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Measles (Rubeola)

Chapter 211 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Viral (incl. HIV)

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Koplik's spots are pathognomonic of measles and appear on the buccal mucosa ~2 days before the rash.
  2. Measles virus is antigenically monotypic, meaning vaccines developed decades ago remain protective worldwide.
  3. Vitamin A supplementation (200,000 IU/day for 2 days) reduces morbidity and mortality in children with measles.
  4. Measles induces a state of immunosuppression lasting weeks to months, increasing susceptibility to secondary bacterial infections.
  5. CDC case definition requires generalized maculopapular rash, fever >= 38.3°C, and cough/coryza/conjunctivitis.
  6. Measles case-fatality rate is 0.01–0.1% in developed countries but can be 5–10% or higher in endemic areas.
  7. Post-measles encephalomyelitis occurs in ~1 in 1000 cases and is an autoimmune disorder triggered by the infection.
  8. Measles vaccination is contraindicated in individuals with severe deficiencies of cellular immunity.
  9. Secondary vaccine failure rates are estimated at ~5% but are likely lower when vaccination takes place after 12 months of age.
  10. Measles is one of the most highly contagious directly transmitted pathogens, with secondary attack rates exceeding 90%.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Measles virus infection: pathogenesis, clinical features, and immune responses

1. DEFINITION & OVERVIEW

Measles is a highly contagious viral disease characterized by a pro-dromal illness of fever, cough, coryza, and conjunctivitis followed by the appearance of a generalized maculopapular rash. Before the widespread use of measles vaccines, it was estimated that measles caused >2 million deaths worldwide each year. Remarkable progress has been made in reducing global measles incidence and mortality rates through measles vaccination. In the United States, high-level coverage with two doses of measles vaccine eliminated endemic measles virus transmission in 2000. However, imported cases and low measles vaccine coverage in some communities threaten this goal. The 1274 measles cases reported in the United States in 2019 represent the highest count since 1992.

1.1 Global Considerations

  • The World Health Organization's (WHO's) Region of the Americas was declared to have eliminated measles in September 2016—the first region in the world to do so.
  • Endemic measles virus transmission was reestablished, and the region lost its measles elimination status.
  • No WHO region has achieved and sustained measles elimination status, highlighting the importance of maintaining high measles vaccination coverage.
  • From 2000 to 2022, the estimated annual number of global measles deaths per year decreased 82%, from 772,854 to 136,216.
  • Measles vaccination prevented an estimated 57.2 million deaths over this period.
  • Despite this progress, >100,000 children die each year from a preventable disease such as measles.
  • The Measles and Rubella Partnership (MRP)—formerly the Measles and Rubella Initiative (MRI)—is working to improve immunization coverage and address setbacks caused by the pandemic.
  • Since its inception in 2001, MRI has played an important role in reducing global measles incidence and mortality rates, providing governments and communities in 88 countries with technical and financial support.
  • In 2023, MRI was rebranded as MRP, and the partnership expanded to formally include longtime partners Gavi, the Vaccine Alliance and the Bill and Melinda Gates Foundation as core partners.

2. EPIDEMIOLOGY

Measles virus is one of the most highly contagious directly transmitted pathogens. Outbreaks can occur in populations in which <10% of persons are susceptible. Chains of transmission are common among household contacts, school-age children, and health care workers. There are no latent or persistent measles virus infections that result in a prolonged infectious period, nor are there animal reservoirs for the virus. Thus, measles virus can be maintained in human populations only by an unbroken chain of acute infections, which requires a continuous supply of susceptible individuals. Newborns become susceptible when passively acquired maternal antibodies are lost, generally before 6–9 months of age. When not immunized, these infants account for the bulk of new susceptible individuals that sustain measles virus transmission.

