Chapter 192. Exanthematous Viral Diseases

Epidemiology

Measles, or rubeola, is a highly contagious disease with worldwide distribution that remains a leading cause of vaccine-preventable deaths in children.1 The peak incidence of infection occurs during the winter and spring months in temperate areas.2 The risk of mortality is highest in developing countries, with most deaths due to complications of the disease.3 In the United States, measles-related deaths occur in 1–3 of every 1,000 reported cases.2

Before the development of a vaccine, measles epidemics in the United States usually occurred in preschool and young school aged children.2,4 A successful immunization program for children and adolescents, particularly in urban areas, has resulted in a greater than 99% decrease in the reported incidence of indigenous measles since the vaccine was first licensed in the early 1960s.2 Yet, cases of measles continue to occur as a result of viral transmission from importation into the United States.2

Improved immunization programs in developing countries have also prevented outbreaks and reduced measles-associated morbidity and mortality. From 2000–2008, global mortality attributed to measles decreased by 78%, from 733,000 to 164,000 deaths.5 However, the reduction in mortality has leveled off and concerns exist regarding the ability of many countries with a high burden of measles mortality to continue effective measles eradication strategies.

Etiology and Pathogenesis

Measles virus, a member of the Paramyxoviridae family, is a heat-labile virus with an RNA core and outer lipoprotein envelope.2,4 Humans are the only natural hosts of the measles virus.2 Measles is spread by direct or airborne droplet exposure. The incubation period is typically 8–12 days, with patients being contagious from 1 to 2 days before onset of symptoms to 4 days after appearance of the rash.2 Both humoral and cell-mediated immunity are needed to control measles virus infection. Immunoglobulin M (IgM) antibodies are detected initially with onset of the rash, followed by a rise in measles-specific IgG titers. The humoral response controls viral replication and confers antibody protection, whereas the cell-mediated response eliminates infected cells.4 A transient immunosuppression occurs during measles virus infection, causing depressed delayed-type hypersensitivity and T-cell counts as well as an increased risk of bacterial infections.4 This process, as well as long-term immunity against measles, is not well understood but may be due to a weak T helper 1 response to the virus.6 Measles virus may use dendritic cells to target lymphoid tissue (CD150 lymphocytes) and disseminate virus throughout the body.7

Clinical Findings

History

The prodrome is typically characterized by fever (up to 40.5°C), malaise, conjunctivitis (palpebral, extending to lid margin), coryza, and cough (brassy or barking), which may last up to 4 days.2,4 Koplik spots, the pathognomonic enanthem of measles, begin as small, bright red macules that have a 1–2-mm blue–white speck within them. They are typically seen on the buccal mucosa near the second molars (Fig. 192-1 and eFig. 192-2.1) 1–2 days before and lasting 2 days after the onset of the rash (see eFig. 192-1.1).2,4 Individuals with preexisting partial immunity (e.g., patients who received exogenous immunoglobulin) may have less severe symptoms but a prolonged incubation period (14–20 days). Conversely, immunosuppressed patients may have more severe disease and can present without the typical rash.2

Cutaneous Lesions

The exanthem is characterized by erythematous, nonpruritic macules and papules that begin on the forehead and behind the ears (Fig. 192-2). The rash quickly progresses to involve the neck, trunk, and extremities (Fig. 192-3 and eFig. 192-3.1). The hands and feet are involved. Lesions may coalesce, especially on the face and neck (see Fig. 192-3.2). The rash usually peaks within 3 days and begins to disappear in 4–5 days. Desquamation may occur as the rash resolves.

Related Physical Findings

The entire illness may last up to 10 days, with some individuals also having vomiting, diarrhea, abdominal pain, splenomegaly, pharyngitis, otitis media, and generalized lymphadenopathy.4 Immunosuppressed patients are at higher risk for pneumonitis, acute encephalitis (1:1000 cases), and other fatal complications.4,8 Viral shedding may also be more persistent in these individuals.2,9

Atypical measles infection is rare, but seen in individuals who received formalin-inactivated measles vaccine (1963–1967) and were subsequently exposed to wild-type virus.4 Symptoms are often more severe with high fever, interstitial pneumonia, pleural effusions, extremity edema, hepatitis, and hyperesthesias occurring more commonly. Coryza, conjunctivitis, and Koplik spots are usually not present. The rash may be maculopapular, hemorrhagic, vesicular, or urticarial and spreads centripetally, making it difficult to distinguish from Rocky Mountain spotted fever.4

Laboratory Tests

The laboratory diagnosis of measles is based on virus detection or positive serologic findings.7 During the prodrome stage, virus can be found in nasopharyngeal secretions, blood, and urine. Viral culture has a low sensitivity for finding the virus but viral immunofluorescence tests may quickly detect measles in throat or nasopharyngeal specimens.10 Indirect enzyme linked immunoassay (ELISA), polymerase chain reaction (PCR), and reverse transcription-PCR assays can detect measles virus in clinical specimens such as nasopharyngeal secretions, oral fluid, serum, dried blood spots collected on filter paper and urine.7,11 Genotyping of viral isolates can determine patterns of transmission and importation. Genome sequencing can differentiate wild type and vaccine virus infection.2

Serologic studies demonstrate measles virus infection with a documented presence of measles IgM antibody and/or a significant increase in measles IgG antibody concentration in paired acute and convalescent titers. IgM antibody increases with the onset of the rash and lasts approximately 1 month. It may be absent or only transient in patients immunized with two vaccine doses.2,12 As the sensitivity of measles IgM assays may vary during the first 3 days after onset of rash, the test should be repeated in any suspected patient with a negative measles IgM assay and a generalized rash lasting more than 72 hours.2 IgG antibody appears 2 weeks after rash onset and peaks 4–6 weeks later.2 In the United States, measles should be reported to the local or state health department.

Differential Diagnosis

(Box 192-1)

Complications

Age-specific rates of complications are highest among children less than 5 years old and adults over 20 years. The most common complications of measles virus infection are otitis media, pneumonia, laryngotracheobronchitis, and diarrhea.2,13 Hepatitis, thrombocytopenia, and encephalitis occur less commonly. Thrombocytopenia-associated purpura may be severe. Pneumonia is the most common fatal complication of measles in children and the most common complication overall in adults.4,14 The disease severity is worse in immunocompromised and malnourished individuals, often resulting in the development of Hecht giant cell pneumonia.15

Subacute sclerosing panencephalitis (SSPE), a rare degenerative central nervous system disease that occurs 7–10 years after wild-type measles infection, is marked by seizures and behavioral and intellectual deterioration.2

Prognosis and Clinical Course

Clinical diagnosis of measles is typically made with onset of the characteristic rash as the prodromal symptoms can mimic influenza-like illnesses. Uncomplicated measles is self-limited, lasting 10–12 days. Malnutrition, immunosuppression, poor health, and inadequate supportive care can worsen the prognosis in any patient. In developing nations, measles is a major cause of infant mortality.

Treatment

Treatment for measles in the majority of cases is supportive, particularly to maintain good hydration. Patients should be on standard and airborne transmission precautions for 4 days after rash onset (entire duration of illness in immunocompromised patients).2 Patients with secondary bacterial infections need to be treated with appropriate antibiotics. Ribavirin may be considered, as it has been shown to inhibit measles virus in tissue culture and reduce the severity and duration of measles in some cases.2,4,16 In trials of patients with subacute sclerosing panencephalitis, however, no benefit was noted with the use of ribavirin.

Malnutrition and vitamin A deficiency can depress cell-mediated immunity in children, increasing the risk and severity of childhood infections. Measles virus infection decreases serum levels of vitamin A and can lead to higher risk of mortality from disease. The World Health Organization (WHO) and the United Nations International Children's Emergency Fund (UNICEF) issued a joint statement that vitamin A should be administered to all children with measles in communities where vitamin A deficiency is known or where measles mortality is at least 1%.2,17 A 2005 Cochrane review of vitamin A supplementation to treat measles in children found an association between using two doses of vitamin A on two consecutive days and a reduced risk of measles mortality in children less than 2 years old.2,18

All individuals at risk (infants less than 1 year of age, pregnant women, unimmunized, and immunocompromised) should receive immunoglobulin prophylaxis within 6 days of exposure to measles virus.2 If given within 72 hours of exposure, the individual may not be infected with the virus.4 Healthy individuals should receive 0.25 mL/kg of intramuscular immunoglobulin, and immunocompromised patients require 0.5 mL/kg.2 Exposed patients (excluding pregnant women and those with impaired immune systems) should also be given the measles vaccine 5–6 months later to confer lasting protection (Box 192-2).

Prevention (Immunizations)

The incidence of measles has decreased worldwide as a direct result of immunization. Two doses of the live attenuated measles vaccine (with first dose at or after 12 months of age) produces detectable levels of antibody in 99% of individuals, conferring lifelong immunity.2,4 Exposure to measles is not a contraindication to immunization. Measles vaccine may even provide protection in some cases if given within 72 hours of the exposure.2

Common potential side effects of measles vaccine include fever, local injection site reaction and transient morbilliform rash (7–10 days after vaccination; lasts 2 days) that resolve without treatment. Less common adverse reactions include thrombocytopenia and transient neurologic reactions.2,19

Measles vaccine administration is contraindicated in individuals who have a moderate to severe illness as well as those who have had an immediate anaphylactic reaction to a previous measles vaccine. It is also contraindicated in pregnant women and those with impaired immune systems (human immunodeficiency virus infection, immunosuppressive therapy). Hypersensitivity reactions can occur to components of the vaccine such as gelatin, neomycin, or egg white cross-reacting proteins.2,20

There have been many unconfirmed, unsubstantiated but widely publicized reports suggesting a potential link between measles-mumps-rubella (MMR) vaccine and the development of autism and possibly inflammatory bowel disease and atopic disorders. Current scientific evidence does not support a causal link between MMR vaccine and autism, inflammatory bowel disease or atopic disorders.21–25

Epidemiology

Rubella virus has a worldwide distribution with outbreaks occurring most frequently in late winter and early spring months. Humans are the only hosts for infection.26 School-aged children, adolescents, and young adults most often develop the disease. Epidemics occasionally occur in developing countries, especially where vaccines are unavailable.

Since introduction of the rubella vaccine in the United States in 1969, the incidences of rubella and congenital rubella syndrome have drastically declined with no widespread epidemics occurring in the United States. Since 2003, fewer than 20 cases are reported annually in the United States.27 Occasional outbreaks have largely been attributed to failure to vaccinate susceptible individuals. Yet, recent serologic surveys indicate that approximately 10% of the United States-born population >5 years old is susceptible to rubella.26,27 Epidemiologic studies have identified that individuals born outside the country or in a vaccine-poor area also have an increased risk of rubella.26

Etiology and Pathogenesis

Rubella is an enveloped positive-stranded RNA virus in the Togaviridae family that is spread through direct or droplet contact from nasopharyngeal secretions.26 Infected individuals shed virus for 5–7 days before and up to 14 days after onset of rash,28 with viremia unlikely after the rash occurs. In most individuals, infection leads to lifelong immunity.

