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See section Infections due to Herpesviruses for a discussion of varicella and roseola, the two other major childhood exanthems.

ERYTHEMA INFECTIOSUM

ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

  • Fever and rash with “slapped-cheek” appearance, followed by a symmetrical, full-body maculopapular rash.

  • Arthritis in older children.

  • Profound anemia in patients with impaired erythrocyte production.

  • Nonimmune hydrops fetalis following infection of pregnant women.

General Considerations

This benign exanthematous illness of school-aged children is caused by the human parvovirus B19. Spread is respiratory, occurring in winter–spring epidemics. A nonspecific mild flulike illness may occur during the viremia at 7–10 days; the characteristic rash occurring at 10–17 days represents an immune response. The patient is viremic and contagious prior to—but not after—the onset of rash.

Approximately half of infected individuals have a subclinical illness. Most cases (60%) occur in children between ages 5 and 15 years, with an additional 40% occurring later in life. Forty percent of adults are seronegative. The secondary attack rate in a school or household setting is 50% among susceptible children and 20%–30% among susceptible adults.

Clinical Findings

Owing to the nonspecific nature of the exanthem and the many subclinical cases, a history of contact with an infected individual is often absent or unreliable. Recognition of the illness is easier during outbreaks.

A. Symptoms and Signs

Typically, the first sign of illness is the rash, which begins as raised, fiery red maculopapular lesions on the cheeks that coalesce to give a “slapped-cheek” appearance. The lesions are warm, nontender, and sometimes pruritic. They may be scattered on the forehead, chin, and postauricular areas, but the circumoral region is spared. Within 1–2 days, similar lesions appear on the proximal extensor surfaces of the extremities and spread distally in a symmetrical fashion. Palms and soles are usually spared. The trunk, neck, and buttocks are also commonly involved. Central clearing of confluent lesions produces a characteristic lacelike pattern. The rash fades in several days to several weeks, but frequently reappears in response to local irritation, heat (bathing), sunlight, and stress. Nearly 50% of infected children have some rash remaining (or recurring) for 10 days. Fine desquamation may be present. Mild low-grade fever, malaise, myalgia, sore throat, and coryza occur in up to 50% of children. These symptoms appear for 2–3 days followed by a week-long asymptomatic phase before the rashes appear.

Purpuric stocking-glove rashes, neurologic disease, and severe disorders resembling hemolytic-uremic syndrome have also been described in association with parvovirus B19.

B. Laboratory Findings

A mild leukopenia occurs early in some patients, followed by leukocytosis and lymphocytosis. Specific IgM and IgG serum antibody tests are available, but care must be used in choosing a reliable laboratory. IgM antibody is present in 90% of patients at the time of the rash. Nucleic acid detection tests are often definitive, but parvovirus DNA may be detectable in blood for prolonged periods. The disease is not diagnosed by routine viral culture.

Differential Diagnosis

In children immunized against measles and rubella, parvovirus B19 is the most frequent agent of morbilliform and rubelliform rashes. The characteristic rash and the mild nature of the illness distinguish erythema infectiosum from other childhood exanthems. It lacks the prodromal symptoms of measles and the lymphadenopathy of rubella. Systemic symptoms and pharyngitis are more prominent with enteroviral infections and scarlet fever.

Complications & Sequelae

A. Arthritis

Arthritis is more common in older patients, beginning with late adolescence. Approximately 10% of older children have severe joint symptoms. Girls are affected more commonly than boys. Pain and stiffness occur symmetrically in the peripheral joints. Arthritis usually follows the rash and may persist for 2–6 weeks, but resolves without permanent damage.

B. Aplastic Crisis and Other Hematologic Abnormalities

Parvovirus B19 replicates primarily in erythroid progenitor cells. Consequently, reticulocytopenia occurs for approximately 1 week during the illness. This goes unnoticed in individuals with a normal erythrocyte half-life, but results in severe anemia in patients with chronic hemolytic anemia.

Pure red cell aplasia, leukopenia, pancytopenia, idiopathic thrombocytopenic purpura, and a hemophagocytic syndrome have been described. Patients with HIV infection and other immunosuppressive illnesses may develop prolonged anemia or pancytopenia. Patients with hemolytic anemia and aplastic crisis, or with immunosuppression, may be contagious and should be isolated while in the hospital.

C. Other End-Organ Infections

Parvovirus has been associated with neurologic syndromes, hepatitis, and suppression of bone marrow lineages. It is implicated as a cause of myocarditis.

