E.J. Mayeaux, Jr., Jan Hood, Sujatha Gubbala
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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.
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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.
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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
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United States epidemiology before the vaccination program:
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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.
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United States epidemiology since the vaccination program:
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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 include2,3:
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ETIOLOGY AND PATHOPHYSIOLOGY
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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).
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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.
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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.
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DIFFERENTIAL DIAGNOSIS
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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).
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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Ⓐ
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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.
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POST EXPOSURE PROPHYLAXIS
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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.
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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
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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.
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1. +
Centers for Disease Control and Prevention. Varicella. In: Hamborsky
J, Kroger
A, Wolfe
S, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 13th ed. Washington D.C. Public Health Foundation, 2015:353–375.
2. +
Leung
J, Bialek
SR, Marin
M. Trends in varicella mortality in the United States: data from vital statistics and the national surveillance system.
Hum Vaccin Immunother. 2015;11(3):662–668.
[PubMed: 25714052]
3. +
Gershon
AA, Gershon
MD. Pathogenesis and current approaches to control of varicella-zoster virus infections.
Clin Microbiol Rev. 2013;26(4):728–743.
[PubMed: 24092852]
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Belay
ED, Bresee
JS, Holman
RC,
et al. Reye's syndrome in the United States from 1981 through 1997.
N Engl J Med. 1999;340(18):1377–1382.
[PubMed: 10228187]
6. +
Centers for Disease Control and Prevention. Updated recommendations for use of VariZIG—United States, 2013.
MMWR Morb Mortal Wkly Rep. 2013;62:574–576.
[PubMed: 23863705]
E.J. Mayeaux, Jr., Richard P. Usatine
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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).
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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
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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.
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ETIOLOGY AND PATHOPHYSIOLOGY
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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
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Age older than 60 years.
Negative vaccine status.
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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
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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
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DIFFERENTIAL DIAGNOSIS
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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).
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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Ⓐ
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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.
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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
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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.
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1. +
Usatine
RP, Clemente
C. Is herpes zoster unilateral?
West J Med. 1999;170(5):263.
[PubMed: 10379216]
2. +
Gnann
JW Jr, Whitley
RJ. Clinical practice. Herpes zoster.
N Engl J Med. 2002;347(5):340–346.
[PubMed: 12151472]
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Oxman
MN. Immunization to reduce the frequency and severity of herpes zoster and its complications.
Neurology. 1995;45(12 Suppl 8):S41–46.
[PubMed: 8545018]
4. +
Harpaz
R, Ortega-Sanchez
IR, Seward
JF; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep. 2008;57(RR-5):1–30.
[PubMed: 18528318]
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Stankus
SJ, Dlugopolski
M, Packer
D. Management of herpes zoster (shingles) and postherpetic neuralgia.
Am Fam Physician. 2000;61(18):2437–44, 2447-2448.
[PubMed: 10794584]
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Opstelten
W, Van Essen
GA, Schellevis
F,
et al. Gender as an independent risk factor for herpes zoster: a population-based prospective study.
Ann Epidemiol. 2006;16(9):692–695.
[PubMed: 16516488]
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Yawn
BP, Saddier
P, Wollan
PC,
et al. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction.
Mayo Clin Proc. 2007;82(11):1341–1349.
[PubMed: 17976353]
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Adour
KK. Otological complications of herpes zoster.
Ann Neurol. 1994;35 Suppl:S62–64.
[PubMed: 8185302]
9. +
Arvin
AM, Pollard
RB, Rasmussen
LE, Merigan
TC. Cellular and humoral immunity in the pathogenesis of recurrent herpes viral infections in patients with lymphoma.
J Clin Invest. 1980;65(4):869–878.
[PubMed: 6244336]
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Opstelten
W, Van Essen
GA, Schellevis
F,
et al. Gender as an independent risk factor for herpes zoster: a population-based prospective study.
Ann Epidemiol. 2006;16:692.
[PubMed: 16516488]
11. +
Dworkin
RH, Johnson
RW, Breuer
J,
et al. Recommendations for the management of herpes zoster.
Clin Infect Dis. 2007;44 Suppl 1:S1.
[PubMed: 17143845]
12. +
Gilden
DH, Kleinschmidt-DeMasters
BK, LaGuardia
JJ,
et al. Neurologic complications of the reactivation of varicella-zoster virus.
N Engl J Med. 2000;342:635.
[PubMed: 10699164]
13. +
Tyring
SK, Beutner
KR, Tucker
BA,
et al. Antiviral therapy for herpes zoster: randomized, controlled clinical trial of
valacyclovir and
famciclovir therapy in immunocompetent patients 50 years and older.
Arch Fam Med. 2000;9(9):863–869.
[PubMed: 11031393]
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Tseng
HF, Chi
M, Smith
N,
et al. Herpes zoster vaccine and the incidence of recurrent herpes zoster in an immunocompetent elderly population.