2.1 Transmission & Seasonality

  • Endemic measles has a typical temporal pattern characterized by yearly seasonal epidemics superimposed on longer epidemic cycles of 2–5 years or more.
  • In temperate climates, annual measles outbreaks typically occur in the late winter and early spring.
  • These annual outbreaks are probably attributable to social networks facilitating transmission (e.g., congregation of children at school) and environmental factors favoring the viability and transmission of measles virus.
  • Measles cases continue to occur during interepidemic periods in large populations but at low incidence.
  • The longer epidemic cycles occurring every several years result from the accumulation of susceptible persons over successive birth cohorts and the subsequent decline in the number of susceptibles following an outbreak.
  • Secondary attack rates among susceptible household and institutional contacts generally exceed 90%.
  • The average age at which measles occurs depends on rates of contact with infected persons, protective maternal antibody decline, and vaccine coverage.
  • In densely populated urban settings with low-level vaccination coverage, measles is a disease of infants and young children.
  • The cumulative incidence can reach 50% by 1 year of age, with a significant proportion of children acquiring measles before 9 months—the age at which the first of two routine vaccine doses are administered in many countries.
  • As measles vaccine coverage increases or population density decreases, the age distribution shifts toward older children.
  • In such situations, measles cases predominate in school-age children.
  • Infants and young children, although susceptible if not protected by maternal antibodies or vaccination, are not exposed to measles virus at a rate sufficient to cause a heavy disease burden in this age group.
  • As vaccination coverage increases further, the age distribution of cases may be shifted into adolescence and adulthood.
  • This distribution is seen in measles outbreaks in the United States and necessitates targeted measles vaccination programs for these older age groups.
  • Some countries have a bimodal distribution, with measles cases predominantly in young infants and adults.
  • Persons with measles are infectious for several days before and after the onset of rash, when levels of measles virus in blood and body fluids are highest and when cough, coryza, and sneezing that facilitate virus spread are most severe.
  • The contagiousness of measles before the onset of recognizable disease hinders the effectiveness of isolation measures.
  • Medical settings are well-recognized sites of measles virus transmission.
  • Children may present to health care facilities during the prodrome, when the diagnosis is not obvious, although the child is infectious and is likely to infect susceptible contacts.
  • Susceptible health care workers can acquire measles from infected children and transmit measles virus to others.
  • Nosocomial transmission can be reduced by maintenance of a high index of clinical suspicion particularly during outbreaks, use of appropriate isolation precautions when measles is suspected, administration of measles vaccine to susceptible children and health care workers, and documentation of health care workers' immunity to measles (i.e., proof of receipt of two doses of measles vaccine or detection of IgG antibodies to measles virus).

2.2 Impact of COVID-19

  • The COVID-19 pandemic caused severe disruptions to immunization activities, further threatening progress toward measles control and elimination.
  • Almost 40 million children were estimated to have missed a dose of measles vaccine in 2021, including 25 million children who missed their first dose.
  • Large-scale measles outbreaks occurred in 22 countries in 2021 and 37 countries in 2022.
  • Over the same period, the estimated number of measles cases and deaths increased by 18% and 43%, respectively.

3. ETIOLOGY & PATHOGENESIS

Measles virus is a spherical, nonsegmented, single-stranded, negative-sense RNA virus and a member of the Morbillivirus genus in the family Paramyxoviridae. Measles was originally a zoonotic infection, arising from animal-to-human transmission of an ancestral morbillivirus thousands of years ago, when human populations attained sufficient size to sustain virus transmission. Although RNA viruses typically have high mutation rates, measles virus is an antigenically monotypic virus, i.e., the surface proteins responsible for inducing protective immunity retained their antigenic structure across time and distance because of their key role in binding cellular receptors. The public health significance of this stability is that measles vaccines developed decades ago from a single strain of measles virus remain protective worldwide. Both wild-type and attenuated measles viruses are inactivated by ultraviolet light and heat, necessitating a cold chain for vaccine transport and storage.

3.1 Pathogenesis

  • Infection is initiated when measles virus is deposited in the respiratory tract, oropharynx, or conjunctivae.
  • During the first 2–4 days after infection, measles virus proliferates locally in the respiratory mucosa, primarily in dendritic cells and lymphocytes, and spreads to draining lymph nodes.
  • Virus then enters the bloodstream by budding from infected lymphocytes, producing the viremia that disseminates infection throughout the body.
  • Replication of measles virus in the target organs, together with the host's immune response, are responsible for the signs and symptoms of measles that occur 8–12 days after infection and mark the end of the incubation period.
  • The incubation period for measles is ~10 days to fever onset and clinical recovery, and 14 days to rash onset.
  • This period may be shorter in infants and longer (up to 3 weeks) in adults.