D. In Utero Infections

Infection of susceptible pregnant women may produce fetal infection with hydrops fetalis. Fetal death occurs in about 6% of cases, most often in the first 20 weeks. This rate of fetal loss is higher than expected in typical pregnancies. Congenital anomalies have not been associated with parvovirus B19 infection during pregnancy.

Treatment & Prognosis

Erythema infectiosum is a benign illness for immunocompetent individuals. Patients with aplastic crisis may require blood transfusions. It is unlikely that this complication can be prevented by quarantine measures, because acute parvovirus infection in contacts is often unrecognized and is most contagious prior to the rash. Pregnant women who are exposed to erythema infectiosum or who work in a setting in which an epidemic occurs should be tested for evidence of prior infection. Susceptible pregnant women should then be followed up for evidence of parvovirus infection. Approximately 1.5% of women of childbearing age are infected during pregnancy. If maternal infection occurs, the fetus should be followed by ultrasonography for evidence of hydrops and distress. In utero transfusion or early delivery may salvage some fetuses. Pregnancies should not be terminated because of parvovirus infection. The risk of fetal death among exposed pregnant women of unknown serologic status is less than 2.5% for homemakers and less than 1.5% for school teachers.

Intramuscular immunoglobulin is not protective. High-dose IVIG has stopped viremia and led to marrow recovery in some cases of prolonged aplasia. Its role in immunocompetent patients and pregnant women is unknown.

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Qiu  J, Soderland-Venemo  M, Young  NS: Human Parvoviruses. Clin Microbiol Rev 2017;30:43
[PubMed: 27806994]
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Rogo  LD, Maokhtari-Azad  T, Kabir  MH, Rezael  F: Human Parvovirus: a review. Acta Virol 2014;58:199
[PubMed: 25283854]

MEASLES (RUBEOLA)

ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

  • Exposure to measles 9–14 days previously.

  • Prodrome (2–3 days) of fever, cough, conjunctivitis, and coryza.

  • Koplik spots (few to many small white papules on a diffusely red base on the buccal mucosa) 1–2 days prior to and after onset of rash.

  • Maculopapular rash spreading from the face and hairline to the trunk over 3 days and later becoming confluent.

  • Leukopenia.

General Considerations

Measles is one of the most contagious infectious diseases of childhood that presents as a febrile exanthema. The attack rate in susceptible individuals is extremely high; spread is via respiratory droplets. Considered eliminated from the United States in 2000, frequent outbreaks have occurred recently (188 in 2015, 70 in 2016, and 100 thus far in 2017), mainly due to accumulation of susceptible because of low vaccination coverage, increasing vaccine hesitancy, and importation. It is recommended that all children receive two doses prior to primary or secondary school entry (see Chapter 10). Morbidity and mortality rates in the developing world are substantial because of underlying malnutrition and secondary infections. Because humans are the sole reservoir of measles, there is the potential to eliminate this disease worldwide.

Clinical Findings

A history of contact with a suspected case may be absent because airborne spread is efficient and patients are contagious during the prodrome. Contact with an imported case may not be recognized. In temperate climates, epidemic measles is a winter–spring disease. Because measles is uncommon in the United States, a high index of suspicion is required during outbreaks.

A. Symptoms and Signs

After 2–3 days of a prodrome of sneezing, eyelid edema, tearing, copious coryza, photophobia, and harsh cough, high fever and lethargy become prominent. Koplik spots are white macular lesions on the buccal mucosa, typically opposite the lower molars that appear in the first 2-4 days of the illness. These are almost pathognomonic for measles, although they may be absent. A discrete maculopapular rash begins when the respiratory symptoms and fever are maximal and spreads quickly from the face to the trunk, coalescing to a bright red. As it spreads to the extremities, the rash fades turning coppery from the face and is completely gone within 6 days; fine desquamation may occur. Diarrhea can occur in young children and lead to hospitalization; persistent fever and cough may signal pneumonia. Measles should be considered in any child with febrile rash illness, especially if recently traveled internationally or exposed to a person with febrile rash illness. Suspected measles cases should be reported to local health department within 24 hours.

B. Laboratory Findings

Lymphopenia is characteristic. Total leukocyte count may fall to 1500/μL. The diagnosis is usually made by detection of measles IgM antibody in serum drawn at least 3 days after the onset of rash, and may be made later by detection of a significant rise in IgG antibody. PCR testing of oropharyngeal secretions or urine is extremely sensitive and specific and can detect infection up to 5 days before symptoms.

C. Imaging

Chest radiographs often show hyperinflation, perihilar infiltrates, or parenchymal patchy, fluffy densities. Secondary consolidation or effusion may be visible.

Differential Diagnosis

Table 40–3 lists other illnesses that may resemble measles.