J Infect Dis. 2012;206:190.
[PubMed: 22669900]
16. +
Yawn
BP, Wollan
PC, Kurland
MJ,
et al. Herpes zoster recurrences more frequent than previously reported.
Mayo Clin Proc. 2011;86:88.
[PubMed: 21220354]
E.J. Mayeaux, Jr., Richard P. Usatine
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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.
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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).
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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.
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ETIOLOGY AND PATHOPHYSIOLOGY
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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.
++
Immunocompromised persons, especially those with human immunodeficiency virus infection, have a much higher risk of developing zoster complications, including HZO.
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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.
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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.
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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).
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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.
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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.
++
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
++
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
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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.
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1. +
Pavan-Langston
D. Herpes zoster ophthalmicus.
Neurology. 1995;45(12 Suppl 8):S50–51.
[PubMed: 8545020]
2. +
Tran
KD, Falcone
MM, Choi
DS,
et al. Epidemiology of herpes zoster ophthalmicus: recurrence and chronicity.
Ophthalmology. 2016;123(7):1469–1475.
[PubMed: 27067924]
4. +
Zaal
MJ, Völker-Dieben
HJ, D'Amaro
J. Prognostic value of Hutchinson's sign in acute herpes zoster ophthalmicus.
Graefes Arch Clin Exp Ophthalmol. 2003;241(3):187–191.
[PubMed: 12644941]
5. +
Liesegang
TJ. Corneal complications from herpes zoster ophthalmicus.
Ophthalmology. 1985;92(3):316–324.
[PubMed: 3873048]
6. +
Liesegang
TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation, and morbidity.
Ophthalmology. 2008;115(2 Suppl):S3–12.
[PubMed: 18243930]
8. +
McGill
J, Chapman
C, Mahakasingam
M.
Acyclovir therapy in herpes zoster infection. A practical guide.
Trans Ophthalmol Soc U K. 1983;103(Pt 1):111–114.
[PubMed: 6362108]
9. +
Gnann
JW Jr, Whitley
RJ. Clinical practice. Herpes zoster.
N Engl J Med. 2002;347(5):340–346.
[PubMed: 12151472]
10. +
Oxman
MN. Immunization to reduce the frequency and severity of herpes zoster and its complications.
Neurology. 1995;45(12 Suppl 8):S41–46.
[PubMed: 8545018]
11. +
Miserocchi
E, Waheed
NK, Dios
E,
et al. Visual outcome in herpes simplex virus and varicella zoster virus uveitis: a clinical evaluation and comparison.
Ophthalmology. 2002;109(8):1532–1537.
[PubMed: 12153807]
12. +
Zaal
MJ, Volker-Dieben
HJ, D'Amaro
J. Visual prognosis in immunocompetent patients with herpes zoster ophthalmicus.
Acta Ophthalmol Scand. 2003;81(3):216–220.
[PubMed: 12780396]
13. +
Tran
KD, Falcone
MM, Choi
DS,
et al. Epidemiology of herpes zoster ophthalmicus: recurrence and chronicity.
Ophthalmology. 2016Jul;123(7):1469–1475.
[PubMed: 27067924]
E.J. Mayeaux, Jr., Luke M. Baudoin, Francis J. DeMarco
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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.
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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.
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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
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ETIOLOGY AND PATHOPHYSIOLOGY
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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
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Failure to receive immunization.
Failure to receive second immunization dose.
Travel to endemic areas.
Exposure to travelers from endemic areas.
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For developing severe measles or for developing complications:
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Measles is a distinct disease characterized by fever, malaise, conjunctivitis, coryza, cough, rash, and Koplik spots.
++
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
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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.
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DIFFERENTIAL DIAGNOSIS
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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.
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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Ⓑ
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REFERRAL OR HOSPITALIZATION
++
Consider hospitalization in the following scenarios:
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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.
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Refer to ophthalmology if there are changes in vision, as measles keratitis can lead to permanent scarring and blindness.
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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.
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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%.
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++
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.
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++
1. +
Katz
SL, Hinman
AR. Summary and conclusions: measles elimination meeting, 16–17 March 2000.
J Infect Dis. 2004;189(Suppl 1):S43–47.
[PubMed: 15106088]
2. +
Zipprich
J, Winter
K, Hacker
J,
et al. Measles outbreak—California, December 2014–February 2015.
MMWR Morb Mortal Wkly Rep. 2015;64(6):153–154.
[PubMed: 25695321]
5. +
Johnson
RT, Griffin
DE, Hirsch
RL,
et al. Measles encephalomyelitis—clinical and immunologic studies.
N Engl J Med. 1984;310:137–141.
[PubMed: 6197651]
6. +
Bellini
WJ, Rota
JS, Lowe
LE,
et al. Subacute sclerosing panencephalitis: more cases of this fatal disease are prevented by measles immunization than was previously recognized.
