Section E: Viral

PATIENT STORY

A 12-year-old girl presents with a 3-day history of an extensive vesicular and pruritic rash (Figure 129-1). The episode started 24 hours before the rash with fever and malaise. The patient is diagnosed with varicella, and no antiviral medications are given. Acetaminophen and/or ibuprofen are recommended for fever and discomfort.

INTRODUCTION

Primary varicella, commonly known as chickenpox, is a highly contagious viral infection characterized by a distinctive rash with the potential to cause serious acute illness and to manifest later as zoster. The epidemiology of chickenpox has changed markedly since 1995 in the United States and other countries with high varicella vaccine coverage.

EPIDEMIOLOGY

• Varicella-zoster virus (VZV) is distributed worldwide. Humans are the only natural reservoir.

• Incidence is seasonal, except in tropical climates, with most cases occurring during the winter and early spring. Peak incidence in the United States is between March and May.¹

United States epidemiology before the vaccination program:

• Estimated incidence of about 4 million/year.

• Essentially everyone acquired varicella before adulthood, most as young children (Figure 129-2).

• Most experienced the illness as a painful but benign and self-limited rash.

• Household infection rate was more than 90% of susceptible individuals¹ (Figure 129-3).

• Complications from varicella accounted for approximately 11,000 hospital admission and 100 deaths annually.¹

• Complications were more prevalent in babies, older adults, and immunocompromised persons; most deaths actually occurred in immunocompetent children and adults.

United States epidemiology since the vaccination program:

• The incidence of chicken pox abruptly declined by 97%.

• A high percentage of remaining cases are breakthrough varicella (infection with wild-type VZV more than 42 days after vaccination).¹

• Complications, including death, also declined dramatically—especially in children and young adults, where it decreased by 99%.²

• Current groups vulnerable to morbidity and mortality include^2,3:

  • Persons living with natural and/or medically induced immunodeficiency

  • Susceptible immigrants from the tropics

ETIOLOGY AND PATHOPHYSIOLOGY

• Chickenpox is caused by a primary infection with the varicella-zoster virus (VZV), a double-stranded, linear DNA herpesvirus.

• VZV is primarily transmitted through the desquamation of vesicular skin lesions, which releases fully infectious viral particles into the air. Current evidence questions the long-held supposition of spread through infected respiratory secretions, although most sources continue to report this and to report infectivity up to 48 hours prior to the formation of the rash.³

• Infectivity, enhanced by scratching, lasts until skin lesions are fully crusted.

• Incubation is approximately 15 days.

• The VZV enters the susceptible host through the respiratory mucosa and conjunctiva.

• The virus replicates locally and in regional lymph nodes, leading to an initial viremia 4–6 days later. Multiple organs are seeded, including the sensory ganglia (important for latent infection), and viral production continues. A second viremia involving the skin occurs about 15 days after exposure and results in the typical skin lesions.¹

• The most frequent complication in healthy children is bacterial skin superinfection (Figure 129-4). Less-common skin complications (seen more frequently in immunosuppressed hosts) include bullous varicella, purpura fulminans, and necrotizing fasciitis.

• Encephalitis is a serious potential complication of chickenpox. One form, acute cerebellar ataxia, occurs mostly in children and is generally followed by complete recovery. The more severe form occurs primarily in adults and may produce delirium, seizures, focal neurologic signs, long-term neurologic sequelae, and death.

• Pneumonia is rare in healthy children but accounts for a majority of serious complications in adults, including pregnant women; mortality rate approaches 30%.¹ VZV pneumonia usually develops insidiously a few days after the initial lesions and presents with progressive tachypnea, dyspnea, and dry cough. Chest x-rays reveal diffuse bilateral infiltrates.

• Immunocompromised patients are at risk for complications with VZV, most commonly encephalitis and pneumonia. Disseminated disease is relatively common in this cohort and can lead to a more fulminant course with multi-organ failure.

• Congenital varicella syndrome, although rare in the United States even before the routine use of the vaccine, can lead to an array of congenital problems. Mortality of this potentially devastating complication has been significantly reduced in recent times through the availability of VZV immune globulin and intensive supportive care.⁴

• Reactivation of latent VZV results in herpes zoster or shingles (see Chapter 130, Zoster).

DIAGNOSIS

CLINICAL FEATURES

• The typical clinical manifestations of chickenpox include a prodrome of fever, malaise, and pharyngitis, followed by the development of a generalized vesicular rash in approximately 24 hours.

• A prodrome of fever and malaise is more common in adults than children and may precede the rash by 1 to 2 days.

• Fever and malaise often accompany the rash for 2–3 days even in healthy children.

• The characteristic pruritic, vesicular rash appears in crops for several days, resulting in lesions of various stages of development throughout its distribution.

• Natural infection in a healthy child generally produces about 200–500 lesions, whereas breakthrough varicella often produces less than 50 and is less likely to cause fever.

• Lesions typically start as vesicle on a red base, which is classically described as a dewdrop on a rose petal (Figure 129-5). The lesions gradually develop a pustular component (Figure 129-6) followed by the evolution of crusted papules (Figure 129-7).

• Breakthrough varicella lesions may present only as papules, without a vesicular component.

• The lesions are pruritic and appear as successive crops of vesicles over 3 to 4 days.

• Coexisting lesions in different stages of development on the face, trunk, and extremities are common (Figure 129-8).

• New lesions stop forming in approximately 4 days, and most lesions have crusted completely by day 7.

TYPICAL DISTRIBUTION

• Body wide: Lesions typically appear first on the head and trunk followed by the extremities. Mucosal membranes may be involved.

LABORATORY TESTING

• Diagnosis is usually based on classic presentation.

• Laboratory testing is helpful when the presentation is atypical, including cases of possible breakthrough varicella; for infection control purposes; and for patients with potentially severe illness, including immunocompromised individuals (Figure 129-9).

• Viral isolation is no longer considered the gold standard for diagnosis, but may be helpful if resistance to antivirals is suspected.³

• Polymerase chain reaction (PCR) is now the diagnostic procedure of choice.³

  • Results are available within 1–2 days, are highly accurate, and are relatively inexpensive.

  • VZV can be readily detected from a variety of bodily sites and fluids, including skin and throat swabs, cerebrospinal fluid and blood, and biopsy or autopsy specimens.

  • The assay may be available at no charge through surveillance laboratories.

  • Use of restriction enzyme treatment of PCR can differentiate between infection from wild-type (WT) VZV and breakthrough infections caused by the vaccine (vOka).

  • Interesting note: Saliva is often positive for VZV DNA in persons under stress, even without disease. Unlike herpes simplex virus, VZV in saliva is not considered infectious.

  • Indirect immunofluorescence can rapidly detect VZV in skin vesicles with reasonable sensitivity, but is less sensitive than PCR and cannot differentiate between WT VZV and vOka.³

• Serologic testing is sometimes used in an attempt to confirm recent illness with VZV or to assess immunologic protection from infection, but problems with this testing limit its utility.

• Humoral immunity does not protect against reactivation of the VZV as zoster.

DIFFERENTIAL DIAGNOSIS

• Herpes simplex infection presents with similar lesions, but is generally restricted to the genital and oral areas. The vesicles of herpes simplex tend to be more clustered in a group rather than the wide distribution of varicella (see Chapter 135, Herpes Simplex).

• Herpes zoster, the manifestation of latent VZV, is classically unilateral and follows dermatomal distribution (see Chapter 130, Zoster).

• Pemphigus and bullous pemphigoid occur most often in adults and are usually not febrile conditions. The bullae are usually larger than the vesicles of varicella (see Chapters 192, Bullous Pemphigoid, and 193, Pemphigus).

• Dermatitis herpetiformis, seen with gluten-induced enteropathy, is characterized by a chronic and intensely pruritic papulovesicular rash over the extremities and on the trunk. There is no fever, and the patient is not systemically ill other than possible symptoms from the enteropathy (see Chapter 194, Other Bullous Disease).

• Impetigo can have bullous or crusted lesions anywhere on the body. The lesions often have mild erythema and a yellowish color to the crusts. Varicella lesions can be secondarily infected, causing a superimposed picture (see Chapter 122, Impetigo).

• The vesicular lesions of hand, foot, and mouth disease (HFMD) are typically flat and painful without the characteristic dew-drop appearance and pruritus of varicella. Atypical HFMD with Coxsackie A6 may be more difficult to differentiate from varicella, as both conditions cause systemic illness (see Chapter 134, Hand Foot Mouth Syndrome).

• Atypical and breakthrough VZV may present similarly to a wide variety of relatively common dermatologic conditions including as miliaria, insect bites, infestations, papular urticaria, guttate psoriasis, secondary syphilis, and contact dermatitis (see respective chapters.)

• VZV should also be considered on the differential diagnosis of acutely ill patients with skin findings (see Chapter 185, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis, and Chapter 187, Vasculitis, which includes Henoch–Schönlein purpura).

MANAGEMENT

FIRST LINE

• Antihistamines are helpful in the symptomatic treatment of pruritus.

• Acetaminophen should be used to treat fever in children, as aspirin use is associated with Reye syndrome in the setting of viral infections.⁵ SORⒶ

• Superinfection may be treated with topical or oral antibiotics.

• Treatment with acyclovir 20 mg/kg PO 4 times daily (max 3200 mg/day) started within the first 24 hours and continued for 5 days should be considered for children at risk for moderate to severe illness; this includes children over the age of 12, those with chronic cutaneous and pulmonary disorders, and patients receiving chronic salicylates or steroids.

• Acyclovir 800 mg PO 4–5 times daily for 5–7 days, ideally started within the first 24 hours of the rash, should be considered for all adults, including both immunocompetent and immunocompromised patients. SORⒶ

SECOND LINE

• Although acyclovir is approved for treatment of varicella in healthy children, the Committee on Infectious Disease of the American Academy of Pediatrics does not consider the routine administration of acyclovir to all healthy children with varicella to be justified. SORⒸ

• Valacyclovir 20 mg/kg PO every 8 hours for 5 days and famciclovir 250 mg PO every 8 hours for 7 to 10 days are considered alternative agents to the more frequently dosed oral acyclovir in adults.

• Early treatment with intravenous acyclovir 10 mg/kg IV every 8 hours given for 7 to 10 days may be effective for treatment of varicella complications, including hepatitis and pneumonia, and may also be useful in the treatment of immunosuppressed patients. SORⒷ Ensure adequate hydration and monitor for adverse reactions.

• IV foscarnet at 90 mg/kg every 12 hours is indicated for acyclovir-resistant varicella in ill patients. Adequate hydration is encouraged.

• Pruritus can be treated with calamine lotion, pramoxine gel, or powdered oatmeal baths.

• Fingernails should be closely cropped to avoid significant excoriation and secondary bacterial infection.

POST EXPOSURE PROPHYLAXIS

• Varicella vaccine is recommended to healthy, non-pregnant persons without immunity who are exposed to VZV. The vaccine may prevent infection and/or substantially modify the risk of severe disease when given within 3–5 days. SORⒷ

• Even after 5 days, susceptible individuals should be vaccinated to protect against future exposures. This live vaccine should not be given to pregnant women or most immunocompromised individuals.