Complications and Sequelae

A. Respiratory Complications

These occur in up to 15% of patients. Bacterial superinfection of the lungs, middle ear, sinus, and cervical nodes are most common. Fever that persists after the third or fourth day of rash and/or leukocytosis suggests such a complication. Bronchospasm, severe croup, and progressive viral pneumonia or bronchiolitis (in infants) also occur. Immunosuppressed patients are at much greater risk for fatal pneumonia than are immunocompetent patients.

B. Cerebral Complications

Encephalitis occurs in 1 in 2000 cases. Onset is usually within a week after appearance of rash. Symptoms include combativeness, ataxia, vomiting, seizures, and coma. Lymphocytic pleocytosis and a mildly elevated protein concentration are usual CSF findings, but the fluid may be normal. Forty percent of patients so affected die or have severe neurologic sequelae.

Subacute sclerosing panencephalitis (SSPE) is a slow measles virus infection of the brain that becomes symptomatic years later in about 1 in 100,000 previously infected children. This progressive cerebral deterioration is associated with myoclonic jerks and a typical electroencephalographic pattern. It is fatal in 6–12 months. High titers of measles antibody are present in serum and CSF.

C. Other Complications

These include hemorrhagic measles (severe disease with multiorgan bleeding, fever, and cerebral symptoms), thrombocytopenia, appendicitis, keratitis, myocarditis, and premature delivery or stillbirth. Mild liver function test elevation is detected in up to 50% of cases in young adults; jaundice may also occur. Measles causes transient immunosuppression; thus, reactivation or progression of tuberculosis (including transient cutaneous anergy) can occur in children.

Prevention

The current two-dose active vaccination strategy provides more than 97% protection. Vaccine should not be withheld for concurrent mild acute illness, tuberculosis or positive tuberculin skin test, breast feeding, or exposure to an immunodeficient contact. The vaccine is recommended for HIV-infected children without severe HIV complications, with CD4 cells ≥ 15%, and preferably receiving antiretroviral therapy.

Treatment and Prognosis

Vaccination prevents the disease in susceptible exposed individuals if given within 72 hours (see Chapter 10). Immunoglobulin (0.25 mL/kg intramuscularly; 0.5 mL/kg if immunocompromised) will prevent or modify measles if given within 6 days. Suspected cases should be diagnosed promptly and reported to the local health department.

Recovery generally occurs 7–10 days after onset of symptoms. Therapy is supportive: eye care, cough relief (avoid opioid suppressants in infants), and fever reduction (acetaminophen, lukewarm baths; avoid salicylates). Secondary bacterial infections should be treated promptly; antimicrobial prophylaxis is not indicated. Ribavirin is active in vitro and may be useful in infected immunocompromised children. In malnourished children, vitamin A supplementation should be given to avoid blindness and decrease mortality.

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Mayo-Wilson  E  et al: Vitamin A supplementation for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis. BMJ 2011;343:d5094
[PubMed: 21868478]
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Moss  WJ, Griffin  DE: Measles. Lancet 2012;379(9811):153
[PubMed: 20120116]

RUBELLA

ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

  • History of rubella vaccination usually absent.

  • Fever with postauricular and occipital adenopathy.

  • Maculopapular rash beginning on face, rapidly spreading to the entire body, and disappearing by fourth day.

  • Congenital infection.

    • Retarded growth and development.

    • Cataracts, retinopathy.

    • Purpuric “blueberry muffin” rash at birth.

    • Jaundice, thrombocytopenia.

    • Deafness.

    • Congenital heart defect.

General Considerations

Rubella is a togavirus that causes a mild, self-limited exanthema (over 80% of infections are subclinical), but infection during pregnancy leads to teratogenicity and miscarriage. Rubella is transmitted by aerosolized respiratory secretions. Patients are infectious 5 days before until 5 days after the rash. Endemic rubella is absent in the United States and the Americas, and congenital rubella in infants born to unimmunized women and the occasional woman who is reinfected in pregnancy, is now very rare. Sporadic cases occur in migrants to the United States from Asia and Africa.

Clinical Findings

The incubation period is 14–21 days. The non-distinctive signs may make exposure history unreliable. A history of immunization makes rubella unlikely but still possible. Congenital rubella usually follows maternal infection in the first trimester.

A. Symptoms and Signs
1. Infection in children

Young children may only have rash. Older patients often have a nonspecific prodrome of low-grade fever, ocular pain, sore throat, and myalgia. Postauricular and suboccipital adenopathy (sometimes generalized) is characteristic. This often precedes the rash by one week or may occur without rash. The rash consists of erythematous discrete maculopapules beginning on the face and spreading to the trunk and extremities within 24 hours. Scarlatiniform, morbilliform and erythema infectiosum-like rash variants may occur. The rash fades from the face to extremities by the third day. Enanthema is usually absent.

