Measles is an acute, highly infectious disease characterized by fever, respiratory symptoms, and a maculopapular rash. Complications are common and may be quite serious. The introduction of an effective live-virus vaccine has dramatically reduced the incidence of this disease in the United States, but measles is still a leading cause of death of young children in many developing countries.

Pathogenesis and Pathology Humans are the only natural hosts for measles virus, although numerous other species, including monkeys, dogs, and mice, can be experimentally infected. The natural history of measles infection is shown in Figure1.

Fig1. Natural history of measles infection. Viral replication begins in the respiratory epithelium and spreads to monocyte-macrophages, endothelial cells, and epithelial cells in the blood, spleen, lymph nodes, lung, thymus, liver, and skin and to the mucosal surfaces of the gastrointestinal, respiratory, and genitourinary tracts. The virus specific immune response is detectable when the rash appears. Clearance of virus is approximately coincident with fading of the rash. IgG, immunoglobulin G; IgM, immunoglobulin M; SSPE, subacute sclerosing panencephalitis.

The virus gains access to the human body via the respiratory tract, where it multiplies locally; the infection then spreads to the regional lymphoid tissue, where further multiplication occurs. Primary viremia disseminates the virus, which then replicates in the reticuloendothelial system. Finally, a secondary viremia seeds the epithelial surfaces of the body, including the skin, respiratory tract, and conjunctiva, where focal replication occurs. Measles can replicate in certain lymphocytes, which aids in dissemination throughout the body. Multinucleated giant cells with intranuclear inclusions are seen in lymphoid tissues throughout the body (lymph nodes, tonsils, appendix). The described events occur during the incubation period, which typically lasts 8–15 days but may last up to 3 weeks in adults.

Patients are contagious during the prodromal phase (2–4 days) and the first 2–5 days of rash, when virus is present in tears, nasal and throat secretions, urine, and blood. The characteristic maculopapular rash appears about day 14 just as circulating antibodies become detectable, the viremia disappears, and the fever falls. The rash develops as a result of interaction of immune T cells with virus-infected cells in the small blood vessels and lasts about 1 week. (In patients with defective cell-mediated immunity, no rash develops.)

Involvement of the central nervous system is common in measles (Figure 2). Symptomatic encephalitis devel ops in about one in 1000 cases. Because infectious virus is rarely recovered from the brain, it has been suggested that an autoimmune reaction is the mechanism responsible for this complication. In contrast, progressive measles inclusion body encephalitis may develop in patients with defective cell mediated immunity. Actively replicating virus is present in the brain in this usually fatal form of disease.

Fig2. Timing of neurologic complications of measles. Whereas encephalitis occurs in about one of every 1000 cases of measles, subacute sclerosing panencephalitis (SSPE) is a rare late complication that develops in about one of 300,000 cases. MIBE, measles inclusion body encephalitis; PIE, postinfectious encephalomyelitis (also called acute disseminated encephalomyelitis). (Adapted with permission from Griffin DE, Bellini WJ: Measles virus. In Fields BN, Knipe DM, Howley PM [editors-in-chief]. Fields Virology, 3rd ed. Lippincott-Raven, 1996.)

A rare late complication of measles is subacute sclerosing panencephalitis (SSPE). This fatal disease develops years after the initial measles infection and is caused by virus that remains in the body after acute measles infection. Large amounts of measles antigens are present within inclusion bodies in infected brain cells, but only a few virus particles mature. Viral replication is defective owing to lack of pro duction of one or more viral gene products, often the matrix protein.

Clinical Findings

 Infections in nonimmune hosts are almost always symptomatic. Measles has an incubation period of 8–15 days from exposure to the onset of rash.

The prodromal phase is characterized by fever, sneezing, coughing, running nose, redness of the eyes, Koplik spots, and lymphopenia. The cough and coryza reflect an intense inflammatory reaction involving the mucosa of the respiratory tract. The conjunctivitis is commonly associated with photophobia. Koplik spots—pathognomonic for measles—are small, bluish white ulcerations on the buccal mucosa opposite the lower molars. These spots contain giant cells and viral antigens and appear slightly before the rash. The fever and cough persist until the rash appears and then subside within 1–2 days. The rash, which starts on the head and then spreads progressively to the chest, the trunk, and down the limbs, appears as light pink, discrete maculo-papules that coalesce to form blotches, becoming brownish in 5–10 days. The fading rash resolves with desquamation. Symptoms are most marked when the rash is at its peak but subside rapidly thereafter.

Modified measles occurs in partially immune persons, such as infants with residual maternal antibody. The incubation period is prolonged, prodromal symptoms are diminished, Koplik spots are usually absent, and the rash is mild.