Congenital rubella occurs when a nonimmunized, susceptible, pregnant woman is exposed to the virus. Transplacental infection of the fetus occurs during the viremic stage. The risk is greatest to a fetus exposed to the virus in the first trimester. Congenitally infected infants may shed the virus through urine, blood, and nasopharyngeal secretions for up to 12 months after birth, thus being a potential source of viral exposure to other susceptible individuals.26,28

Clinical Findings

History

Primary rubella infection is typically a mild, subclinical disease, particularly in adults.26,28 The prodrome is characterized by low-grade fever, myalgias, headache, conjunctivitis, rhinitis, cough, sore throat, and lymphadenopathy; symptoms that may last up to 4 days and often resolve with appearance of rash. Up to 50% of children with primary rubella infection may have a subclinical infection29 or present only with lymphadenopathy or rash (no prodrome).28 Conversely, older adults may have more severe and persistent prodromal symptoms that may make distinction from rubeola difficult in some situations. The presence of Koplik spots in the mouth favors rubeola. As the prodrome resolves and the rash begins to appear, some patients develop an enanthem consisting of tiny red macules on the soft palate and uvula (Forschheimer spots).30 This enanthem is not diagnostic for rubella.

Cutaneous Lesions

The exanthem, occurring 14–17 days after exposure, is characterized by pruritic pink to red macules and papules that begin on the face, quickly progressing to involve neck, trunk, and extremities (Fig. 192-4 and “Rubella At a Glance”).28 Lesions on the trunk may coalesce, whereas those on the extremities often remain more discrete. The rash usually begins to disappear in 2–3 days, unlike rubeola, which can be more persistent and clears the head and neck first. Desquamation may follow resolution of the rash.

Related Physical Findings

Lymphadenopathy is usually most severe in the posterior cervical, suboccipital, and postauricular lymph nodes and is noted up to 7 days before the rash appears.26 Enlargement of the nodes may persist for several weeks.

Adults, particularly women (up to 70%), may develop arthritis with rubella infection.26 Both small and large joints may be affected. Joint symptoms often first appear as the rash fades and can last several weeks. In some individuals, the symptoms may become persistent or recurrent. Joint swelling may progress to form a joint effusion.

Laboratory Tests

Diagnosis is typically made using serology to detect rubella-specific IgM antibody (up to 8 weeks after infection) or to document a fourfold rise in antibody titer in acute and convalescent-phase serum.26,30 Hemagglutination inhibition (less common), complement fixation, immunofluorescence assay, and ELISA are some of the methods used to detect antibodies.11 As with measles, rubella cases should be reported to local or state health departments.

Viral culture (nose, throat, blood, urine, CSF, and synovial fluid) is sensitive but often difficult due to the influence of timing, collection procedure and transport on the specimen.11 Reverse transcription PCR may be used to detect rubella virus from throat swab or oral fluid with subsequent genotyping of strains to identify a source during outbreaks.11,31 Complete blood cell count usually shows leukopenia with relative neutropenia. Increased numbers of atypical lymphocytes or abundant plasma cells may be noted as well. Patients with meningeal involvement have lymphocytes in the cerebrospinal fluid (CSF).

Congenital Rubella Syndrome

Women who are infected with rubella during pregnancy may only exhibit minor clinical symptoms. The effects, however, of rubella infection on the fetus can be profound,28 with the greatest risk of fetal malformation in the early stages of pregnancy. Up to 85% of fetuses exposed to rubella within the first 12 weeks of gestation develop serious sequelae such as: microcephaly with mental retardation, congenital heart disease (ventricular septal defect, patent ductus arteriosus, pulmonary artery stenosis), sensorineural deafness, cataracts, glaucoma, low birth weight, and fetal death.27,28,30 Neonatal manifestations of congenital infection include: growth retardation, interstitial pneumonitis, radiolucent bone disease, hepatosplenomegaly, thrombocytopenia, and dermal erythropoesis “blueberry muffin lesions.”26

Diagnosis of congenital rubella infection is obtained by isolating rubella virus in the throat, cataracts, urine, or CSF of the affected neonate. Serologic testing is not as sensitive but is easily available for confirmatory testing. IgM antibody can be detected from birth to 1 month of age; IgG antibody titers may be stable or increase over several months. Laboratory confirmation of congenital infection in children >1 year old is difficult as viral isolation is rare.26,28

Differential Diagnosis

(Box 192-3)

Complications

Rarely, rubella infection may lead to encephalitis (1 in 6,000 cases),30 with mortality rates varying from 0% to 50%.30 Other rare complications include: peripheral neuritis, optic neuritis, myocarditis, pericarditis, hepatitis, orchitis, and hemolytic anemia.28 Transient thrombocytopenia has been described in 1 in 3,000 children (usually girls); first appearing within days of rash onset and lasting days to months.28,32 Recently, cases of rubella-associated hemophagocytic syndrome and encephalitis have been described.33,34 Congenital rubella syndrome may predispose patients to developing diabetes mellitus.35

Prognosis and Clinical Course

Rubella is typically a self-limited disease. Infants who have congenital rubella are infectious until viral shedding from the nasopharynx and urinary tract ends. The majority of infants (85%) infected in utero excrete virus in the first month of life; 1%–3% continue to excrete virus in the second year of life.26,30 Pregnant women caring for these infants are at risk for developing rubella. Clinical course depends on how severely affected the fetus is from intrauterine infection.

Treatment

Treatment of primary, uncomplicated rubella is supportive. Standard and droplet precautions are recommended for patients with rubella for 7 days after rash onset.26 In nonpregnant individuals, rubella vaccine administration within 3 days of exposure may theoretically prevent illness, though this is yet to be proven.26 Limited data indicate that intramuscular immune globulin (0.55 mL/kg) as postexposure prophylaxis of rubella-susceptible patients may decrease infection, viral shedding and rate of viremia.26 However, absence of clinical signs after administration of immune globulin in a pregnant woman does not assure that congenital infection did not occur. IgM antibody can be used to detect maternal infection after exposure, even after immune globulin administration.26

Neonates with congenital rubella syndrome require supportive care as well as appropriate attention to significant health issues. These infants are contagious and should be isolated to prevent transmission to susceptible individuals.26,28 Contact isolation is recommended for these infants until they are at least 12 months old or if repeated cultures are negative after 3 months of age.26

Prevention (Immunizations)

Rubella vaccine is typically administered as part of a threefold vaccine (MMR) or fourfold vaccine (MMRV) at 12–15 months of age and again at 4–6 years of age. Seroconversion after a single dose of MMR vaccine occurs in 95% of individuals.26,27 It is imperative that individuals at risk for rubella infection are immunized, such as health care workers, military recruits, college students, and recent immigrants.26 Individuals are considered immune to rubella if they have documented vaccination with a live MMR on or after their first birthday, serologic evidence of rubella immunity, or were born after 1957 (except women of child-bearing age).26,30

Potential adverse reactions to rubella vaccine occur in susceptible individuals and include: fever (6–12 days after vaccine), morbilliform rash, lymphadenopathy, and arthralgia.26 Febrile seizures occur more frequently in children 1–2 years old when receiving the first MMR vaccine.26

Pregnant women should not receive the rubella vaccine due to theoretical risk to the fetus.36 Any woman receiving the rubella vaccine should not become pregnant for 28 days. Infants of vaccinated breast-feeding mothers may become infected with rubella via breast milk. Typically, they develop a mild erythematous exanthem of macules and papules with no serious effects.30 As rubella infection confers lifelong immunity, a woman who is reexposed during pregnancy has a low risk of having her fetus contract congenital rubella. Concern about possible infection can be addressed by looking for IgM antibodies in fetal serum (cordocentesis).

Epidemiology

Erythema infectiosum (fifth disease) is worldwide in distribution, can occur throughout the year, and can affect all ages. It tends to occur in epidemics, especially associated with school outbreaks in the late winter and early spring. Serologic studies show increasing prevalence of antibodies with age. Various studies indicate that from 15% to 60% of children 5–19 years of age and 30%–60% of adults are seropositive.37 Seroprevalence increases to greater than 90% in the elderly.37 Previous infection with B19 seems to confer lifelong immunity.

The incubation period for erythema infectiosum is from 4 to 14 days.38 After intranasal inoculation of parvovirus-infected serum to healthy volunteers, low-grade fever and nonspecific complaints occurred at the time of viremia, 6–14 days after inoculation, and the rash appeared at day 17 or 18.39 Parvovirus B19 is thought to be transmitted primarily by the respiratory route via aerosolized droplets during the viremic phase, and B19 DNA has been found in respiratory secretions of viremic patients.39 After the rash of erythema infectiosum appears, B19 is not found in respiratory secretions and is usually not present in the serum. This suggests that persons with erythema infectiosum are infectious only before the onset of the rash.

The virus seems to be effectively spread after close contact. The secondary attack rate among susceptible household contacts is approximately 50%. Transmission may occur via blood transfusion, from blood products, and vertically from mother to fetus.40 The transmission of B19 through blood transfusion is particularly problematic because the nonenveloped virus is not killed by the solvent detergents or heat that are used to inactivate HIV and hepatitis viruses.41

Etiology and Pathogenesis

The B19 virus belongs to the family Parvoviridae and the genus Erythrovirus.42 B19 lacks an envelope and contains single-stranded DNA. It is the smallest single-stranded DNA-containing virus known to infect humans, measuring 18–26 μm in diameter. Parvoviruses are widespread in veterinary medicine, but animal parvoviruses are not thought to be transmissible to humans.41

The pathogenesis of erythema infectiosum is unknown, but the mechanism may involve immune complexes. The more serious manifestations of parvovirus infection relate to the fact that the virus infects and lyses erythroid progenitor cells. Evidence suggests that the blood group P antigen (globoside) is a receptor of parvovirus. Because some individuals lack P antigen, they are not susceptible to infection with B19.43 In patients with increased red blood cell destruction or loss who depend on compensatory increase in red cell production to maintain stable red cell indices, B19 infection may lead to transient aplastic crisis. Such patients include those with anemia associated with acute or chronic blood loss. When parvovirus infects the erythroblasts in a developing fetus with decreased red cell survival, the result may be hemolysis and anemia.44 Anemia may trigger congestive heart failure, edema (fetal hydrops), and possibly fetal death.

Clinical Findings

Parvovirus B19 in Children

Most infections caused by B19 are asymptomatic and unrecognized. Fifth disease, the most common clinical picture associated with the virus, usually begins with nonspecific symptoms such as headache, coryza, and low-grade fever approximately 2 days before the onset of the rash.45 Patients may have headache, pharyngitis, fever, malaise, myalgias, coryza, diarrhea, nausea, cough, and conjunctivitis coinciding with the rash. Approximately 10% of children with erythema infectiosum develop arthralgias or arthritis. Large joints are affected more often than small joints.45 Occasionally, children may present with chronic joint complaints suggestive of juvenile idiopathic arthritis.46

The characteristic rash begins with confluent, erythematous, edematous plaques on the malar eminences, the “slapped cheeks” (Fig. 192-5). As the facial rash fades over 1–4 days, pink to erythematous macules or papules appear on the trunk, neck, and extensor surfaces of the extremities. These lesions have some central fading, giving them a lacy or reticulated appearance (Fig. 192-6).45 The rash can be morbilliform, confluent, circinate, or annular, and there have been reports of palmar and plantar involvement.38 The eruption typically lasts 5–9 days, but can recur for weeks or months with triggers such as sunlight, exercise, temperature change, bathing, and emotional stress. In some outbreaks, pruritus is a major feature of the rash in children.38

There have been occasional reports of parvovirus B19 associated with vascular purpura, including Henoch–Schönlein purpura.47 An enanthem consisting of erythema of the tongue and pharynx and red macules on the buccal mucosa and palate can occur.