3.2 Immune Responses

  • Host immune responses to measles virus are essential for viral clearance, clinical recovery, and the establishment of long-term protective immunity.
  • Early nonspecific (innate) immune responses during the prodromal phase include activation of natural killer cells and increased production of antiviral proteins.
  • The adaptive immune responses consist of measles virus-specific antibody and cellular responses.
  • The protective efficacy of antibodies to measles virus is illustrated by the immunity conferred to infants from passively acquired maternal antibodies and the protection of exposed, susceptible individuals after administration of anti–measles virus immunoglobulin.
  • The first measles virus-specific antibodies produced after infection are of the IgM subtype, with a subsequent switch to predominantly IgG1 and IgG3 isotypes.
  • The IgM antibody response is typically absent following reexposure or revaccination and serves as a marker of primary infection.
  • The importance of cellular immunity to measles virus is demonstrated by the ability of children with agammaglobulinemia (congenital inability to produce antibodies) to recover fully from measles and the contrasting picture for children with severe defects in T lymphocyte function who often develop severe or fatal disease.
  • The initial predominant T 1 response (characterized by interferon-γ) is essential for viral clearance.
  • The later T 2 response (characterized by interleukin-4) promotes the development of measles virus-specific antibodies that are critical for protection against reinfection.
  • The duration of protective immunity following wild-type measles virus infection is generally thought to be lifelong.
  • Immunologic memory to measles virus includes both continued production of measles virus-specific antibodies by long-lived plasma cells and memory B cells as well as circulation of measles virus-specific CD4+ and CD8+ T lymphocytes.
  • However, the intense immune responses induced by measles virus infection are paradoxically associated with depressed responses to unrelated (non–measles virus) antigens.
  • This state of immunosuppression persists for at least several weeks to months beyond resolution of the acute illness, enhances susceptibility to secondary infections with bacteria and viruses that cause pneumonia and diarrhea, and is thus responsible for a substantial proportion of measles-related morbidity and deaths.
  • Delayed-type hypersensitivity responses to recall antigens, such as tuberculin, are suppressed, and cellular and humoral responses to new antigens are impaired.
  • Reactivation of latent tuberculosis and remission of autoimmune diseases after measles have been described and are attributed to this period of immune suppression.
  • Importantly, measles results in reductions in the magnitude and diversity of antibodies against previously encountered viral and bacterial antigens, impairing immunologic memory.
  • This mechanism may explain why child morbidity and mortality due to other infectious diseases may be increased for >2 years after measles.

4. CLINICAL MANIFESTATIONS

In most persons, the signs and symptoms of measles are highly characteristic. Fever and malaise beginning ~10 days after exposure are followed by cough, coryza, and conjunctivitis. These signs and symptoms increase in severity over 4 days. Koplik's spots develop on the buccal mucosa ~2 days before the rash appears. Koplik's spots are pathognomonic of measles and consist of bluish white dots ~1 mm in diameter surrounded by erythema. The lesions appear first on the buccal mucosa opposite the lower molars but rapidly increase in number and may involve the entire buccal mucosa. They fade with the onset of rash. The characteristic rash of measles begins 2 weeks after infection, when the clinical manifestations are most severe, and signal the host's immune response to the replicating virus. Headache, abdominal pain, vomiting, diarrhea, and myalgia may be present. The rash of measles begins as erythematous macules behind the ears and on the neck and hairline. The rash progresses to involve the face, trunk, and arms, with involvement of the legs and feet by the end of the second day. Areas of confluent rash appear on the trunk and extremities, and petechiae may be present. The rash fades slowly in the same order of progression as it appeared, usually beginning on the third or fourth day after onset. Resolution of the rash may be followed by desquamation, particularly in undernourished children. Because the characteristic rash of measles is a consequence of the cellular immune response, it may not develop in persons with impaired cellular immunity. These persons have a high case–fatality rate and frequently develop giant cell pneumonitis caused by measles virus.

4.1 Prodromal Phase

  • Fever and malaise beginning ~10 days after exposure.
  • Followed by cough, coryza, and conjunctivitis.
  • Signs and symptoms increase in severity over 4 days.