• Varicella zoster immune globulin (VariZIG) dosed by weight in recently exposed susceptible individuals (maximum efficacy within 96 hours) can attenuate the disease. Access to this product is limited in the United States and is primarily reserved for exposed individuals who are immunocompromised or pregnant, and for neonates and preterm infants.⁶

• Antivirals are not typically indicated for prophylaxis, but some experts recommend oral acyclovir to prevent secondary cases (which tend to be more severe) within a household.

PREVENTION

• All immunocompetent children younger than 13 years of age should receive 2 doses of varicella-containing vaccine, with the first dose administered at 12 to 15 months of age and the second dose at 4 to 6 years of age (i.e., before first grade). SORⒶ The second dose can be administered at an earlier age, provided the interval between the first and second dose is at least 3 months.¹

• All adolescents and adults without evidence of immunity to varicella should receive 2 doses of varicella separated by 4–6 weeks.¹ Particular effort should be expended to identify and immunize susceptible non-pregnant women of childbearing age and family members of immunocompromised individuals.

• Varicella vaccine is contraindicated in individuals allergic to gelatin or neomycin, in immunosuppressed individuals, and in pregnancy.

• Varicella vaccine is available alone (Varivax, Merck) and in combination with live-attenuated measles-mumps-rubella (ProQuad, Merck). The combination is only licensed for use in children aged 12 months through 12 years. When both vaccines are indicated, the combined vaccine is preferred.¹

• Both vaccines contain the live attenuated Oka strain of VZV and produce an equivalent antibody response.¹

FOLLOW-UP

• Follow-up is unnecessary for immunocompetent children and adults without complications.

PATIENT EDUCATION

• Avoid scratching the blisters and keep fingernails short. Scratching may lead to superinfection.

• Calamine lotion, pramoxine gel, and oatmeal (Aveeno) baths may help relieve itching.

• Do not use aspirin or aspirin-containing products to relieve fever. The use of aspirin is associated with development of Reye syndrome, which may cause death.

• Emergency precautions should be given to all persons, especially those at high risk of complications.

• Isolate infected patients until all lesions are fully crusted and advise prophylaxis for all susceptible exposed persons.

REFERENCES

PATIENT STORY

A 75-year-old woman presented with a severely painful case of herpes zoster in a lower abdominal/lower extremity distribution. Groups of vesicles were becoming bullae and leading to erosions (Figure 130-1). The woman was treated with oral analgesics and an oral antiviral medication. Her primary care physician treated her zoster aggressively in an attempt to prevent postherpetic neuralgia (PHN).

INTRODUCTION

Herpes zoster (shingles) is a syndrome characterized by a painful, usually unilateral vesicular eruption that develops in a restricted dermatomal distribution (Figures 130-1 and 130-2).^1-3

SYNONYMS

Shingles.

EPIDEMIOLOGY

• According to the Centers for Disease Control and Prevention (CDC), 32% of persons in the United States will experience zoster during their lifetimes, accounting for about 1 million cases annually.⁴ Older age groups account for the highest incidence of zoster. Approximately 4% of patients will experience a second episode of herpes zoster.⁵

• More zoster cases have been observed among women, even when controlling for age.⁶

• Herpes zoster occurs more frequently and more severely in immunosuppressed patients, including transplantation patients.

ETIOLOGY AND PATHOPHYSIOLOGY

• After primary infection with either chickenpox or vaccine-type varicella-zoster virus (VZV), a latent infection is established in the sensory dorsal root ganglia. Reactivation of this latent VZV infection results in herpes zoster (shingles).

• Both sensory ganglia neurons and satellite cells surrounding the neurons serve as sites of VZV latent infection. During latency, the virus expresses only a small number of viral proteins.

• How the virus emerges from latency is not clearly understood. Once reactivated, virus spreads to other cells within the ganglion. The dermatomal distribution of the rash corresponds to the sensory fields of the infected neurons within the specific ganglion.³

• Loss of VZV-specific cell-mediated immune response is responsible for reactivation.³

• The pain associated with zoster infections and PHN is thought to result from injury to the peripheral nerves and altered central nervous system processing.

• The most common complications are PHN and bacterial superinfection that can delay healing and cause scarring of the zoster lesions.

• Approximately 19% of patients develop complications that may include⁷:

  • PHN—The most common complication is seen in 10% at 90 days⁷ (see below).

  • Ocular complications, including uveitis and keratitis (seen in 4%)⁷ (see Chapter 131, Zoster Ophthalmicus).

  • Bell palsy and other motor nerve plastic (seen in 3%).⁷

  • Bacterial skin infection (seen in 2%).⁷

  • Meningitis caused by central extension of the infection.

  • Herpes zoster oticus (Ramsay Hunt syndrome) (Figure 130-3) includes the triad of ipsilateral facial paralysis, ear pain, and vesicles in the auditory canal and auricle.⁸ Disturbances in taste perception, hearing (tinnitus, hyperacusis), lacrimation, and vestibular function (vertigo) may occur.

  • Other rare complications may include acute retinal necrosis, transverse myelitis, encephalitis, leukoencephalitis, contralateral thrombotic stroke syndrome, and granulomatous vasculitis.⁹

• Immunosuppressed patients are at increased risk for complications, including severe complications such as broader dermatomal involvement, disseminated infection, visceral involvement, pneumonitis, and/or meningoencephalitis.

• PHN is the persistence of pain, numbness, and/or dysesthesias precipitated by movement or in response to stimuli in the affected dermatome for more than 1 month after the onset of zoster. The incidence of PHN in the general population is 1.38 per 1000 person-years, and it occurs more commonly in individuals older than age 60 years and in immunosuppressed individuals.³

• In a large study, rates of zoster-associated pain (PHN) persisting at least 90 days were:

  • 10% overall; 12% in women and 7% in men.

  • Ages 22 to 59 years—5% overall; 6% in women and 5% in men.

  • Ages 60 to 69 years—10% overall; 14% in women and 5% in men.

  • Ages 70 to 79 years—17% overall; 18% in women and 15% in men.

  • Age 80 years and older—20% overall; 23% in women and 13% in men.⁷

RISK FACTORS

ZOSTER

• Older age³.

• Underlying malignancy.

• Disorders of cell-mediated immunity.

• Chronic lung or kidney disease.

• Autoimmune disease.

• Female sex.¹⁰

PHN

• Age older than 60 years.

• Negative vaccine status.

DIAGNOSIS

CLINICAL FEATURES

• A deep burning pain and sometimes redness in a dermatomal pattern is the most common first symptom and can precede the rash by days to weeks (Figure 130-4). A prodrome of fever, dysesthesias, malaise, and headache leads in several days to a dermatomal vesicular eruption.

• The rash may start as erythematous papules but usually quickly becomes grouped vesicles or bullae which evolve into pustular or hemorrhagic lesions within 3 to 4 days (Figures 130-1, 130-2, 130-3, 130-4, 130-5, 130-6). The lesions typically crust in approximately a week, with complete resolution within 3 to 4 weeks.⁵

TYPICAL DISTRIBUTION

• The rash is generally limited to one dermatome in immunocompetent patients, but sometimes affects neighboring dermatomes. Rarely, a few scattered vesicles are located away from the involved dermatome as a result of release of VZV from the infected ganglion into the bloodstream.³ If there are more than 20 lesions distributed outside the dermatome affected, the patient has disseminated zoster. The thoracic and lumbar dermatomes are the most commonly involved. Occasionally zoster will be seen on the extremities (see Figure 130-5).

• Approximately 80% of patients have significant systemic symptoms such as headache, fever, malaise, or fatigue.¹¹

• Rarely, the dermatomal pain may be related to herpes zoster but without the typical rash, which is known as zoster sine herpete.¹²

LABORATORY TESTING

• Meningitis associated with VZV infection can be diagnosed by cerebrospinal fluid showing pleocytosis.

DIFFERENTIAL DIAGNOSIS

• Pemphigus and other bullous diseases present with blisters, but not the classic dermatomal distribution (see Chapters 191, Overview of Bullous Disease and 193, Pemphigus).

• Molluscum contagiosum presents with white or yellow flat-topped papules with central umbilication caused by a pox virus. The lesions are more firm and, unless irritated, do not have a red base as seen with zoster (see Chapter 136, Molluscum Contagiosum).

• Scabies may present as a pustular rash that is not confined to dermatomes and usually has characteristic lesions in the webs of the fingers (see Chapter 149, Scabies).

• Insect bites are often suspected by history and can occur over the entire body.

• Folliculitis presents with characteristic pustules arising from hair shafts (see Chapter 123, Folliculitis).

• Zoster mimics coronary artery disease when it presents with chest pain before the vesicles are visible.

• Herpes simplex infection presents with similar lesions but is usually restricted to the perioral region, genital area, buttocks, and fingers (see Chapter 135, Herpes Simplex).

MANAGEMENT

NONPHARMACOLOGIC

• Calamine lotion and topically administered lidocaine may be used to reduce pain and itching. SORⒸ

MEDICATIONS

FIRST LINE

• The objectives of treatment of herpes zoster include (a) hastening the resolution of the acute viral infection, (b) treatment of the associated pain, and (c) prevention of PHN.

• Antiviral agents used in the treatment of herpes zoster include acyclovir (Zovirax), famciclovir (Famvir), and valacyclovir (Valtrex), all started within 72 hours of the onset of the rash (Table 130-1).¹³ SORⒶ

SECOND LINE

• Adding corticosteroids to acyclovir therapy may accelerate times to crusting and healing, return to uninterrupted sleep, resumption of full activity, and discontinuation of analgesic. Data are lacking for combining corticosteroids with other antivirals.

• Pain can be managed with nonprescription analgesics or narcotics. Pain should be treated aggressively. This may actually prevent or lessen the severity of PHN. Narcotic analgesics with hydrocodone are appropriate when needed. SORⒸ

• Treatment of herpes zoster with steroids does not reduce the prevalence of PHN.

• Treatment of PHN includes tricyclic antidepressants, gabapentin (Neurontin), pregabalin (Lyrica), glucocorticoids, and/or opioid analgesics (Table 130-2).

• Treatment of herpes zoster early with valacyclovir, famciclovir, or amitriptyline does reduce pain of PHN at 6 months.

PREVENTION

• During its October 2017 meeting, the Advisory Committee on Immunization Practices (ACIP) voted to recommend preferential use of the herpes zoster subunit (HZ/su; Shingrix) vaccine over the previously recommended herpes zoster live (Zostavax) vaccine for adults 50 and older, even if they previously received the Zostavax immunization. The HZ/su is a non-live, recombinant subunit glycoprotein vaccine given intramuscularly in a series of two 0.5-mL doses, with the second dose given 2 to 6 months after the first. Clinical trials on the HZ/su vaccine showed it was more effective and provided longer-lasting protection than the one-dose Zostavax vaccine.¹⁴

• Use of varicella (chickenpox) vaccine has not led to an increase in vaccine-associated herpes zoster in immunized patients or in the general population, and has led to an overall decrease in herpes zoster.⁸

PROGNOSIS

• Recurrence of clinical zoster is uncommon in immunocompetent patients.¹⁵ Recurrences are much more common in the immunocompromised patients.¹⁶

FOLLOW-UP

• Follow-up is based on the severity of the case and the immune status of the patient.

