typically involving large joints. Arthritis in adult women.
CNS and peripheral neuropathy occur in persons with altered immunity.
Differential Diagnosis
Children with Erythema Infectiosum. Childhood exanthems, Haemophilus influenzae cellulitis, adverse cutaneous drug reaction.
Adults with Arthritis. Lyme arthritis, rheumatoid arthritis, rubella.
Diagnosis
Usually made on clinical findings. Demonstration of IgM anti-HPVB19 antibodies or IgG seroconversion. Demonstration of HPVB19 in serum. During aplastic crisis: absence of reticulocytes, falling hemoglobin, hypoplasia or aplasia of erythroid series in bone marrow.
Course
Cutaneous. “Slapped cheeks” are noted first, fading over 1–4 days. Then, reticulated rash appears on the trunk, neck, and extensor extremities. Eruption lasts 5–9 days but characteristically can recur for weeks or months.
Arthralgias. Self-limited, lasting 3 weeks, but may persist for several months or years.
Aplastic Crisis. In patients with chronic hemolytic anemias, transient aplastic crisis may occur, manifested by worsening anemia, fatigue, and pallor.
Fetal B19 Infection. Intrauterine infection may be complicated by nonimmune fetal hydrops secondary to infection of RBC precursors, hemolysis, severe anemia, tissue anoxia, and high-output heart failure. Risk <10% after maternal infection.
Immunocompromised Host. Prolonged chronic anemia associated with persistent lysis of RBC precursors. At risk: HIV disease, congenital immunodeficiencies, acute leukemia, organ transplants, systemic lupus erythematosus, and infants <1 year. Responds to intravenous immunoglobulin (IVIg).
Treatment
Symptomatic.
Gianotti–Crosti Syndrome ICD-9: 057.8 ICD-10: L44.4 
Cutaneous reaction pattern associated with primary infection and immune response to viruses, bacteria, and vaccines.
Etiologic Agents:
Viruses: EBV, CMV, hepatitis B virus (ayw strain), coxsackievirus, parainfluenza virus, respiratory syncytial virus, rotavirus, adenovirus, echovirus, pox virus, poliovirus, parvovirus, HIV, hepatitis A virus, hepatitis C virus.
Bacteria: Mycoplasma pneumoniae, Borrelia burgdorferi, Bartonella henselae, group A streptococcus.
Vaccines: influenza, diphtheria, tetanus, pertussis, BCG, H. influenzae type b, oral polio.
Epidemiology. Occurs in children 6 months to 12 years. Manifestation of immune response to transient viremia with immune complex deposition in the skin.
Clinical Manifestation
Discrete, nonpruritic, erythematous, monomorphic papules (Fig. 27-29). Lesions become coalescent. Face, buttocks, and extensor surfaces of extremities; symmetric. Typically, the trunk is spared. Duration is 2–8 weeks.
Figure 27-29. Gianotti–Crosti syndrome A 6-year-old boy with multiple red papules becoming confluent of the cheeks.
Synonym: Papular acrodermatitis of childhood (PAC)
Dengue ICD-9: 061 ICD-10: A90 
Self-limited systemic viral infection transmitted from mosquitoes to humans.
Incidence Globally 50 million cases annually.
Clinical Syndromes
Dengue Fever. Arthralgia–rash syndrome with abrupt onset of fever and muscle and joint pains, usually with retro-orbital pain, photophobia, and lymphadenopathy. Rash: early flushing; later macules/papules; purpura.
Dengue Hemorrhagic Fever. Increased vascular permeability and plasma leakage from blood vessels into tissues, thrombocytopenia, bleeding manifestations (frank hemorrhage to spontaneous petechiae or elicited by tourniquet test). Plasma leakage causes a rise in hematocrit, effusions, and edema, especially in chest, abdomen (Fig. 27-30).
Figure 27-30. Dengue hemorrhagic fever A 39-year-old with fever and rash after a trip to Malaysia. Dermal hemorrhage and petechiae on normal tanned (A) and white skin are seen on the buttocks 48 hours later [white islands in a see of red (B)]. (Courtesy of C Hafner et al. Hemorrhagic dengue fever after trip to Malaysia. Hautarzt. 2006;57(8):705–707.)
Dengue Shock Syndrome. Occurs when leakage or bleeding, or both, are sufficient to induce hypovolemic shock.
Etiology and Epidemiology
Etiology. Flavivirus, single-stranded RNA virus. Four distinct dengue serotypes (DEN-1, -2, -3, -4). Arthropod-borne virus (arbovirus). Infection confers lifelong protection against that serotype, but cross-protection between serotypes is of short duration. Infection with virus of a different serotype after the primary attack is more apt to result in severe disease, dengue hemorrhagic fever, or dengue shock syndrome.
Vector. Transmitted by the bite of the Aedes aegypti mosquito; less commonly A. albopictus. Mosquito acquires virus by feeding upon viremic human; remains infective for life.
Demography. 2.5 billion people live in dengue endemic areas; 50–100 million cases of dengue worldwide annually. Most cases occurring in United States are imported in travelers returning from the tropics. Year-round transmission between latitudes 25°N and 25°S. Increased incidence associated with rapid urban population growth, overcrowding, lax mosquito control, and climate change.
Pathogenesis of severe syndrome involves preexisting dengue antibody. Virus–antibody complexes formed within a few days of second dengue infection; non-neutralizing enhancing antibodies promote infection of higher numbers of mononuclear cells, followed by release of cytokines, vasoactive mediators, and procoagulants, leading to the disseminated intravascular coagulation.
Clinical Manifestation
Incubation Period. 3–7 days after bite of infected mosquito. Most dengue virus infections are asymptomatic.
Febrile Phase. High temperature (≥238.5°C) accompanied by headache, vomiting, myalgia, and joint pain. In some cases, a transient macular rash (Fig. 27-30A). Petechiae and bruising may be noted at venipuncture sites (Fig. 27-30B). Lasts for 3–7 days after which most patients recover with complications.
Critical Phase. Becomes apparent around the time of defervescence, evidenced by increasing hemoconcentration, hypoproteinemia, pleural effusions, and ascites. Hemorrhagic manifestations occur, manifested by major skin bleeding, gastrointestinal (GI), or vaginal bleeding. Moderate-to-severe thrombocytopenia common, followed by rapid recovery during recovery phase.
Recovery Phase. Altered vascular permeability resolves after 48–72 hours. A second rash may be appearing during recovery phase, mild macules/papules to severe, pruritic suggesting leukocytoclastic vasculitis. Rash resolves with desquamation over 1–2 weeks. Profound fatigue persists for several weeks after recovery.
Differential Diagnosis
Other arborviral infection such as chikungunya and viral exanthems. Disease with local prevalence: typhoid, malaria, leptospirosis, viral hepatitis, rickettsial diseases, and bacterial sepsis.
Diagnosis
Consider diagnosis in travelers with febrile illness recently returned from endemic areas. During febrile phase, detection of viral nucleic acid in serum diagnostic. IgM seroconversion between paired samples is confirmatory finding.
Treatment
Symptomatic supportive therapy (http://www.cdc.gov/dengue!).
Herpes Simplex Virus Disease ICD-9: 054 
ICD-10: B00 
Whether first symptomatic or recurrent may “typically” present clinically with grouped vesicles arising on an erythematous base on keratinized skin (Fig. 27-31) or mucous membrane. Most HSV infections are “atypical,” with patch(es) of erythema, small erosions, fissures, or subclinical lesions that shed HSV.
Following primary infection, HSV persists in sensory ganglia for the life of the patient, recurring with lessening in immunity.
Clinical Manifestation:
In healthy individuals, recurrent infections are asymptomatic or minor, resolving spontaneously or with antiviral therapy.
With host defense defects, mucocutaneous lesions can be extensive, chronic, or disseminate to skin or viscera.
Figure 27-31. Herpes simplex: Typical lesion A 39-year-old male with lesion on the abdomen above the waist. Grouped vesicles on an erythematous base/plaque are seen. The lesion is recurrent.
Etiology and Epidemiology
Etiology. HSV-1 and HSV-2.
• Labialis: HSV-1 (80–90%), HSV-2 (10–20%).
• Urogenital: HSV-2 (70–90%), HSV-1 (10–30%).
• Herpetic whitlow: <20 years of age usually HSV-1; >20 years of age, usually HSV-2.
• Neonatal: HSV-2 (70%), HSV-1 (30%).
Transmission. Most transmission occurs when persons shed virus but lack symptoms or lesions. Usually skin–skin, skin–mucosa, mucosa–skin contact. Herpes gladiatorum transmitted by skin-to-skin contact in wrestlers. Most commonly young adults; range, infancy to senescence.
Factors for Recurrence. Approximately one-third of persons who develop herpes labialis will experience a recurrence; of these, one-half will experience at least two recurrences annually. Usual factors for herpes labialis: skin/mucosal irritation [ultraviolet (UV) radiation], menstruation, fever, common cold, altered immune states, and site of infection (genital herpes recurs more frequently than labial). Host defense defections: HIV disease, malignancy (leukemia/lymphoma), transplantation (bone marrow, solid organ), chemotherapy, systemic glucocorticoids, other immunosuppressive drugs, and radiotherapy.
