William J. Moss and Samuel L. Katz
Measles virus infection is one of the most important infectious diseases of humans and has caused millions of deaths since its emergence as a zoonosis thousands of years ago. Prior to the development and widespread use of measles vaccines, measles was estimated to cause between 5 and 8 million deaths worldwide each year. Remarkable progress in reducing measles incidence and mortality has been made. In the United States, high coverage with two doses of measles vaccine has eliminated endemic measles virus transmission. These achievements attest to the enormous public health significance of measles vaccination.
As measles control efforts are increasingly successful, public perceptions of the risk of measles diminish and are replaced by concerns of possible adverse events associated with measles vaccine. As a consequence, numerous measles outbreaks have occurred in communities opposed to vaccination on religious or philosophical grounds6 or because of unfounded fears of serious adverse events.7 Pediatricians can and should play a role in emphasizing the importance of childhood immunizations and dispelling myths and misunderstandings.
EPIDEMIOLOGY
Measles virus is one of the most highly contagious pathogens, and outbreaks can occur in populations in which less than 10% of persons are susceptible. Chains of transmission commonly occur among household contacts, school-age children, and health care workers. There are no latent or persistent measles virus infections that result in prolonged contagiousness and no animal reservoirs. Thus, measles virus can only be maintained in human populations by an unbroken chain of acute infections, requiring a continuous supply of susceptible individuals.
When endemic, measles typically has a typical temporal pattern characterized by yearly seasonal epidemics superimposed on longer epidemic cycles of 2 to 5 years or more. In temperate climates, annual measles outbreaks typically occur in the late winter and early spring. Secondary attack rates in susceptible household and institutional contacts generally exceed 90%. In densely populated urban settings with low vaccination coverage rates, measles is a disease of young children. As vaccination coverage increases, the age distribution of cases may be shifted into adolescence and young adulthood, as seen in measles outbreaks in the United States,4,12 necessitating targeted measles vaccination programs for these older age groups.
PATHOPHYSIOLOGY
Measles virus is a spherical, nonsegmented, single-stranded, negative-sense RNA virus and a member of the Morbillivirus genus in the family of Paramyxoviridae. Although RNA viruses typically have high mutation rates, measles virus is considered to be an antigenically monotypic virus, meaning that the surface proteins responsible for inducing protective immunity have retained their antigenic structure across time and space. The public health significance is that measles vaccines developed decades ago from a single measles virus strain remain protective worldwide. Measles virus is killed by ultraviolet light and heat. Attenuated measles vaccine viruses retain these characteristics, necessitating a cold chain for transporting and storing measles vaccines.
Measles virus is transmitted primarily by respiratory droplets over short distances and, less commonly, by small particle aerosols that remain suspended in the air for long periods of time. Direct contact with infected secretions can transmit measles virus, but the virus does not survive long on fomites.
Infection is initiated when measles virus reaches epithelial cells in the respiratory tract, oropharynx, or conjunctivae. Wild-type measles virus strains preferentially bind to SLAM (CD150), expressed on activated T cells, B cells, and antigen-presenting cells, whereas laboratory-adapted strains can also bind CD46, which is expressed on all nucleated cells. Measles virus thus infects lymphocytes and dendritic cells, as well as respiratory epithelial cells, which contributes to systemic spread. During the first 2 to 4 days after infection, measles virus proliferates locally in the respiratory mucosa and spreads to draining lymph nodes where further replication occurs. Virus then enters the bloodstream in infected leukocytes, primarily monocytes,14 producing the primary viremia that disseminates infection throughout the reticuloendothelial system. Further replication results in a secondary viremia that begins 5 to 7 days after infection and disseminates measles virus to tissues throughout the body. Replication of measles virus in these target organs, together with the host immune response, is responsible for the signs and symptoms that occur 8 to 12 days after infection and mark the end of the incubation period.
The incubation period for measles, the time from infection to clinical disease, is approximately 10 days to the onset of fever and 14 days to the onset of rash. The incubation period may be shorter in infants or following a large inoculum of virus, and may be longer (up to 3 weeks) in adults.
CLINICAL MANIFESTATIONS
In most children, the signs and symptoms of measles are highly characteristic. Approximately 10 days after exposure, fever and malaise signal the onset of illness (Fig. 316-1). Cough, coryza, and conjunctivitis follow promptly. A gradual worsening of symptoms accompanies a steady rise in fever over the next 4 days. With the onset of rash 14 days after infection, the clinical picture attains maximal severity. Constitutional symptoms throughout this 10-day period vary, but headache, abdominal pain, vomiting, diarrhea, and myalgia are frequent complaints. Fever reaching 40°C (104°F) to 41°C (105.8°F), often accompanied by chills, is not unusual when the rash is most florid.