PATIENT EDUCATION

• Herpes zoster in an immunocompetent host is contagious from contact with open lesions and possible airborne particles.¹⁷ The lesions are no longer infectious once they become dry and crust over.

• Patients with disseminated zoster or with zoster and who are immunocompromised should be isolated from nonimmune individuals.

• Individuals who have not had varicella and are exposed to a patient with herpes zoster are only at risk of developing primary varicella and not herpes zoster.

REFERENCES

PATIENT STORY

A 44-year-old HIV-positive Hispanic man presented with painful herpes zoster of his right forehead (Figure 131-1). He was particularly worried because his right eye was red, painful, and very sensitive to light (Figure 131-2). On physical examination, there was significant conjunctival injection, corneal punctate epithelial erosions, and clouding, and a small layer of blood in the anterior chamber (hyphema). The pupil was somewhat irregular. Along with the hyphema and ciliary flush, this indicated an anterior uveitis. The patient had a unilateral ptosis on the right side with limitations in elevation, depression, and adduction of the eye secondary to cranial nerve III palsy from the zoster. The patient was immediately referred to ophthalmology and the anterior uveitis, corneal involvement, and cranial nerve III palsy were confirmed. The ophthalmologist started the patient on topical ophthalmic preparations of erythromycin, moxifloxacin, prednisolone, and atropine. Oral acyclovir was also prescribed. Unfortunately, the patient did not return for follow-up until 6 months later, when he returned to the ophthalmologist with significant corneal scarring (Figure 131-3). The patient is currently on a waiting list for a corneal transplantation.

INTRODUCTION

Herpes zoster is a common infection caused by varicella-zoster virus, the same virus that causes chickenpox. Reactivation of the latent virus in neurosensory ganglia produces the characteristic manifestations of herpes zoster (shingles). Herpes zoster outbreaks may be precipitated by aging, poor nutrition, immunocompromised status, physical or emotional stress, and excessive fatigue. Although zoster most commonly involves the thoracic and lumbar dermatomes, reactivation of the latent virus in the trigeminal ganglia may result in herpes zoster ophthalmicus (HZO) (Figures 131-1, 131-2, 131-3, 131-4, 131-5, 131-6, 131-7).

SYNONYMS

Ocular herpes zoster.

EPIDEMIOLOGY

• Incidence rates of HZO complicating herpes zoster range from 8% to 56%.¹

• In the United States, there are an estimated incidence of 3.2 cases per 1000 person-years and a male-to-female ratio of 4:1. The peak incidence is between the ages of 50 and 79 years, with the highest rates in patients over age 80 years.²

• Ocular involvement is not correlated with age, gender, or severity of disease.

ETIOLOGY AND PATHOPHYSIOLOGY

• Serious sequelae may occur, including chronic ocular inflammation, vision loss, and disabling pain. Early diagnosis is important to prevent progressive corneal involvement and potential loss of vision.³

• Because the nasociliary branch of the first (ophthalmic) division of the trigeminal (fifth cranial) nerve innervates the globe (see Figure 131-7), the most serious ocular involvement develops if this branch is involved.

• Classically, involvement of the side of the tip of the nose (Hutchinson sign) has been thought to be a clinical predictor of ocular involvement via the external nasal nerve (see Figures 131-5 and 131-6). The Hutchinson sign is a powerful predictor of ocular inflammation and corneal denervation with relative risks of 3.35 and 4.02, respectively. In one study, the manifestation of herpes zoster skin lesions at the dermatomes of both nasociliary branches (at the tip, the side, and the root of the nose) was invariably associated with the development of ocular inflammation.⁴

• Epithelial keratitis is the earliest potential corneal finding (see Figure 131-2). On slit-lamp examination, it appears as multiple, focal, swollen spots on the cornea that stain with fluorescein dye. They may either resolve or progress to dendrite formation. Herpes zoster virus dendrites form branching or frondlike patterns that have tapered ends and stain with fluorescein dye. These lesions can lead to anterior stromal corneal infiltrates.

• Stromal keratitis occurs in 25% to 30% of patients with HZO and is characterized by multiple fine granular infiltrates in the anterior corneal stroma. The infiltrates probably arise from antigen–antibody reaction and may be prolonged and recurrent.⁵

• Anterior uveitis evolves to inflammation of the iris and ciliary body and occurs frequently with HZO (see Figure 131-2). The inflammation is usually mild, but may cause a mild intraocular pressure elevation. The course of disease may be prolonged, especially without timely treatment, and may lead to glaucoma and cataract formation.

• Herpes zoster virus is the most common cause of acute retinal necrosis. Symptoms include blurred vision and/or pain in one or both eyes, and signs include peripheral patches of retinal necrosis that rapidly coalesce, occlusive vasculitis, and vitreous inflammation. It commonly causes retinal detachment. Bilateral involvement is observed in one-third of patients, but may be as high as 70% in patients with untreated disease. Treatment includes long courses of oral and intravenous acyclovir (Zovirax), and corticosteroids.⁶

• Varicella-zoster virus is a member of the same family (Herpesviridae) as herpes simplex virus, Epstein-Barr virus, and cytomegalovirus.

• The virus damages the eye and surrounding structures by neural and secondary perineural inflammation of the sensory nerves. This often results in corneal anesthesia.

• Conjunctivitis, usually with Staphylococcus aureus, is a common complication of HZO.

RISK FACTORS

• Immunocompromised persons, especially those with human immunodeficiency virus infection, have a much higher risk of developing zoster complications, including HZO.

DIAGNOSIS

CLINICAL FEATURES

• The syndrome usually begins with a prodrome of low-grade fever, headache, and malaise that may start up to 1 week before the rash appears.

• Unilateral pain or hypesthesia in the affected eye, forehead, top of the head, and/or nose may precede or follow the prodrome. The rash starts with erythematous macules along the involved dermatome, then rapidly progresses over several days to papules, vesicles, and pustules (see Figures 131-4, 131-5, 131-6). The lesions rupture and typically crust over, requiring several weeks to heal completely.

• With the onset of a vesicular rash along the trigeminal dermatome, hyperemic conjunctivitis, episcleritis, and lid droop (ptosis) can occur (see Figure 131-6).

• Approximately two-thirds of patients with HZO develop corneal involvement (keratitis).¹ The epithelial keratitis may feature punctate or dendritiform lesions (see Figure 131-2). Complications of corneal involvement can lead to corneal scarring (see Figure 131-3).⁷

• Iritis (anterior uveitis) occurs in approximately 40% of patients and can be associated with hyphema and an irregular pupil (see Figure 131-2).¹

• Rarely, zoster can be associated with cranial nerve palsies.

TYPICAL DISTRIBUTION

• The frontal branch of the first division of the trigeminal nerve (which includes the supraorbital, supratrochlear, and external nasal branch of the anterior ethmoidal nerve) is most frequently involved, and 50% to 72% of patients experience direct eye involvement (see Figure 131-7).¹

• Although HZO most often produces a classic dermatomal rash in the trigeminal distribution, a minority of patients may have only cornea findings.

DIFFERENTIAL DIAGNOSIS

• Bacterial or viral conjunctivitis presents as eye pain and foreign body sensation associated with discharge but no rash (see Chapter 18, Conjunctivitis).

• Trigeminal neuralgia presents with facial pain but without the rash or conjunctival findings.

• Glaucoma presents as inflammation, pain, and injection, but without the rash or conjunctival findings (see Chapter 21, Glaucoma).

• Traumatic abrasions usually present with a history of trauma and corneal findings but no other zoster findings (see Chapter 17, Corneal Foreign Body and Corneal Abrasion).

• Pemphigus and other bullous diseases present with blisters, but not in a dermatomal distribution (see Chapter 191, Overview of Bullous Disease).

MANAGEMENT

MEDICATIONS

• The standard treatment for HZO is to initiate antiviral therapy with acyclovir (800 mg, 5 times daily for 7 to 10 days), valacyclovir (1000 mg 3 times daily for 7 or 14 days), or famciclovir (500 mg orally 3 times a day for 7 days), as soon as possible so as to decrease the incidence of dendritic and stromal keratitis as well as anterior uveitis.⁸ SORⒶ Therapy should be initiated within 72 hours of presentation to maximize the potential benefits.

• Oral acyclovir, valacyclovir, and famciclovir in patients with ophthalmic involvement have comparable outcomes. Treatment is most commonly oral acyclovir, but intravenous acyclovir (10 mg/kg 3 times daily for 7 days) may be considered in immunocompromised patients or the rare patient who is extremely ill.⁹ SORⒶ

• Topical steroid ophthalmic drops are applied to the involved eye, after examination by the ophthalmologist, to reduce the inflammatory response and control immune keratitis and iritis.^1,3 SORⒷ

• The ophthalmologist may prescribe a topical cycloplegic (such as atropine) to treat the ciliary muscle spasm that is painful in iritis. SORⒸ

• Topical ophthalmic antibiotics may also be prescribed to prevent secondary infection of the eye. SORⒸ

• As in all cases of zoster, pain should be treated effectively with oral analgesics and other appropriate medications. Early and effective treatment of pain may help to prevent postherpetic neuralgia (see Chapter 130, Zoster).

• Topical anesthetics should never be used with ocular involvement because of their corneal toxicity. SORⒷ

• Secondary infection, usually S. aureus, may develop and should be treated with broad-spectrum topical and/or systemic antibiotics.

REFERRAL OR HOSPITALIZATION

• Referral to an ophthalmologist urgently should be initiated when eye involvement is seen or suspected.

• Hospital admission should be considered for patients with loss of vision, severe symptoms, immunosuppression, or involvement of multiple dermatomes, or for those with significant facial bacterial superinfection.

PREVENTION

• The herpes zoster vaccine reduces the incidence of herpes zoster by 51% compared with placebo.¹⁰ In those who do develop zoster, the duration of pain and discomfort is shorter and the incidence of postherpetic neuralgia (PHN) is greatly reduced. It reduces the incidence of PHN from 1.38 to 0.46 per 1000 person-years.¹⁰

PROGNOSIS

• Approximately 50% of patients with HZO develop complications. Systemic antiviral therapy can lower the emergence of complications.^11,12

• HZO can become chronic or relapsing. The overall 1-, 3-, and 5-year recurrence rates for either recurrent eye disease or rash is 8%, 17%, and 25%, respectively. Ocular hypertension and uveitis are associated with an increased risk of recurrent and chronic HZO.¹³

FOLLOW-UP

• Early diagnosis is critical to prevent progressive corneal involvement and potential loss of vision. Patients with herpes zoster should be informed that they should present for medical care with any zoster involving the first (ophthalmic) division of the trigeminal nerve or the eye itself.