Pathogenesis. Primary HSV infection occurs through close contact with a person shedding virus at a peripheral site, mucosal surface, or secretion. Transmission occurs via inoculation onto susceptible mucosal surface or break in skin (Fig. 27-32A). After exposure to HSV, the virus replicates in epithelial cells, causing lysis of infected cells, vesicle formation, and local inflammation. After primary infection at inoculation site, HSV ascends peripheral sensory nerves and enters sensory (Fig. 27-32B) or autonomic nerve root (vagal) ganglia, where latency is established. Retrograde transport of HSV among nerves and establishment of latency are not dependent on viral replication in skin or neurons; neurons can be infected in the absence of symptoms (Fig. 27-32C).
Figure 27-32. Herpes labialis (A) With primary HSV infection, virus replicates in the oropharyngeal epithelium, ascends peripheral sensory nerves into the trigeminal ganglion. Herpes labialis (B) HSV persists in a latent phase within the trigeminal ganglion for the life of the individual. (C) Various stimuli initiate reactivation of latent virus, which then descends sensory nerves to the lips or perioral skin, resulting in recurrent herpes labialis.
Latency can occur after both symptomatic and asymptomatic primary infection. Periodically, HSV may reactivate from its latent state and virus particles then travel along sensory neurons to skin and mucosal sites to cause recurrent disease episodes (Fig. 27-32). Recurrent mucocutaneous shedding can be associated with or without (asymptomatic shedding) lesions; virus can be transmitted to a new host when shedding occurs.
Recurrences usually occur in the vicinity of the primary infection; may be clinically symptomatic or asymptomatic.
Clinical Manifestation
See “Nongenital Herpes Simplex Virus Infection,” p. 663.
Laboratory Examinations
Tzanck Smear (Fig. 27-33). Optimally, fluid from intact vesicle is smeared thinly on a microscope slide, dried, and stained with either Wright or Giemsa stain. Positive, if acantholytic keratinocytes or multinucleated giant acantholytic keratinocytes are detected. Positive in 75% of early cases, either primary or recurrent.
Antigen Detection Direct Fluorescent Antibody (DFA). Monoclonal antibodies, specific for HSV-1 and HSV-2 antigens, detect and differentiate HSV antigens on smear from lesion.
Figure 27-33. Herpes simplex virus: positive Tzanck smear A giant, multinucleated keratinocyte on a Giemsa-stained smear obtained from a vesicle base. Compare the size of the giant cell to that of the neutrophils also seen in this preparation. An isolated acantholytic keratinocyte is also seen. Identical findings are present in lesions caused by varicella zoster virus.
Diagnosis
HSV infection confirmed by viral culture or antigen detection. Seroconversion diagnoses first-episode infections. Antibodies to (g)H1 or (g)G2 may take 2–6 weeks to develop.
Recurring herpes can be ruled out if seronegative for HSV antibodies.
Treatment
Prevention. Avoid skin-to-skin contact during outbreaks.
Topical Antiviral Therapy. Minimal efficacy. Acyclovir 5% ointment, apply 6 times daily for 7 days. Penciclovir 1% cream every two hours while awake for recurrent orolabial infection.
Oral Antiviral Therapy Drugs. Acyclovir, valacyclovir, and famciclovir. Valacyclovir, the prodrug of acyclovir, has a better bioavailability and is nearly 85% absorbed after oral administration. Famciclovir is equally effective for cutaneous HSV infections.
Acyclovir 400 mg 3 times daily or 200 mg 5 times daily for 7–10 days.
Valacyclovir 1 g twice daily for 7–10 days.
Famciclovir 250 mg 3 times daily for 5–10 days.
Recurrences. Most recurrences do not benefit from oral acyclovir. Continuous oral maintenance therapy (e.g. valaciclovir 500 mg/day) may be effective in severe recurrent disease.
Nongenital Herpes Simplex 
Nongenital HSV infection, whether primary or recurrent, is often asymptomatic.
Lesions may present as group vesicles on an erythematous base (Fig. 27-31) or as recurrent erythematous plaque ± erosions.
For genital HSV infection, see Section 30.
Clinical Manifestation
Primary HSV Infection. Asymptomatic primary infection is common. Symptomatic primary HSV is characterized by vesicles at the site of inoculation (Fig. 27-34), and may be associated with regional lymphadenopathy, and systemic symptoms (fever, headache, malaise, myalgia). Primary herpetic gingivostomatitis is the most common symptom complex accompanying primary HSV infection in children. Primary herpetic vulvovaginitis is seen most often in young women (see also Section 30).
Figure 27-34. Herpes simplex: primary infection of the palm A 28-year-old female with a painful lesion on the palm for 3 days. A cluster of grouped pustules is seen on the palm. A red lymphangitis extends proximally on the wrist. The axillary lymph nodes were tender and enlarged. HSV-2 was detected on DFA. No antibodies to HSV-1 or -2 were detected, thus a primary infection.
Erythematous papules that quickly evolve to grouped vesicles, and pustules occur at the site of inoculation (Fig. 27-34). Vesicles are often fragile, rupturing easily, to form erosions as the overlying epidermis sloughs. The most common sites of primary HSV infection are the mouth, anogenitalia, and hand/fingers. Erosions heal in 2–4 weeks, often with resultant postinflammatory hypo- or hyperpigmentation, uncommonly with scarring.
Regional Lymphadenopathy. May be tender.
Primary Herpetic Gingivostomatitis. Oral mucosa usually involved only in primary HSV infection with vesicles that quickly slough to form erosions (Fig. 27-35) at any site in the oropharynx: scanty to numerous. Gingival erythema, edema, and tenderness, edema. Severe pain. Perioral facial involvement with vesicles and erosions common.
Figure 27-35. Herpes simplex: primary infection with gingivostomatitis A 43-year-old female with history of atopic dermatitis. Multiple, very painful erosions on the lower perioral skin, lips, and tongue. Tzanck smear was positive. HSV-1 detected on DFA. Methicillin-sensitive S. aureus (MSSA) was isolated on bacterial culture (secondary infection of herpetic lesions). HSV infection recurred on the face but without oral involvement.
Recurrent Herpes. Prodrome of tingling, itching, or burning sensation usually precedes any visible skin changes by 24 hours. Systemic symptoms are usually absent. Grouped vesicles on erythematous base that evolve to erosions and crusts (Fig. 27-36A–D). Recurrent intraoral HSV is rare.
Figure 27-36. Herpes labialis: recurrent herpes labialis (A) Edematous lateral upper lip 24 hours after onset of tingling sensation. (B) Grouped vesicles on moustache area 48 hours after onset of symptoms. (C) Crusted erosion on upper lip and moustache area 7 days after onset of symptoms. (D) Painful erosion on the lower lip for 5 weeks in a 66-year-old female with severe dermatoheliosis and actinic cheilitis. The diagnosis was made on lesional biopsy.
Trigeminal Nerve HSV Infections
• Perioral infection. Recurrent facial herpes or cold sores are common (Fig. 27-36). Often preceded by prodromal symptoms (tingling, pain, burning sensation, itching). Severe recurrences may complicate laser-resurfacing surgery.
• Ocular infections. Recurrent keratitis is a major cause of corneal scarring and visual loss, Continuous suppression therapy is recommended.
• Herpetic facial paralysis. Reactivation of geniculate ganglion infection implicated in pathogenesis of idiopathic facial palsy (Bell palsy). HSV-1 shedding detected in 40% of cases.
• Herpes gladiatorum. Transmission occurs during contact sports (wrestling, rugby, football). Also occurs in cervical or lumbosacral dermatomes.
Cervical and Thoracic Sensory Nerve HSV Infections
• Herpetic whitlow. Infection of the tip of finger or thumb; uncommonly toe. Prior to “Universal Precautions,” occurred in health-care professionals, especially dental personnel. Associated with painful neuritis in the affected finger (Fig. 27-37) and forearm.
Figure 27-37. Herpes simplex virus infection: herpetic whitlow A 19-year-old male with painful finger lesions for 3 days. Painful, grouped, confluent vesicles on an erythematous edematous base of the distal finger were the first (and presumed primary) symptomatic infection.
• HSV infection of the nipple. Related to transmission of HSV from infant to mother during breast feeding.
• HSV infections of the lumbosacral sensory nerves. When lumbosacral ganglia become infected subsequent to anogenital herpes, recurrent lesions can occur on genitalia as well as buttocks, thighs, and perianal mucosa. Perianal herpes does not necessarily imply direct anal inoculation of HSV. Herpes in the sacral dermatome may be accompanied by asymptomatic HSV reactivation/shedding from genital mucosa.
Complications of HSV Infections of Peripheral Sensory Nervous System
• Eczema herpeticum. Usually follows auto-inoculation of HSV (most commonly orolabial herpes) to atopic dermatitis (see “Herpes Simplex Virus: Widespread Cutaneous Infection Associated with Cutaneous Immunocompromise,” below p. 668).
• S. aureus secondary infection. Often occurs with eczema herpeticum.
• Erythema multiforme. In some individuals with recurrent HSV infections, erythema multiforme may occur with each recurrence (Fig. 27-38; see “Erythema Multiforme,” Section 14).
Figure 27-38. Herpes simplex virus infection: recurrent erythema multiforme A 31-year-old male with recurrent herpes labialis and disseminated lesions. Recurrent herpes labialis on the lower lip and IRIS-like edematous papules on the dorsum of the hand.