Parvovirus B19 in Adults

Acute arthropathy is the primary manifestation of B19 viral infection in adults.48 It occurs mainly in women and affects the small joints of the hands and, knees. Other joints, such as the spine and costochondral joints, are occasionally involved. This symmetric polyarthritis is usually of sudden onset and is self-limited but can be persistent or recurrent for months. It may mimic Lyme arthritis or rheumatoid arthritis.

The constitutional symptoms are usually more severe in adults than in children.49 Fever, adenopathy, and a mild arthritis without a rash is the usual course. Women are more likely than men to have joint complaints and rash, whereas men often present with only a flu-like illness.48 Some adults may have fatigue, malaise, and depression for weeks after the infection. Asymptomatic infection can certainly occur in adults as well as in children. In one outbreak, 26% of adults were reported to be asymptomatic.48 Parvovirus B19 can cause numbness and tingling of the fingers with or without other features of fifth disease.50 Pruritus that is sometimes severe can occur with or without a rash. It has been suggested that if pruritus is a complaint in a patient with acute-onset arthritis, parvovirus should be considered as a possible cause.

The rash in adults, if present at all, is usually macular and blotchy or lacy, often on the extremities, and rarely demonstrates the characteristic slapped-cheek appearance.48 Other cutaneous manifestations associated with B19 infection in adults include purpura, vesicles and pustules, palmoplantar desquamation, a morbilliform exanthem with Koplik spots, and livedo reticularis.

Papular Purpuric Gloves‐and-Socks Syndrome

In 1990,51 a unique syndrome of pruritic erythema and edema of the hands and feet with petechiae, fever, and oral erosions was described. This rare exanthem, now known as papular purpuric gloves-and-socks syndrome, seems to affect teenagers and adults. However, it can affect children also.52 Patients usually have mild prodromal symptoms of fatigue and low-grade fever, myalgias, and arthralgias. Subsequently, itchy, painful, symmetric edema and erythema of the distal hands and feet occurs.53 Purpuric papules appear on the hands and feet with abrupt demarcation at the wrists and ankles. The enanthem, if present, arises on the lips, soft palate, and buccal mucosa. The syndrome resolves spontaneously within 2 weeks. Although many viruses have been implicated as causative agents for papular purpuric gloves-and-socks syndrome, B19 is the virus proven to cause the syndrome.54 Importantly, papular purpuric gloves-and-socks syndrome is contagious when the eruption is present, in contrast to erythema infectiosum.

Laboratory Tests

In patients with erythema infectiosum, laboratory results are usually normal, including reticulocyte count, hematocrit, and tests of liver and renal function. Patients with aplastic crisis have reticulocytopenia and anemia, the severity of which depends on the degree of underlying anemia. Reticulocytopenia, anemia, lymphopenia, neutropenia, and thrombocytopenia can occur in healthy individuals with B19 infection, although these are usually not significant enough to cause clinical symptoms. The erythrocyte sedimentation rate is rarely elevated, and rheumatoid factor has been positive in some cases of parvovirus-associated arthritis.

Detection of recent infection is usually performed with assays for IgM antibody. Radioimmunoassay or ELISA techniques can detect IgM within a few days after onset of illness. IgM can be measured for up to 6 months in many cases, although there is a decline in titer in the second month after onset. IgG can be identified with the same techniques by the seventh day of illness and lasts for years and is therefore best for documenting past infection. Parvovirus antibody is often not detectable in immunodeficient persons.

Special Tests

Histologic examination of various tissues demonstrates homogeneous, intranuclear inclusions with peripheral condensation of chromatin in erythroid precursor cells.55 Electron microscopy of these inclusions reveals parvovirus-like particles.55 In fetal tissues, a leukoerythroblastic reaction may also be seen. The histopathologic changes in the skin of patients with erythema infectiosum include a sparse superficial perivascular lymphocytic infiltrate that is not considered diagnostic.

PCR is used to detect B19 DNA.56 This technique is considered one of the most sensitive approaches for detection of the virus within a number of different specimens including serum or plasma, amniotic fluid, placental or fetal tissue, or bone marrow. It is considered the test of choice in an immunocompromised patient. Immunohistochemical techniques can be used to detect B19 parvovirus antigen in a number of different tissues.

Differential Diagnosis

(Box 192-4)

Complications

As more attention is focused on parvovirus B19, an increasing number of complications are recognized. Subclinical infection is quite common. However, this virus can be responsible for a variety of hematologic, rheumatologic, and neurologic abnormalities.

Transient Aplastic Crisis

Parvovirus B19 is the most common cause of transient aplastic crisis in patients with chronic hemolytic anemias.57 This has been demonstrated in sickle cell anemia, hereditary spherocytosis, heterozygous β-thalassemia, pyruvate kinase deficiency, and autoimmune hemolytic anemia, as well as in other conditions of decreased red cell production or increased red cell destruction. The aplastic crisis may be the initial manifestation of the underlying hematologic disease.58 Patients typically have fever and constitutional complaints, followed 1 week later by fatigue, pallor, and worsening anemia.59 Cutaneous manifestations are rarely seen with the aplastic crisis. The hemoglobin may fall below 4 μg/dL and is not associated with reticulocyte production. Bone marrow examination shows hypoplasia or aplasia of the erythroid series. Red blood cell transfusion may be necessary, and most patients recover in 1 week, although the problem can be fatal if untreated. Transient red cell aplasia can occur in healthy persons without underlying hematologic abnormalities.60 It is likely that the aplasia is missed in individuals without disorders of shortened erythrocyte survival because the hemoglobin does not drop low enough to cause symptoms.

Chronic B19 Infection

In immunocompromised patients, B19 infection can cause a serious, prolonged anemia from persistent lysis of red blood cell precursors.60 Parvovirus-related chronic anemia has been reported in HIV-infected patients, as well as in transplant recipients and those with congenital immunodeficiencies, acute leukemias, lupus erythematosus, and during the first year of life without immunodeficiency. These patients respond dramatically to intravenous γ globulin, suggesting that antibody is the main defense to human parvovirus infection.61

Fetal B19 Infection

Fetal infection with B19 may result in either an unaffected fetus or spontaneous abortion (especially in the first half of pregnancy), hydrops fetalis in the second half of pregnancy, congenital anemia, and even late fetal death.62 Nonimmune fetal hydrops is the most common complication of intrauterine infection with B19. Because B19 virus can infect erythroid precursors, extensive hemolysis can occur in the fetus, leading to severe anemia, tissue anoxia, high-output heart failure, and generalized edema. The fetus may show ultrasonographic evidence of subcutaneous edema, ascites, pleural effusion, pericardial effusion, placental edema, and polyhydramnios. The overall risk of fetal death is not clearly known, but recent studies suggest that this risk is approximately 6.5% with maternal infection.62 The risk of fetal death for a woman with unknown serologic status is estimated to be less than 2.5% after a household exposure and less than 1.5% after a significant work exposure. It seems that in B19-infected pregnant women, most fetuses are not infected; if they are infected, usually there is not an adverse outcome.63 Furthermore, approximately one-half of women of childbearing age are immune to parvovirus infection because of prior infection.

Because parvoviruses are known teratogens in animals, there has been much concern about whether they cause birth defects in humans. In sera collected from 253 infants with a wide range of congenital abnormalities, there was no parvovirus-specific IgM detected to suggest recent infection.64 There has been one report of a B19-infected abortus with eye abnormalities,65 and another of an infected abortus with cleft lip, cleft palate, and micrognathia.66 Rare reports describe cardiac abnormalities.67 neurologic problems,68 and “blueberry muffin” nodules.69 It has been concluded from these few studies that parvovirus B19 is not a common cause of birth defects.

Other Complications

There are reports of B19 infection causing encephalitis, meningitis, brachial neuritis, a myasthenia-like syndrome, and motor weakness. Parvovirus infection has been blamed for a granulomatosis with polyangiitis (Wegener's) illness,70 polyarteritis nodosa,71 Kawasaki disease,72 and a systemic lupus erythematosus-like picture.73 In addition, there are reports of other hematologic complications including idiopathic thrombocytopenic purpura, transient neutropenia, myocarditis, a hemophagocytic syndrome, and the Blackfan–Diamond syndrome.

Prognosis and Clinical Course

Parvovirus B19 infection in healthy individuals is self-limited. The eruption of erythema infectiosum and the parvovirus arthropathy usually resolve in 1–2 weeks, but can recur or persist for months. If untreated, transient aplastic crisis can be fatal, but most patients recover in 1 week. Chronic anemia from B19 usually resolves if treated with γ globulin. Fetal hydrops can lead to fetal death if not treated.

Treatment

There is no specific treatment available for parvovirus B19 infection. Erythema infectiosum is a benign condition, and usually no treatment is necessary. Supportive therapy for relief of fatigue, malaise, pruritus, and arthralgia may be needed. The chronic anemia of persistent B19 infection may be treated successfully with commercially available intravenous immunoglobulin, which contains neutralizing anti-B19 antibodies. Transient aplastic crisis, which can be life threatening, may require oxygen therapy and blood transfusion.

Serologic testing for B19 IgG and IgM should be offered to pregnant women who are exposed to parvovirus B19. Infected pregnant women are followed by frequent ultrasonograms. Evidence of hydrops fetalis warrants umbilical cordocentesis to check for anemia, viral DNA, IgG, and IgM. The management of infected fetuses is controversial. Some physicians advocate observation because spontaneous resolution is common. Fetuses with severe anemia and compromise are usually managed with intrauterine exchange transfusion, but this procedure does carry risk (Box 192-5).

Prevention

There is currently no vaccine to prevent parvovirus B19 infection. Candidate vaccines are in clinical trials.74 It is not known whether immunoglobulin given around the time of exposure prevents infection or alters the course of the disease.

Because patients with erythema infectiosum are no longer infectious by the time they develop the illness, control measures directed toward these individuals are not likely to be effective. If these persons are hospitalized, no special precautions need to be taken. Because the virus is transmitted before the rash appears, the disease is easily spread in situations of close prolonged contact such as schools, day care centers, workplaces, and homes.

Patients with aplastic crisis or immunosuppression with chronic B19 anemia may have high-titer viremia and are particularly infectious. These individuals should be placed in respiratory and contact isolation if hospitalized, and pregnant health care providers should not care for them directly. Hospital workers are at risk of contracting nosocomial infections from these patients75 and could spread the virus to patients if adequate precautions are not taken.

Epidemiology

Epstein–Barr virus (EBV) is a worldwide pathogen with more than 90% of adults latently infected.76 In developed countries, most cases of primary infection occur during adolescence or early adulthood, and clinically may present as infectious mononucleosis.77 Primary infection may occur during childhood; however, is often subclinical, probably because children are better able to clear the infection. In developing countries, most of the population is infected during childhood, thus infectious mononucleosis is much less common.

EBV is transmitted primarily by saliva through close contact.78 Viral replication occurs during primary infection, allowing infectious viral particles to be shed from the oropharynx. There are also reports of EBV acquired via blood transfusion.79 It is also thought that EBV may be transmitted through breast milk80 and genital secretions.81

Etiology and Pathogenesis

EBV, also called human herpesvirus 4 (HHV-4), belongs to the Herpesviridae family and is approximately 180–200 nm in diameter.78 The double-stranded DNA genome encodes approximately 100 proteins and is enclosed within a capsid. The capsid is surrounded by an envelope, composed primarily of glycoprotein gp350. CD21 is present on the surface of B cells and binds with gp350, allowing entry of EBV into the cell.