The conjunctivitis causes edema of the lids, increased lacrimation, and, frequently, photophobia. Sharply demarcated transverse linear injection of the lower lid margins, called a Stimson line, is present before the more generalized conjunctival inflammation obscures it. Among infants with nutritional deficiencies, especially of vitamin A, more severe ocular involvement with corneal ulcers may lead to permanent scarring and loss of vision. The hacking cough is distressing, with a progressive increase in frequency and severity. With the abrupt fall in temperature, after rash has covered the entire body, the catarrhal symptoms subside dramatically, but the cough persists for another 7 to 10 days.
FIGURE 316-1. Clinical features of measles. (Source: Expanded Programme on Immunization Team. Manual for the Laboratory Diagnosis of Measles and Rubella Virus Infection. 2nd ed. 2007.)
Koplik spots, pathognomonic of measles, appear 24 to 48 hours before the exanthem. They consist of bluish white dots about 1 mm in diameter surrounded by a rose-red areola (Fig. 316-2). They tend to appear first on the buccal mucosa opposite the lower molars. With the onset of rash they fade, and frequently by the second day of the eruption, they have disappeared.
The rash commences as discrete, irregular, erythematous macules behind the ears, on the neck, and along the hairline. As the rash progresses caudad over the ensuing 24 hours to involve the face, trunk, and arms, careful palpation will reveal a papular component (Fig. 316-3). Involvement of the legs and feet by the end of the second day or early in the third day finds the lesions on the cheeks already coalescent; in severe infections, confluent areas of rash also appear on the trunk and extremities. The exanthem fades slowly, in the same order of progression as its initial appearance, a process that usually begins by the third or fourth day after onset.
The marked generalized lymphadenopathy and splenomegaly that arise early in the course of the acute illness may persist for several weeks. High fever at the peak of illness may be accompanied by marked irritability, somnolence, or a state of delirium, but these are transient and resolve with the disappearance of pyrexia. They do not correlate with the occurrence of subsequent central nervous system complications. Black measles, a severe form of the disease with a generalized hemorrhagic rash; bleeding from the nose, mouth, and gastrointestinal tract; and marked systemic toxicity, is rare. This form of measles was reported more frequently in the past and probably represented a form of disseminated intravascular coagulation.
FIGURE 316-2. Koplik spots.
The differential diagnosis of measles includes other causes of fever, rash, and conjunctivitis, such as rubella, Kawasaki disease, infectious mononucleosis, roseola, scarlet fever, typhus, Rocky Mountain spotted fever, enterovirus or adenovirus exanthems, and rashes due to drug sensitivity (especially barbiturates, hydantoins, penicillins, and sulfonamides).
DIAGNOSIS
Measles is readily diagnosed on clinical grounds by clinicians familiar with the disease. Koplik spots are especially helpful because they appear early and are pathognomonic of measles. The Centers for Disease Control and Prevention (CDC) case definition for measles requires (1) a generalized maculopapular rash of at least 3 days’ duration; (2) fever of at least 38.3°C (101°F); and (3) cough, coryza, or conjunctivitis.15
Serology is the most common method of laboratory diagnosis. A fourfold or greater increase in measles virus–specific IgG antibody levels between acute and convalescent sera, or the detection of measles virus–specific IgM in a single specimen of serum or saliva, are considered diagnostic of acute infection. The presence of IgG antibodies to measles virus in a single serum specimen is evidence of prior infection or immunization. Primary infection in the normal host results in detectable antibodies within 1 to 3 days of rash onset and reaches peak levels in 2 to 4 weeks. Measles virus–specific IgM antibodies may not be detectable until 4 to 5 days or more after rash onset and usually fall to undetectable levels within 4 to 8 weeks of rash onset.16
TREATMENT AND OUTCOMES
Except for general supportive measures, such as hydration and antipyretics, there is no specific antiviral therapy for persons with uncomplicated measles. Secondary bacterial infections are a major cause of morbidity and mortality following measles, and effective case management involves prompt treatment with antibiotics.19
Vitamin A treatment results in marked reductions in morbidity and mortality. Although vitamin A deficiency is not a recognized problem in the United States, many American children with measles have low serum vitamin A levels, and these children have increased morbidity following measles. Therefore, the American Academy of Pediatrics recommends the administration of two consecutive daily doses of vitamin A (200,000 IU orally for children 1 year and older; 100,000 IU for children 6 months to 1 year of age) be considered for children 6 to 24 months of age hospitalized for measles and its complications, as well as for children with measles older than 6 months who have immunodeficiency, ophthalmologic evidence of vitamin A deficiency, impaired intestinal absorption, moderate to severe malnutrition, or recent immigration from areas where high measles mortality rates have been observed.20 The World Health Organization recommends administration of two daily doses of 200,000 IU of vitamin A to all children with measles 12 months of age or older. Lower doses (100,000 IU) are recommended for children younger than 12 months.
FIGURE 316-3. Measles rash. (Source: Reprinted, with permission, from Moss WJ, Griffin DE. Global measles elimination. Nature Reviews Microbiology. 2006; 4:903.)