General Findings. Fever may be present during symptomatic primary herpetic gingivostomatitis. Regional Lymphadenopathy. Nonfluctuant, tender; usually unilateral.
CNS. Signs of aseptic meningitis: headache, fever, nuchal rigidity, CSF pleocytosis with normal sugar content, and positive HSV CSF culture.
Differential Diagnosis
Primary Intraoral HSV Infection. Aphthous stomatitis, hand foot and mouth disease, herpangina, erythema multiforme.
Recurrent Lesion. Fixed drug eruption.
Laboratory Examinations
See p. 662.
Diagnosis
Clinical suspicion confirmed by Tzanck smear, viral culture, or antigen detection DFA.
Course
Recurrences of HSV tend to become less frequent in time. Eczema herpeticum may complicate various dermatoses. Patients with host defense defects may experience cutaneous dissemination of HSV, systemic dissemination of HSV, and chronic herpetic ulcers (see also Chronic Herpetic Ulcers). Erythema multiforme (see Section 14) may complicate each recurrence of herpes, occurring 1–2 weeks after an outbreak.
Treatment
See p. 662.
Neonatal Herpes Simplex ICD-9: 771.2 ICD-10: P35.2 
Risk factors for neonatal HSV infection: primary genital herpes in mother at time of delivery, absent maternal anti-HSV antibody, procedures on fetus, father with HSV infection.
Etiology. The majority of infections are caused by HSV-2; HSV-1 is more virulent in the newborn and associated with higher morbidity and mortality
Transmission. In utero (<5%); intrapartum (85%); postnatal acquisition. Mother is the most common source of infection. There is usually no clinical indication of shedding at the time of delivery. Shedding also occurs from uterine cervix. Incubation period in neonate: 4–21 days.
Demography. Ninety-five percent of newborns with HSV infection contract it during labor and delivery (Figs. 27-39 and 27-40). Risk of transmission of HSV-2 from mother to newborn higher when primary infection occurs in third trimester. Maternal antibodies transferred to fetus and protect against fetal infection.
Figure 27-39. Herpes simplex in neonate Fever and skin lesion. Vesicles and crusted erosions on the upper lip and large geographic ulcerations of the tongue, i.e., herpetic gingivostomatitis.
Figure 27-40. Herpes simplex virus infection: neonatal Neonate with skin lesion. Grouped and confluent vesicles with underlying erythema and edema on the shoulder, arising at the inoculation site.
Clinical Manifestation
Skin, Eyes, Mouth Herpes Simplex. Localized infection. Vesicles and erosions on skin, eyes, mouth. Occurs at sites of trauma such as fetal scalp electrodes, extractors (vacuum and forceps), and circumcision. Margin of eyes and nasopharynx, Disseminated Herpes. Disseminated infection. ±Vesicles, erosions. Hepatitis, pneumonitis, disseminated intravascular coagulation. Difficult to diagnose in that up to 70% of infants have no mucocutaneous lesions.
CNS Infection. ± Vesicles, erosions. Encephalitis. Presentation: seizures, tremors, lethargy, unstable temperature, irritability, feeding problem, bulging fontanelle.
Treatment
See p. 662.
Eczema Herpeticum 
HSV infects altered epidermis, most commonly atopic dermatitis causing eczema herpeticum. Other dermatoses subject to HSV infection include Darier disease, thermal burns, Hailey–Hailey disease, immunobullous disease, ichthyosis vulgaris, and cutaneous T cell lymphoma.
Epidemiology. HSV-1 > HSV-2. More common in children. May be transmitted from parental herpes labialis to child with atopic dermatitis, especially if erythrodermic.
Clinical Manifestation
Primary Eczema Herpeticum. May be associated with fever, malaise, and irritability. When recurrent, history of prior similar lesions; systemic symptoms less severe. Lesions begin in abnormal skin and may extend peripherally for several weeks during primary or recurrent HSV infections. Secondary infection with S. aureus is relatively common and may be painful.
Cutaneous Lesions. Vesicles evolving into “punched-out” erosions (Fig 27-41). Vesicles are first confined to eczematous skin. In contrast to primary or recurrent HSV eruptions, in eczema herpeticum, lesions are not grouped but disseminated within the dermatosis. May later spread to normal-appearing skin. Erosions may become confluent, producing large denuded areas (Fig. 27-42). Successive crops of new vesiculation may occur. Common sites: face, neck, and trunk.
Figure 27-41. Herpes simplex: eczema herpeticum A 36-year-old male with recurrent periorbital painful crusted erosions and atopic dermatitis. Small-crusted erosion on the eyelids. DFA detected HSV-1. Bacterial culture reported MSSA. The herpetic infection had not affected the cornea.
Figure 27-42. Herpes simplex: extensive eczema herpeticum Confluent and discrete crusted erosions associated with erythema and edema of the face of a female with atopic dermatitis.
General Examination. Primary infection may be associated with fever and lymphadenopathy.
Differential Diagnosis
Widespread Vesiculopustules/Erosions. Varicella, disseminated VZV infection, disseminated (systemic) HSV infection.
Diagnosis
Clinical, confirmed by detection of HSV on culture or antigen detection. Rule out secondary infection by S. aureus.
Course and Treatment
Untreated, primary episode of eczema herpeticum runs its course with resolution in 2–6 weeks. Recurrent episodes tend to be milder and not associated with systemic symptoms. Systemic dissemination can occur, especially with host defense defects. For treatment, see p. 662.
Herpes Simplex with Host Defense Defects 
In persons with host defense defects, herpes simplex may present as extensive local involvement, chronic herpetic ulcers, or skin disease associated with systemic HSV infection.
Host Defense Defects. HIV disease, leukemia/lymphoma, bone marrow transplantation, chemotherapy for solid organ or BMT, autoimmune diseases, malnutrition.
Pathogenesis. After HSV viremia, disseminated cutaneous or visceral disease may occur. Factors determining whether severe localized disease, cutaneous dissemination, or visceral dissemination will occur are not well defined.
Clinical Manifestation
Primary Herpetic Infection. Local infection may be widespread on the face (Fig. 27-43), oropharynx, and anogenital region with initial vesiculation followed by crusted erosions. Without antiviral therapy, lesions may persist to become chronic herpetic ulcers.
Figure 27-43. Herpes simplex: primary infection in HIV disease A 35-year-old male with HIV disease (CD4 cell count, 400/mL). Confluent vesicles and erosions with underlying erythema and edema (5-6-days duration) in the beard area. Gingivostomatitis and acute lymphadenopathy were also present, with onset of 5 days after orogenital sex.
Recurrent Herpes Simplex. With advanced HIV disease especially, mucocutaneous disease can be severe: fingers with herpetic whitlow (Fig. 27-44A), oropharyngeal ulcers (Fig. 27-44B), esophageal ulcers, and anorectal ulcers. Systemic dissemination (Fig. 27-46) can occur from these sites, associated visceral HSV infection. Recurrent herpes simplex is manifested as persistent erosions and chronic ulcers. Chronic herpetic ulcers that persist in spite of adequate antiviral therapy (Fig. 27-45) (acyclovir, valacyclovir, famciclovir) are usually caused by acyclovir-resistant HSV.
Figure 27-44. A 52-year-old male with advanced HIV disease had chronic herpetic ulcers on nares, finger, and tongue. (A) Herpetic whitlow with ulcer on the distal finger; nail had been avulsed by hand surgeon. (B) Chronic deep painful ulcer on the dorsolateral tongue.
Figure 27-45. Herpes simplex: chronic herpetic ulcers A 40-year-old female with advanced HIV disease. Ulcers were caused by acyclovir resistant HSV, healed with foscarnet, but recurred.
Figure 27-46. Disseminated herpes simplex 60-year old male with lymphoma. Disseminated erosions, ulcerations with hemorrhagic crusts on necrotic bases. Patients often have HSV visceral infection (lungs, liver, brain).
Oropharyngeal Ulcers. Large ulcerations occur on the tongue, hard palate, gingivae. Linear ulcerations occur on the tongue (Fig. 27-44B).
Esophageal Ulcers. Usually associated with oropharyngeal herpetic ulcer. Esophagoscopy demonstrates mucosal erosions/ulceration.
Anogenital Ulcers. Acute ulceration of the vulva, penis, scrotum, and/or perineum may become chronic ulcers unless effectively treated. In individuals infected with acyclovir-resistant HSV, ulcerations do not respond to usual antiviral therapies. Anal ulcers usually occur via enlargement of perianal ulcers. Herpetic proctitis: sigmoidoscopy shows friable mucosa and ulcerations.
Mucocutaneous Dissemination. Disseminated (nongrouped) vesicles and pustules often hemorrhagic with inflammatory halo; quickly rupture, resulting in “punched-out” erosions. Lesions may be necrotic and then ulcerate (Fig. 27-46).
General Examination. Widespread visceral involvement (liver, lungs, adrenals, GI tract, CNS) can occur in persons with severe host defense defects.
Differential Diagnosis
Chronic Herpetic Ulcers. Chronic VZV infection, wound infection, pressure ulcer
Anorectal Ulcers. HPV-induced SCC, Crohn disease
Mucocutaneous Dissemination. Varicella or disseminated herpes zoster (HZ), eczema herpeticum.
