• Recurrent vesicular eruptions occurring in orolabial (classically HSV-1) and genital (classically HSV-2) regions

• Primary infection = first infection with virus (may → symptoms); latency = virus lies dormant in sensory (dorsal root) ganglia; reactivation/recurrence (may → symptoms)

• Genital herpes RFs: 15 to 30 years old, ↑sexual partners, lower income/education, HIV(+) (vice versa too – genital HSV-2 → ↑HIV risk), and homosexuality

• Pathogenesis

■ Infection can occur without clinical lesions (and often does), and virus may still be shed

■ HSV-1 spread by saliva/secretions and HSV-2 spread by sexual contact → viral replication at skin/mucous membrane → retrograde axonal flow to dorsal root ganglia → latency and subsequent reactivation

■ HSV can evade host immune system (e.g., ↓expression of CD1a by APCs, ↓TLR signaling)

■ Reactivation triggers: stress, UV (UVB > UVA), fever, injury (e.g., chemical peel or fractionated laser), and immunosuppression

• Clinical presentation

■ Classic appearance: grouped/clustered vesicles on a red base

○ Can become pustules, erosions (with classic scalloped borders due to coalescence), and ulcers, ultimately crusting over and healing within 6 weeks

■ 1° infection: 3 to 7 days postinfection → prodromal symptoms (tender lymphadenopathy, malaise, anorexia, and fever) → mucocutaneous lesions +/− pain/tenderness/burning/tingling just before lesions erupt

■ Recurrent infections: generally milder than 1° infections, have 24 hour prodrome of tingling/itch/burning

■ Orolabial infection

○ 1° HSV can be severe (gingivostomatitis in children; pharyngitis/mononucleosis-like in adults)

○ Mouth (esp. buccal mucosa and gingivae; favors anterior mouth unlike herpangina) and lips (recurrent lesions prefer vermilion border) affected

■ Genital herpes

○ 1° infection often asymptomatic, but can → painful/tender erosions on external genitalia, vagina, cervix, buttocks, and perineum (women) +/− lymphadenopathy/dysuria (women mainly)

♦ 1° worse in women – ↑% extragenital involvement, urinary retention, and aseptic meningitis (10%)

○ Recurrent – mildly symptomatic with few vesicles lasting about 1 week; frequency of outbreaks usually decreases over time

■ Other HSV presentations

○ Eczema herpeticum: widespread, sometimes severe HSV infection in areas of atopic dermatitis, Hailey-Hailey, or Darier’s disease (Fig. 5-2) +/− systemic symptoms, lymphadenopathy, may be life-threatening; ↑in children

♦ ↑with filaggrin mutations

♦ Usually HSV-1; associated with Th2 shift in immune system

♦ ↑in patients with severe atopic dermatitis w/ onset <5 years old, ↑IgE levels, ↑eosinophils, and food/environmental allergies

♦ Have been associated with topical calcineurin inhibitors

○ Herpetic whitlow: infection of digits (HSV-1 in children and HSV-2 in adults) w/ vesiculation/pain/swelling; recurrence seen; bimodal peaks at <10 years old and 20 to 40 years old

○ Herpes gladiatorum: HSV-1 infection 2° to athletic contact (classically on lateral neck/side of face and forearm)

○ HSV folliculitis (herpetic sycosis): follicle-based vesicles/pustules in beard-area (HSV-1)

○ Severe/chronic HSV: large, chronic ulcers may involve respiratory or GI tract; more common in immunocompromised

○ Ocular HSV: keratoconjunctivitis w/ lymphadenopathy and branching dendritic corneal ulcer; blindness may occur (HSV-2 in newborns; HSV-1 otherwise)

○ HSV encephalitis: most common fatal viral encephalitis in the United States (>70% die without tx); can be associated with mutations in TLR-3 or UNC-93B; usually HSV-1; fever/altered mentation/strange behavior; temporal lobe #1 site

○ Neonatal HSV– see Pediatric Dermatology section

• Diagnosis

■ Viral culture (high specificity, low sensitivity), direct fluorescent antibody assays, serology (Western blot = gold standard), PCR (most sensitive/specific), and Tzanck smear (multinucleated epithelial giant cells; best when done on acute lesions)