Most children with measles recover and develop long-term protective immunity to reinfection. Measles case fatality proportions vary, depending on the average age of infection, nutritional and immunologic status of the population, measles vaccine coverage, and access to health care. Vaccinated children, should they develop disease after exposure, have less severe disease and significantly lower mortality rates. In developed countries, less than 1 in 1000 children with measles dies. In endemic areas in sub-Saharan Africa and Southeast Asia, the measles case fatality proportion may be 5% to 10% or higher. Measles is a major cause of child deaths in refugee camps and in internally displaced populations, where measles case fatality proportions have been as high as 20% to 30%.26
COMPLICATIONS
A wide variety of complications may be observed during the acute stage of measles or shortly thereafter. The respiratory tract is involved most often, but severe gastroenteritis also occurs. Acute laryngotracheobronchitis (croup) may cause sufficient airway obstruction to require tracheostomy, especially in children younger than 3 years. A rare but almost uniformly fatal interstitial pneumonia (giant cell pneumonia) has been noted in immuno-compromised children, including those with HIV-1 infection, who develop a progressive persistent measles virus infection without the typical exanthem and with a unique failure to form measles virus–specific antibodies. The radiographic picture reveals a marked interstitial pattern emanating from both hilar regions.
A benign asymptomatic keratoconjunctivitis that accompanies measles may persist for as long as 4 months. More severe corneal lesions occur in malnourished children. Transient electrocardiographic abnormalities are common, but true myocarditis is rare. The diffuse lymphadenopathy that accompanies measles involves the mesenteric nodes and is believed to cause the abdominal pain that commonly occurs. Symptoms and signs identical to those of acute appendicitis may result in surgical intervention during the prodromal period.
Complications of bacterial origin result principally from invasion of the respiratory tract by pyogenic organisms. Otitis media and bronchopneumonia are most common. Peribronchitis and interstitial pneumonitis are seen in nearly all children with measles and resolve rapidly after the development of rash and the subsidence of fever. A second fever spike, or failure of the initial spike to drop after the eruption has reached its peak, suggests a secondary bacterial infection. The appearance of peripheral leukocytosis with a shift to the left is confirmatory. A chest radiograph may disclose bronchopneumonia or a pattern of segmental or lobar involvement.
During the early viremic phase of measles, there is a thrombocytopenia of insufficient magnitude to cause spontaneous bleeding. Another rare and unexplained postinfectious complication, thrombocytopenic purpura, appears 4 to 14 days after the rash and may produce marked skin purpura, genitourinary and gastrointestinal bleeding, and epistaxis.
Of those syndromes that can follow measles, the most dreaded are the various central nervous system complications. Acute postinfectious measles encephalomyelitis is the most common neurologic complication of measles. It is rare in children younger than 2 years, but occurs in about 1 in 1000 cases of measles in older children and somewhat more frequently in adults.23 The onset is usually during the first week after the start of the rash and is typically abrupt, with irritability, headache, vomiting, and confusion, and progressing rapidly to obtundation and coma. These manifestations are frequently accompanied by seizures and recurrence or accentuation of fever. A second form of measles encephalitis, subacute sclerosing panencephalitis (SSPE), is a rare delayed complication of measles that occurs in approximately 1 in 10,000 cases.24 Typically, SSPE presents in children 6 to 8 years after measles that occurred in early childhood, generally prior to 2 years of age.25 The onset is insidious, with symptoms of progressive loss of cortical function developing over months. Patients subsequently develop ataxia, progressive mental deterioration, and extrapyramidal dyskinesias, including choreoathetosis and dystonic posturing. The third form of measles encephalitis, measles inclusion body encephalitis (MIBE), is a progressive, generally fatal, measles virus infection of the brain that occurs in immunocompromised patients.
PREVENTION
Active immunization for measles is discussed in Chapter 244. The proportions of children who develop protective levels of antibody after measles vaccination are approximately 85% at 9 months of age and 95% at 12 months of age.28
Human immunoglobulin (IG) given shortly after exposure can attenuate the clinical course of measles. In immunocompetent persons, administration of IG within 72 hours of exposure usually prevents measles virus infection and almost always prevents clinical measles. IG administered up to 6 days after exposure will still prevent or modify the disease. Prophylaxis with IG is recommended for susceptible household and nosocomial contacts who are at risk of developing severe measles, particularly children younger than 1 year, immunocompromised persons (including HIV-1–infected persons previously immunized with live-attenuated measles vaccine), and pregnant women. Except for premature infants, children younger than 6 months will usually be partially or completely protected by passively acquired maternal antibody. If measles is diagnosed in a mother, all unimmunized children in the household should receive IG. The recommended dose of IG is 0.25 mL/kg of body weight given intramuscularly. Immunocompromised persons should receive 0.5 mL/kg. The maximum total dose is 15 mL. Intravenous immune globulin (IGIV) contains antibodies to measles virus, and the usual dose of 100 to 400 mg/kg should provide adequate prophylaxis for measles exposures occurring as long as 3 weeks or more after IGIV administration.