4.2 Koplik's Spots

  • Develop on the buccal mucosa ~2 days before the rash appears.
  • Pathognomonic of measles.
  • Consist of bluish white dots ~1 mm in diameter surrounded by erythema.
  • Lesions appear first on the buccal mucosa opposite the lower molars.
  • Rapidly increase in number and may involve the entire buccal mucosa.
  • Fade with the onset of rash.

4.3 Rash Progression

  • Begins 2 weeks after infection.
  • Begins as erythematous macules behind the ears and on the neck and hairline.
  • Progresses to involve the face, trunk, and arms.
  • Involvement of the legs and feet by the end of the second day.
  • Areas of confluent rash appear on the trunk and extremities.
  • Petechiae may be present.
  • Fades slowly in the same order of progression as it appeared, usually beginning on the third or fourth day after onset.
  • Resolution of the rash may be followed by desquamation, particularly in undernourished children.

5. DIFFERENTIAL DIAGNOSIS

The differential diagnosis of measles includes other causes of fever, morbilliform rash, and conjunctivitis, including rubella, Kawasaki disease, infectious mononucleosis, roseola, scarlet fever, Rocky Mountain spotted fever, enterovirus or adenovirus infection, and drug sensitivity. Rubella is a milder illness without cough and with distinctive posterior auricular or suboccipital lymphadenopathy. The rash of roseola (exanthem subitum) appears after fever has subsided. The atypical lymphocytosis in infectious mononucleosis contrasts with the leukopenia commonly observed in children with measles. Anecdotal reports have described the recovery of previously healthy pregnant and immunocompromised patients with measles pneumonia and of immunocompromised patients with measles encephalitis after treatment with aerosolized and IV ribavirin. However, the clinical benefits of ribavirin in measles have not been conclusively demonstrated in clinical trials.

5.1 Rubella

  • Milder illness.
  • Without cough.
  • Distinctive posterior auricular or suboccipital lymphadenopathy.

5.2 Roseola

  • Rash appears after fever has subsided.

5.3 Infectious Mononucleosis

  • Atypical lymphocytosis contrasts with the leukopenia commonly observed in children with measles.

6. INVESTIGATIONS & DIAGNOSIS

Measles is readily diagnosed on clinical grounds by clinicians familiar with the disease, particularly during outbreaks. Koplik's spots are especially helpful because they appear early and are pathognomonic. Clinical diagnosis is more difficult (1) during the prodromal illness; (2) when the rash is attenuated by passively acquired antibodies or prior immunization; (3) when the rash is absent or delayed in immunocompromised children or severely undernourished children with impaired cellular immunity; and (4) in regions where the incidence of measles is low and other pathogens are responsible for most illnesses with fever and rash. The 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. Serology is the most common method of laboratory diagnosis. The detection of measles virus-specific IgM in a single specimen of serum or oral fluid is considered diagnostic of acute infection, as is a four-fold or greater increase in measles virus-specific IgG antibody levels between acute- and convalescent-phase serum specimens. Primary infection in the immunocompetent host results in antibodies that are often detectable within 1–3 days of rash onset and reach peak levels in 2–4 weeks. However, measles virus-specific IgM antibodies may not be detectable until 4–5 days or more after rash onset, resulting in false-negative test results if the specimen is obtained too early, and usually fall to undetectable levels within 4–8 weeks of rash onset. Several methods for measurement of antibodies to measles virus are available. Neutralization tests are sensitive and specific, and the results are highly correlated with protective immunity. However, these tests require propagation of measles virus in cell culture and thus are expensive and laborious. Commercially available measles IgM enzyme immunoassays are most frequently used. Measles can also be diagnosed by isolation of the virus in cell culture from respiratory secretions, nasopharyngeal or conjunctival swabs, blood, or urine. Direct detection of giant cells in respiratory secretions, urine, or tissue obtained by biopsy provides another method of diagnosis. For detection of measles virus RNA by reverse-transcription polymerase chain reaction, primers targeted to highly conserved regions of measles virus genes are used. Extremely sensitive and specific, this assay may also permit identification and characterization of measles virus genotypes for molecular epidemiologic studies and can distinguish wild-type from vaccine virus strains.