Diagnosis
Clinical suspicion confirmed by Tzanck smear, positive HSV antigen detection DFA, or isolation of HSV on viral culture.
Course and Treatment
For treatment, see p. 662. In HIV disease, persons successfully treated with ART experience reduction in frequency and severity of HSV recurrences. Infection with acyclovir-resistant strains results in chronic, progressive ulcerations that persist and/or continue to enlarge despite oral and IV acyclovir treatment.
Varicella Zoster Virus Disease
ICD-9:052 ICD-10:B01
Varicella zoster virus is a HHV that infects 98% of adults.
Primary VZV infection Varicella or chicken pox is nearly always symptomatic and characterized by disseminated pruritic vesicles. During primary infection, VZV establishes lifelong infection in sensory ganglia.
When immunity to VZV declines, VZV reactivates within the nerve cell, traveling down the neuron to the skin, where it erupts in a dermatomal pattern, i.e., HZ or shingles.
With host defense defects, primary and reactivated VZV infections is often more severe, associated with higher morbidity rates and some mortality.
VZV vaccine has reduced the incidence of varicella and HZ.
Etiology and Epidemiology
Etiology. VZV, a herpesvirus. Structurally similar to other herpesviruses.
Age of Primary Infection. Without immunizaton, 90% of cases occur in children <10 years, <5% in persons older than 15 years. With immunization (Varivax), the incidence is markedly reduced.
Transmission. Airborne droplets and direct contact. Patients are contagious several days before varicella exanthem appears and until last crop of vesicles. Crusts are not infectious. VZV can be aerosolized from skin of persons with HZ, causing varicella in susceptible contacts.
Pathogenesis. VZV enters through mucosa of upper respiratory tract and oropharynx, followed by local replication, primary viremia, replication in cells of reticuloendothelial system, secondary viremia, and dissemination to skin and mucous membranes. Localization of VZV in the basal cell layer of epidermis is followed by virus replication, ballooning degeneration of epithelial cells, and accumulation of edema fluid with vesiculation. During the course of varicella, VZV passes from the skin lesions to the sensory nerves, travels to the sensory ganglia, and establishes latent infection. Immunity to VZV occurs with primary infection ebbs naturally and with altered immunity, which results in VZV replication in sensory ganglia. VZV then travels down the sensory nerve, resulting in initial dermatomal symptoms, followed by skin lesions. Since the neuritis precedes the skin involvement, pain or itching appears before the skin lesions are visible. The locations of pain are varied and relate directly to the ganglion where VZV has emerged from latency to active infection. Prodromal symptoms may appear initially in the trigeminal, cervical, thoracic, lumbar, or sacral dermatome. Postherpetic neuralgia(PHN) is complex regional pain syndrome (Fig. 27-49).
Laboratory Examinations
VZV Antigen Detection DFA. Smear of vesicle fluid or scraping from ulcer base/margin: DFA test detects VZV-specific antigen. Sensitive and specific method for identifying VZV-infected lesions. Higher yield than VZV cultures.
Tzanck Smear. Cytology of fluid or scraping from base of vesicle or pustule shows both giant and multinucleated acantholytic epidermal cells (as does that of HSV infections) (Fig. 27-33).
Serology. Seroconversion documents primary VZV infection.
Dermatopathology. Lesional skin or visceral biopsy specimen shows multinucleated giant epithelial cells indicating HSV-1, HSV-2, or VZV infection. Immunoperoxidase stains specific for HSV-1, HSV-2, or VZV antigens can identify the specific herpesvirus.
VZV: Varicella 
The highly contagious primary infection caused by VZV. Synonym: Chicken pox.
Characterized by successive crops of pruritic vesicles that evolve to pustules, crusts, and, at times, scars.
Primary infection occurring in adulthood may be complicated by pneumonia and encephalitis.
Epidemiology
Incidence. Incidence of varicella has decreased as vaccination coverage has increased. Prior to 1995, 3–4 million cases in the United States annually.
Clinical Manifestation
Vesicular lesions occur in successive crops. Often single, discrete lesions: scanty in number in children; more numerous in adults. Initial lesions are papules (often not observed) that may appear as whealsand quickly evolve to vesicles, superficial and thin-walled with surrounding erythema. Vesicles rapidly evolve to pustules and crusted erosions over an 8- to 12-hour period. With subsequent crops, all stages of evolution may be noted simultaneously, i.e., papules, vesicles, pustules, crusts, i.e., polymorphic (Fig. 27-47).
Figure 27-47. Varicella A 20-yearold female with pruritic eruption for 2 days. Multiple, pruritic, erythematous papules, vesicles on the face and neck. Several vesicles have evolved to crusted erosion. DFA detected VZV. No antibodies to VZV were detected.
Crusted erosions heal in 1–3 weeks, leaving a pink, somewhat depressed base. Characteristic punched-out permanent scars may persist (Fig. 27-48).
Figure 27-48. Post-varicella scars A 28-year-old male with punched out scars on face. Varicella, which had been severe, had occurred 6 months previously. These scars may improve with time but persist for life.
Distribution. First lesions begin on face (Fig. 27-48) and scalp, spreading inferiorly to trunk and extremities. Most profuse in areas least exposed to pressure, i.e., back between shoulder blades, flanks, axillae, popliteal, and antecubital fossae. Density highest on trunk and face, less on extremities. Palms and soles usually spared.
Mucous Membranes. Vesicles (not often observed) and subsequent shallow erosions (2–3 mm). Most common on palate. Less common on other mucosal sites.
General Examination. VZV pneumonitis occurs with increased frequency in adolescents and adults. CNS involvement with cerebellar ataxia and encephalitis can occur.
“Malignant” varicella occurs in persons with host defense defects. Pneumonitis, hepatitis, encephalitis, disseminated intravascular coagulation, and purpura fulminans may occur.
Differential Diagnosis
Disseminated HSV infection, cutaneous dissemination of zoster, eczema herpeticum, rickettsialpox, enterovirus infections.
Diagnosis
Usually made on clinical findings alone. Seroconversion, i.e., fourfold or greater rise in VZV titers.
Course
The most common complication in children <5 years is secondary bacterial infection. Varicella encephalitis and Reye syndrome occur in children 5–11 years of age. Two percent of fetal varicella associated with maternal varicella in first trimester of pregnancy. Fetal varicella syndrome, characterized by limb hypoplasia, eye and brain damage, and skin lesions. Varicella in immunocompromised may be complicated by hepatitis, encephalitis, and hemorrhagic complications.
Treatment
Immunization. Vaccination is 80% effective in preventing symptomatic VZV infection; 5% of immunized children develop rash.
Symptomatic Therapy. Antihistamines lotions; avoid antipyretics due to risk of Reye syndrome.
Antiviral Agents. Decrease severity of course if given within 24 hours of onset.
Neonates: Acyclovir 10 mg/kg every 8h for 10 days.
Children: (2 to 18 yrs) Valaciclovir 20 mg/kg every 8 h for 5 days or acyclovir 20 mg/kg every 6 h for 5 days.
Adolescents: Valaciclovir 1 g PO every 8 h for 7 days. Immunocompromised: Valaciclovir 1 g PO for 7 to 10 days; or acyclovir 800 mg by mouth 5 times a day or famciclovir 500 mg by mouth every 8 h for 7 to 10 days.
Severely immunocompromised: acyclovir 10 mg/kg IV every 8 h for 7 to 10 days.
Acyclovir resistant: Foscarnet 40 mg/kg IV every 8 h until resolution.
VZV: Herpes Zoster ICD-9: 053 ICD-10: B02 
An acute dermatomal infection associated with reactivation of VZV. Synonym: Shingles.
Characterized by unilateral dysesthesia. A vesicular or bullous eruption limited to a dermatome(s) innervated by a corresponding sensory ganglion.
Postherpetic neuralgia is a major morbidity.
Etiology and Epidemiology
The epidemiology of VZV infections is changing due to immunization with live (attenuated) virus vaccine for prevention of varicella in children and HZ in older adults. The cumulative lifetime incidence of HZ is 10–20% and higher in those with host defense defects.
Pathogenesis. In varicella VZV passes from lesions in the skin and mucosa via sensory fibers centripetally to sensory ganglia. In the ganglia, the virus establishes lifelong latent infection. Reactivation occurs in those ganglia in which VZV has achieved the highest density and is triggered by immunosuppression, trauma, tumor, or irradiation (see risk factors). Reactivated virus can no longer be contained. Virus multiplies and spreads centrifugally, antidromically down the sensory nerve to the skin/mucosa where it produces the characteristic vesicles (Fig. 27-49).
Figure 27-49. Varicella and herpes zoster (A) During primary VZV infection (varicella or chicken pox), virus infects sensory ganglia. (B) VZV persists in a latent phase within ganglia for the life of the individual. (C) With diminished immune function, VZV reactivates within sensory ganglia, descends sensory nerves, and replicates in skin.
Clinical Manifestation
Herpes zoster manifests in three distinct clinical stages: (1) prodrome, (2) active infection, and (3) PHN.
Prodrome. Pain, tenderness, paresthesia in the involved dermatome (Fig. 27-50) precedes the eruption. Pain can mimic angina or acute abdomen. Allodynia: heightened sensitivity to mild stimuli. Zoster sine herpete: Nerve involvement can occur without cutaneous zoster. Flu-like constitutional symptoms can occur during prodrome and active infection.