J Infect Dis. 2005;192:1686–1693.
[PubMed: 16235165]
9. +
Hamborsky
J, Kroger
A, Wolfe
S, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases, 13th Edition: The Pink Book. Washington, DC: Public Health Foundation; 2015.
Khaled Z. Aqeel, Anisha R. Turner, E.J. Mayeaux, Jr.
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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.
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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.
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Erythema infectiosum, parvovirus B19 infections, slapped cheek syndrome.
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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Ⓑ
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ETIOLOGY AND PATHOPHYSIOLOGY
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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
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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.
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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.
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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
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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.
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DIFFERENTIAL DIAGNOSIS
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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).
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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Ⓒ
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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
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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
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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.
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1. +
Obeid
OE. Molecular and serological assessment of parvovirus B19 infections among sickle cell anemia patients.
J Infect Dev Ctries. 2011;5(07):535–539.
[PubMed: 21795822]
3. +
Valentin
M, Cohen
P. Pediatric parvovirus B19: spectrum of clinical manifestations.
Cutis. 2013;92(4):179–184.
[PubMed: 24195090]
4. +
de Jong
EP, Walther
FJ, Kroes
AC, Oepkes
D. Parvovirus B19 infection in pregnancy: new insights and management.
Prenat Diagn. 2011;31:419–425.
[PubMed: 21351281]
5. +
Dijkmans
AC, de Jong
EP, Dijkmans
BA,
et al. Parvovirus B19 in pregnancy: prenatal diagnosis and management of fetal complications.
Curr Opin Obstet Gynecol. 2012;24:95–101.
[PubMed: 22249146]
6. +
Crane
J, Mundle
W, Boucoiran
I,
et al. Parvovirus B19 infection in pregnancy.
J Obstet Gynaecol Can. 2014;36:1107–1116.
[PubMed: 25668048]
7. +
Temesgen
Z, Baddour
LM, Steckelberg
JM. Mayo Clinic Infectious Diseases Board Review. Rochester, MN: Mayo Clinic Scientific Press; 2012.
8. +
Wallace
R, Snyder
M. What should you tell pregnant women about exposure to parvovirus?
J Fam Pract. 60(12):765–766.
[PubMed: 22163362]
9. +
O'Grady
J. Fifth and sixth diseases: more than a fever and a rash. Clin Rev. 24(10):E1–5.
Theresa Thuy Vo, E.J. Mayeaux, Jr., Steven N. Bienvenu
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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.
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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
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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.
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ETIOLOGY AND PATHOPHYSIOLOGY
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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.
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CLINICAL FEATURES—HISTORY AND PHYSICAL
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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.
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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
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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.
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DIFFERENTIAL DIAGNOSIS
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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.
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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 reaction20,21). 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Ⓒ
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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
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REFERRAL OR HOSPITALIZATION
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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
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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.
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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.
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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.
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E.J. Mayeaux, Jr., Jonathan B. Karnes
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An 11-year-old girl presents with multiple warts on the fingertips that have been present for 3 months (Figure 137-1). She occasionally bites at the warts. Mom has tried over-the-counter freezing, but it was very uncomfortable for her daughter. Although the family is anxious about them spreading, you recommend watchful waiting, and in 6 months all warts have completely resolved.
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Human papillomaviruses (HPVs) are DNA viruses that infect skin and mucous membranes. Infection is usually confined to the epidermis and does not result in disseminated systemic infection. The most common clinical manifestation of these viruses is warts (verrucae). There are more than 200 distinct HPV subtypes based on DNA testing. Some tend to infect specific body sites or types of epithelium. Some types have potential to cause malignant change, but this is rare on keratinized skin.
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Verrucae, verruca vulgaris, common warts.
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Nongenital cutaneous warts are widespread worldwide and are more common in children, with a peak incidence in the teenage years and a sharp decline thereafter.1
They are most commonly caused by HPV types 1 to 5, 7, 27, 29.1
High-risk HPV has been isolated in warts but the significance is unclear.2
Common warts account for approximately 70% of non-genital cutaneous warts.3
Common warts occur most commonly in children and young adults (Figures 137-1 and 137-2).4
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ETIOLOGY AND PATHOPHYSIOLOGY
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Infection with HPV occurs by skin-to-skin contact. It starts with a break in the integrity of the epithelium caused by maceration or trauma that allows the virus to infect the basal layers.
Warts may infect the skin on opposing digits, causing "kissing warts" (Figure 137-3).
Individuals with subclinical infection may serve as a reservoir for HPVs.
An incubation period following inoculation lasts for approximately 2 to 6 months.
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Young age1.
Disruption to the normal epithelial barrier.
More common among meat handlers.5
Atopic dermatitis.
Nail biters more commonly have multiple periungual warts.
Conditions that decrease cell-mediated immunity such as HIV (Figure 137-4) and immunosuppressant drugs (Figure 137-5).
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