PATIENT EDUCATION

• Zoster of the eye is a very serious vision-threatening illness that requires strict adherence to medical therapy and close follow-up.

• Viral transmission to nonimmune individuals from patients with herpes zoster can occur, but it is less frequent than with chickenpox. Virus can be transmitted through contact with secretions.

REFERENCES

PATIENT STORY

An 18-month-old boy, who is visiting family in San Antonio with his parents from Central America, presents with a 3-day history of fever, malaise, conjunctivitis, coryza, and cough. He had been exposed to a child with similar symptoms approximately 2 weeks prior. A day before, he developed a maculopapular rash that blanches under pressure (Figures 132-1 and 132-2). His shot records are unavailable, but his mother states that his last vaccine was before age 1 year. He is diagnosed with measles and supportive care is provided.

INTRODUCTION

Measles is a highly communicable, acute, viral illness that is still one the most serious infectious diseases in human history. Until the introduction of the measles vaccination, it was responsible for millions of deaths worldwide annually. Although the epidemiology of this disease makes eradication a possibility, the ease of transmission and the low percentage of nonimmunized population that is required for disease survival have made eradication of measles extremely difficult.

EPIDEMIOLOGY

• A major outbreak in the United States from 1989 to 1991 prompted changes in immunization policies which led to the initiation of two measles, mumps, rubella (MMR) vaccines administered prior to kindergarten.

• This change in practice led to all-time lows in cases reported, and in 2000 the CDC declared that the United States had achieved measles elimination (defined as interruption of year-round endemic measles transmission).¹

• Despite the declaration of elimination, measles cases continue to be reported in the United States, with most cases being linked to incomplete vaccinations. In 2015, an outbreak was noted when 110 patients in California were diagnosed with measles in association with a theme park. Of those patients, 45% were unvaccinated, 43% had unknown or undocumented vaccination status, and 5% had only one dose of measles-containing vaccination.² Among 37 vaccine-eligible patients, 28 (76%) were intentionally unvaccinated because of personal beliefs.²

• The worldwide incidence of measles was reduced from 280,525 cases in 2014 to 195,762 in 2015 according to WHO Global and Regional Immunization Profile. In 2015, approximately 85% of the world's target population received one dose of measles vaccine, up from 84% in 2014, and 61% received 2 doses, up from 58% in 2014.³

ETIOLOGY AND PATHOPHYSIOLOGY

• Measles is caused by the measles virus, a member of the family Paramyxoviridae, genus Morbillivirus (hence the name morbilliform rash).

• It is highly contagious, is transmitted by airborne droplets, and commonly causes outbreaks.

• Classic measles infection starts with the incubation phase, which is usually asymptomatic and lasts for 10 to 14 days. It starts after entry of the virus into the respiratory mucosa with local viral replication. The infection then spreads to regional lymphatic tissues, and then throughout the body through the bloodstream.

• The prodrome phase starts with the appearance of systemic symptoms including fever, malaise, anorexia, conjunctivitis, coryza, and cough (Figure 132-3). The respiratory symptoms are caused by mucosal inflammation from viral infection of epithelial cells. Patients may develop Koplik spots, which are small whitish, grayish, or bluish papules with erythematous bases that develop on the buccal mucosa, usually near the molar teeth (Figure 132-4). The prodrome usually lasts for 2 to 3 days.

• The classic measles rash (Figures 132-1, 132-2, and 132-5) is maculopapular and blanches under pressure. Clinical improvement in symptoms typically ensues within 2 days. Three to 4 days after the rash first appears, it begins to fade to a brownish color, which is followed by fine flaking. The cough may persist for up to 2 weeks.

• Fever persisting beyond the third day of rash suggests a measles-associated complication.

• Immunity after measles infection is thought to be lifelong in most cases. Measles reinfection occasionally occurs, but it is extremely rare.

• Atypical measles is a measles variant that occurs in previously vaccinated persons. Patients develop high fever and headache 7 to 14 days after exposure and often present with a dry cough and pleuritic chest pain. Two to 3 days later, a rash develops that spreads from the extremities to the trunk. The rash may be vesicular, petechial, purpuric, or urticarial. Patients may develop respiratory distress, peripheral edema, hepatosplenomegaly, paresthesias, or hyperesthesia.

• The measles virus can cause a variety of clinical syndromes, including the classic childhood illness and a less intense form in persons with suboptimal levels of antimeasles antibodies.

• Measles virus infection can also result in more severe illness, including lymphadenopathy, splenomegaly, laryngotracheobronchitis (croup), giant cell pneumonia, and measles inclusion body encephalitis in immunocompromised patients.⁴ This form occurs in the very old and young, in those with vitamin A deficiency, and in pregnant women.

• Postinfection neurologic syndromes can occur. Postinfectious encephalomyelitis is a demyelinating disease that presents during the recovery phase and is thought to be caused by a postinfectious autoimmune response.⁵ The major manifestations include fever, headache, neck stiffness, ataxia, mental status changes, and seizures. Cerebrospinal fluid (CSF) analysis demonstrates lymphocytosis and elevated proteins. Postinfectious encephalomyelitis has a 10% to 20% mortality rate, and residual neurologic abnormalities are common.⁵

• Subacute sclerosing panencephalitis (SSPE) is a progressive, fatal, neurologic degenerative disease that may represent a persistent infection of the central nervous system with a variant of the virus. It usually occurs in patients younger than 20 years of age and 7 to 10 years after natural measles.⁶ Patients develop neurologic symptoms, myoclonus, dementia, and eventually flaccidity or decorticate rigidity.

• Measles in pregnancy is a rare entity in areas that practice vaccination. Premature births may be more common in gravid women with measles, but there is no clear evidence of teratogenicity.⁷

RISK FACTORS

For developing measles:

• Failure to receive immunization.

• Failure to receive second immunization dose.

• Travel to endemic areas.

• Exposure to travelers from endemic areas.

For developing severe measles or for developing complications:

• Immunodeficiency.

• Malnutrition.

• Pregnancy.

• Vitamin A deficiency.

• Age younger than 5 years or older than 20 years.

DIAGNOSIS

Measles is a distinct disease characterized by fever, malaise, conjunctivitis, coryza, cough, rash, and Koplik spots.

CLINICAL FEATURES

Koplik spots appear during the prodrome phase and are pathognomonic for measles infection; they occur approximately 48 hours before the characteristic measles exanthem. The classic blanching rash is usually adequate to make a tentative diagnosis. The most rapid and accurate test to confirm acute measles is a blood test for measles-specific immunoglobulin (Ig) M antibodies. By waiting until the third day of the rash, a false-negative IgM result can be avoided.⁸

TYPICAL DISTRIBUTION

The rash begins on the face and spreads centrifugally to involve the neck, trunk, and, finally, the extremities. The lesions may become confluent, especially on the face. This cranial-to-caudal rash progression is characteristic of measles.

DIFFERENTIAL DIAGNOSIS

• Upper respiratory tract infections—The prodrome stage of measles can be confused with an upper respiratory infection (URI), except that significant fever is typically present with measles infection.

• Fordyce spots—Tiny yellow-white granules on the buccal or lip mucosa caused by benign ectopic sebaceous glands that may be mistaken for Koplik spots. Fordyce spots do not have an erythematous base.

• Alternative diagnoses that may be confused with the measles rash include Rocky Mountain spotted fever, infectious mononucleosis, scarlet fever, Kawasaki disease, toxic shock syndrome, dengue fever, and simple drug eruption (see Chapter 212, Cutaneous Drug Reactions).

• Measles can usually be distinguished clinically from rubella, erythema infectiosum (parvovirus B19 infection), roseola, and enteroviral infection by the intensity of the measles rash, its subsequent brownish coloration, and the disease course.

MANAGEMENT

NONPHARMACOLOGIC

• The treatment of measles is mostly supportive. Suspected cases of measles should be immediately reported to the local or state department of health.

MEDICATIONS

• Measures to control spread of infection should not be delayed for laboratory confirmation. Vaccine should be promptly administered to all susceptible persons, or they should be removed from the outbreak setting for a minimum of 3 weeks. SORⒸ

• Giving serum immune globulin 0.25 mL/kg of body weight to a maximum dose of 15 mL to a susceptible person within 6 days of exposure to measles can prevent or modify disease. This is especially important in patients in whom the risk of complications of measles is higher, such as pregnant women, children younger than 1 year of age, and immunocompromised patients. SORⒸ

• Vitamin A reduces morbidity and mortality and is recommended by the World Health Organization (WHO) for children in areas where vitamin A deficiency is prevalent or where the mortality from measles exceeds 1%.⁷ SORⒷ

REFERRAL OR HOSPITALIZATION

Consider hospitalization in the following scenarios:

• Difficulty breathing or noisy breathing—Bronchopneumonia occurs in 5% to 10% of patients.

• Changes in behavior, confusion—May be a harbinger of acute disseminated encephalomyelitis.

• There is dehydration, which can be the result of diarrhea, vomiting, and poor oral intake.

Refer to ophthalmology if there are changes in vision, as measles keratitis can lead to permanent scarring and blindness.

PREVENTION

• Measures to control spread of infection should not be delayed for laboratory confirmation. Vaccine should be promptly administered to all susceptible persons, or they should be removed from the outbreak setting for a minimum of 3 weeks.

• Initial and booster immunization.

• Avoidance of endemic areas without being fully immunized.

• Adequate nutrition and handwashing.

PROGNOSIS

• The disease is typically self-limited. Measles typically lasts approximately 10 to 14 days from the beginning of the prodrome to the fading of the eruption.

• Approximately 30% of measles cases have one or more complications. Complications of measles are more common among patients younger than 5 years of age and adults 20 years of age and older. Centers for Disease Control and Prevention (CDC)–reported measles complications include⁹:

  • Diarrhea—8%.

  • Otitis media—7%.

  • Pneumonia—6%.

  • Encephalitis—0.1%.

  • Seizures—0.6% to 0.7%.

  • Death—0.2%.

FOLLOW-UP

• Have patients watched for changes that indicate more severe disease or complications and follow up if these occur.

• Make sure return appointments for full vaccination are scheduled.

PATIENT EDUCATION

• Drink plenty of fluids to avoid dehydration. Use antipyretics/analgesics to control fever and discomfort. Avoid aspirin to prevent Reye syndrome.

• Avoid exposure to other individuals, particularly unimmunized children and adults, pregnant women, and immunocompromised persons, until at least 4 days after rash onset.

REFERENCES

PATIENT STORY

A 2-year-old boy presents with mild flu-like symptoms and a rash. He had erythematous malar rash and a "lace-like" erythematous rash on the trunk and extremities (Figures 133-1 and 133-2). The "slapped cheek" appearance made the diagnosis easy for fifth disease. The parents were reassured that this would go away on its own. The child returned to daycare the next day.