Figure 27-50. Dermatomes The cutaneous fields of peripheral sensory nerves.
Dermatomal Lesions (Figs. 27-51 to 27-56). Papules (24 hours) → vesicles-bullae (48 hours) → pustules (96 hours) → crusts (7–10 days). New lesions continue to appear for up to 1 week. Erythematous, edematous base (Fig. 27-51) with superimposed clear vesicles, sometimes hemorrhagic. Vesicles erode forming crusted erosions. Dermatomal crusting usually resolves in 2–4 weeks.
Figure 27-51. Herpes zoster A 65-year old male with scar from prior thyroid carcinoma surgery. Erythematous plaque with early vesiculation in left C-2 dermatome. This presentation is common and diagnosis often missed. The lesions was mildly pruritic.
Figure 27-52. Herpes zoster A 67-year old Chinese female with dermatomal zoster in L-mandibular branch of the trigeminal nerve. Bullae, vesicle, and erosions are seen. (A) L-face. (B) Tongue with erosions and deviation associated with motor involvement. Other than flu-like symptoms, she was relatively free of symptoms.
Figure 27-53. Herpes zoster right T-2 distribution A 60-year-old male being treated with prednisone for eczema has painful lesion for 3 days. Dermatomal grouped and confluent vesicles on the R-back and arm.
Figure 27-54. Herpes zoster: atrophic scar A 90-year-old female with a history of herpes zoster 14 years previously. Hypopigmented dermatomal (V1) scar is seen on the right forehead at the site of prior zoster.
Figure 27-55. VZV: necrotizing herpes zoster Confluent, crusted ulcerations on an inflammatory base in several contiguous dermatomes in an elderly male with leukemia.
Figure 27-56. Multidermal herpes zoster with host defense defect. 72-year-old male with pityriasis rubra pilaris with erythroderma is being treated with prednisone and methotrexate. Multiple dermatomal erosions are seen on the chest and buttock with dissemination.
Distribution. Unilateral, dermatomal (Fig. 27-50). Two or more contiguous dermatomes may be involved. Noncontiguous dermatomal zoster is rare (Fig. 27-56).
Hematogenous dissemination to other skin sites in 10% of healthy individuals (Fig. 27-56). Site of Predilection. Thoracic (>50%), trigeminal (10–20%), lumbosacral, and cervical (10–20%).
Mucous Membranes. Vesicles and erosions occur in mouth (Fig. 27-52B), vagina, and bladder, depending on dermatome involved.
Lymphadenopathy. Regional nodes draining the area are often enlarged and tender.
Sensory or Motor Nerve Changes. Detectable by neurologic examination. Sensory defects (temperature, pain, touch) and (mild) motor paralysis (Fig. 27-52B), e.g., facial palsy.
Ophthalmic Zoster. Nasociliary involvement of V-1 (ophthalmic) branch of the trigeminal nerve occurs in about one-third of cases and is heralded by vesicles on the side and tip of the nose (Fig. 27-54). Complications include uveitis, keratitis, conjunctivitis, retinitis, optic neuritis, glaucoma, proptosis, cicatricial lid retraction, and extraocular muscle palsies. Acute retinal necrosis more common with immune deficiency.
Delayed Contralateral Hemiparesis. Typical presentation is headache and hemiplegia occurring in a patient with recent history of HZ ophthalmicus.
Constitutional Symptoms. Prodromal stage and active vesiculation: flu-like symptoms. Chronic stages: depression is very common in individuals with PHN.
Postherpetic Neuralgia. Characterized by constant, severe, stabbing or burning, dysesthetic pain that may persist for months or years in a minority of patients, especially in elderly.
Differential Diagnosis
Prodromal Stage/Localized Pain. Can mimic migraine, cardiac or pleural disease, an acute abdomen, or vertebral disease.
Dermatomal Eruption. HSV infection, photoallergic (poison ivy, poison oak) contact dermatitis, erysipelas, and necrotizing fasciitis.
Diagnosis
Prodromal Stage. Suspect zoster in older or immunocompromised with unilateral pain.
Active Vesiculation. Clinical findings usually adequate; may be confirmed by Tzanck test, DFA, or viral culture to rule out HSV infection.
Postherpetic Pain Syndrome. By history and clinical findings.
Course
Dissemination of Zoster. ≥20 lesions outside the affected or adjacent dermatomes—occurs in up to 10% of patients, usually with immune defects.
VZV can disseminate hematogenously to skin and to viscera.
Neurological complications: meningoencephalitis, cerebral vascular syndromes, cranial nerve syndromes [trigeminal (ophthalmic) branch (HZ ophthalmicus), facial and auditory nerves (Ramsay Hunt syndrome)], peripheral motor weakness, and transverse myelitis. Visceral involvement: pneumonitis, hepatitis, pericarditis/myocarditis, pancreatitis, esophagitis, enterocolitis, cystitis, and synovitis.
Postherpetic Pain Syndrome. The risk of postherpetic neuralgia is 40% in patients >60 years with resolution in 87% at 6 months. The highest incidence is in ophthalmic zoster. Does not appear to be more common in immune defects than in the general population.
Pain with HZ is associated with neural inflammation, nerve infection during the acute reactivation, and neural inflammation and scarring with PHN.
Treatment
Prevention. Vaccination against VZV with a live attenuated vaccine reduces the burden of illness by >60% and incidence of zoster by 51%.
Antiviral Therapy. Oral famciclovir 500 mg every 8 h for 7 days or valaciclovir 1 g every 8 h for 7 days or acyclovir 800 mg 5 times a day for 7 days.
Mildly immunocompromised: As above but for up to 10 days. Severely immunocompromised: acyclovir 10 mg/kg IV every 8 h for 7–10 days.
Acyclovir resistant: IV foscarnet 40 mg/kg IV every 8h until resolution.
Supportive Therapy. Bed rest, sedation, pain management with narcotic analgesics; moist dressings.
Postherpetic Neuralgia. Gabapentin, pregabalin, tricyclic antidepressants, i.e. doxepin, capaicin cream topically. Nerve block.
VZV: Host Defense Defects
Host Defense Defects. Immunosuppression, especially from lymphoproliferative disorders, cancer chemotherapy; HIV disease; immunosuppressive therapy.
Primary and reactivation VZV disease can be more severe with disseminated cutaneous and infection.
Clinical Manifestation
Herpes zoster: severe dermatomal disease (Fig. 27-55)
Herpes Zoster with Cutaneous Dissemination. Variable numbers of vesicles or bullae are seen at any mucocutaneous site (Fig. 27-57). The condition thus appears clinically as zoster plus varicella.
Figure 27-57. Varicella zoster virus infection: disseminated cutaneous, in an immunocompromised patient Hundreds of vesicles and pustules on erythematous bases of the trunk of a patient with lymphoma. Note the absence of grouping of lesions seen in herpes simplex or herpes zoster. The eruption is indistinguishable from varicella and must be differentiated from disseminated HSV infection.
Herpes Zoster with Persistent Dermatomal Infection. Chronic ulcers persist for months. Papular or verrucous dermatomal lesions (Fig. 27-58).
Figure 27-58. VZV: chronic zoster in HIV disease A 42-year-old male with advanced untreated HIV disease. Discrete and confluent hyperkeratotic papules/nodules in several contiguous dermatomes persistent for 2 years.
Eye. Acute retinal necrosis occurs in the absence of apparent conjunctival or cutaneous involvement with subsequent loss of vision.
Visceral Dissemination. Encephalitis, polyneuritis, myelitis, vasculitis; pneumonitis; hepatitis; pericarditis/myocarditis; pancreatitis; enterocolitis.
Human Herpesvirus-6 and- 7 Disease
ICD-9: 058 ICD-10: B10
Primary HHV-6 and HHV-7 infections cause exanthema subitum or roseola infantum, characterized by high fever in a healthy infant (9–12 months old), defervescence in 3 days followed by sudden appearance of exanthem.
Etiology. HHV-6 (variants -6A and -6B) and HHV-7 share genetic, biologic, and immunologic features and are T cell tropic. At birth, most children have passively transferred anti-HHV-6 and anti-7 IgG. Primary infection is acquired via oropharyngeal secretions. HHV-6 antibodies reach a nadir at 4–7 months and increase throughout infancy. By 12 months, two-thirds of children become infected, with peak antibody levels reached at 2–3 years of age. Similarly, HHV-7 antibodies reach nadir at 6 months, with level peaking at 3–4 years of age. Latent infection may persist for the lifetime of the individual.
Pathogenesis. HHV-6B causes exanthema subitum; pathogenesis of the exanthema is like immune response to viral antigens. HHV-6B reactivation occurs in transplant recipients and can cause encephalitis, bone marrow suppression, and pneumonitis.
Clinical Manifestation
Prodrome. High fever ranging from 38.9° to 40.6°C. Remains consistently high, with morning remission, until the fourth day, when it falls precipitously to normal, coincident with the appearance of rash. Infant remarkably well despite high fever. Asymptomatic primary HHV-6 and HHV-7 infection is common.
Exanthem Subitum or Roseola Infantum. Small blanchable pink macules and papules, 1–5 mm in diameter (Fig. 27-59). Lesions may remain discrete or become confluent. Distribution: trunk and neck.