6.1 CDC Case Definition

  • Generalized maculopapular rash of at least 3 days' duration.
  • Fever of at least 38.3°C (101°F).
  • Cough, coryza, or conjunctivitis.

6.2 Serology

  • Detection of measles virus-specific IgM in a single specimen of serum or oral fluid is considered diagnostic of acute infection.
  • Four-fold or greater increase in measles virus-specific IgG antibody levels between acute- and convalescent-phase serum specimens is diagnostic.
  • Primary infection in the immunocompetent host results in antibodies that are often detectable within 1–3 days of rash onset and reach peak levels in 2–4 weeks.
  • Measles virus-specific IgM antibodies may not be detectable until 4–5 days or more after rash onset.
  • Measles virus-specific IgM antibodies usually fall to undetectable levels within 4–8 weeks of rash onset.
  • Neutralization tests are sensitive and specific, and the results are highly correlated with protective immunity.
  • Commercially available measles IgM enzyme immunoassays are most frequently used.

6.3 Other Methods

  • Isolation of the virus in cell culture from respiratory secretions, nasopharyngeal or conjunctival swabs, blood, or urine.
  • Direct detection of giant cells in respiratory secretions, urine, or tissue obtained by biopsy.
  • Reverse-transcription polymerase chain reaction (RT-PCR) using primers targeted to highly conserved regions of measles virus genes.
  • Extremely sensitive and specific.
  • May permit identification and characterization of measles virus genotypes for molecular epidemiologic studies.
  • Can distinguish wild-type from vaccine virus strains.

7. MANAGEMENT & TREATMENT

There is no specific antiviral therapy for measles. Treatment consists of general supportive measures such as hydration and administration of antipyretic agents. Because secondary bacterial infections are a major cause of morbidity and death attributable to measles, effective case management involves prompt antibiotic treatment for patients who have clinical evidence of bacterial infection, including pneumonia and otitis media. Vitamin A (available in oral and parenteral formulations) is effective for the treatment of measles and can markedly reduce rates of morbidity and mortality. The WHO recommends administration of once-daily oral doses of 200,000 IU of vitamin A for 2 consecutive days to all children with measles who are ≥12 months of age. Lower doses are recommended for younger children: 100,000 IU per day for children 6–11 months of age and 50,000 IU per day for children <6 months old. A third dose is recommended 2–6 weeks later for children with evidence of vitamin A deficiency. While such deficiency is not a widely recognized problem in the United States, many American children with measles do, in fact, have low serum levels of vitamin A, and these children experience increased measles-associated morbidity. Anecdotal reports have described the recovery of previously healthy pregnant and immunocompromised patients with measles pneumonia and of immunocompromised patients with measles encephalitis after treatment with aerosolized and IV ribavirin. However, the clinical benefits of ribavirin in measles have not been conclusively demonstrated in clinical trials.

7.1 Supportive Care

  • Hydration.
  • Administration of antipyretic agents.

7.2 Antibiotics

  • Prompt antibiotic treatment for patients who have clinical evidence of bacterial infection.
  • Includes pneumonia and otitis media.

7.3 Vitamin A Supplementation

  • WHO recommends administration of once-daily oral doses of 200,000 IU of vitamin A for 2 consecutive days to all children with measles who are ≥12 months of age.
  • Lower doses are recommended for younger children:
  • 100,000 IU per day for children 6–11 months of age.
  • 50,000 IU per day for children <6 months old.
  • A third dose is recommended 2–6 weeks later for children with evidence of vitamin A deficiency.
  • While such deficiency is not a widely recognized problem in the United States, many American children with measles do, in fact, have low serum levels of vitamin A, and these children experience increased measles-associated morbidity.

7.4 Ribavirin

  • Anecdotal reports have described the recovery of previously healthy pregnant and immunocompromised patients with measles pneumonia and of immunocompromised patients with measles encephalitis after treatment with aerosolized and IV ribavirin.
  • The clinical benefits of ribavirin in measles have not been conclusively demonstrated in clinical trials.