INTRODUCTION

Fifth disease is also commonly referred to as erythema infectiosum or slapped cheek syndrome. The name derives from the fact that it represents the fifth of the six common childhood viral exanthems described. Transmission occurs through respiratory secretions, possibly through fomites, and parenterally via vertical transmission from mother to fetus and by transfusion of blood or blood products.

SYNONYMS

Erythema infectiosum, parvovirus B19 infections, slapped cheek syndrome.

EPIDEMIOLOGY

• Fifth disease is common throughout the world, with antiparvovirus B19 immunoglobulin (Ig) G reported in approximately 50% to 70% of the United States, Asia, or Europe depending on the geographic location.¹ The only known host for B19 is humans.²

• Most individuals become infected during their school years, with the peak incident rates occurring in 6- to 14-year-old children and the age-specific risk being highest in children 7 to 9 years old.^1,3

• Fifth disease is very contagious via the respiratory route and occurs more frequently between late winter and early summer, specifically between December and July, with April accounting for 16% of infections.³ Up to 50% of the population is seropositive for antiparvovirus B19 IgG by age 18 years.³ In some communities, there are cycles of local epidemics every 4 to 7 years lasting up to 6 months at a time.^1,4,5

• Most cases of infection in pregnant women seem to occur in late spring and summer.⁶ Thirty percent to 40% of pregnant women lack measurable IgG to the infecting agent and are, therefore, presumed to be susceptible to infection.⁷ About 1% to 16% of susceptible pregnant women will develop serologic evidence in pregnancy.^6,8 The risk of infection increases with increased exposure, such as working in nursery schools, after-school clubs, or daycare centers; having serious medical conditions; having stressful jobs; or having a first child or more than three children.⁶ Infection during pregnancy can in some cases lead to fetal death, although most fetuses infected with parvovirus have spontaneous resolution with no adverse long-term developmental sequelae.^6,8 SORⒷ

ETIOLOGY AND PATHOPHYSIOLOGY

• Fifth disease is a mild viral febrile illness with an associated rash caused by parvovirus B19 (Figure 133-3).

• Most persons with parvovirus B19 infection never develop the clinical picture of fifth disease.

• Parvovirus B19 infects rapidly dividing cells and is cytotoxic for erythroid progenitor cells.

• After initial infection, a viremia occurs with an associated precipitous drop in the reticulocyte count and anemia. The anemia is rarely clinically apparent in healthy patients, but can cause serious anemia if the red blood cell count is already low. Patients with a chronic anemia such as sickle cell or thalassemia may experience a transient aplastic crisis.¹

• Vertical transmission can result in congenital infection if a woman becomes infected during her pregnancy, with the transmission rate being 17% to 33%.⁶ Transplacental transmission occurs in as many as 33% of cases, with the highest risk of fetal infection occurring between the 9th and 20th weeks of gestation and within 2 to 4 weeks of maternal infection.⁸ The risk of a fetal loss (loss rate of 13%) or hydrops fetalis is greatest (loss rate of 4.7%) when the infection occurs within the first 20–25 weeks of gestation, compared to 0.5% and 2.3% after 20 weeks of gestation, respectively.⁶

RISK FACTORS

• Exposure to infected children.

• Reception of blood products.

DIAGNOSIS

• Diagnosis is typically made based on the patient's clinical features.

• The diagnosis of parvovirus B19 infection can also be made by IgG and IgM antibody testing, although polymerase chain reaction assays may also be helpful in certain situations. Nevertheless, it is recommended that serologic testing be reserved for pregnant women or patients with chronic hemolytic conditions or severe or persistent arthropathy.⁹

• The diagnosis of fetal parvovirus B19 infection relies primarily on PCR on amniotic fluid or fetal blood for B19 IgM.

CLINICAL FEATURES

• Fifth disease is usually a biphasic illness, starting with upper respiratory tract symptoms that may include headache, fever, sore throat, pruritus, coryza, abdominal pain, diarrhea, and/or arthralgias. These constitutional symptoms coincide with onset of viremia, and they usually resolve for about a week before the next stage begins.

• The second stage is characterized by a classic erythematous malar rash with relative circumoral pallor or "slapped cheek" appearance in children (Figures 133-1 and 133-4) followed by a "lace-like" erythematous rash on the trunk and extremities (Figures 133-2 and 133-5). Arthropathy affecting the hands, wrists, knees, and ankles may precede the development of a rash in adults. The course is usually self-limited.

TYPICAL DISTRIBUTION

• The rash starts with the classic slapped cheek appearance (see Figures 133-1 and 133-4). Then an erythematous macular rash occurs on the extremities. After several days, the extremities rash fades into a lacy pattern (see Figures 133-2 and 133-5). The lacy rash/exanthem may wax and wane for up to 3 weeks, with flaring triggered by exercise, sun exposure, bathing in hot water, or stress.⁹

LABORATORY TESTING

• Laboratory studies are not usually needed, as the diagnosis can be made by history and physical exam. Serum B19-specific IgM may be ordered in pregnant women exposed to fifth disease. Serum B19-specific IgM can usually be detected 10 days after infection and can persist for 3 months, while serum B19-specific IgG is produced 2 weeks after inoculation and presumably lasts for life.⁹ After 3 weeks, infection is also indicated by a fourfold or greater rise in serum B19-specific IgG antibody titers.

• Patients with symptoms of anemia, a history of increased red blood cell (RBC) destruction (e.g., sickle cell disease, hereditary spherocytosis), or with decreased RBC production (e.g., iron-deficiency anemia) should be tested for anemia.

• Pregnant women who are exposed to or have symptoms of parvovirus infection should have serologic testing to assess maternal immunity and determine whether evaluation for fetal hydrops is necessary.⁸ SORⒸ Prior to 20 weeks' gestation, women testing positive for acute infection (i.e., positive IgM and negative IgG) should be counseled concerning the low risk of fetal loss and congenital anomalies.

IMAGING

• If serologic testing in pregnant women is positive, some experts recommend that the patient should receive serial ultrasounds to look for signs of fetal hydrops.⁶ SORⒸ Intrauterine transfusion is currently the only effective treatment to alleviate fetal anemia.⁶

DIFFERENTIAL DIAGNOSIS

• Acute rheumatic fever presents as a fine papular (sandpaper) rash in association with a Streptococcus infection (see Chapter 36, Scarlet Fever and Strawberry Tongue).

• Allergic-hypersensitivity reactions (erythema multiforme, erythema nodosum, and cutaneous vasculitis) often involve the arms and legs but rarely affect the face (see Hypersensitivity Syndromes section).

• Lyme disease presents with an expanding rash with central clearing (see Chapter 227, Lyme Disease).

• Measles produces a blanching rash that begins on the face and spreads centrifugally to involve the neck, trunk, and finally the extremities. It tends to become more confluent instead of lacy with time (see Chapter 132, Measles).

MANAGEMENT

NONPHARMACOLOGIC

• Fifth disease is usually self-limited and requires no specific therapy.

• See "Patient Education" below for further information about parvovirus B19 infections in pregnancy.

MEDICATIONS

FIRST LINE

• Nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen therapy may alleviate fevers and arthralgias. SORⒸ

SECOND LINE

• If needed, a low-dose oral corticosteroid can be used without prolonging the viral illness.⁹ SORⒸ

• Rarely, an immunocompromised patient with hematologic complications may require intravenous immunoglobulin treatment or, in severe cases, bone marrow transplantation.⁹ SORⒸ

• Transient aplastic anemia is very rare but may be severe enough to require transfusion until the patient's red cell production recovers. SORⒸ

PREVENTION

• Because it is spread through respiratory secretions and possibly through fomites, good hand sanitation and infection-control techniques are recommended.

• Infected individuals should avoid excessive heat or sunlight, which can cause rash flare-ups.

• Excluding pregnant women from the workplace is unwarranted (SORⒸ, expert opinion), as infection rates are similar in a variety of maternal workplace environments (SORⒶ, prospective cohort studies).⁸

PROGNOSIS

• The rash of erythema infectiosum usually is self-limiting, but may last weeks to months with exacerbations.

• Aplastic anemia usually lasts up to 2 weeks but may become chronic. The onset of erythema infectiosum rash usually indicates that reticulocytosis has returned and aplastic crisis will not occur.

• Studies of the long-term effects on children of maternal parvovirus B19 infection suggest most infants do not have long-term adverse sequelae.⁵

PATIENT EDUCATION

• Explain to parents that the disease is usually self-limited. Normal activities may be pursued as tolerated with sun protection or avoidance.

• Children who present with the classic findings of fifth disease are past the infectious state and can attend school and daycare.

• During pregnancy, a woman who has an acute infection prior to 20 weeks' gestation should be counseled concerning the low risks of fetal loss and congenital anomalies. Beyond 20 weeks' gestation, some physicians recommend repeated ultrasounds to look for signs of fetal hydrops.

REFERENCES

PATIENT STORY

A 1-year-old boy presents to the clinic with lesions on his face, trunk and extremities (Figure 134-1). Two days ago, the patient had a fever of 103°F and was very irritable. No one in the family has this rash. On exam, a flat oval vesicle was seen on the hand following skin lines (Figure 134-2). The physician diagnosed hand, foot, and mouth disease. She suspected that it was caused by Coxsackievirus A6 because of the high fever and the wide distribution of lesions. The physician recommended fluid and antipyretics as needed, and the disease resolved without complications.

INTRODUCTION

Hand, foot, and mouth disease (HFMD) is a viral illness that may affect humans and some animals and has a distinct clinical presentation. The disease occurs worldwide and was typically caused by Coxsackievirus A16. Worldwide outbreaks with a more virulent Coxsackievirus A6 started as early as 2008.¹

EPIDEMIOLOGY

• In temperate climates, the peak incidence is in summer and early fall. Outbreaks and sporadic episodes have occurred during winter months.²

• Typical HFMD caused by Coxsackievirus A16 generally has a mild course. It mostly occurs in infants and children up to 8 years old.³

• Atypical HFMD caused by Coxsackievirus A6 (CVA6) has a more severe course and affects young children and adults.^1,2

• There is no racial or gender predilection.

ETIOLOGY AND PATHOPHYSIOLOGY

• HFMD is most commonly caused by members of the enterovirus genus, especially Coxsackievirus. Epidemic infections in the United States were usually caused by Coxsackievirus A16 and enterovirus 71 before Coxsackievirus A6 began to appear.

• Outbreaks of strains of EV71 enterovirus producing large epidemics of HFMD with significant morbidity and mortality have occurred in east and southeast Asia. Enterovirus 71 was first isolated in California, USA, in 1969.⁴

• Atypical presentations of HFMD caused by Coxsackievirus A6 have been reported in Asian and Europe since 2008 and in the United States since 2011.^5-8 In the fall of 2011 and early winter of 2012, 63 cases of apparent but more severe HFMD from four U.S. states were reported to the Centers for Disease Control and Prevention (CDC). Polymerase chain reaction (PCR) and gene sequencing detected an A6 strain of coxsackievirus in 74% of clinical specimens from 34 cases.⁵

• Coxsackievirus infections are highly contagious. For example, an outbreak of 53 cases of HFMD was caused by CVA6 in military training base in Texas.⁹ Transmission occurs via aerosolized droplets of nasal and/or oral secretions via the fecal–oral route, or from contact with skin lesions. During epidemics, the virus is spread from child to child and from mother to fetus.