■ Histology: intraepidermal vesicle + slate-gray enlarged keratinocytes (ballooning degeneration) which are multinucleated with margination of chromatin

○ +/− Cowdry A inclusions (eosinophilic inclusion bodies) within nucleus, epidermal necrosis, multicellular dermal infiltrate, and perivascular cuffing

• Treatment

■ Orolabial: oral penciclovir/valacyclovir, topical penciclovir, or topical acyclovir/hydrocortisone combination

■ Genital: oral acyclovir/famciclovir/valacyclovir

○ Use meds w/in first 48 hours → ↓pain/healing time/viral shedding

○ Suppressive daily doses may be given in patients with >6 outbreaks of orolabial/genital HSV per year (also ↓viral shedding)

■ May need IV acyclovir in eczema herpeticum, neonatal HSV, or severe HSV in immunosuppressed

■ Foscarnet or cidofovir for acyclovir-resistant HSV (more common in immunosuppressed patients)

• Boards factoid: HSV-1 is the most common cause of EM minor (herpes associated EM; HAEM)

• Causes varicella (chickenpox) and herpes zoster (shingles)

• Varicella is the 1° infection and herpes zoster is the reactivation of the latent infection (more common in immunosuppressed and elderly and can → death, e.g., via SIADH development in disseminated zoster patients)

• Primary varicella incidence has decreased because of VZV vaccination

• Herpes zoster occurs in 20% of adults, 50% of immunocompromised

■ Elderly at highest risk

■ RFs: physical and emotional stress, fever, trauma, and immunosuppression

■ Whites > nonwhites

• Pathogenesis

■ Transmitted via aerosolized droplets and direct contact with lesional fluid

○ Contagious from 1 to 2 days before lesion develops in varicella until all lesions crusted over

■ After primary varicella infection, VZV travels to dorsal root ganglion and stays dormant – if reactivated later will replicate, travel down sensory nerve to the skin, and present as herpes zoster

• Clinical presentation

■ Primary varicella

○ Primarily self-limited in healthy individuals

♦ More severe disease in adolescents and adults

○ Prodromal symptoms: fever, fatigue, and myalgias

○ Cephalocaudal progression of classic lesions described as “dew drops on rose petal:” vesicles on an erythematous base that become pustular, then crust over

♦ Crops of lesions in various stages

○ Vaccine-associated varicella zoster may rarely develop after the vaccine is administered – represents mild case of chickenpox that may start at injection site

○ Primary varicella in pregnancy

♦ Congenital varicella syndrome: cutaneous scarring; CNS/ocular/limb anomalies; risk greatest if infection occurs during first 20 weeks of gestation; exposed fetus may develop reactivation (herpes zoster) in childhood

♦ Neonatal varicella: perinatal varicella transmission (within 5 days before delivery until 2 days postdelivery); disease is severe (up to 30% mortality) because of the lack of protective maternal antibodies

■ Herpes zoster: prodrome (itch, tingling, hyperesthesia, and pain) → painful grouped vesicles on red base in a dermatomal pattern

○ Trunk = most common location (thoracic); face #2 (cranial; trigeminal nerve most common nerve involved); lumbar #3, and sacral #4

○ Postherpetic neuralgia: pain, potentially chronic, after lesions have cleared; more common, severe and chronic in elderly

○ In HIV patients, lesions more persistent and thickened

○ Disseminated disease = dermatomal disease + >20 lesions outside of dermatome +/− visceral involvement; almost exclusively seen in immunosuppressed (AIDS, lymphoreticular malignancy, long-term immunosuppressive medication use, etc.); increased risk of life-threatening pneumonitis and encephalitis

○ Vasculopathies (usually of CNS, but also peripheral arteries) are a worrisome delayed complication

○ Dermatomal-specific herpes zoster findings:

♦ Ramsay-Hunt syndrome: disease of geniculate ganglion of facial nerve (CN-VII) may → ear pain, vesicles on tympanic membrane and EAM; ipsilateral facial nerve paralysis, dry mouth/eyes, anterior 2/3 tongue taste loss, and auditory (e.g., deafness and tinnitus) and equilibrium issues (vestibulocochlear nerve)