EBV infects B lymphocytes directly within the oral mucosa or infects mucosal epithelial cells, which then infect the B lymphocytes.82–84 The infected B cells are activated, and their population is expanded. These B lymphocytes allow dissemination of the virus throughout the lymphoreticular system.85 A clonal expansion of cytotoxic T lymphocytes allows recovery from primary infection and is the source of the atypical lymphocytes associated with EBV infection.86 Symptoms likely result from this immunologic response.

EBV establishes an indefinite latent infection within the B cells, during which time low levels of the latent proteins are produced.86 The previously linear DNA forms a circular structure, called an episome. Thereafter, B cells may reactivate and reinfect the oropharynx; replication and shedding of the viral DNA allows transmission of the virus to new hosts.78,85

Clinical Findings

History

There is an incubation period of 30–50 days. Primary infection with EBV in adolescents and adults typically results in infectious mononucleosis, or the “kissing disease.” The classic triad of fever, lymphadenopathy, and pharyngitis are noted in more than 50% of patients.78 The fever may range from 37.5°C (99.5°F) to 40.5°C (104.9°F) and lasts 1–3 weeks. Lymphadenopathy is tender and characteristically found in the posterior cervical chain. Examination of the posterior pharynx may vary from mild erythema to grossly enlarged tonsils with white exudates.85

Cutaneous Lesions

Seventy percent to 100% of patients with infectious mononucleosis develop an eruption when antibiotics, specifically ampicillin, are administered.83 Similar rashes have been reported with other antibiotics, such as amoxicillin, cephalexin, erythromycin, and levofloxacin. The rash typically begins 7–10 days after the initial administration of antibiotics. A pruritic, erythematous, morbilliform, or scarlatiniform eruption is noted on the trunk and extremities. The rash has been described as copper colored. Coalescence may be observed on the extensor surfaces and dependent areas. (Fig. 192-7 and see eFig. 192-7.1). The palms, soles, or oral mucosa may be involved. Clearance, which is usually within 7 days,87 is accompanied by prominent desquamation.86 The rash is thought to be a result of EBV-induced antibodies that are produced in response to the administered drug; these antibodies subsequently form immune complexes, which fix complement.83 This exanthem does not usually indicate a permanent allergy to the medication.87

An exanthem due to EBV alone occurs in a minority of cases (approximately 5%–15%),83,87 and can similarly be morbilliform and pruritic; however, usually it commences during the first few days of illness and resolves faster, typically in 1–6 days.86,87 Periorbital and eyelid edema may be seen in up to 50% of those with infectious mononucleosis.89 In approximately 25% of cases, an enanthem is noted. Six to 20 petechiae, measuring 0.5–1.0 mm, may be visualized at the junction of the hard and soft palate. Lesions may coalesce forming larger lesions.

Erythema multiforme, erythema nodosum, acrocyanosis, erythema annulare centrifugum, pityriasis lichenoides, palmar dermatitis, cold urticaria, and granuloma annulare have all been reported during infection with EBV.86

Genital ulcers may occur during primary infection with EBV (Fig. 192-8).90,91 They may occur prior to the onset of other features of infectious mononucleosis or occasionally after the fever and lymphadenopathy.92 They are well circumscribed, painful, and deep with a red-violaceous border. The base of the ulcer can be clear, seropurulent, or with granulation tissue. They frequently occur on the labia minora.93 If bilateral, they are often symmetric with a “kissing” pattern. It is unclear at this point whether the ulcer is caused directly by the virus or whether it is due to a host immune response. Biopsy is typically nonspecific and nondiagnostic. The ulcers heal in approximately 2–3 weeks, and treatment is symptomatic.

EBV is currently the most common cause of Gianotti–Crosti syndrome.94 In children, primary infection with EBV is often mild or asymptomatic; as a result, typical features of infectious mononucleosis are usually not observed.86

Related Physical Findings

Associated symptoms and signs may include fatigue, rigors, headache, and hepatosplenomegaly.95

Laboratory Tests

Most patients with infectious mononucleosis demonstrate lymphocytosis, with lymphocytes often accounting for more than 50% of the absolute white blood cell count.96 Atypical lymphocytes are a hallmark, and typically represent more than 10% of total lymphocytes; most of these cells represent activated T cells responding to infected B cells.78 Mild, transient neutropenia97 and thrombocytopenia98 are common. Transaminases are elevated in more than 80% of patients with infectious mononucleosis.99

The presence of heterophile antibodies confirms most cases of infectious mononucleosis.100 Heterophile antibodies recognize antigens on the erythrocytes from a number of different species, including horses, sheep, bulls, and humans; however, they do not recognize EBV. They are thought to be a result of polyclonal stimulation during the viral infection,101 and can occasionally be detected (false positives) in other illnesses such as lymphoma, hepatitis, or autoimmune disease.100 Heterophile antibodies typically appear within 1 week of the onset of symptoms, peak within 2–5 weeks, and may persist for up to 1 year. They are not the ideal diagnostic test in children less than 4 years old, as sensitivity is quite low.95 In the past, the Paul–Bunnell test had been used with sheep erythrocytes.100,96 Currently, the more sensitive monospot test is used, which is a latex agglutination assay with horse erythrocytes to look for heterophile antibodies. Up to 10% of patients with EBV mononucleosis never develop heterophile antibodies; this is referred to as heterophile-negative mononucleosis.

A number of antibodies specific to EBV develop in the course of disease as well.100,95 Measurement of these specific antibodies may be warranted if infectious mononucleosis is suspected and heterophile antibodies are negative. IgM and IgG antibodies form to viral capsid antigen (VCA) and are both present at onset of disease. IgM VCA antibodies wane after approximately 3 months; IgG VCA antibodies persist for life and are a marker for previous infection. IgG antibodies to EBV nuclear antigen develop 6–12 weeks into the course of disease and also persist for life. IgG to early antigen develops at the onset of disease and is made up of two subsets of antibodies, anti-D and anti-R. The presence of anti-D antibodies suggests recent infection, although 30% of patients do not produce antibodies at all. Anti-R antibodies have no clinical significance. Thus, primary infection may be most easily diagnosed in the presence of IgM and IgG VCA antibodies as well as negative IgG EBV nuclear antigen antibodies.102

Histopathology

The morbilliform exanthem associated with EBV demonstrates nonspecific histopathologic findings.103 There is usually a mild perivascular infiltrate of inflammatory cells. Specific cutaneous manifestations may show their characteristic pathologies.

Differential Diagnosis

(Box 192-6)

Complications

Complications of infectious mononucleosis occur in approximately 20% of patients and include airway obstruction, autoimmune hemolytic anemia or thrombocytopenia, neutropenia,85 myocarditis, and hepatitis.80 Neurologic complications occur in approximately 5% of patients.85 Examples include encephalitis, meningitis, and Guillain–Barré syndrome.78 The risk of splenic rupture is estimated at 0.1% and is spontaneous in greater than one-half of cases.104 Between 3% and 30% of patients with infectious mononucleosis also have concomitant group A streptococcal pharyngitis.96 Finally, in some patients, fatigue and hypersomnia can persist up to 6 months.105

Prognosis and Clinical Course

Recovery from infectious mononucleosis is typically over 2–3 weeks without specific treatment.100 Disease may be more protracted in older adults. Chronic active EBV infection occurs rarely.78 It begins as a primary EBV infection and persists for more than 6 months with severe illness and histologic evidence for organ disease. EBV DNA or antigens can be demonstrated from tissue, and usually EBV antibody titers are significantly elevated.

Treatment

Treatment for uncomplicated infectious mononucleosis is symptomatic (Box 192-7).95 Acetaminophen or nonsteroidal anti-inflammatory agents may be useful in treating the fever or throat discomfort. Because splenomegaly is often an associated finding, contact sports should be avoided until the spleen has returned to its normal size to avoid splenic rupture.

Systemic corticosteroids may decrease the duration of fever or pharyngeal symptoms, but in general, are not recommended for uncomplicated disease.77

There have been complications such as encephalitis or meningitis associated with steroid treatment of infectious mononucleosis. Oral steroids may be considered in patients showing signs of impending airway obstruction, thrombocytopenia, or hemolytic anemia.

A meta-analysis of five randomized controlled trials evaluating acyclovir in the treatment of infectious mononucleosis showed that there was decreased oropharyngeal shedding of the EBV; however, there was no overall clinical benefit demonstrated.106 A multicenter, double-blind, placebo-controlled study involving 94 patients with acute infectious mononucleosis revealed that acyclovir and prednisolone also reduced oropharyngeal replication of virus but did not affect duration of symptoms.107

Prevention

Because infectious mononucleosis is often mistaken for a bacterial infection, antibiotics may initially be used to treat. Antibiotics should be avoided in infectious mononucleosis as an exanthem is much more likely to occur in this setting.

Vaccinations are currently being investigated and may prove to be helpful in preventing EBV infections in the future, particularly in high-risk patients.78

Oral Hairy Leukoplakia

Lymphoproliferative Disease and Malignancy

The latent infection established by EBV has been linked to the development of several malignancies, including nasopharyngeal carcinoma, Burkitt lymphoma, and Hodgkin lymphoma.78 EBV-associated malignancies occur mainly in patients who are immunocompromised due to HIV infection, congenital immunodeficiencies, or those who receive immunosuppressant therapy such as organ transplant recipients. It is thought that the latent infection of B cells allows transformation and immortalization, allowing the development of a neoplasm to occur.114 Different EBV genes are expressed in each type of malignancy and the biology is quite complex.

Nasopharyngeal carcinoma occurs sporadically in the United States and in Western Europe, is common among Alaskan Eskimos, and is endemic in Southern China, Southeast Asia, and in the Mediterranean basin.115 This neoplasm may clinically present with bloody nasal drainage, otitis media, or cranial nerve palsies. Metastasis to the lymph nodes occurs early; thus lymphadenopathy of the head or neck may be the initial presentation. Skin metastases can rarely be the presenting sign, usually appearing as dermal or subcutaneous nodules.116 Clubbing and dermatomyositis have rarely been reported in association with nasopharyngeal carcinoma. EBV is present in the malignant epithelial cells yet is not found in the lymphocytes.78

African Burkitt lymphoma is a mature B-cell neoplasm endemic to Equatorial Africa that involves overexpression of the c-myc oncogene.117 It typically affects children and presents with tumors of the jaw or facial bones.117,118 A sporadic subtype in Western Europe or the United States demonstrates abdominal involvement. The immunodeficient subtype typically occurs in HIV-positive patients and appears most frequently in the abdomen. Virtually all cases of endemic Burkitt lymphoma are associated with EBV as well as a previous malarial infection, whereas the sporadic variant is associated with EBV is less than 20% of cases.118,119 Dissemination to the skin is extremely rare; however, marked lymphadenopathy is commonly observed.118 Biopsy of lesions show a neoplasm of medium-sized cells with abundant basophilic cytoplasm, as well as apoptotic debris and macrophages ingesting apoptotic tumor cells, creating the “starry sky” appearance.