2. Congenital infection

More than 80% of women infected in the first 4 months of pregnancy (25% near the end of the second trimester) deliver an affected infant; congenital disease occurs in less than 5% of women infected later in pregnancy. Later infections can result in isolated defects, such as deafness. The main manifestations are as follows:

A. GROWTH RETARDATIONBetween 50% and 85% of infants are small at birth and remain so.

B. CARDIAC ANOMALIESPulmonary artery stenosis, patent ductus arteriosus, ventricular septal defect.

C. OCULAR ANOMALIESCataracts, microphthalmia, glaucoma, retinitis.

D. DEAFNESSSensorineural (> 50% of cases).

E. CEREBRAL DISORDERSChronic encephalitis; retardation.

F. HEMATOLOGIC DISORDERSThrombocytopenia, dermal nests of extramedullary hematopoiesis or purpura (“blueberry muffin” rash), lymphopenia.

G. OTHERSHepatitis, osteomyelitis, immune disorders, malabsorption, diabetes.

B. Laboratory Findings

Leukopenia is common, and platelet counts may be low. Congenital infection is associated with low platelet counts, abnormal liver function tests, hemolytic anemia, and CSF pleocytosis in the newborn period. Virus may be isolated from oral secretions or urine from 1 week before to 2 weeks after onset of rash. Children with congenital infection are infectious for months. Direct RNA amplification (PCR) is very sensitive. Serologic immunoassay diagnosis is best made by demonstrating a fourfold rise in antibody titer between specimens drawn 1–2 weeks apart. The first should be drawn promptly, because titers increase rapidly after onset of rash; both specimens must be tested simultaneously by a single laboratory. Rubella IgM is present in 50% of patients at the onset of the rash, but in almost all by 5 days later. Because the decision to terminate a pregnancy is usually based on serologic results, testing must be done carefully.

C. Imaging

Pneumonitis and bone metaphyseal longitudinal lucencies may be present in radiographs of children with congenital infection.

Differential Diagnosis

Rubella may resemble infections due to measles, enterovirus, adenovirus, EBV, roseola, parvovirus, and T gondii. Drug reactions may also mimic rubella. Because public health implications are great, sporadic suspected cases should be confirmed serologically or virologically. Congenital rubella must be differentiated from congenital CMV infection, toxoplasmosis, zika and syphilis.

Complications & Sequelae

A. Arthralgia and Arthritis

Both occur more often in adult women. Polyarticular involvement (fingers, knees, wrists) lasting a few days to weeks is typical. Frank arthritis occurs in a small percentage of patients. It may resemble acute rheumatoid arthritis.

B. Encephalitis

With an incidence of about 1:6000, this is a parainfectious encephalitis associated with a low mortality rate. A syndrome resembling SSPE (see section on Measles) has also been described in congenital rubella.

C. Rubella in Pregnancy

Infection in the mother as in older children is self-limited and not severe.

Prevention

Rubella is one of the infections that could be eradicated (see Chapter 10 for the indication and efficacy of rubella vaccine). Standard prenatal care should include rubella antibody testing. Seropositive mothers are at no risk; seronegative mothers are vaccinated after delivery.

A pregnant woman possibly exposed to rubella should be tested immediately; if seropositive, she is considered protected and without risk to the fetus. If she is seronegative, a second specimen should be drawn in 4 weeks, and both specimens should be tested simultaneously. Seroconversion in the first trimester is associated with high fetal risk; such women require counseling regarding therapeutic abortion.

When pregnancy termination is not an option, some experts recommend intramuscular administration of immunoglobulin (up to 0.55 mL/kg IM) within 72 hours after exposure in an attempt to prevent infection. Only very small fractions of IgG are transferred to the fetus in early pregnancy and the efficacy of this practice is unknown.

Treatment & Prognosis

Symptomatic therapy is sufficient. Arthritis may improve with administration of anti-inflammatory agents. The prognosis is poor in congenitally infected infants, in whom most defects are irreversible or progressive. The severe cognitive defects in these infants seem to correlate closely with the degree of growth failure.

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Lambert  N, Strebel  P, Orensterin  W, Icenogle  J, Poland  GA: Rubella. Lancet 2015 Jun 6;385(9984):2297–2307
[PubMed: 25576992] .
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White  SJ  et al: Measles, mumps, and rubella. Clin Obstet Gynecol 2012;55(2):550
[PubMed: [PMID:t 22510638]

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