♦ Aseptic meningitis and/or vasculopathy (encephalitis) if CN-V affected

♦ Hearing impairment/deafness if CN-VIII affected

♦ Eye involvement (herpes zoster ophthalmicus) if CN-II, CN-III, or CN-V affected

➔ Hutchinson’s sign (involvement of the side and tip of nose): indicates disease of the external division of the V1 nasociliary branch; may → to ocular involvement (e.g., keratitis, uveitis, acute retinal necrosis, and visual loss) 3/4 of time

➔ Uveitis is most common form of ocular involvement; keratitis #2

♦ Bell’s palsy if CN-VII affected

♦ Back dermatome complications

➔ Cervical: motor neuropathy of arm (with possible atrophy) and diaphragm weakness

➔ Thoracic: abdominal wall pseudohernia and weakness of muscles

➔ Lumbar: motor neuropathy of leg (with possible atrophy)

♦ Possible urinary hesitancy/retention if sacral dermatomes involved

♦ Possible dilatation, constipation, pseudo-obstruction, reduced anal sphincter tone w/ thoracic/lumbar/sacral zoster

• Diagnosis: Tzanck smear, DFA, PCR (sensitive, fast), viral culture (specific, not sensitive), serology (four-fold increase in IgG titer can retrospectively confirm prior infection), and skin biopsy (similar appearance to HSV, but immunohistochemistry can differentiate)

• Treatment

■ Primary varicella

○ Treatment with systemic acyclovir or valacyclovir within 3 days of lesion onset → ↓severity/duration disease

♦ Oral administration appropriate in healthy children/adults

♦ IV acyclovir in immunocompromised patients

○ Post-exposure prophylaxis

♦ Varicella vaccine may be given within 72 to 120 hours of exposure in nonimmune, immunocompetent individuals >12 months

♦ VZIg (Varicella zoster immunoglobulin) should be administered within 96 hours of exposure in immunocompromised, pregnant females, and neonates

➔ IVIg may alternatively be administered

♦ Oral acyclovir can be administered within 7 to 10 days of exposure

○ Primary prevention = varicella vaccination

♦ Live attenuated virus recommended as a 2 dose vaccination series; part of primary immunization series

♦ Initial dose at 12 to 15 months, booster dose at 4 to 6 years

♦ Contraindicated in pregnancy and in immunocompromised patients

○ Sequelae of primary varicella

♦ Reye’s syndrome in setting of aspirin administration (now rare)

♦ Pneumonia more common in older individuals; high mortality if untreated

♦ Encephalitis, cerebella ataxia, and hepatitis

■ Herpes zoster

○ Antiviral treatment with acyclovir (IV form in immunosuppressed), famciclovir, or valacyclovir is best given within 72 hours; prednisone helps with acute pain but has no effect on course or development of PHN

♦ ↓duration of lesions/pain

♦ ↓rate of postherpetic neuralgia (PHN) in patients >50 years old

♦ Valacyclovir and famciclovir preferable to acyclovir

○ PHN: tricyclic antidepressants (e.g., nortriptyline), gabapentin, 8% capsaicin patch, pregabalin, opioid analgesics, and lidocaine patch

○ Live attenuated vaccine → ≈50%↓ in development of disease and 67%↓ in PHN; for immunocompetent patients >60 years old

• Causes infectious mononucleosis plus many other disorders (e.g., oral hairy leukoplakia, hydroa vacciniforme, Gianotti-Crosti syndrome, genital ulcers, and various hematologic disorders/malignancies (e.g., Burkitt’s lymphoma, NK/T-cell lymphoma, post-transplant lymphoproliferative disorder, and nasopharyngeal carcinoma)

• Pathogenesis: transmission via saliva/blood → infects mucosal epithelial cells initially → B-cells (where virus can lay dormant and evade immune system via production of EBNA-1 protein and latent membrane protein-2)

■ Incubation period of 1 to 2 months; symptoms develop with viral replication

■ In patients with ↓cell-mediated immunity, infected B-cells may continue to replicate → lymphoproliferative disorders (cell-mediated immunity appears to be more important than humoral, conferring immunity after first mononucleosis episode)

• Clinical features

■ Mononucleosis: typically young adults w/ pharyngitis, fever, and cervical lymphadenopathy