8. COMPLICATIONS & PROGNOSIS

Most complications of measles involve the respiratory tract and include the effects of measles virus itself and secondary bacterial infections. Giant cell pneumonitis due to replication of measles virus in the lungs can develop in immunocompromised persons. Acute laryngotracheobronchitis (croup) can occur during measles and may result in airway obstruction, particularly in young children. Many children with measles develop diarrhea, which contributes to and can exacerbate existing undernutrition. Most complications of measles result from secondary bacterial infections of the respiratory tract that are attributable to a state of immune suppression after acute measles. Otitis media and bronchopneumonia are most common. Recurrence of fever or failure of fever to subside with the rash suggests secondary bacterial infection. Severe complications of measles involve the central nervous system (CNS). Post-measles encephalomyelitis complicates ~1 in 1000 cases, affecting mainly older children and adults. Encephalomyelitis occurs within 2 weeks of rash onset and is characterized by fever, seizures, and a variety of neurologic abnormalities. The finding of periventricular demyelination, the induction of immune responses to myelin basic protein, and the absence of measles virus in the brain suggest that post-measles encephalomyelitis is an autoimmune disorder triggered by the measles virus infection. Rarer CNS complications that occur months to years after acute infection are measles inclusion body encephalitis (MIBE) and subacute sclerosing panencephalitis (SSPE). In contrast to post-measles encephalomyelitis, MIBE and SSPE are caused by persistent measles virus infection. MIBE is a rare but fatal complication that affects individuals with defective cellular immunity and typically occurs months after infection. SSPE is a slowly progressive disease characterized by seizures and progressive deterioration of cognitive and motor functions, with death occurring 5–15 years after measles virus infection. SSPE most often develops in persons infected with measles virus at <2 years of age. Most persons with measles recover and develop long-term protective immunity to reinfection. Measles case–fatality proportions vary with the average age of infection, the nutritional and immunologic status of the population, measles vaccine coverage, and access to health care. Among previously vaccinated persons who do become infected, disease is less severe and mortality rates are significantly lower. In most developed countries, the case–fatality rate is 0.01–0.1%, but in endemic areas of sub-Saharan Africa, the measles case–fatality rate may be 5–10% or even higher. Measles is a major cause of childhood deaths in refugee camps and in internally displaced populations, where case–fatality rates have been as high as 20–30%.

8.1 Respiratory Complications

  • Giant cell pneumonitis due to replication of measles virus in the lungs.
  • Can develop in immunocompromised persons.
  • Acute laryngotracheobronchitis (croup) can occur during measles.
  • May result in airway obstruction, particularly in young children.
  • Many children with measles develop diarrhea, which contributes to and can exacerbate existing undernutrition.
  • Most complications of measles result from secondary bacterial infections of the respiratory tract.
  • Otitis media and bronchopneumonia are most common.
  • Recurrence of fever or failure of fever to subside with the rash suggests secondary bacterial infection.

8.2 CNS Complications

  • Post-measles encephalomyelitis complicates ~1 in 1000 cases.
  • Affects mainly older children and adults.
  • Occurs within 2 weeks of rash onset.
  • Characterized by fever, seizures, and a variety of neurologic abnormalities.
  • Finding of periventricular demyelination, the induction of immune responses to myelin basic protein, and the absence of measles virus in the brain suggest that post-measles encephalomyelitis is an autoimmune disorder triggered by the measles virus infection.
  • Rarer CNS complications that occur months to years after acute infection are measles inclusion body encephalitis (MIBE) and subacute sclerosing panencephalitis (SSPE).
  • MIBE is a rare but fatal complication that affects individuals with defective cellular immunity and typically occurs months after infection.
  • SSPE is a slowly progressive disease characterized by seizures and progressive deterioration of cognitive and motor functions, with death occurring 5–15 years after measles virus infection.
  • SSPE most often develops in persons infected with measles virus at <2 years of age.

8.3 Prognosis

  • Most persons with measles recover and develop long-term protective immunity to reinfection.
  • Measles case–fatality proportions vary with the average age of infection, the nutritional and immunologic status of the population, measles vaccine coverage, and access to health care.
  • Among previously vaccinated persons who do become infected, disease is less severe and mortality rates are significantly lower.
  • In most developed countries, the case–fatality rate is 0.01–0.1%.
  • In endemic areas of sub-Saharan Africa, the measles case–fatality rate may be 5–10% or even higher.
  • Measles is a major cause of childhood deaths in refugee camps and in internally displaced populations, where case–fatality rates have been as high as 20–30%.