Hodgkin disease is a malignant lymphoma with bimodal age distribution.120 In developed countries, the peaks are in young adulthood and in older adults. In developing countries, children as well as older adults are more frequently affected. EBV is associated with Hodgkin lymphoma in 30%–50% of cases. EBV is linked to Hodgkin disease more commonly in developing countries, in children, and in the setting of immunodeficiency. The majority of patients have a painless mass, frequently in the neck.121 Hodgkin disease has associated skin lesions in 17%–53% of patients.122 The majority of cutaneous findings are nonspecific and considered paraneoplastic in nature. Examples include severe pruritus, eczema, ichthyosis, urticaria, erythroderma, erythema nodosum, and associated mycosis fungoides. Cutaneous infiltration by Hodgkin disease is rarer, and typically occurs in the setting of advanced disease. Findings may include ulcerated nodules, plaques, tumors, papules, or erythroderma. Pathology consists predominantly of an inflammatory infiltrate with scattered characteristic Reed–Sternberg cells, which are CD30+, CD15+, binucleate large cells with eosinophilic nuclei.120 Treatment is radiotherapy, chemotherapy, or a combination.

Certain types of cutaneous T-cell lymphoma have been found to be associated with the EBV. Chronic ulcers, subcutaneous nodules, and violaceous tumors have been noted in patients with angiocentric T/natural killer-cell lymphomas, T large-cell lymphomas, and systemic T-cell lymphoma with cutaneous involvement.123 Necrotic nasal masses, which may affect surrounding skin as well, can also occur in angiocentric T/natural killer-cell lymphomas. EBV may also be associated with subcutaneous panniculitic T-cell lymphoma, which clinically presents as a panniculitis.124 Histologically, there are atypical lymphocytes in the lobules of the fat as well as phagocytizing “beanbag cells” (eFig. 192-8.1).

Vesiculopapular lesions on the face of a child, resembling hydroa vacciniforme, may be associated with EBV and have a malignant potential. Hypersensitivity to mosquito bites with erythematous swellings or ulcers may also be linked to latent EBV infections. This phenomenon may indicate high risk for progression to a malignant neoplasm.

Kikuchi Histiocytic Necrotizing Lymphadenitis

Epidemiology

Gianotti–Crosti Syndrome, also known as infantile papular acrodermatitis and papular acrodermatitis of childhood, is a common, self-limited dermatosis seen worldwide. It affects infants and children between the ages of 6 months and 12 years with the peak age of presentation being 1–6 years of age. Cases have a seasonal predilection, most often occurring in spring and early summer. In children, there is neither an ethnic nor sexual predilection.129,130 There have been only scattered case reports in adults, exclusively in women.

Etiology and Pathogenesis

GCS is a cutaneous reaction pattern associated with viruses, bacteria, and vaccines. The exact pathogenesis is unclear. However, there is some suggestion that immunizations or immune imbalance may enhance the risk of developing the exanthem following certain infections. A recent study showed an increased incidence of a personal or family history of atopy in children with GCS.131

Historically, it was thought to be induced exclusively by hepatitis B, but over time other infectious triggers have been identified. When hepatitis B is the causative agent, subtype ayw is most frequently seen.132 However, with widespread immunization against Hepatitis B, most cases found in Europe, India, the United States, and Canada are not associated with Hep B infection. EBV is the most common cause in the United States and can be due to initial infection or reactivation.133 Other associated viruses include cytomegalovirus, enterovirus, respiratory syncytial virus, rotavirus, adenovirus, echovirus, pox virus, poliovirus, coxsackie virus (A16, B4, and B5), parvovirus B19, HIV, hepatitis A, hepatitis C, mumps virus, HHV-6, vaccinia virus, rubella virus and parainfluenza virus. Bacterial pathogens include Mycoplasma pneumoniae, Borrelia burgdorferi, Bartonella henselae, and group A β-hemolytic streptococcus. Immunizations that have been associated include influenza, diptheria-pertussis-tetanus (DPT), bacillus Calmette–Guérin, Haemophilus influenzae type b, MMR, hepatitis B, Japanese encephalitis and oral polio vaccine. Although many groups have tried using both electron microscopy and immunohistochemistry, neither viral particles nor viral antigens have been demonstrated in skin lesions of GCS.134,135 Thus, today it is accepted that the mechanism of lesion development does not involve a direct local interaction between viral antigens and immune-competent cells inthe skin.

Clinical Findings

History

Before the onset of the exanthem, a nonspecific prodrome of upper respiratory tract symptoms with fever and pharyngitis plus lymphadenopathy may be present.

Cutaneous Lesions

Regardless of the cause, the clinical features in all cases tend to be the same. Typically, patients abruptly develop multiple coalescing, monomorphous, flat-topped or dome-shaped, red–brown papules and papulovesicles (Fig. 192-9 and see eFig.192-9.1 and eFig. 192-9.2). Lesions can be pruritic and, rarely, hemorrhagic. Papules vary from 1 to 10 mm in diameter (see Fig. 192-9B) and are distributed symmetrically on the cheeks, extensor surfaces of the extremities, and the buttocks. The trunk, palms, and soles are usually, but not always, spared. Occasionally, the small papules coalesce into large plaques. Cutaneous lesions evolve over a few days and last for 2–8 weeks.

Related Physical Findings

Constitutional symptoms, including malaise, low-grade fevers, and diarrhea, are sometimes seen at time of presentation, but are usually mild. Patients can develop lymphadenopathy, especially of the cervical, axillary, and inguinal chains.136

Laboratory Tests

In most patients, the diagnosis is established on clinical findings and no further diagnostic testing is necessary. In patients with hepatomegaly, further diagnostic testing, including complete blood cell count and liver enzymes, may be warranted. Lymphocytosis or lymphopenia are common and do not require further diagnostic evaluation. If there are elevations in the liver enzymes, evaluation for hepatitis or EBV should be performed. If hepatitis is suggested, checking anti-hepatitis A IgG and IgM, hepatitis B surface antigen and core antibody, and anti-hepatitis C IgG is indicated.

Differential Diagnosis

(Box 192-8)

Complications

Complications are rare with the majority of cases having a self-limited and mild course. On rare occasions, when GCS is associated with hepatitis B infection, chronic liver disease with subsequent liver failure can occur.137

Prognosis and Clinical Course

In the vast majority of cases, GCS is a self-limited, benign process that usually resolves within 3–4 weeks. The course is quite variable, with the skin findings lasting anywhere from 5 days to 12 months.136,138 Lesions heal without scarring, and, rarely, postinflammatory hypopigmentation or hyperpigmentation is seen. Lymphadenopathy can last for several months.132 In cases associated with hepatitis B, an anicteric viral hepatitis evolves and may not be seen until 2 weeks after cutaneous lesions are seen. Most of the time, the hepatitis is self-limited.

Treatment

No treatment is necessary in the majority of cases. In some patients, medium potency topical steroids may decrease the duration of lesions when applied once daily for 1–2 weeks. However, patients should be monitored closely because worsening of findings with topical steroid use has been documented.139 In severe cases, systemic, pulsed corticosteroids may be administered.140 Oral antihistamines or topical anti-itch lotions may diminish severe pruritus.

Prevention

There is no known way to prevent GCS.

Epidemiology

Human cytomegalovirus (HCMV) is ubiquitous around the world. The seroprevalence in the population increases with age, with 10%–20% of children infected before they reach puberty.141 By adulthood, the prevalence of HCMV is 40%–100%. For unclear reasons, there is a higher prevalence in developing countries and areas of low socioeconomic status. HCMV is the most common congenital viral infection in humans with an incidence of 0.2%–2.2% of live births in the United States.142 Five percent to 17% of congenital infections exhibit neurodevelopmental sequelae.143 Nearly all HIV-infected patients are infected with HCMV.144 It is a significant cause of morbidity in bone marrow transplant (BMT) and solid organ transplant (SOT) patients, with 50%–90% of patients infected.142

Etiology and Pathogenesis

Clinical Findings

Congenital Human Cytomegalovirus Infection

History

Congenital HCMV (cytomegalic inclusion disease of the newborn) occurs mostly in children of primiparous women with primary infection during pregnancy. Fifty-five percent of maternal primary HCMV infections results in intrauterine HCMV infection of the fetus, and approximately one-third of those are symptomatic.149 Reactivation or secondary HCMV infection of a HCMV-immune woman during pregnancy rarely results in symptomatic HCMV infection for the baby.149

Cutaneous Lesions

Cutaneous findings in the newborn include a petechial rash secondary to thrombocytopenia, jaundice due to hepatitis and blueberry muffin lesions (Fig. 192-10) from dermal erythropoiesis. In one study, approximately 70% of children with symptomatic congenital HCMV infections had petechiae and jaundice.150 Dermal erythropoiesis, also known as thrombocytopenic purpura or blueberry muffin syndrome, can also be seen with congenital rubella,151 toxoplasmosis, and blood dyscrasias. These purpuric lesions are present at birth and evolve during the first 24–48 hours of life. They are papular and range from 2 to 10 mm in diameter. Lesions are initially dark blue to violaceous and fade to red or copper–brown. They regress during the first 6 weeks of life despite continued presence of the virus. Histology shows plaque-like aggregates of nucleated cells and nonnucleated erythrocytes in the reticular dermis.152

Related Physical Findings

Related findings include hepatosplenomegaly in virtually all newborns, microcephaly, periventricular calcifications, ventriculomegaly, encephalitis, chorioretinitis, hearing loss or neurodevelopmental sequelae, intrauterine growth retardation, and postnatal failure to thrive. Studies show that 22%–65% of symptomatic and 6%–23% of asymptomatic children have hearing loss after congenital HCMV infection.153

Perinatal Human Cytomegalovirus Infections

History

Perinatal infection with HCMV is very different from congenital HCMV infection, without diffuse visceral or central nervous system involvement.149 Transmission of the virus occurs via cervical secretions, breast milk, or blood transfusions between 4 and 16 weeks of age. It is usually asymptomatic, although it may be manifested by self-limited lymphadenopathy, hepatosplenomegaly, or afebrile pneumonitis.

Cutaneous Lesions

There are usually no cutaneous findings with perinatal HCMV infection. Uncommon presentations for HCMV infection in infants and children include scleroderma, Giartti–Crosti syndrome128,154 gray pallor, hepatosplenomegaly with self-limited respiratory deterioration in preterm infants,155 and cutaneous vasculitis.155 Perineal ulcers have been reported in an immunocompetent preterm infant.156

Human Cytomegalovirus Infection in Immunocompetent Adults and Children

History

Although primary HCMV infection in the immunocompetent patient is usually asymptomatic, some can present with an infectious mononucleosis-like picture.157 Approximately 10% of infectious mononucleosis cases are caused by HCMV. Symptoms and signs are indistinguishable from EBV-induced mononucleosis, including fever, malaise, splenomegaly, hepatitis, peripheral, and atypical lymphocytosis. Unlike EBV mononucleosis, HCMV-induced mononucleosis patients do not typically have pharyngitis and lymphadenopathy.158 Given the lack of heterophile antibodies, HCMV mononucleosis is also known as heterophile-negative mononucleosis. Postperfusion syndrome is the term used when HCMV mononucleosis occurs between 3 and 6 weeks after exposure to blood products.159

Reactivation of various herpesviruses including HCMV, EBV, HHV6, and HHV7 has been reported in the setting of drug induced hypersensitivity syndrome (DIHS), which, in some cases, might lead to multiorgan failure after the offensive drug is discontinued.160

Cutaneous Lesions

A few patients with HCMV mononucleosis develop a rubelliform or morbilliform eruption; if given ampicillin, 80%–100% develop a morbilliform rash within 1 week (see eFig. 192-10.1).161 There have been reports of erythema nodosum162 and urticaria83 associated with acute HCMV mononucleosis. Cutaneous ulcers due to CMV have been reported in patients with severe cases of DIHS.163

Human Cytomegalovirus and the Immunocompromised

History

Immunocompromised patients are at risk for HCMV primary infection as well as reactivation resulting in persistent viremia and disseminated systemic disease.164 Immunosuppressive agents such as azathioprine and cyclophosphamide alone can reactivate HCMV disease, as can systemic corticosteroids in conjunction with other immunosuppressive agents.