○ Splenomegaly (and possible rupture) +/− hepatomegaly

○ ↑LFTs in subset of patients

○ Lymphocytosis (up to 40% atypical lymphocytes)

○ May have nondistinct polymorphous (e.g., urticarial, morbilliform) eruption in 5% to 10% occurring within first week of illness

♦ Centrifugal spread

♦ Petechial lesions on eyelid and hard/soft palate junction

♦ +/− genital ulcers (esp. females)

○ Ampicillin/amoxicillin → “hypersensitivity” skin reaction (itchy generalized morbilliform eruption → desquamation)

■ Oral hairy leukoplakia: corrugated white plaque typically on lateral tongue, with strong HIV association; more common in smokers

■ Gianotti-Crosti syndrome and papular-purpuric glove and stocking syndrome (more common w/ parvovirus B19, though) may occur in setting of EBV infection

• Diagnosis:

■ Monospot test: nonspecific, confirms presence of IgM heterophilic antibodies which are often present in EBV infection and may persist for months after infection; 85% of older children/adults are positive during second week of infection, but Monospot is often negative in younger children

■ EBV-specific antibodies: higher sensitivity in younger children; can be useful in determining current vs prior infection (Table 5-1)

○ VCA (viral capsid antigen) IgM/IgG, EA (early antigen) IgG, and EBNA IgG

■ CBC may reveal lymphocytosis with atypical lymphocytes and thrombocytopenia

■ Transaminitis may be present

■ Positive heterophilic antibody (>1 : 40) and >10% atypical lymphocytes suggests acute infection

■ PCR to EBV DNA may be performed from tissue or blood; RT-PCR available from lymphoid cells

• Treatment:

■ Supportive care

■ Oral corticosteroids may be considered for severe cases of tonsillitis

■ Avoid contact sports until splenomegaly resolves (risk for splenic rupture)

■ Rare sequelae: upper airway obstruction, aseptic meningitis, meningoencephalopathy, myocarditis, pericarditis, and renal failure

• Transmitted via body fluids, fomites, vertical transmission, transplanted organs, and hematopoietic stem cells

• Infects leukocytes → dissemination → various organs → latency

■ Most infections are asymptomatic in healthy adults; however, can cause severe disease in utero (TORCH), or in immunosuppressed/transplant patients (CMV retinitis/blindness, meningoencephalitis, pneumonitis, GI ulcers)

■ After the 1° infection, very low risk of reactivation, except for immunocompromised patients

• Cutaneous features in adults

■ Mononucleosis-like presentation (e.g., sore throat, fever, lymphadenopathy, and hepatosplenomegaly) may be associated with nonspecific exanthem (e.g., morbilliform)

○ If ampicillin given → eruption (as in infectious mononucleosis)

■ Recalcitrant ulcers of perineum or leg in HIV patients; these patients may also get verrucous plaques, vesicles, and/or nodules

• Diagnosis via human fibroblast culture (gold standard), but faster methods include shell vial assay, PCR, and serologic testing; histology of ulcers may show enlargement of endothelial cells with pathognomonic “owl’s eye” (intranuclear) inclusions

• Ganciclovir (IV) and valganciclovir (oral) are first-line treatments

• One of the most common viral exanthems of childhood (discussed in detail in Pediatric Dermatology chapter); up to 15% of infants may develop febrile seizures, but otherwise follows a generally benign course in healthy pts

■ 95% of pts are between 6 months to 3 years of age

• Virus remains latent in T cells for life → reactivation has been a/w pityriasis rosea (along with HHV-7) and DRESS syndrome (along with EBV, CMV and HHV-7)

• Lymphotropic virus that shares significant homology with HHV-6 and may participate in co-infection w/HHV-6

• Although not definitively causative of any disease, it has been a/w pityriasis rosea (along with HHV-6), and a subset of exanthem subitum cases (co-infection with HHV-6; unique clinical presentation)

• Etiologic factor for Kaposi sarcoma – discussed in Neoplastic Dermatology chapter

• Also associated with multicentric Castleman disease, primary effusion lymphoma (PEL), and paraneoplastic pemphigus