• The incubation period averages 3 to 6 days. Initial viral implantation is in the GI tract mucosa, and it then spreads to lymph nodes within 24 hours. Viremia rapidly ensues, with spread to the oral mucosa and skin. Rarely, aseptic meningitis may occur. Usually by day 7, a neutralizing antibody response develops, and the virus is cleared from the body.

• HFMD may also result in neurologic problems such as a polio-like syndrome, aseptic meningitis, encephalitis, acute cerebellar ataxia, acute transverse myelitis, Guillain-Barré syndrome, and benign intracranial hypertension. Rarely, cardiopulmonary complications such as myocarditis, interstitial pneumonitis, and pulmonary edema may occur.^10-12

• Infection in the first trimester of pregnancy may lead to spontaneous abortion or intrauterine growth retardation.

RISK FACTORS

• Attendance at childcare centers.

• Contact with HFMD.

DIAGNOSIS

CLINICAL FEATURES—HISTORY AND PHYSICAL

• A prodrome lasting 12 to 36 hours is usually the first sign of HFMD, and it usually consists of typical general viral infection symptoms with anorexia, abdominal pain, fever, emesis, and diarrhea.² In typical HFMD, a fever, if present, is generally below 101°F.^12,13

• Skin and mucosal findings include an oral enanthem and skin exanthem, which can occur together or separately.^13-15 Lesions heal spontaneously in 7 to 10 days.

• Each lesion in typical HFMD begins as a 2- to 10-mm erythematous macule, which develops a gray, oval, football-shaped vesicle (Figure 134-3) that parallels the skin tension lines in its long axis (Figure 134-4). The oral lesions (Figure 134-5) begin as erythematous macules, evolve into 2- to 3-mm vesicles on an erythematous base, and then rapidly become ulcerated. The oral lesions are painful and may interfere with eating. The skin lesions are not generally pruritic.

• Atypical, severe HFMD (CVA6) may be associated with fever as high as 103° to 105°F and may produce much more extensive, denser rash in more locations, with greater malaise and likelihood of anorexia, dehydration, and pain.⁵

• Atypical (CVA6) HFMD may produce lesions that are very protean in their character and evolution. Early lesions are usually maculovesicular as with the milder A16 form, but may coalesce (Figure 134-6). Others may be vesiculobullous and may drain, or simply papular (Figure 134-7) and ulcerative (Figure 134-8).^4,6,7

• Cervical or submandibular lymphadenopathy may be present.

TYPICAL DISTRIBUTION

• Skin lesions of the milder form (A16) develop on the hands, feet, and/or buttocks, and oral lesions may involve the palate, buccal mucosa, gingiva, and/or tongue. Lesions on the hands and feet are largely limited to the palmar and plantar surfaces (Figures 134-3 and 134-4).

• Atypical, severe HFMD (A6) produces a much more extensive rash, and may include the lips and perioral area of the face (Figure 134-6), arms, legs, knees genitalia, trunk, buttocks, perianal area, and distinctively the dorsal areas of the hands (Figure 134-8) and feet as well as palmar and plantar surfaces The lesions may concentrate in areas of active or dormant eczema, known as "eczema coxsackium."^2,5

LABORATORY TESTING

• Laboratory tests are usually not needed for diagnosis. Diagnosis is typically made clinically, based on history and appearance/location of enanthem and exanthem. If there is diagnostic uncertainty and a change in management based on diagnosis (e.g., CVA6 vs. HSV in eczema herpeticum), viral testing can be performed.¹⁶ It is much easier, less expensive, and faster to get amplified probe testing for HSV than to get viral testing for Coxsackieviruses. If HSV is the cause, antivirals are available, whereas there are no antivirals that affect the course of HFMD.

• For epidemiologic research, genotyping to determine the specific virus causing the HFMD is offered by the CDC. Guidelines for specimen collection can be found on the CDC website—https://www.cdc.gov/laboratory/specimen-submission/cdc-lab-tests.pdf. Because turnaround time is 14 days, this testing is not valuable for clinical management.

DIFFERENTIAL DIAGNOSIS

• Aphthous stomatitis presents as single or multiple painful ulcers in the mouth without skin eruptions (see Chapter 43, Aphthous Ulcer).

• Chickenpox presents with body-wide vesicular lesions in multiple crops (see Chapter 129, Chickenpox).

• Erythema multiforme demonstrates body-wide target lesions that also involve the skin of the palms and soles (see Chapter 185, Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis).

• Herpes simplex presents with painful recurrent ulcerations of the lips or genitals without simultaneous hand or foot lesions unless there is a herpetic whitlow on the hand (see Chapter 135, Herpes Simplex).

• Eczema herpeticum (HSV in persons with atopic dermatitis) lesions may resemble eczema coxsackium (CVA6 in patients with atopic dermatitis). Careful exam usually reveals the typical perioral/intraoral lesions and concurrent hand and foot distribution of HFMD. Unfortunately, some cases of eczema coxsackium have not manifested intraoral lesions, or lesions on hands or feet.² Then it helps to get rapid amplified probe testing for HSV to determine the virus involved. This is crucial, as specific antiviral therapy is available for HSV.¹⁷

• Id reaction (autoeczematization) occurs as a pruritic, papulovesicular eruption due to hypersensitivity response to fungal antigens. This rash is particularly pruritic, and the fungal infection is often on the feet. The papulovesicles are usually smaller in size than those in HFMD, and the presence of a fungal infection points toward an Id reaction.

• Gianotti–Crosti syndrome (papular acrodermatitis of childhood) presents as papules and/or papulovesicles on the extremities and buttocks in children during or within a few weeks after a viral infection (Figure 134-9). The child does not usually appear ill, and the parents bring the child for evaluation because the papular eruption can be frightening. The papulovesicles are very similar in appearance and distribution to atypical HFMD. Look for flat oblong vesicles on the palmar and plantar regions along with lesions in the mouth to differentiate HFMD from Gianotti–Crosti syndrome.

MANAGEMENT

FIRST LINE

• The treatment of HFMD is supportive therapy.¹⁸ Usually the mouth lesions are not as painful as in herpes gingivostomatitis. If there is a lot of mouth pain leading to poor oral intake, the following medications may be considered. Topical oral anesthetics such as 2% lidocaine gel by prescription or 20% topical benzocaine (Orabase) nonprescription may be used to treat painful oral ulcers, but are not routinely recommended given lack of evidence of benefit from clinical trials¹⁹ and potential harm (e.g. systemic absorption, allergic reaction^20,21). Benzocaine is not safe in children under 2 years of age because of the risk of methemoglobinemia.²² SORⒸ

• Acetaminophen or NSAIDs may be used to manage fever and treat arthralgias. SORⒸ Aspirin should not be used in viral illnesses in children younger than 12 years of age to prevent Reye syndrome. SORⒸ

SECOND LINE

Studies are being conducted in Asia for alternative treatment modalities including interferon-α,^23,24 ribavirin aerosol,^25,26 low-level laser,²⁷ and immunoglobulin.²⁸

REFERRAL OR HOSPITALIZATION

• Indications for hospitalization include: (1) inability to maintain adequate hydration, (2) development of neurologic or cardiovascular complications, and (3) inability to differentiate eczema coxsackium from eczema herpeticum.²⁹

PREVENTION

• Good handwashing is critical to reduce the spread of disease, both at home and at daycare facilities experiencing cases. Virus may be shed in stool for at least several weeks.

• Infants and children with active skin lesions of HFMD should be excused from daycare facilities. Adults with active lesions should stay out of work.

• A vaccine against enterovirus 71 has entered phase III clinical trials in Asia and has shown efficacy of 95.1% for up to 2 years.^30,31 Currently, there are still obstacles for mass production.

PROGNOSIS

• HFMD caused by coxsackievirus A16 is generally a mild self-limited illness that resolves in around 7 to 10 days. Typical HFMD may rarely recur, persist, or cause serious complications.

• CVA6 resulted in a high rate of hospitalization (about 1 in 5 cases) in 63 cases reported to the CDC. Fortunately, there were no deaths. CVA6 may also cause palmar plantar desquamation 1 to 2 weeks afterwards. Lesions tend to heal completely if not complicated.

• Beau's lines (see Chapter 198, Normal Nail Variants) and onychomadesis (loss of nail) may occur many weeks later, followed by complete healing.^5,15

• HFMD is usually followed by complete recovery without scarring.

• Uncommon CNS involvement (meningitis, encephalitis) has been the cause of rare morbidity and mortality associated with HFMD.

PATIENT EDUCATION

• Educate parents of young children to watch for signs of dehydration owing to decreased oral intake secondary to mouth pain.

• To reduce viral spreading, do not rupture blisters.

• The patient may attend school once fever and symptoms subside, no new lesions have appeared, and all lesions have dried or scabbed over.³²

• The virus that causes HFMD may be shed in the patient's stool for weeks.

• Report any neurologic symptoms to healthcare providers immediately.

• Good handwashing and contact precautions are critical to preventing spread to others.

REFERENCES

PATIENT STORY

A 32-year-old man presents with complaints of a 1-week history of multiple painful vesicles on the shaft of his penis associated with tender groin adenopathy (Figure 135-1). The vesicles broke 2 days ago and the pain has increased. He had similar lesions 1 year ago but never went for a healthcare examination at that time. He has had 3 different female sexual partners in the past 2 years but has no knowledge of them having any sores or diseases. He was given the presumptive diagnosis of genital herpes and a course of acyclovir. His herpes polymerase chain reaction (PCR) came back positive, and his rapid plasma reagin (RPR) and HIV tests were negative.

INTRODUCTION

Herpes simplex virus (HSV) infection can involve the skin, mucosa, eyes, and central nervous system. HSV establishes a latent state followed by viral reactivation and recurrent local disease. Perinatal transmission of HSV can lead to significant fetal morbidity and mortality.

EPIDEMIOLOGY

HSV affects more than one-third of the world's population, with the 2 most common cutaneous manifestations being genital (Figures 135-1, 135-2, 135-3, 135-4) and orolabial herpes (Figures 135-5, 135-6, 135-7).¹

The Centers for Disease Control and Prevention (CDC) reports that at least 50 million persons in the United States have genital HSV-2 infection. Over the past decade, the percentage of Americans with genital herpes infection in the United States has remained stable. Most persons infected with HSV-2 have not been diagnosed with genital herpes.²

Genital HSV-2 infection is more common in women (approximately 1 of 5 women 14 to 49 years of age) than in men (approximately 1 of 9 men 14 to 49 years of age). Transmission from an infected male to his female partner is believed to be more likely than from an infected female to her male partner.