Figure 27-59. Exanthema subitum Multiple, blanchable macules and papules on the back of a febrile child, which appeared as the temperature fell. (Courtesy of Karen Wiss, MD.)
General Findings. Absent in presence of high fever. Febrile seizures are common.
Differential Diagnosis
See “Infectious Exanthems p. 647.”
Serology. Demonstration of IgM anti-HHV-6 or anti-HHV-7 antibodies or IgG seroconversion.
Diagnosis
Usually made on clinical findings.
Course
Exanthem subitum is self-limited with rare sequelae. In some cases, high fever may be associated with seizures. Intussusception associated with hyperplasia of intestinal lymphoid tissue and hepatitis reported. As with other HHV infections, HHV-6 and HHV-7 persist throughout the life of the patient. The role of HHV-6 and HHV-7 in the pathogenesis of pityriasis rosea is being investigated.
Human Immunodeficiency Virus Disease ICD-9: 042–044 ICD-10: B20-B24 
HIV originated in nonhuman primates in sub-Saharan Africa, evolving from simian immunodeficiency virus (SIV). Transmission to humans occurred in the early 20th century and has been linked to eating bush meats.
HIV disease is characterized by a progressive quantitative and qualitative deficiency of the subset of T lymphocytes referred to as helper T cells occurring in a setting of polyclonal immune activation.
Acquired immunodeficiency syndrome (AIDS), the endstage of HIV disease, was first recognized in the United States (1981) and shortly after in Europe.
Transmission of HIV occurs during sexual intercourse, exposure to blood or blood product, perinatal exposure.
Primary HIV infection may be symptomatic with acute HIV seroconversion illness.
Clinical manifestations are of opportunistic infections and neoplasms. Clinical course is highly variable.
Treatment. When available, combination antiretroviral therapy (cART) is very effective in management of this chronic disease.
U.S. Department of Health and Human Services treatment guidelines for HIV disease: http://www.aidsinfo.nih.gov/
Updates on epidemiologic data from the Centers for Disease Control and Prevention (CDC): http://www.cdcnpin.org/
Etiology and Epidemiology
Etiology. HIV disease caused primarily by HIV-1 M group of viruses. HIV-2 causes disease in western Africa and other foci.
Transmission. Sexual intercourse, exposure to blood or blood product, perinatal or breast milk. Risk factors for acquisition: Genital ulcer disease, HIV-infected partner with high viral load (transmission more efficient), and receptive anal intercourse.
Demography. 34 million persons living with HIV infection in 2010. 22.5 million in sub-Saharan Africa. HIV disease has caused 30 million deaths since first recognized in 1981. In the United States, 1.1 million living with HIV disease in the United States (January 1, 2010) with 21% unaware of their infections and 56,000 new infections annually.
Pathogenesis. After primary HIV infection, billions of virions are produced and destroyed each day; a concomitant daily turnover of actively infected CD4+ cells is also in the billions. HIV infection is relatively unique among human viral infections in that, despite robust cellular and humoral immune responses that are mounted after primary infection, HIV is not cleared completely from the body. Chronic HIV disease follows primary infection with varying degrees of virus replication.
Clinical Manifestation
Dermatologic disorders are nearly universal during the course of HIV disease. Some disorders are highly associated with HIV disease, and their diagnosis often warrants HIV serotesting: acute retroviral syndrome, KS, oral hairy leukoplakia, proximal subungual onychomycosis, bacillary angiomatosis, eosinophilic folliculitis, chronic herpetic ulcers, any sexually transmitted disease, and skin findings of injecting drug use. Moderate risk for HIV disease is associated with HZ, molluscum contagiosum (multiple facial in adult), and candidiasis (oropharyngeal, esophageal, or recurrent vulvovaginal). Possible risk for HIV disease: generalized lymphadenopathy, seborrheic dermatitis, and aphthous ulcers (recurrent, refractory to therapy).
Acute HIV Infection. Acute viral illness with exanthem.
Unique to HIV disease acute HIV seroconversion illness (acute retroviral syndrome), oral hairy leukoplakia, eosinophilic folliculitis, pruritic popular eruption of HIV disease, and bacillary angiomatosis.
Cutaneous Inflammatory Disorders. Seborrheic dermatitis, atopic dermatitis, prurigo nodularis, psoriasis, xerosis, eosinophilic folliculitis, pruritus with secondary changes of excoriation, adverse cutaneous drug reactions.
Opportunistic Infections. Molluscum contagiosum, VZV infection, herpes simplex, HPV infections. S. aureus infections, bacillary angiomatosis, and mucosal candidiasis. Dermatophytoses. Systemic fungal infections with dissemination to skin.
Opportunistic Neoplasms. KS, HPV-induced dysplasia and invasive SCC (cervix, anus), Merkel cell carcinoma, non-Hodgkin and Hodgkin lymphoma, and primary CNS lymphoma.
IRIS occurs weeks or months after initiating cART, resulting from restored immunity to specific infectious or noninfectious antigens. Untreated mycobacterial and fungal coinfection predispose to IRIS. IRIS occurs most often in persons starting cART with CD4+ T cell count < 50/μL who experience a precipitous drop in viral load; IRIS associated by an increase in CD4 cell count and/or a rapid decrease in HIV viral load. A paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating therapy characterizes the syndrome. Potential mechanisms for the syndrome include a partial recovery of the immune system or exuberant host immunologic responses to antigenic stimuli. The infectious pathogens most frequently implicated in the syndrome are Mycobacteria, VZV, HSV, and CMV. Also, eosinophilic folliculitis and ACDE.
World Health Organization disease staging system for HIV infection and disease 2005:
• Primary HIV infection: May be either asymptomatic or associated with acute retroviral syndrome.
• Stage I: HIV infection is asymptomatic with a CD4 count of greater than 500/μL. May include generalized lymph node enlargement.
• Stage II: Mild symptoms that may include minor mucocutaneous manifestations and recurrent upper respiratory tract infections. A CD4 count of less than 500/μL.
• Stage III: Advanced symptoms that may include unexplained chronic diarrhea for longer than a month, severe bacterial infections including tuberculosis of the lung as well as a CD4 count of less than 350/μL.
• Stage IV or AIDS: Severe symptoms that include toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs, and KS. A CD4 count of less than 200/μL.
CDC 2008. In this system, HIV infections are classified based on CD4 counts and clinical symptoms.
• Stage 1: CD4 count ≥ 500 cells/μL and no AIDS defining conditions.
• Stage 2: CD4 count 200–500 cells/μL and no AIDS defining conditions.
• Stage 3: CD4 count ≤ 200 cells/μL or AIDS defining conditions.
• Unknown: if insufficient information is known to make one of the above classifications.
AIDS diagnosis remains even if, after treatment, the CD4+ T cell count rises to above 200 per μL of blood or other AIDS-defining illnesses are cured.
Laboratory Examinations
Diagnosis of HIV Infection HIV disease is diagnosed and monitored by measuring HIV RNA and antigens, CD4 cell counts, and serotesting (http://www.cdc.gov/std/treatment/2010/hiv. htm) (see Table 27-2).
TABLE 27-2 LABORATORY DIAGNOSIS OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION
Course
The clinical course of HIV disease is highly variable in each person (Fig. 27-60). Symptomatic primary infection occurs often. A prolonged asymptomatic state following primary infection is common. Opportunistic infections and neoplasms occur in advanced disease. Early in the pandemic, prophylaxis for opportunistic infections and treatment of opportunistic infections improved morbidity and mortality. Currently, cART has been very effective in the majority of persons but may give rise to the metabolic syndrome and lipodystrophy.
Figure 27-60. Typical disease course in an individual with HIV disease. (Source: Fauci AS et al. Immunopathogenic mechanisms of HIV infection. Ann Intern Med. 1996;124(7):654–663, with permission.)
Treatment
Guidelines for antiretroviral therapy (ART) evolve as new drugs become available and local resources. Websites for updated guidelines of ART are as follow:
• United States: http://www.aidsinfo.nih.gov/guidelines
• World Health Organization: http://www.who.int/hiv/topics/treatment/en/
Acute HIV Syndrome ICD-10: B23.0
Primary HIV Infection. Up to 70% of primary infections are symptomatic, 3–4 weeks after exposure. Symptoms range from asymptomatic to severe.
Infectious mononucleosis-like syndrome with fever, lymphadenopathy, and neurologic and GI symptoms.
Infectious exanthema, enanthem, and mucocutaneous ulcerations.
Clinical Manifestation
General Findings. Fever, pharyngitis, lymphadenopathy, headache/retro-orbital pain, arthralgias/myalgias, lethargy/malaise, anorexia/weight loss, nausea/vomiting/diarrhea. Neurologic findings: meningitis, encephalitis, peripheral neuropathy, and myelopathy.
Exanthem. Appears 2–3 days after onset of fever, lasting 5–8 days. Morbilliform rash [infectious exanthem (Fig. 27-61], with pink macules, papules up to 1 cm in diameter. Lesions remain discrete. Upper thorax and collar region, face, arms, scalp, thighs.
Figure 27-61. Acute HIV syndrome: exanthem Discrete, erythematous macules and papules on the anterior trunk; associated findings were fever and lymphadenopathy. (Courtesy of Armin Rieger, MD.)