The most common complication of measles is otitis media (5–9% of cases).

Pneumonia caused by secondary bacterial infection is the most common life-threatening complication of measles. This occurs in fewer than 10% of cases in developed countries but is much more frequent (20–80%) in developing countries. Pulmonary complications account for more than 90% of measles-related deaths. Viral pneumonia develops in 3–15% of adults with measles, but fatalities in this instance are rare.

Giant cell pneumonia is a serious complication in children and adults with deficiencies in cell-mediated immunity. It is believed to be caused by unrestrained viral replication and has a high fatality rate.

Complications involving the central nervous system are the most serious. About 50% of children with regular measles register electroencephalographic changes. Acute encephalitis occurs in about one in 1000 cases. There is no apparent correlation between the severity of the measles and the appearance of neurologic complications. Postinfectious encephalomyelitis (acute disseminated encephalomyelitis) is an autoimmune disease associated with an immune response to myelin basic protein. The mortality rate in encephalitis associated with measles is about 10–20%. The majority of survivors have neurologic sequelae.

SSPE, the rare late complication of measles infection, occurs with an incidence of about one in 10,000 to one in 100,000 cases. The disease begins insidiously 5–15 years after a case of measles; it is characterized by progressive mental deterioration, involuntary movements, muscular rigidity, and coma. It is usually fatal within 1–3 years after onset. Patients with SSPE exhibit high titers of measles antibody in cerebrospinal fluid and serum and defective measles virus in brain cells. With the widespread use of measles vaccine, SSPE has become less common.

Immunity

 There is only one antigenic type of measles virus. Infection confers lifelong immunity. Most so called second attacks represent errors in diagnosis of either the initial or the second illness.

The presence of humoral antibodies indicates immunity. Protective immunity is attributed to neutralizing antibodies against the H protein. However, cellular immunity appears to be essential for clearing the virus and for long-lasting protection. Patients with immunoglobulin deficiencies recover from measles and resist reinfection, but patients with cellular immune deficiencies do very poorly when they acquire measles infections. The role of mucosal immunity in resistance to infections is unclear.

Measles immune responses are involved in disease pathogenesis. Local inflammation causes the prodromal symptoms, and specific cell-mediated immunity plays a role in development of the rash.

Measles infection causes immune suppression—most importantly in the cell-mediated arm of the immune system— but is observed to affect all components. This is related to the serious secondary infections and may persist for months after measles infection.

Laboratory Diagnosis

Typical measles is reliably diagnosed on clinical grounds; laboratory diagnosis may be necessary in cases of modified or atypical measles.

A. Antigen and Nucleic Acid Detection

 Measles antigens can be detected directly in epithelial cells from respiratory secretions, the nasopharynx, conjunctiva, and urine. Antibodies to the nucleoprotein are useful because that is the most abundant viral protein in infected cells.

Detection of viral RNA by RT-PCR is a sensitive method that can be applied to a variety of clinical samples for measles diagnosis.

B. Isolation and Identification of Virus

Nasopharyngeal and conjunctival swabs, blood samples, respiratory secretions, and urine collected from a patient during the febrile period are appropriate sources for viral isolation. Monkey or human kidney cells or a lymphoblastoid cell line (B95-a) are optimal for isolation attempts. Measles virus grows slowly; typical cytopathic effects (multinucleated giant cells containing both intranuclear and intracytoplasmic inclusion bodies) take 7–10 days to develop. Shell vial culture tests can be completed in 2–3 days using fluorescent antibody staining to detect measles antigens in the inoculated cultures. However, virus isolation is technically difficult.

C. Serology

Serologic confirmation of measles infection depends on a fourfold rise in antibody titer between acute-phase and convalescent-phase sera or on demonstration of measles-specific IgM antibody in a single serum specimen drawn between 1 and 2 weeks after the onset of rash. ELISA, HI, and neutralization tests all may be used to measure measles antibodies, although ELISA is the most practical method.

Dried blood spots and oral fluids appear to be useful alternatives to serum for detection of measles antibody in areas where serum samples are difficult to collect and handle.

The major part of the immune response is directed against the viral nucleoprotein. Patients with SSPE display an exaggerated antibody response, with titers 10- to 100-fold higher than those seen in typical convalescent sera.

Epidemiology

The key epidemiologic features of measles are as follows: The virus is highly contagious, there is a single serotype, there is no animal reservoir, inapparent infections are rare, and infection confers lifelong immunity. Prevalence and age incidence of measles are related to population density, economic and environmental factors, and the use of an effective live virus vaccine.