• Single-stranded (+)sense RNA virus belonging to Togaviridae family; classified as an “arbovirus” because has arthropod vector

• Transmitted by Aedes (A. aegypti > A.albopictus) mosquitoes; endemic to Africa/India/Southeast Asia

• Symptoms: high fever, marked joint symptoms, (“Chikungunya” is an African word for “crooked/bent joints”) neuropathic acral findings, and headache/nausea/vomiting

• Cutaneous presentation: → morbilliform eruption (50%–75% of pts), mucosal aphthous-like ulcers, postinflammatory pigmentation of face/extremities, acral/facial edema, bullous eruptions in infants, and ecchymoses

• Icosahedral, single-stranded RNA virus within the Flaviviridae family

■ Flaviviridae family includes Yellow fever, Dengue fever, Japanese encephalitis, West Nile virus, and Zika virus

○ All are termed “arboviruses” because they are viruses that are transmitted by arthropods (mosquitoes or ticks most commonly)

○ Review the excellent JAAD 2016 CME article by Nawas et al, Emerging infectious diseases with cutaneous manifestations

• Most commonly transmitted via bites from infected Aedes aegypti and Aedes albopictus mosquitos

■ Virus may also be transmitted via blood transfusions, sexual contact, and most importantly, vertically (from mother to fetus) during pregnancy → microcephaly and other fetal anomalies

• In 2016, the WHO classified Zika as a global threat and the CDC raised issued their highest alert due to Zika’s association with microcephaly and possible a/w Guillain-Barré syndrome

• Clinical features:

■ No gender or age predilection

■ Incubation period of 3–12 days → 20% of infected adults develop mild symptoms lasting up to 1-2 weeks

○ Systemic symptoms: fever, myalgia, arthralgia, headache, and conjunctivitis

○ Mucocutaneous symptoms:

♦ Nonspecific, diffuse morbilliform/scarlatiniform eruption (begins 3 to 12 days after initial infection w/cephalocaudal progression; starts on face → spreads to trunk/extremities) → rash begins to subside after 3 days and completely resolves within 1 week of onset, sometimes with desquamation

♦ Mild hemorrhagic manifestations (petechiae and bleeding gums)

■ Unfortunately, there are no unique clinical features to differentiate Zika from other arbovirus infections → must consider dengue and chikungunya infection in your differential diagnosis

• Diagnosis:

■ Confirmed with RT-PCR or ELISA during initial phase (first 7 days) of infection

○ Later in disease course, may check Zika-specific IgM antibodies and plaque reduction neutralization tests

• Treatment:

■ Currently no vaccine exists, and no specific anti-viral therapies are available; avoid aspirin and NSAIDs (can worsen hemorrhagic sequelae)

■ Prevention is critical!

○ People traveling to endemic areas should wear long-sleeved shirts and pants, stay in cool rooms that have screens on windows and doors, and use insect repellents (DEET); pregnant women should avoid travel to Zika-endemic areas!

• Like Zika, West Nile virus and Yellow fever, Dengue is an arbovirus in the Flaviviridae family; also transmitted by Aedes aegypti mosquitoes

• Wide range of clinical presentations:

■ Asymptomatic infection: most common presentation (75% of cases)

■ Mild Dengue: very nonspecific, mimicking any other viral infection

■ Classic Dengue fever: fever, diffuse morbilliform/scarlatiniform rash (50% of cases), severe headache/myalgia/arthralgia, retroorbital pain, +/− petechial mucosal lesions, epistaxis and gingival bleeding

○ Classic Dengue fever rash: widespread erythema with characteristic white islands of sparing → heals with desquamation

■ Dengue hemorrhagic fever (DHF): more severe than classic Dengue fever; most likely to develop when a patient previously infected with 1 serotype is subsequently infected with a different viral serotype

○ Most common in children younger than 15yo

○ Symptoms: lethargy/weakness, vomiting, facial flushing, and circumoral cyanosis

• Diagnosis:

■ Confirmed with RT-PCR or ELISA during initial/acute phase of disease, or IgM serologies later in disease course

■ Neutropenia helps distinguish from Chikungunya virus

• Treatment: No specific treatment; mainly supportive; avoid aspirin and NSAIDs (can worsen hemorrhagic sequelae)