Oropharyngeal Lesions. Pharyngitis. Enanthem: red macules, on hard and soft palate. Aphthous-like ulcers: tonsils, palate, buccal mucosa; esophageal ulcers. Uncommonly, oral candidiasis.
Genital Lesions. Aphthous-type painful ulcers. Prepuce of penis, scrotum, anus, and anal canal.
Differential Diagnosis
Infectious Exanthems. Adverse cutaneous drug reaction.
Diagnosis
Demonstrated seroconversion of anti-HIV antibodies by ELISA, confirmed by Western blot, confirms diagnosis of primary HIV infection. Detection of HIV RNA and HIV antigens.
Course
The mean duration of symptomatic illness in 13 days. Prolonged symptomatic primary infection is associated with more rapid decline of immune function.
Pruritus and Pruritic Eruptions. Pruritus is a common symptom in persons with advanced HIV disease. Primary or secondary dermatoses are usually the cause. Eosinophilic folliculitis and popular pruritic eruption of HIV disease are primary pruritic disorders occurring exclusively in HIV disease.
An atopic-like diathesis (atopic dermatitis, allergic rhinitis, asthma) may become manifest. Findings secondary to chronic rubbing and scratching include excoriations, lichen simplex chronicus, prurigo nodularis, and hyperpigmentation (Figs. 27-62 and 27-64). Secondary S. aureus infection (impetiginization, furunculosis, or cellulitis) occur in traumatized lesions. Ichthyosis vulgaris and xerosis are common in advanced HIV disease and may be associated with mild pruritus. Protease inhibitors (particularly indinavir) may cause a retinoid dermatitis, which occurs soon after initiation of therapy. Idiopathic pruritus is associated with CD4+ T cell counts < 200/μL and viral load >55,000 copies/mL, while cART has been associated with a decrease in idiopathic pruritus.
Figure 27-62. Eosinophilic folliculitis A 38-year-old male with HIV disease. Multiple pruritic red papules on the face and neck occurred shortly after reinstituting cART. This represents the immune reconstitution inflammatory syndrome (IRIS), occurring as immune parameters improve.
Eosinophilic Folliculitis 
A chronic pruritic dermatosis occurring in persons with advanced HIV disease. May occur before cART or flare with IRIS following initiation of cART.
Clinical Manifestation. Extremely pruritic small pink to red, edematous, folliculocentric papules (Fig. 27-62), and less commonly pustules. Lesions tend to develop symmetrically above the nipple line on the chest, proximal arms, head, and neck. Secondary changes, S. aureus infections, and dyspigmentation are common (Fig. 27-63).
Laboratory Findings. Lesional biopsy shows an inflammatory infiltrate of lymphocytes and eosinophils at the level of the isthmus and sebaceous gland. Peripheral eosinophilia.
Treatment. A short tapered course of prednisone gives immediate relief of symptoms, e.g., 70 mg tapering by 5 or 10 mg daily. Lesions and symptoms often recur within a few weeks of completion of prednisone. Isotretinoin is also effective.
Figure 27-63. Eosinophilic folliculitis A 31-year-old African female with advanced HIV disease. Multiple pruritic edematous papules on the face and neck with marked postinflammatory hyperpigmentation. No the absence of lesions and pigmentation on the adjacent chest.
Papular Pruritic Eruption of HIV 
Epidemiology. Prevalence high in developing nations, often the initial presenting manifestation of HIV disease. Rarely reported in Europe and North America. Papular pruritic eruption (PPE) appears to be a marker of advanced HIV disease; >80% of person with PPE have CD4+ T cell counts < 100/μL (100). Etiopathogenesis is unclear; may represent a hypersensitivity reaction to arthropod bites.
Clinical Manifestation. Urticarial papules and occasionally noninfectious pustules; occasionally folliculocentric. Usually symmetric and distributed primarily on the extremities, and less commonly on the trunk and face (Fig. 27-64), because intense pruritus, multiple excoriations, marked post-inflammatory hyperpigmentation, and scarring are usually present.
Treatment. Immune reconstitution with cART is an effective treatment for PPE, though several months of therapy may be required for lesions to resolve.
Figure 27-64. Papular pruritic eruption of HIV disease A 23-year-old African female with multiple excoriated papules on the arms and fewer lesions on the trunk. Primary lesions are thought to arise at sites of insect bites. (Courtesy of Adam Lipworth, MD.)
Photosensitivity in HIV Disease (see Section 10)
Idiopathic photosensitivity may be the presenting complaint of advanced HIV disease. Photosensitive eruptions present with two distinct morphologies: photodistributed lichenoid eruptions (Fig. 27-65) and photodistributed eczematous eruptions. cART and other drugs cause photosensitive eruptions. Risk factors for photosensitivity include African ethnicity and cART. Photosensitivity occurs in association with other diseases such as porphyria cutanea tarda, chronic actinic dermatitis, lichenoid photoeruption, and photosensitive granuloma.
Figure 27-65. Lichenoid photosensitive eruption A 45-year-old African female with advanced HIV disease. Violaceous hyperpigmented plaques in sun-exposed sites on the face. Depigmentation has occurred within a plaque on the forehead. Other than HIV disease, neither underlying systemic disease nor drug exposure were identified.
Oral Hairy Leukoplakia ICD-10: K13.3
Etiology. EBV emerges from latency in advanced HIV disease and causes benign mucosal hyperplasia. Occurs with CD4+ cell count <300/μL
Clinical Manifestation. Asymptomatic, but stigmatization of HIV disease. White or grayish-white, well-demarcated plaques (Fig. 27-66) with corrugated texture. Most commonly on the lateral and inferior surfaces of the tongue. Often present bilaterally. Oropharyngeal candidiasis often present as well.
Differential Diagnosis. Pseudomembranous candidiasis (thrush), geographic or migratory glossitis, tobacco-associated leukoplakia, mucous patch of secondary syphilis, and SCCIS.
Diagnosis. Clinical diagnosis. Lesions do not rub off; does not clear with adequate anticandidal therapy.
Course. Usually resolves with cART and immune restoration. Recurs when cART failing.
Treatment. Podophyllin 25% in tincture of benzoin applied to the lesion with a cotton-tipped applicator for 5 minutes. Effective cART results in regression and clearing of OHL.
Figure 27-66. Hairy leukoplakia A 32-year-old male with advanced HIV disease. White plaques on the lateral tongue with corduroy-like pattern.
Adverse Cutaneous Drug Eruptions in HIV Disease
ICD-9: 693.0 ICD-10: L27.0 
Incidence of ACDEs is estimated to be as much as 100 times more common in persons with HIV disease compared to that in the general population, becoming more frequent with advancing immunodeficiency.
Exanthematous or morbilliform eruptions are the most common manifestation, accounting for up to 95% of cases.
Other morphologies such as urticaria, erythema multiforme major, erythema multiforme minor, toxic epidermal necrolysis, lichenoid eruptions, vasculitis, and fixed drug eruptions also occur. Twenty percent of persons report systemic symptoms (fever, headache, myalgias, arthralgias).
CART can cause a wide spectrum of ACDE.
Etiology and Epidemiology
Most common drugs causing adverse cutaneous drug eruptions (ACDE) in HIV disease are aminopenicillins and sulfa drugs. Factors associated with increased risk of drug eruptions include female gender, CD4+ T cell count <200/μL, CD8+ T cell count > 460/μL, and history of prior drug eruptions. The incidence of toxic epidermal necrolysis is markedly increased in advanced HIV disease with a mortality rate 20%.
Pathogenesis. Incidence increases with progressive HIV disease, and decline and dysregulation of immune function. After immune reconstitution by cART, some persons who previously tolerated a drug may develop allergic cutaneous drug reactions, a manifestation of IRIS.
Classification
Drug eruptions can mimic many dermatoses and must be first on the differential diagnosis in the appearance of a sudden symmetric eruption (see Section 23).
Exanthematous or morbilliform eruptions macules and papules. Account for 95% of ACDE in HIV disease as in the general population.
Retinoid Dermatitis. Indinavir has a retinoid effect on skin and can cause eczematous dermatitis, chronic paronychia, cheilitis, and pyogenic granuloma.
Lipodystrophy syndrome: See below.
Treatment
In most cases, the implicated or suspected drug should be discontinued. In cases of urticaria/angioedema or early Stevens–Johnson syndrome, ACDE can be life threatening. Shortterm oral corticosteroid therapy may be effective in reducing the risk of adverse drug eruptions.
Adverse Effects of Antiretroviral Therapy
Six classes of antiretroviral medications are currently in use:
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• Protease inhibitors
• NRTIs)
• Integrase inhibitors
• Chemokine receptor 5 antagonists
• Entry inhibitors.
These medications are associated with a variety of cutaneous adverse effects, including hypersensitivity reactions, lipodystrophy, retinoid-like effects, hyperpigmentation, nail changes, and injection site reactions (Table 27-3).
TABLE 27-3 ADVERSE EFFECTS OF ANTI RETROVI RAL DRUGS
Lipodystrophy and Metabolic Syndromes
HIV disease-related lipodystrophy is characterized by abnormal fat distribution with lipohypertrophy, lipoatrophy, or both. Abnormal fat distribution is often accompanied by metabolic abnormalities, i.e., elevation of fasting glucose and insulin levels, hypertriglyceridemia, hypercholesterolemia, and decreased high-density lipoprotein.