Transmission occurs predominantly via the respiratory route (by inhalation of large droplets of infected secretions). Fomites do not appear to play a significant role in transmission. Hematogenous transplacental transmission can occur when measles occurs during pregnancy.

A continuous supply of susceptible individuals is required for the virus to persist in a community. A population size approaching 500,000 is necessary to sustain measles as an endemic disease; in smaller communities, the virus dis appears until it is reintroduced from the outside after a critical number of nonimmune persons accumulates.

Measles is endemic throughout the world. In general, epidemics recur regularly every 2–3 years. A population’s state of immunity is the determining factor; the disease will flare up when there is an accumulation of susceptible children. The severity of an epidemic is a function of the number of susceptible individuals. When the disease is introduced into isolated communities where it has not been endemic, an epidemic builds rapidly and attack rates are almost 100%. All age groups develop clinical measles, and the mortality rate may be as high as 25%.

In industrialized countries, measles occurs in 5- to 10-year-old children; in developing countries, it commonly infects children younger than 5 years. Measles rarely causes death in healthy people in developed countries. However, in malnourished children in developing countries where ade quate medical care is unavailable, measles is a leading cause of infant mortality. Those with immunologic disorders, such as advanced human immunodeficiency virus infections, are at risk of severe or fatal measles. The World Health Organization estimated in 2005 that there were 30–40 million measles cases and 530,000 deaths annually worldwide. Measles is a major global cause of mortality among children younger than 5 years, and measles deaths occur disproportionately in Africa and Southeast Asia.

The World Health Organization and the United Nations International Children’s Emergency Fund established a plan in 2005 to reduce measles mortality through immunization activities and better clinical care of cases. Between 2000 and 2008, the numbers of measles cases and of measles deaths were estimated to be reduced by more than 75%.

Measles cases occur throughout the year in temperate climates. Epidemics tend to occur in late winter and early spring.

There were 540 measles cases in the United States from 1997 to 2001, 67% of which were linked to imports (persons infected outside the United States). Over an 8-year period (1996–2004), 117 passengers with imported measles cases were considered infectious while traveling by aircraft. Despite the highly infectious nature of the virus, only four secondary spread cases were identified.

Measles was declared eliminated from the United States in 2000. However, imported cases have caused multiple out breaks, particularly in communities declining measles vaccination. Typically, measles causes about 50–100 cases annually, but over 600 cases were reported in 2014, with 23 outbreaks. To sustain elimination of measles transmission, vaccine coverage rates need to exceed 90%. Since the first dose of vaccine is given at 12–15 months, infants less than 1 year are at particular risk for severe complications in communities with low measles vaccine coverage.

Treatment, Prevention, and Control

Vitamin A treatment in developing countries has decreased mortality and morbidity. Measles virus is susceptible in vitro to inhibition by ribavirin, but clinical benefits have not been proved.

A highly effective and safe attenuated live measles virus vaccine has been available since 1963. Measles vaccine is available in monovalent form and in combination with live attenuated rubella vaccine (MR), live attenuated rubella and mumps vaccines (MMR), and live attenuated varicella vaccine (MMRV). Measles vaccines are derived from the Edmonston strain of measles virus and protect against all wild measles viruses. However, because of failure to vaccinate children and because of infrequent cases of vaccine failure, measles has not been eliminated from the world, but it has been eliminated from the United States.

Mild clinical reactions (fever or mild rash) occur in 2–5% of vaccines, but there is little or no virus excretion and no transmission. Immunosuppression occurs as with measles, but it is transient and clinically insignificant. Antibody titers tend to be lower than after natural infection, but studies have shown that vaccine-induced antibodies persist for up to 33 years, indicating that immunity is probably lifelong.

It is recommended that all children, health care workers, and international travelers be vaccinated. Contraindications to vaccination include pregnancy, allergy to eggs or neomycin, immune compromise (except that caused by infection with human immunodeficiency virus), and recent administration of immunoglobulin.

The use of killed measles virus vaccine was discontinued by 1970; some vaccinated individuals became sensitized and developed severe atypical measles when infected with wild virus.

Quarantine is not effective as a control measure because transmission of measles occurs during the prodromal phase.

 Rinderpest

Rinderpest, the world’s most devastating disease of cattle, was caused by rinderpest virus, a relative of measles virus. In 2010, rinderpest was declared to be eradicated from the earth after a successful global effort launched in 1994. This rep resented the first animal disease (and the second disease in human history after smallpox) to be eradicated worldwide. It was accomplished by widespread vaccination programs and long-term monitoring of cattle and wildlife.

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