Solid Organ Transplant Recipients

SOT recipients not infected with HCMV receive an organ from an HCMV-positive individual are at highest risk of developing HCMV disease posttransplantation. Other risk factors include therapy with anti-T-cell antibody (OKT3)165 and those who undergo HHV-6 seroconversion.166 Initial infection of the transplanted organ is followed by pneumonitis, enteritis, hepatitis, retinitis, and central nervous system disease.167

Bone Marrow Transplant Patients

The risk of HCMV disease in BMT patients is lower with the use of seronegative donors and use of leukocyte-depleted blood products.168 Risk factors for reactivation include a seropositive recipient, graft-versus-host disease (GVHD), and T-cell depletion of allograft. Pneumonitis has a 60%–80% mortality without treatment and 50% mortality with antiviral treatment and cytomegalovirus immune globulin.

Human Immunodeficiency Virus-Infected Patients

HCMV retinitis was seen in up to 25% of HIV-infected patients before the use of highly active antiretroviral therapy (HAART).169 Now, immune recovery vitreitis with posterior segment inflammation is seen as CD4 counts recover after initiation of HAART.170 Encephalopathy, peripheral polyradiculopathy, pneumonitis,167 and colitis171 may occur.

Cutaneous Lesions

Cutaneous manifestations of HCMV disease in immunocompromised patients are rare compared with involvement of other organs. Perianal and rectal ulceration are most common (Fig. 192-11).172 Also seen are indurated hyperpigmented nodules or plaques,173 papular and purpuric eruptions,172 vesiculobullous lesions,174 purpura, petechiae,175 indurated plaques, and nodules (see eFig. 192-11.1). Verrucous and necrotic nodules have been reported in HIV-infected patients.164 Some of these cutaneous manifestations may be caused by infection of the endothelium of cutaneous blood vessels.176

Laboratory Tests

The gold standard for diagnosis of HCMV infection is viral culture from blood using human fibroblasts. Infection is determined by cytopathic effect. However, it takes days to several weeks to see the cytopathic effect in culture. The diagnosis of congenital HCMV infection can be made by detection of virus in urine or saliva via culture or PCR (Fig. 192-12).177

The characteristic histologic feature of cytomegalovirus (CMV) infection is cytomegalic cells with nuclear inclusions. In the skin, enlarged endothelial cells with large intranuclear inclusions and a clear halo (owl's eye cells) are seen in small dermal vessels.178 Cytopathic changes seen in the vascular lumen vary according to the stage of infection of each cell, including intranuclear and intracytoplasmic inclusions (Figure 192-13). Histologic diagnosis is specific but sensitivity is low.179

Various fast and reliable methods for detection of HCMV antigens and nucleic acids in cells and tissue are available. These include HCMV antigenemia assay (detects pp65 in peripheral blood neutrophils), hybrid capture assay (detects HCMV DNA in leukocytes), and quantitative and qualitative PCR. In immunocompetent individuals, IgM is usually positive during primary infection. The reported sensitivity of commercially available ELISA for HCMV IgM varies. Rheumatoid factor and EBVIgM may yield false-positive results.180 IgG may be negative during active infection, but subsequent fourfold rise in IgG titer is indicative of infection.

The diagnosis of invasive CMV disease can be challenging because the presence of the virus does not mean causality given that the virus establishes latency after primary infection.

Differential Diagnosis

(Boxes 192-9 and 192-10)

Complications

Possible complications of postnatal HCMV infection include interstitial pneumonia, hemolytic anemia, splenic infarction, thrombocytopenia and hemolytic anemia, hepatitis, Guillain–Barré syndrome, meningoencephalitis, myocarditis, arthritis, and gastrointestinal/genitourinary syndromes (i.e., colitis, esophagitis, cervicitis, and urethral syndromes).143,149

Prognosis and Clinical Course

HCMV disease in immunocompetent individuals is usually self-limited. In immunocompromised patients with systemic HCMV disease, the prognosis is poor and mortality 85%.181

Treatment

HCMV infection in immunocompetent hosts is usually asymptomatic or self-limited, not requiring treatment with antiviral drugs. Ganciclovir, valacyclovir, foscarnet, and cidofovir have been approved for systemic treatment of HCMV disease.182 HAART is effective in suppressing HCMV viremia and preventing CMV retinitis in acquired immunodeficiency syndrome patients without end-organ disease.183 Ganciclovir and valacyclovir are also used for HCMV prophylaxis.143,182 None of these drugs is recommended for treatment of symptomatic congenital HCMV infection.

Prevention

Prevention of HCMV infection in transplanted patients can be achieved with use of blood and tissues from HCMV-negative donors.168 Preemptive (at time of high risk for disease but before symptoms) or prophylactic treatment can be used for immunocompromised individuals at risk of infection from blood transfusions or organ transplantation with ganciclovir.149 Risk factors evaluated for preemptive therapy include CMV viremia and GVHD. The use of prophylactic versus preemptive therapy remains controversial.184–186

Epidemiology

HHV-6 has been identified as a causative agent for exanthem subitum (ES), also known as roseola infantum and sixth disease.187 ES is usually seen in children ages 6 months to 4 years.188–190 The seroprevalence of HHV-6 in the adult population is greater than 95%.189 Seroprevalence is high in the first few weeks of life and subsequently declines as maternal antibodies wane. It rises again by 1 year of age, with its peak between 3 and 5 years of age, and declines with advancing age.190,192–194 There is a discrepancy between the seroprevalence of HHV-6 and the incidence of ES, mainly thought to be due to the varied clinical manifestations of HHV-6 infection and subclinical HHV-6 infection.195 Primary HHV-6 infection in children can result in a subclinical infection or an acute febrile illness without cutaneous manifestations.196–197 There is seasonal variation of HHV-6 infection with highest incidence in spring; summer and fall epidemics have also been reported.191

Etiology and Pathogenesis

HHV-6 is a member of the β-Herpesviridae subfamily. There are two distinct variants by restriction enzyme analysis, HHV-6a and -6b.198 They are different in their immunologic, biologic,199 and genetic198 characteristics. HHV-6b causes ES, but it is unclear what diseases, if any, are caused by HHV-6a.200

The cellular receptor for HHV-6 is CD46.201 The mode of transmission is proposed to be via nasopharyngeal viral shedding from healthy individuals.202 Airborne transmission is likely via saliva.203 HHV-6 has been isolated from the saliva of healthy individuals188–190 and viral shedding is intermittent, not associated with changes in antibody titers.188 HHV-6 DNA is found in the cervix of infected women,204 raising the question of possible perinatal infection, although children of mothers with positive swabs do not acquire early HHV-6 infection. HHV-6 DNA has also been found in fetal tissue from spontaneous abortions.205,206 HHV-6 is not transmitted through breast milk.191 Transmission in transplant patients can occur via the grafted organ.207,208 The incubation period for HHV-6 infection is 5–15 days, with an average of 10 days. Viremia in immunocompetent children lasts 3–4 days in ES, whereas viremia from HHV-6 reactivation in allogeneic BMT patients lasts weeks.209

HHV-6 replicates in salivary glands,210 where it can establish a persistent infection.191 It is tropic for CD4+ T lymphocytes in vitro211,212 and establishes latency in human peripheral blood monocytes/macrophages213 and early bone marrow progenitors.214 HHV-6 genome is able to integrate into the host cell DNA at the ends of chromosomes 1, 17, and 22.191

HHV-6 can reactivate from latency in immunosuppressed individuals.191,206,215 A synergistic effect on disease of HHV-6 and CMV has been described in renal transplant recipients.216,217 HIV and HHV-6 also appear to be synergistic. The clinical importance of this finding remains to be elucidated. Unlike in transplant patients, there does not seem to be one specific clinical syndrome of HHV-6 infection in HIV-infected patients.191

Clinical Findings

History

Primary infection with HHV-6 results in an acute febrile illness typically in children 6 months to 1 year of age.191 The fever lasts approximately 3–7 days191 and can be followed by the characteristic rash of roseola in a minority of children.197,218,219

HHV-6 infection is seen in 40%–50% of transplant recipients (BMT more than SOT) and peaks at 2–4 weeks posttransplantation. Approximately one-half of these infections result in symptomatic disease with bone marrow suppression.220

Cutaneous Lesions

Exanthem Subitum

Palpebral edema can be evident from the first to third day of fever, resulting in a “sleepy” appearance, and resolves after a day of the exanthema.221 Erythematous papules on the soft palate (Nagayama spots) may precede the viral exanthema.221 The exanthem is seen from 1 day before to 1–2 days after the fever fades and lasts for 3–5 days.221 It is characterized by rose red macules or papules 2–5 mm in diameter, surrounded by a white halo. These are distributed mainly on the neck and trunk and sometimes on the face and proximal extremities (Fig. 192-14). Desquamation is not usually seen.

Transplant Recipients

A rash similar to acute GVHD has been described in pediatric patients undergoing BMT who have HHV-6 reactivation.222,223 Fever and/or rash are the most common manifestations of HHV-6 infections in SOT recipients.191

Human Immunodeficiency Virus Patients

HHV-6 can be an opportunistic pathogen in HIV patients, causing encephalitis and pneumonitis in some cases.191 But most case reports do not show one consistent clinical syndrome in HIV patients.191

Pityriasis Rosea

(See Chapter 42 and Section “Human Herpesvirus 7”).

Rosai–Dorfman Disease

(See Chapter 148).

HHV-6 genome has been detected in tissue from patients with sinus histiocytosis with massive lymphadenopathy or Rosai–Dorfman disease,224 and immunohistochemical studies suggest a possible pathogenic involvement.225

Related Physical Findings

Patients with ES may have high fever, malaise, inflamed tympanic membranes, conjunctival injection, gastrointestinal and respiratory tract symptoms, cervical lymphadenopathy, and bulging fontanelle.221,226 A mononucleosis-like infection, which is EBV- and CMV-negative, has been attributed to HHV-6 in children and adults.

Laboratory Tests

Although laboratory results may be variable in HHV-6 primary infection, one can see leukopenia (between 3,000 and 6,000 cells/mm3) with an increased percentage of lymphocytes between days 3 and 6 of the illness. White blood cell count elevation can be seen at the beginning of the febrile phase. HHV-6 infection is usually benign and self-limited; however, in atypical cases, serologic studies may be valuable. This can be done by ELISA or by indirect immunofluorescence. Anti-HHV-6 IgM antibodies are a marker of recent infection or reactivation, but 5% of adults may be IgM seropositive at any time. IgM develops after 5–7 days of infection, peaks at 2–3 weeks, and disappears in 2 months. IgM alone is not reliable.227 A fourfold IgG increase between acute and convalescent sera IgG indicates active infection.