Pathogenesis. Lipohypertrophy is most commonly associated with protease inhibitor therapy, while lipohypertrophy is frequently associated with NRTIs, particularly the thymidine analogues stavudine and zidovudine. HIV disease by itself may induce changes in fat distribution and metabolic anomalies such as insulin resistance.
Clinical Manifestation. Lipohypertrophy presents with central obesity, cushingoid habitus (“buffalo hump”), increased neck girth (Fig. 27-67), increased abdominal girth due to intraabdominal fat (“protease pouch” or “crix belly”), and breast enlargement. Facial lipoatrophy, most pronounced on the cheeks and temples, is striking and stigmatizing for HIV disease (Fig. 27-68). Lipoatrophy of subcutaneous fat produces a pseudoathletic appearance with a prominent venous pattern and musculature on the extremities, buttocks. In cohort persons with HIV disease treated with ART, the overall prevalence of lipodystrophy was 38%, while the prevalence of lipoatrophy alone was 16% and lipohypertrophy alone was 12%. The prevalence of lipid anomalies was 49% and the prevalence of glucose disorders was 20%.
Figure 27-67. Lipohypertrophy A 51-year-old male with advanced HIV disease. Increase subcutaneous fatty tissue of neck with “buffalo hump on upper back.” Gynecomastia was also present. Lipoatrophy was present on the face. His weight was normal.
Figure 27-68. Lipoatrophy A 61-year-old male with advanced HIV disease. Striking loss of fat is seen on cheeks and temples. Lipohypertrophy of the neck and upper back were also present.
Treatment of lipodystrophy remains challenging. Substitution of regimens containing stavudine and zidovudine has been shown to be of partial benefit for lipoatrophy. Facial lipoatrophy has been treated with soft tissue fillers with varying degrees of success.
Variations in Common Mucocutaneous Disorders in HIV Disease
Early in HIV disease when immune function is relatively intact, common dermatoses, ACDEs, and infections present as typical clinical manifestations have the usual course, and respond to standard therapies.
With progressive decline in immune function, each of these characteristics of a disease can be strikingly altered.
With effective management with cART and immune reconstitution, diseases either do not occur, resolve without specific therapy, or respond more readily to therapy.
Kaposi Sarcoma
Early in the HIV epidemic in the United States and Europe, 50% of men who have sex with men (MSM) had KS at the time of initial AIDS diagnosis. In persons with HIV disease, the risk for KS is 20,000 times that of the general population and 300 times that of other immunosuppressed individuals. In untreated HIV disease, KS may progress rapidly with extensive mucocutaneous and systemic involvement. KS in persons successfully treated with cART does not occur, resolves without specific therapy other than immune reconstitution, or responds better to chemotherapies (see also “Kaposi Sarcoma,” Section 21).
Nonmelanoma Skin Cancers
The incidence of a SCC is increased in advanced HIV disease. Infection with oncogenic types of HPV is the more common cause of SCC. Cervix, external genitalia, and the anorectal areas are the most common involved sites for SCC in situ and invasive SCC. The incidence of UV light-induced invasive SCC is increased in advanced HIV disease in persons with skin phototypes I to III with much UVL exposure during early decades of life. These SCCs can be quite aggressive, invading locally, growing rapidly, and metastasizing by lymphatics and blood, with increased morbidity and mortality.
Aphthous Ulcers
Recurrent aphthous ulcers occur more frequently, become larger (often >1 cm), and/or become chronic with advanced HIV disease. Ulcers may extensive and/or multiple; commonly involving the tongue, gingiva, lips, and esophagus, causing severe odynophagia with rapid weight loss. Intralesional triamcinolone. Prednisone 70 mg tapered by 10 or 5 mg per day over 7 or 14 days. In resistant cases, thalidomide is an effective agent (see also “Aphthous Ulcers,” Section 33).
Staphylococcus aureus Infection
S. aureus is the most common cutaneous bacterial pathogen in the general population and in HIV disease. The nasal carriage rate of S. aureus is up to 50%, twice that of HIV-seronegative control groups. In most instances, S. aureus infections are typical, presenting as primary infections (folliculitis, furuncles, carbuncles), secondarily infections (excoriations, eczema, scabies, herpetic ulcer, KS), cellulitis, or venous access device infections, all of which can be complicated by bacteremia and disseminated infection. Methicillin-resistant S. aureus (MRSA) infections, if not identified, may be more severe because of delay in initiation of effective anti-MRSA therapy (see also Section 25).
Dermatophytoses
Epidermal dermatophytosis can be extensive, recurrent, and difficult to eradicate. Proximal subungual onychomycosis occurs in advanced HIV disease, presents as a chalky-white discoloration of the undersurface of the proximal nail plate, and is an indication for HIV serotesting (see also “Dermatophytoses,” Section 26, and “Fungal Infections: Onychomycosis,” Section 32).
Mucosal Candidiasis
Mucosal candidiasis affecting the upper aerodigestive tracts and/or vulvovagina is common in HIV disease. Oropharyngeal candidiasis, the most common presentation, is often the initial manifestation of HIV disease and is a marker for disease progression. Esophageal and tracheobronchial candidiasis occur in advanced HIV disease and are AIDS-defining conditions. The incidence of cutaneous candidiasis may be increased; with insulin resistance associated with cART, balanoposthitis can be seen. In young children, chronic candidal paronychia and nail dystrophy occur (see also “Candidiasis,” Section 26).
Disseminated Fungal Infection
Latent pulmonary fungal infections with Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, and Penicillium marneffei can be reactivated in HIV disease and disseminated to the skin and other organs. The most common cutaneous presentation of disseminated infection is molluscum contagiosum-like lesions on the face; other lesions such as nodules, pustules, ulcers, abscesses, or a papulosquamous eruption resembling guttate psoriasis (seen with histoplasmosis) also occur (see also “Disseminated Cryptococcosis,” “Histoplasmosis,” and “Disseminated Coccidioidomycosis,” Appendix C).
Herpes Simplex
HSV-1 or -2 infection is common opportunistic infections of HIV disease. Most reactivation is subclinical. Anogenital reactivation is particularly frequent. With advancing HIV disease, early lesions present with erosions or ulcerations associated with epidermal necrosis without vesicle formation. Untreated, these lesions may evolve to large, painful ulcers with rolled margins in the oropharynx, esophagus, and anogenitalia. Treatment of HSV reduces genital and plasma HIV RNA levels (see also “Herpes Simplex with Host Defense Defects, p. 669”).
Varicella-Zoster Virus (VZV) Infection
Primary VZV infection (varicella or chicken pox) in HIV disease can be severe, prolonged, and complicated by visceral VZV infection, bacterial secondary infection, and death. HZ occurs in 25% of persons during the course of HIV disease, associated with modest decline in immune function. Cutaneous dissemination of HZ is relatively common; however, visceral involvement is rare. With increasing immunodeficiency, VZV infection can present clinically as chronic dermatomal verrucous lesions; one or more chronic painful ulcers or ecthymatous lesions within a dermatome; crusted erosions, ulcer, or nodule. Untreated, these lesions persist for months. HZ can recur within the same dermatome(s) or in other dermatomes. VZV can infect the CNS causing a rapidly progressive chorioretinitis with acute retinal necrosis, chronic encephalitis, myelitis, radiculitis, or meningitis. Extensive HZ may heal with hypertrophic or keloidal scar (see also “VZV: Host Defense Defects, p. 680”).
Molluscum Contagiosum
In advanced HIV disease, molluscum contagiosum has up to 18% prevalence; the severity of molluscum contagiosum is a marker for advanced immunodeficiency. Patients may have multiple small papules or nodules or large tumors, >1 cm in diameter, most commonly arising on the face (Fig. 27-69), especially the beard area, the neck, and intertriginous sites. Cyst-like mollusca occur on the ears. Occasionally, mollusca can arise on the non-hair-bearing skin of the palms/soles (see also “Molluscum Contagiosum p. 629”).
Figure 27-69. Molluscum contagiosum, confluent A 51-year-old female with advance HIV disease. (A) Extensive and confluent facial nodules were disfiguring. (B) Lesions resolved with electrodessication.
Human Papillomavirus Infection
With advancing immunodeficiency, cutaneous and/or mucosal warts can become extensive and refractory to treatment. Of more concern, however, HPV-induced intraepithelial neoplasia, termed squamous intraepithelial lesion(SIL), is a precursor to invasive SCC, arising most often on the cervix, vulva, penis, perineum, and anus (Fig. 27-70). In females with HIV disease, the incidence of cervical SIL is six to eight times that of controls. The current trend toward longer median survival of patients with advanced HIV may lead to an increased incidence of HPV-associated neoplasia and invasive SCC in the future. SIL on the external genitalia, perineum, or anus is best managed with local therapies such as imiquimod cream, cryosurgery, electrosurgery, or laser surgery rather than with aggressive surgical excision (see also “Human Papillomavirus: Mucosal Infections,” Section 30).
Figure 27-70. Squamous cell carcinoma in situ A 32-year-old female with HIV disease and cervical dysplasia. A subtle velvety plaque is seen on the vulva superior to the clitoris.
Syphilis
The clinical course of syphilis in persons with HIV disease is most often the same as in the normal host. However, an accelerated course with the development of neurosyphilis or tertiary syphilis has been reported within months of initial syphilitic infection (see also “Syphilis,” Section 30).