Orolabial herpes is the most prevalent form of herpes infection and often affects children younger than 5 years of age (Figure 135-7), although all age groups are affected. The duration of the illness is 2 to 3 weeks, and oral shedding of virus may continue for as long as 23 days.¹

Herpetic whitlow is an intense painful infection of the hand involving the terminal phalanx of one or more digits. In the United States, the estimated annual incidence is 2.4 cases per 100,000 persons.³

ETIOLOGY AND PATHOPHYSIOLOGY

• HSV belongs to the family Herpesviridae and is a double-stranded DNA virus.

• HSV exists as 2 separate types (types 1 and 2), which have affinities for different epithelia.³ Ninety percent of HSV-2 infections are genital, whereas 90% of those caused by HSV-1 are oral–labial.

• HSV enters through abraded skin or intact mucous membranes. Once infected, the epithelial cells die, forming vesicles and creating multinucleated giant cells.

• Retrograde transport into sensory ganglia leads to lifelong latent infection.¹ Reactivation of the virus may be triggered by immunodeficiency, trauma, fever, and UV light.

• Genital HSV infection is usually transmitted through sexual contact. When it occurs in a preadolescent, the possibility of abuse must be considered.

• Evidence indicates that 21.9% of all persons in the United States 12 years or older have serologic evidence of HSV-2 infection, which is more commonly associated with genital infections.⁴

• As many as 90% of those infected are unaware that they have herpes infection and may unknowingly shed virus and transmit infection.⁵

• Primary genital herpes has an average incubation period of 4 days, followed by a prodrome of itching, burning, or erythema (Figure 135-8).

• With both types, systemic symptoms are common in primary disease and include fever, headache, malaise, abdominal pain, and myalgia.⁶ Recurrences are usually less severe and shorter in duration than the initial outbreak.^1,6

• Maternal–fetal transmission of HSV is associated with significant morbidity and mortality. Manifestations of neonatal HSV include localized infection of the skin, eyes, and mouth, central nervous system (CNS) disease, or disseminated multiple organ disease. The CDC and the American College of Obstetricians and Gynecologists recommend that cesarean delivery should be offered as soon as possible to women who have active HSV lesions or, in those with a history of genital herpes, symptoms of vulvar pain or burning at the time of delivery.

• Herpetic whitlow occurs as a complication of oral or genital HSV infection and in medical personnel who have contact with oral secretions (Figures 135-9 and 135-10).

• Toddlers and preschool children are susceptible to herpetic whitlow if they have herpes labialis and engage in thumb-sucking or finger-sucking behavior.

• Like all HSV infections, herpetic whitlow usually has a primary infection, which may be followed by subsequent recurrences. The virus migrates to the peripheral ganglia and Schwann cells where it lies dormant. Recurrences observed in 20% to 50% of cases are usually milder and shorter in duration.

RISK FACTORS

• Multiple sexual partners.

• Female gender.

• Low socioeconomic status.

• HIV infection.

DIAGNOSIS

CLINICAL FEATURES

• The diagnosis of HSV infection may be made by clinical appearance. Many patients have systemic symptoms, including fever, headache, malaise, and myalgias. Nontypical cases should be confirmed with laboratory testing.²

• Orolabial herpes typically takes the form of painful vesicles and ulcerative erosions on the tongue, palate, gingiva, buccal mucosa, and lips (see Figures 135-5, 135-6, 135-7).

• Genital herpes presents with multiple transient, painful vesicles that appear on the penis (see Figures 135-1 and 135-2), vulva (see Figure 135-3), buttocks (Figures 135-4 and 135-11), perineum, vagina or cervix, and tender inguinal lymphadenopathy.⁶ The vesicles break down and become ulcers that develop crusts while these are healing.

• Recurrences typically occur 2 to 3 times a year. The duration is shorter and less painful than in primary infections. The lesions are often single, and the vesicles heal completely by 8 to 10 days.

• UV radiation in the form of sunlight may trigger outbreaks, another reason to use sun protection when outdoors. Sunlight triggers recurrence of orolabial HSV-1, an effect that is not fully suppressed by acyclovir.

LABORATORY STUDIES

• The gold standard of diagnosis is viral isolation by tissue culture and PCR testing.²

  • PCR is extremely sensitive (96%) and specific (99%) and is preferred for all testing.² It is used for cerebrospinal fluid (CSF) testing in suspected HSV encephalitis or meningitis.²

  • The culture sensitivity rate is only 50% and depends upon the stage at which the specimen is collected. The sensitivity is highest at first in the vesicular stage and declines with ulceration and crusting. The tissue culture assay can be positive within 48 hours but may take longer.

• HSV-specific glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1) type-specific HSV serologic assays are 80%–98% specific. Because nearly all HSV-2 infections are sexually acquired, the presence of type-specific HSV-2 antibody implies anogenital infection. Type-specific HSV serologic assays might be useful in patients with recurrent symptoms and negative HSV cultures and an asymptomatic patient with a partner with genital herpes. Screening for HSV-1 and HSV-2 in the general population is not indicated.²

• The Tzanck test and antigen detection tests have lower sensitivity rates than viral culture and should not be relied on for diagnosis.²

• The CDC does not currently recommend routine type 2 HSV testing in someone with no symptoms suggestive of herpes infection (i.e., for the general population).⁷

• If the herpes was acquired by sexual contact, screening should be performed for other sexually transmitted diseases (STDs), such as syphilis and HIV.

• Biopsy is usually unnecessary unless no infectious etiology is found for a genital lesion and a malignancy is suspected.

DIFFERENTIAL DIAGNOSIS

• Syphilis produces a painless or mildly painful, indurated, clean-based ulcer (chancre) at the site of exposure. It is best to investigate for syphilis or coexisting syphilis in any patient presenting for the first time with a genital ulcer of unproven etiology (see Chapter 225, Syphilis).

• Chancroid produces a painful deep, undermined, purulent ulcer that may be associated with painful inguinal lymphadenitis (see Chapter 225, Syphilis).

• Drug eruptions produce pruritic papules or blisters without associated viral symptoms (see Chapter 212, Cutaneous Drug Reactions).

• Behçet disease produces ulcerative disease around the mouth and genitals, possibly before onset of sexual activity (Figure 135-12).

• Acute paronychia presents as a localized abscess in a nail fold and is the main differential diagnosis in the consideration of herpetic whitlow (see Chapter 202, Paronychia).

• Felon—A red, painful infection, usually bacterial, of the fingertip pulp. It is important to distinguish whitlow from a felon (where the pulp space usually is tensely swollen), as incision and drainage of a felon is needed, but should be avoided in herpetic whitlow because it may lead to an unnecessary secondary bacterial infection.

MANAGEMENT

NONPHARMACOLOGIC

• Women with active primary or recurrent genital herpetic lesions at the onset of labor should deliver by cesarean section to lower the chance of neonatal HSV infection.² SORⒶ

MEDICATIONS

• Acyclovir is a guanosine analog that acts as a DNA chain terminator which, when incorporated, ends viral DNA replication. Valacyclovir is the l-valine ester prodrug of acyclovir that has enhanced absorption after oral administration and high oral bioavailability. Famciclovir is the oral form of penciclovir, a purine analog similar to acyclovir. They must be administered early in the outbreak to be effective, but are safe and extremely well-tolerated.⁶ SORⒶ

Genital herpes:

• Antiviral therapy is recommended for an initial genital herpes outbreak. Table 135-1 shows the dosages for antiherpes drugs. Although systemic antiviral drugs can partially control the signs and symptoms of herpes episodes, no therapy eradicates latent virus.⁸

• Acyclovir, famciclovir, and valacyclovir are equally effective for episodic treatment of genital herpes, but famciclovir appears somewhat less effective for suppression of viral shedding.² SORⒷ

• Effective episodic treatment of herpes requires initiation of therapy during the prodrome period or within 1 day of lesion onset. Providing the patient with a prescription for the medication with instructions to initiate treatment immediately when symptoms begin improves efficacy.² SORⒷ

• IV acyclovir therapy at 5 to 10 mg/kg IV every 8 hours for 2 to 7 days followed by oral antiviral therapy to complete at least 10 days of total therapy should be provided for patients who have severe HSV disease or complications.² SORⒸ

• HSV strains resistant to acyclovir have been detected in immunocompromised patients, so other antivirals (e.g., famciclovir) need to be considered in these patients. SORⒸ

• Topical medication for HSV infection is generally not effective. Topical penciclovir applied every 2 hours for 4 days reduces clinical healing time by approximately 1 day.^1,2

• All patients with a first episode of genital herpes should receive antiviral therapy, as even with mild clinical manifestations initially, they can develop severe or prolonged symptoms.

• Toxicity of these 3 antiviral drugs is rare, but in patients who are dehydrated or who have poor renal function, the drug can crystallize in the renal tubules, leading to a reversible creatinine elevation or, rarely, acute tubular necrosis. Adverse effects, usually mild, include nausea, vomiting, rash, and headache. Lethargy, tremulousness, seizures, and delirium have been reported rarely in studies of renally impaired patients.⁹

Oral herpes:

Table 135-2 provides an overview of treatments for herpes labialis.

• In the treatment of primary orolabial herpes, oral acyclovir (200 mg 5 times daily for 5 days) accelerates healing by 1 day and can reduce the mean duration of pain by 36%.¹⁰ SORⒶ

• The oral lesions in primary herpes gingivostomatitis can lead to poor oral intake especially in children and the elderly (Figure 135-13). To prevent dehydration, the following medications may be considered. Topical oral anesthetics such as 2% viscous lidocaine by prescription or 20% topical benzocaine over the counter (OTC) may be used to treat painful oral ulcers. SORⒸ A solution combining aluminum and magnesium hydroxide (liquid antacid) and 2% viscous lidocaine has been reported as helpful when swished and spit out several times a day as needed for pain. SORⒸ

• Docosanol cream (Abreva) is available without prescription for oral herpes. One randomized controlled trial (RCT) of 743 patients with herpes labialis showed a faster healing time in patients treated with docosanol 10% cream compared with placebo cream (4.1 vs. 4.8 days), as well as reduced duration of pain symptoms (2.2 vs. 2.7 days).¹¹ More than 90% of patients in both groups healed completely within 10 days.¹¹ Treatment with docosanol cream, when applied 5 times per day and within 12 hours of episode onset, is safe and somewhat effective.¹²

PREVENTION

• Barrier protection using latex condoms is recommended to minimize exposure to genital HSV infections (see "Patient Education" below).

• Suppressive therapy with antiviral drugs reduces the frequency of genital herpes recurrences by 70% to 80% in patients with frequent recurrences.² SORⒶ Traditionally this is reserved for use in patients who have more than 4 to 6 outbreaks per year (see Table 135-1).

• Short-term prophylactic therapy with acyclovir for orolabial HSV may be used in patients who anticipate intense exposure to UV light. Early treatment of recurrent orolabial HSV infection with famciclovir 250 mg 3 times daily for 5 days can markedly decrease the size and duration of lesions.¹³ SORⒶ

FOLLOW-UP

The patient should return for follow-up if pain is uncontrolled or superinfection is suspected. The patient should be periodically evaluated for the need for suppressive therapy based on the number of recurrences per year.