Laboratory tests vary in their ability to distinguish latent virus from actively replicating virus. PCR detection of HHV-6 DNA in cell-free serum, plasma, or CSF indicates active replication, whereas a positive PCR from cellular material does not indicate active replication because the virus can be found latent in cells. Viral culture is not used routinely because it is technically difficult and may take more than 1 week. A combination of a positive serum IgM with positive PCR of whole blood DNA in patients older than 3 months of age has excellent specificity and sensitivity, and positive and negative predictive value for primary infection.196,228 Although not routinely available, quantitative PCR allows fast, sensitive, and absolute quantitation of viral load, making it a method of choice.

Complications

Febrile seizures are thought to occur in 10% of children with primary HHV-6 infection.191 Rarely, encephalitis has been reported in children with fatal or severe sequelae such as hemiparesis.196 Although usually a benign infection, rare complications include hepatitis, hemophagocytic syndrome, pneumonitis, and thrombocytopenia.191,195 Hemophagocytic syndrome has been reported on reactivation of HHV-6 in an immunocompetent adult.229

HHV-6 infection or reactivation in the immunocompromised can also result in hepatitis,208 pneumonitis,230,231 bone marrow suppression,232,233 and graft dysfunction or rejection.215 Reactivation of HHV-6 in the immunocompromised host can result in encephalitis and/or encephalopathy.191 There have been reports of fulminant multifocal demyelinating disease in both immunocompetent and immunocompromised patients. The contribution of HHV-6 infection to progressive multifocal leukoencephalopathy or multiple sclerosis is being studied.191

Prognosis and Clinical Course

ES is benign and self-limiting. Treatment may be necessary for atypical cases with complications and in immunosuppressed patients. Primary infection can be fatal in the immunocompromised host.

Treatment

There are no controlled clinical trials, and no compounds have been formally approved for treatment of HHV-6 infection. The same drugs used for HCMV treatment and prophylaxis have been used for HHV-6. The activities of various antiviral compounds against HHV-6 have been tested in vitro.234,235 Several case reports support the clinical effectiveness of ganciclovir in HHV-6 treatment and prophylaxis.191 Foscarnet and cidofovir might also prove to be useful.189 New antiherpesvirus drugs are being developed, although most are not active against HHV-6.191 Further studies are needed before treatment and prophylaxis can be recommended.

Prevention

Prophylaxis with ganciclovir may prevent HHV-6 reactivation in BMT and stem cell transplant recipients,236 but low-dose prophylaxis may facilitate the development of resistance. Preemptive therapy (treatment after systemic detection of virus but before clinical symptoms of disease) has been proposed instead.191

Epidemiology

In seroconversion studies, 10% of ES cases are caused by HHV-7.237 Primary infection occurs during childhood, but later than238 and at a slower rate than infection with HHV-6239; both viruses are ubiquitous in adulthood. HHV-7 can be isolated from saliva samples of healthy seropositive adults.240

Etiology and Pathogenesis

HHV-7 is a member of the β-Herpesviridae family. It has significant homology to HHV-6; however, it is serologically and biologically distinct. It was initially isolated from CD4+ T lymphocytes from a healthy adult 241 has been identified as the cellular receptor for HHV-7.242

HHV-7 establishes persistent infection in salivary glands,243 transmission might be through saliva.195 Latent virus can be activated in vitro from peripheral blood mononuclear cells244 and its DNA can be found in CD4+ T cells. Similar to many other herpesviruses,245,246 HHV-7 can downregulate expression of CD4247 and major histocompatibility complex class I,248 which may play a role in establishment of latency or pathogenesis. Reactivation of HHV-7 occurs more often than reactivation of HHV-6.239

Clinical Findings

Exanthem Subitum

HHV-7 causes a small subset of ES cases. When HHV-7 is associated, ES tends to occur later in life than when HHV-6 is associated.196 The rash associated with HHV-7 is lighter in color and occurs later in the course of the disease than HHV-6-associated ES.249

Pityriasis Rosea

(See Chapter 42).

HHV-7 DNA has been isolated from skin biopsy specimens, peripheral blood mononuclear cell, and plasma of patients with pityriasis rosea and not controls.250 However, these findings have not been confirmed by other studies.251–254 It is possible that the inflammatory milieu in pityriasis rosea activates HHV-7 and HHV-6 within the lesions, but there is no evidence for causality.

Lichen Planus

HHV-7 DNA and virion-like structures have been found in lesional lichen planus skin samples compared to nonlesional skin and psoriatic skin samples.255 Although suggestive, further studies are needed to establish a causal relationship. HHV-7 has also been found to be the associated with febrile seizures in children.256

Laboratory Tests

There is limited cross reactivity between HHV-7 and HHV-6 in serologic studies.257 Due to high prevalence, a single positive IgG is not sufficient to establish a diagnosis. Culture from peripheral blood mononuclear cells takes 1–3 weeks, and it is not widely available. PCR is more widely available and is useful for timely diagnosis. Diagnosis of active infection by PCR can only be made from acellular material such as CSF, serum, or plasma, because the virus is latent in peripheral blood mononuclear cells and tissue. Immunohistochemical studies for viral antigens in biopsy specimens can be performed.258

Differential Diagnosis

(Box 192-11)

Complications

Complications of HHV-7-associated ES include acute hemiplegia and febrile seizures with CSF findings consistent with encephalitis259 and hepatitis.

Prognosis and Clinical Course

ES is a self-limiting disease, which does not require specific antiviral treatment. Disease in immunocompromised can be more serious and require treatment.

Treatment

Treatment for HHV-7 has not been evaluated in clinical trials but could be guided by treatment recommendations for HHV-6.

Human enteroviruses may cause a variety of exanthems and clinical syndromes. They are small, single-stranded RNA picornaviruses and include echovirus, coxsackievirus A and B, enterovirus, and poliovirus.260 Most enteroviral infections are benign. However, nonpolio enteroviruses are the most common cause of aseptic (viral) meningitis.261 Enteroviruses can also cause life-threatening infections with encephalitis, myocarditis, and sepsis.261 These are more common in neonates and immunocompromised individuals. Enteroviral infections are seen throughout the year, but many epidemics occur in the summer and fall. The viruses are primarily spread via the fecal–oral route or more rarely oral–oral or respiratory routes. Common source water exposures may also be responsible. Typical incubation period is 3–6 days.

The exanthems seen with enteroviruses are often nonspecific and not very dramatic, with small pink macules and papules that resolve in a few days. Petechiae and purpura are frequently present (Figs. 192-15A and 192-15B). When a petechial rash due to an enterovirus accompanies high fever and meningeal signs and symptoms, the clinical picture may mimic meningococcemia.

Hand-Foot-Mouth Disease

Epidemiology

Hand-foot-mouth disease (HFMD) is the best-recognized enteroviral exanthem with worldwide distribution that is usually self-limited. There is a slight male predominance. Children less then 10 years of age are most frequently affected and infected adults rarely show signs of infection. Similar to exanthems caused by other enteroviruses, HFMD occurs more during summer and fall in temperate climates and throughout the year in the tropics.170,262–268 Outbreaks may be sporadic or in epidemics. The largest recorded epidemic was in Taiwan in 1998. This epidemic was caused by enterovirus 71 and affected over 120,000 people and caused 78 deaths.269 Children under the age of 5 years were the most severely affected and the majority of deaths were secondary to pulmonary edema and hemorrhage.

Transmission is via the fecal–oral route and, less commonly, respiratory inhalation. There is a high transmission rate among household contacts as has been documented with studies of epidemics.268 Once inhaled or ingested, virus replication ensues in the oropharynx and/or gastrointestinal tract with subsequent viremia. The incubation period of HFMD is believed to be short, lasting 3–6 days, with viral shedding lasting up to 5 weeks.270

Etiology and Pathogenesis

HFMD is caused by a number of nonpolio enteroviruses, including coxsackieviruses A5, A7, A9, A10, A16, B1, B2, B3, B5, echoviruses, and other enteroviruses. The most common causes are coxsackie A16 and enterovirus 71. Enteroviruses belong to the Picornaviridae family, which are single-stranded RNA viruses.

Clinical Findings

History

After an incubation phase of 3–6 days, affected individuals may complain of a low-grade fever, malaise, abdominal pain, and upper respiratory tract symptoms.

Cutaneous Lesions

Nearly all cases of HFMD have painful oral lesions. These are generally few in number and are found on the tongue (Figs. 192-16A and 192-17A), buccal mucosa, hard palate, and, less frequently, the oropharynx. The lesions start as bright pink macules and papules that progress to small 4–8 mm vesicles with surrounding erythema. These quickly erode and form yellow to gray erosions surrounded by an erythematous halo. The time between vesicle and erosion is short, and most patients have erosions by the time they visit their physician.

Cutaneous peripheral lesions are present in two-thirds of patients and appear soon after the oral lesions.271 The lesions are most common on the palms, soles (see Figs. 192-16B and 192-16C and 192-17B and 192-17C), sides of hands and feet, buttocks (see eFig. 192-17.1) and, occasionally, external genitalia, and on the face and legs. They evolve similarly to the oral lesions, starting as red macules that become clear oval, elliptical (football shaped), or triangular vesicles with surrounding red halos (see Figs. 192-16 and 192-17) The number of lesions ranges from few to numerous and run parallel to the skin lines on fingers and toes. After crusting, they heal in 7–10 days.

Related Physical Findings

HFMD usually begins with a nonspecific prodrome, including low-grade fever [38°C–39°C (100.4°F–102.2°F)] that lasts 1–2 days, malaise, and, occasionally, abdominal pain or upper respiratory tract symptoms. Sore throat or sore mouth is common and may lead to poor oral intake and dehydration. Cervical and submandibular lymphadenopathy may be present.

Laboratory Tests

No laboratory tests are indicated. If an epidemic is suspected, stool and throat cultures may be helpful in determining the strain and, therefore, possible complications.

Special Tests

Historically, enteroviral infection was verified by viral culture, which lacked sensitivity, and suckling mouse inoculation, which detected neutralizing antibodies. Confirmation of enteroviral infection can be done by using viral culture or PCR-based assays. Virus can be recovered from skin vesicles as well as throat and stool swabs. PCR is most widely employed for CSF samples and can help to identify serotypes in severe enteroviral infection.

Skin biopsies are not typically performed. Nonspecific findings such as intraepidermal blister formation from vacuolar and reticular degeneration of keratinocytes is seen as in other viral blisters.