PATIENT EDUCATION

Measures to prevent genital HSV infection:

• Abstain from sexual activity or limit number of sexual partners to prevent exposure to the disease.

• Use condoms to protect against transmission, but this is not foolproof as ulcers can occur on areas not covered by condoms.

• Prevent autoinoculation by patting dry affected areas, not rubbing with towel.

• Studies show that patients may shed virus when they are otherwise asymptomatic. A link between HSV genital ulcer disease and sexual transmission of HIV has been established. Safer sex practices should be strongly encouraged to prevent transmission of HSV to others and acquiring HIV by the patient.

REFERENCES

PATIENT STORY

An 8-year-old girl is brought to the office because of an outbreak of bumps on her face for the past 3 months (Figure 136-1). Occasionally she scratches them, but she is otherwise asymptomatic. The mother and child are unhappy with the appearance of the molluscum contagiosum and chose to try topical therapy. A topical treatment was chosen to avoid the risk of hypopigmentation that can occur in dark-skinned individuals with cryotherapy.

An 11-year-old girl was also seen with molluscum on her face. The child and her mother decided to try cryotherapy as her treatment. She tolerated the treatment with liquid nitrogen in a Cryogun (Figure 136-2). The molluscum disappeared without scarring or hypopigmentation after 2 treatments.

INTRODUCTION

Molluscum contagiosum is a viral skin infection that produces pearly papules that often have a central umbilication. It is seen most commonly in children, but can also be transmitted sexually among adults.

EPIDEMIOLOGY

• Molluscum contagiosum infection has been reported worldwide. An Australian seroepidemiology study found a seropositivity rate of 23%.¹

• Up to 5% of children in the United States have clinical evidence of molluscum contagiosum infection.² It is a common, nonsexually transmitted condition in children (see Figures 136-1, 136-2, 136-3, 136-4).

• The number of cases of molluscum in U.S. adults increased in the 1980s with the onset of the HIV/AIDS epidemic. Since the introduction of highly active antiretroviral therapy (HAART), the number of molluscum contagiosum cases in HIV/AIDS patients has decreased.³ However, the prevalence of molluscum contagiosum in patients who are HIV-positive may still be as high as 5% to 18% (Figures 136-5).^4,5

ETIOLOGY AND PATHOPHYSIOLOGY

• Molluscum contagiosum is a benign condition that is often transmitted through close contact in children and through sexual contact in adults.

• It is a large DNA virus of the Poxviridae family of poxvirus. It is related to the orthopoxviruses (variola, vaccinia, smallpox, and monkeypox viruses).

• Molluscum replicates in the cytoplasm of infected epithelial cells. It causes a chronic localized skin infection consisting of dome-shaped pearly papules on the skin.

• Like most of the viruses in the poxvirus family, molluscum is spread by direct skin-to-skin contact. It can also spread by autoinoculation when scratching, touching, or treating lesions. Any single lesion is usually present for approximately 2 months, but autoinoculation often causes continuous crops of lesions.

RISK FACTORS

• Common childhood disease.

• Molluscum contagiosum may be more common in patients with atopic dermatitis based on reported prevalence rates for atopic dermatitis of 18% to 45% in patients with molluscum, which exceeds the prevalence of 10% to 20% in the general pediatric population (Figure 136-6).^2,6

• The disease also may be spread by participation in contact sports.²

• It is also associated with immunodeficient states such as in HIV infection (see Figure 136-5) and with immunosuppressive drug treatment.

DIAGNOSIS

CLINICAL FEATURES—HISTORY AND PHYSICAL

• Firm, multiple, 2- to 5-mm dome-shaped papules with a characteristic shiny surface and umbilicated center (Figure 136-7). Not all the papules have a central umbilication, so it helps to take a moment and look for a papule that has this characteristic morphology. If all features point to molluscum and no single lesion has central umbilication, do not rule out molluscum as the diagnosis.

• The lesions range in color from pearly white, to flesh-colored, to pink or yellow.

• Pruritus may be present or absent.

TYPICAL DISTRIBUTION

• The lesions may appear anywhere on the body except the palms and soles. The number of lesions may be greater in an HIV-infected individual.

• Typically in adults and occasionally in children, they are found around the genitalia, inguinal area, buttocks, or inner thighs. In children, the lesions are often on the trunk or face.

• If a child is found to have molluscum contagiosum in the genital area, a history and physical exam should be directed at looking for other clues that might indicate sexual abuse (see Chapter 10, Child Sexual Abuse). Not all cases of molluscum in this area will be secondary to sexual abuse (Figure 136-8).

LABORATORY TESTING

• Sexually active adolescents and adults with genital lesions should be evaluated for other sexually transmitted diseases, including HIV and syphilis.

DERMOSCOPY/BIOPSY

• The typical dermoscopic appearance of a molluscum lesion is a round pearly papule with crown-like vessels surrounding central oval globules (Figure 136-9).

• If confirmation is needed, smears of the caseous material expressed from the lesions can be examined directly under the microscope looking for molluscum bodies (enlarged keratinocytes that are engorged with viral inclusion bodies).

• Hematoxylin and eosin (H&E) staining from a shave biopsy usually reveals keratinocytes that contain eosinophilic cytoplasmic inclusion bodies.⁵ If a single lesion is suspicious for basal cell carcinoma (BCC), perform a shave biopsy.

DIFFERENTIAL DIAGNOSIS

• Scabies is caused by Sarcoptes scabiei mite and can be transmitted through close or sexual contact. The itching and excoriations are greater than seen with molluscum. Scabies papules and burrows differ in appearance from the stuck-on pearly umbilicated papules of molluscum (see Chapter 149, Scabies).

• Dermatofibromas—Firm to hard nodules ranging in color from flesh to black that typically dimple downward when compressed laterally. Usually not seen in crops as in molluscum. These nodules are deeper in the dermis and do not appear stuck on like molluscum.

• BCCs are also pearly and raised but are rarely found in pediatric populations. Usually not seen in crops as in molluscum. If a single lesion could be a BCC or molluscum, a biopsy is warranted (see Chapter 177, Basal Cell Carcinoma).

• Genital warts may be flat and grossly resemble molluscum but they lack the characteristic shiny surface and central umbilication (see Chapter 139, Genital Warts).

MANAGEMENT

FIRST LINE

NONPHARMACOLOGIC

• Treatment of nongenital lesions is usually not medically mandatory as the infection is usually self-limited and spontaneously resolves after a few months. Treatment may be performed in an attempt to decrease autoinoculation and hasten resolution. Patients and parents of children often want treatment for cosmetic reasons and when watchful waiting fails.

• A 2017 Cochrane Database systematic review investigated the efficacy of treatments for nongenital molluscum contagiosum in healthy individuals and found insufficient evidence to conclude that any treatment was definitively effective.⁷ SORⒶ

• In the HIV-infected patient, molluscum may resolve after control of HIV disease with HAART.³ SORⒷ

• Immunocompromised patients should have a full-body skin examination to ensure that all lesions are identified. Treatment is still optional but should proceed in patients whose parents desire intervention.

SURGICAL

• Cryotherapy applied by cotton-tipped applicator or sprayer is a physical method used to eradicate molluscum.^8-10 SORⒶ Hypopigmentation (which may be permanent) is a potential side effect, especially in skin of color. Cryotherapy is painful and scary to most young children. For older children and brave younger children, it is an easy treatment. Some parents are so upset with the molluscum they will ask the physician to proceed with treatment despite the child's screaming protestations. It is best to offer topical therapy under those circumstances. Other choices involve using topical anesthetic cream and distractions such as smartphones to keep children happy while treating their molluscum.

• Curettage is another physical method.⁸ SORⒷ It can be performed with or without anesthesia in adults and brave children. Some patients state that the lidocaine injections hurt more than the curettage and prefer no anesthesia. Topical anesthesia with anesthetic creams or sprays is another option.

MEDICATIONS

• Cantharidin is a topical blistering agent that was studied in 300 children for molluscum, and the parents reported 90% of children experienced lesion clearing and 8% experienced lesion improvement (Figure 136-10). SORⒷ Furthermore, 95% of parents stated they would use cantharidin therapy again.¹¹ Local erythema, burning, pruritus, and inflammation were reported side effects. Fortunately, the application is painless because the blistering occurs after the child leaves the office (see Figure 136-10). It can be a good choice for children if one can get the cantharidin compounded in a nearby pharmacy.

• Podophyllotoxin 0.5% (Condylox) is an antimitotic agent that is indicated for the treatment of genital warts. The efficacy of podophyllotoxin was established in a randomized trial of lesions located on the thighs or genitalia. SORⒶ Local erythema, burning, pruritus, inflammation, and erosions can occur with the use of this agent. The safety and efficacy of this drug has not been established in young children.¹² In a randomized trial of 150 males (ages 10 to 26 years), the patients applied 0.5% podophyllotoxin cream, 0.3% podophyllotoxin cream, or placebo twice daily for three consecutive days per week for up to 4 weeks. The 0.5% podophyllotoxin was group had 92% clearance (16% for placebo).¹²

SECOND LINE

• Tretinoin cream¹¹ 0.1% or gel 0.025% applied daily is commonly used but not FDA-approved for this indication. SORⒷ

• Trichloroacetic acid and salicylic acid¹³ are topical keratolytic chemicals that can be applied by the physician in the office. SORⒷ Local irritation is common.

• Topical imiquimod 5% was found in small trials to be effective, but a recent systematic review found that it was no more effective than vehicle alone.⁶

COMPLEMENTARY/ALTERNATIVE THERAPY

• ZymaDermis is a nonprescription, topical, homeopathic agent that is marketed for the treatment of molluscum contagiosum, but no published studies have evaluated its efficacy or safety.

• Potassium hydroxide has been used for molluscum but has not proved to be statistically significant when compared to placebo.¹⁴

• Pulsed dye lasers have shown to be safe and effective in case reports and small uncontrolled studies. One prospective study of 19 children between 2 and 13 concluded that all patients tolerated the 585 nm laser well and 84.3% had complete lesion resolution with one treatment.¹⁵

PREVENTION

• Molluscum contagiosum is a common childhood disease.

• Limiting sexual exposure or number of sexual contacts may help prevent exposure in adults.

• Genital lesions should be treated to prevent spread by sexual contact (Figure 136-11).

PROGNOSIS

• In immunocompetent patients, lesions usually spontaneously resolve within several months. In a minority of cases, disease persists for a few years.¹⁶

FOLLOW-UP

• Have patients watch for complications that may include irritation, inflammation, and secondary infections. Lesions on eyelids may be associated with follicular or papillary conjunctivitis, so eye irritation should prompt a visit to an eye care specialist.

PATIENT EDUCATION

• Instruct patients to avoid scratching to prevent autoinoculation.

REFERENCES