Differential Diagnosis

(Box 192-12)

Complications

Patients rarely experience complications from HFMD. One rare complication, called eczema coxsackium, occurs in individuals with eczema. These patients develop disseminated cutaneous viral infection similar to that seen in eczema herpeticum.272 The most common serious complication associated with HFMD is aseptic meningitis. Aseptic meningitis is rarely life threatening, and patients do not develop permanent sequelae. Epidemics in Taiwan of enterovirus 71 have resulted in severe disease with encephalitis, encephalomyelitis, polio-like syndromes, myocarditis, pulmonary edema, pulmonary hemorrhage, and death.266,267,273 Serious complications are less frequent in cases associated with coxsackievirus A16 than with enterovirus 71.266

Prognosis and Clinical Course

HFMD is usually a benign, self-limited illness that resolves within 7–10 days. Occasionally, cases associated with more prolonged fever, systemic symptoms, diarrhea, and joint pains have been reported.274

Treatment

Treatment is typically supportive with attempts to reduce discomfort. Early treatment with milrinone, a cyclic phosphodiesterase inhibitor, has the potential to significantly reduce mortality in the management the enterovirus 71-induced illness.275 Intravenous administration of human IgG has been used in China since 2000, with some success, to treat severe cases of enterovirus 71 infection.276

Prevention

During epidemics, public health measures should be instituted to decrease morbidity. Measures such as universal precautions, dissuading attendance at childcare centers or kindergarten, and isolating affected individuals have been suggested.277 Vaccine development is underway.276

Herpangina

Epidemiology

Herpangina is a self-limited exanthem seen in children around the world. There is no ethnic or sexual predilection. Children are affected most commonly between 3 and 10 years of age. Most outbreaks in temperate climates are seen in the summer and fall. Herpangina is caused by multiple types of coxsackie viruses (most frequently subtypes A8, A10, and A16), echoviruses, and enteroviruses.278 Transmission is via fecal–oral, respiratory inhalation, or oral–oral spread in the majority of cases.

Etiology and Pathogenesis

Enteroviruses belong to the family of Picornaviridae, which are single-stranded RNA viruses. Herpangina may occur sporadically or in epidemics. Epidemics have been traced to coxsackievirus A types 1, 2, 3, 4, 5, 6, 8, 10, 22, and B1 as well as echovirus types 16 and 25 and enterovirus 71. Replication ensues in the pharynx and gastrointestinal tract, with subsequent viremia. The incubation period is about 4 days,279 and viral shedding may continue for days to months.

Clinical Findings

History

The presenting signs and symptoms of herpangina are sudden onset of fever, chills, sore throat, headache, dysphagia, and body aches. The fever ranges from 37.5°C to 41.5°C (99.5°F–106.7°F). There may be a prodrome of listlessness, irritability, and anorexia a few hours before the onset of fever.

Cutaneous Lesions

Lesions are 1–2 mm, yellow–white papulovesicles with surrounding erythema that progress to erosions (Fig. 192-18). They are seen most frequently on the anterior pillars of the tonsillar fauces (or tonsillar pillars), followed by the uvula, tonsils and soft palate. They are less frequently seen on the tongue and buccal mucosa. The number of lesions may vary from very few to numerous. They can occur in small clusters and later coalesce and ulcerate leaving a shallow, punched out grayish–yellow crater 2–4 mm in diameter. Resolution occurs over 5–10 days.

Laboratory Tests

No laboratory tests are indicated.

Special Tests

Historically, enteroviral infection has been verified by viral culture that lacked sensitivity and suckling mouse inoculation looking for neutralizing antibodies. Recently, PCR has been found to be very effective in detection and identification of enterovirus serotypes. PCR could be very useful if it were to become widely available.280

Differential Diagnosis

(Box 192-13). Herpangina is located in the posterior oropharynx. Herpetic gingivostomatitis more commonly presents with labial and skin involvement.

Complications

Occasionally, patients suffer febrile seizures associated with the fever that is present in the first few days of infection. There have been rare case reports of serious complications, including myocarditis, encephalitis, meningitis, and pulmonary edema.

Treatment

The main goal of treatment is pain management. Viscous lidocaine, antihistamine mouthwashes and allopurinol mouthwash may be of benefit in relieving symptoms. Adequate fluid intake is encouraged to prevent dehydration.

Prognosis and Clinical Course

The fever rarely lasts longer then 4 days, whereas oral lesions spontaneously resolve several days after their eruption. The prognosis is good, and the course is most often benign.

Prevention

Once infected, a person has lifelong immunity to that particular strain. Recurrence of herpangina may occur but would be from one of the other strains.

Cherry et al first described a syndrome in 1969 in which four children with acute echovirus infection (two with echovirus 25 and two with echovirus 32) developed small 2–4 mm red papules that resembled angiomas on the face and extremities.281 The papules blanched on pressure and were surrounded by a small 1–2 mm halo. The eruption was short lived and typically resolved within 10 days. Patients often had associated fever, malaise, headache, diarrhea, and respiratory complaints.

Other children and adults have been described with similar outbreaks. Although a virus is likely to cause eruptive pseudoangiomatosis, echoviruses have not been consistently confirmed as the causative agent.282–284

Named for its occurrence as an epidemic in Boston, this exanthem was found to be caused by echovirus 16. Clinical manifestations ranged from a light pink “roseola-like” exanthem to morbilliform or vesicular exanthems in more severe cases. Lesions were mostly localized to the face, chest and back and rarely the extremities. Small ulcerations were also found on the soft palate and tonsils.285,286

Epidemiology

Rotavirus is a major cause of diarrheal illness in children under 2 years of age.287 Rotaviral infections occur worldwide, affecting children in both developing and developed countries.288 In the United States, the peak of rotaviral infections occurs in the winter. Typically, rotavirus appears in the Southwestern United States in November and reaches the Northeast by March.

Rotavirus is transmitted primarily by the fecal–oral route.289 It has also been postulated that transmission via respiratory droplets and contaminated water is possible. The virus may survive on hands for at least 4 hours, and, in addition, ten infectious rotaviral particles may be all that is needed to transmit the infection. Once transmitted, viral shedding may commence as early as 48 hours before the development of symptoms and continue for 4–7 days thereafter. Asymptomatic shedding is also common.290 Because of frequent diaper changing and contact between infected toddlers, day care centers often have outbreaks.289 The fact that soap and water alone are relatively ineffective in removing virus from contaminated hands allows easier transmissibility.291

Children between the ages of 6 months and 2 years are most often affected. There is a male predominance that is poorly understood.292 Adults can also become infected; they are often household members of infected children.293

Etiology and Pathogenesis

Clinical Findings

History

After an incubation period of 1–3 days, symptoms of rotaviral infection commence.289 Typically, fever and vomiting are followed by nonbloody diarrhea (often 10–12 episodes per day), which occasionally results in moderate to severe dehydration.292,297,298 Respiratory symptoms and otitis media may be present. In general, illness is less severe in adults.294 Vomiting and diarrhea are usually present; however, fever and respiratory symptoms are absent.293

Cutaneous Lesions

Rotaviral infections are not associated with specific dermatologic manifestations; however, several clinical pictures have been reported.300 A generalized exanthem possibly related to rotavirus has been described.299–301 Pink–red macules and papules appear 3–6 days after the onset of the diarrhea and as defervescence occurs. The asymptomatic rash progresses from the trunk to the extremities and, finally, to the face within hours. The exanthem then fades over approximately 3 days in the same order as it appeared.

Other dermatologic manifestations have been described. GCS occurs in response to a number of different viruses. Two toddlers had GCS with diarrhea 4 and 7 days before the eruption, and rotavirus was isolated from the stool cultures.302 A third case of Gianotti–Crosti was reported without gastrointestinal symptoms.303 Rotavirus was isolated from the stool culture, and all other suspected viruses yielded negative results. A child with acute hemorrhagic edema of infancy was found to be associated with a rotaviral infection.303

Related Physical Findings

It has been noted that rotavirus is associated with respiratory symptoms and otitis media in up to 50% of cases.289

Laboratory Tests

Laboratory values may be unremarkable; however, it is not unusual to find a mild hyperchloremic metabolic acidosis.304 Occasionally, liver transaminases may be mildly elevated. Hypernatremia, elevated albumin, and elevated uric acid, when detected, are likely the result of dehydration. Fecal leukocytes may be detected; however, they are usually not significant.304

Special Tests

Differential Diagnosis

Complications

Rotaviral infections may lead to persistent gastrointestinal symptoms, including diarrhea, gastroparesis, and lactose deficiency. Immunosuppressed patients and malnourished patients in developing countries are most at risk for protracted disease.309 In addition, there have been many associated conditions/syndromes reported, including seizures,310 encephalopathy,311 aseptic meningitis,312 hepatic abscess,313 acute myositis,314 pneumonia,315 sudden infant death syndrome,316 Reye syndrome,317 biliary atresia,318 and Kawasaki disease.319 It has also been suggested that rotaviruses have been associated with necrotizing enterocolitis320 and intussusception.321

Prognosis and Clinical Course

Rotaviral infection in the United States resolves, on average, within 5–7 days, without any sequelae.297,304 In developing countries, where poverty and malnutrition are common, children are most likely to experience chronic symptoms.309 Death from rotaviral infection is not uncommon in developing countries due to dehydration.295

Treatment

Because there are no specific antiviral agents directed against the rotavirus, therapy is aimed at correcting dehydration and electrolyte imbalance. Oral rehydration is necessary. The World Health Organization recommends the oral rehydration solution, which consists of an isotonic salt solution with glucose supplementation or oral rehydration solution light, which has reduced osmolarity.322 Intravenous fluids may be necessary if the patient is unable to rehydrate orally or if there is severe dehydration and should ideally consist of lactated Ringer or normal saline. Antibiotics are ineffective, and antimotility agents are not recommended for young children.

Prevention

Infection control is an important means of preventing rotaviral infections.322 It is important to disinfect contaminated surfaces with quaternary ammonium compounds that contain 40% alcohol273,305 or chlorhexidine gluconate in 70% ethanol.289 Currently, two orally administered live rotavirus vaccines are available in the United States.323

Epidemiology

Unilateral laterothoracic exanthem (ULE), also known as asymmetric periflexural exanthem of childhood (APEC), has a seasonal variation and occurs most frequently in late winter and early spring.307 It typically occurs in children from 1 to 5 years of age but may be seen from 8 months to 10 years.324 Rare cases in adults have been reported.325 There is a slight female predominance and it is more common in Caucasians.

Etiology and Pathogenesis

The etiology is unknown, but because of its seasonality and associated viral symptoms and lack of response to antibiotics, a viral trigger is suspected. The distinct clinical presentation may be a manifestation of a variety of infectious agents. The pathogenesis is also unknown.

Clinical Findings

History

Mild upper respiratory tract, low-grade fever, or gastrointestinal tract symptoms precede the eruption in a majority of patients.

Conjunctivitis and fatigue may be present.

Cutaneous Lesions

The lesions are usually 1–2-mm pinpoint, pruritic, pink papules that begin in a large flexural region like the axillae or groin and spread centrifugally (Fig. 192-19 and eFig. 192-19.1). A variety of morphologies have been described, including macules, papules, morbilliform, annular, scarlatiniform, and annular. The initial lesion is often a pink papule with a surrounding pale halo.307 The eruption typically becomes bilateral and more widespread within 5–15 days, but a unilateral and asymmetric distribution remains. The eruption is often quite pruritic.

Related Physical Findings

Lymphadenopathy is seen in 70% of patients. This often manifests as a large (1–3 cm) mobile lymph node at the site where the rash starts.

Laboratory Tests

No laboratory tests are indicated.

Differential Diagnosis

(Box 192-14)

Complications

There has not been documentation of complications after ULE.

Prognosis and Clinical Course

The rash typically lasts from 2 to 6 weeks but may last as long as 2 months. Resolution is spontaneous and without scarring. During the healing stage, desquamation and postinflammtory pigment change may also be present as the exanthem resolves.

Treatment

Treatment for ULE is typically focused on controlling pruritus. This can be done with topical corticosteroids, antiitch lotions, and oral antihistamines.

Prevention

There is no known way to prevent ULE.