9. PREVENTION & VACCINATION

Standard doses of currently licensed measles vaccines are safe for immunocompetent children and adults. Fever up to 39.4°C (103°F) occurs in ~5–15% of seronegative vaccine recipients, and ~5% of vaccine recipients develop a transient rash. Mild transient thrombocytopenia has been reported, with an incidence of 1 case per ~40,000 MMR recipients. Since the publication of a report in 1998 falsely hypothesizing that MMR vaccine may cause a syndrome of autism and intestinal inflammation, much public attention has focused on this purported association. The events that followed publication of this report led to diminished vaccine coverage in the United Kingdom and provide important lessons in the misinterpretation of epidemiologic evidence and the communication of scientific results to the public. The publication that incited the concern was a case series describing 12 children with a regressive developmental disorder and chronic enterocolitis; 9 of these children had autism. In 8 of the 12 cases, the parents associated onset of the developmental delay with MMR vaccination. This simple temporal association was misinterpreted and misrepresented as a possible causal relationship, first by the lead author of the study and then by elements of the media and the public. Subsequently, many comprehensive reviews and additional epidemiologic studies refuted evidence of a causal relationship between MMR vaccination and autism, and the offending publication was retracted. Measles vaccines are often combined with other live attenuated virus vaccines, such as those for mumps and rubella (MMR) and for mumps, rubella, and varicella (MMRV). The recommended age of first vaccination varies from 6 to 15 months and represents a balance between the optimal age for seroconversion and the probability of acquiring measles before that age. The proportions of children who develop protective levels of antibody after the first measles vaccination approximate 85% at 9 months of age and 95% at 12 months. Common childhood illnesses concomitant with vaccination may reduce the level of immune response, but such illnesses are not valid reasons to withhold vaccination. Measles vaccines have been well tolerated and immunogenic in children and adults living with HIV, although antibody levels may wane more rapidly. Because of the potential severity of wild-type measles virus infection in children living with HIV, routine measles vaccination is recommended except for those who are severely immunocompromised. Measles vaccination is contraindicated in individuals with other severe deficiencies of cellular immunity because of the possibility of disease due to progressive pulmonary or CNS infection with the vaccine virus. The duration of vaccine-induced immunity is at least several decades, if not longer. Rates of secondary vaccine failure 10–15 years after immunization have been estimated at ~5% but are likely lower when vaccination takes place after 12 months of age. Decreasing antibody concentrations do not necessarily imply a complete loss of protective immunity as a secondary immune response usually develops after reexposure to measles virus, with a rapid rise in antibody titers in the absence of overt clinical disease.

9.1 Active Immunization

  • Standard doses of currently licensed measles vaccines are safe for immunocompetent children and adults.
  • Fever up to 39.4°C (103°F) occurs in ~5–15% of seronegative vaccine recipients.
  • ~5% of vaccine recipients develop a transient rash.
  • Mild transient thrombocytopenia has been reported, with an incidence of 1 case per ~40,000 MMR recipients.
  • Measles vaccines are often combined with other live attenuated virus vaccines, such as those for mumps and rubella (MMR) and for mumps, rubella, and varicella (MMRV).
  • The recommended age of first vaccination varies from 6 to 15 months.
  • The proportions of children who develop protective levels of antibody after the first measles vaccination approximate 85% at 9 months of age and 95% at 12 months.
  • Common childhood illnesses concomitant with vaccination may reduce the level of immune response, but such illnesses are not valid reasons to withhold vaccination.
  • Measles vaccines have been well tolerated and immunogenic in children and adults living with HIV, although antibody levels may wane more rapidly.
  • Because of the potential severity of wild-type measles virus infection in children living with HIV, routine measles vaccination is recommended except for those who are severely immunocompromised.
  • Measles vaccination is contraindicated in individuals with other severe deficiencies of cellular immunity because of the possibility of disease due to progressive pulmonary or CNS infection with the vaccine virus.
  • The duration of vaccine-induced immunity is at least several decades, if not longer.
  • Rates of secondary vaccine failure 10–15 years after immunization have been estimated at ~5% but are likely lower when vaccination takes place after 12 months of age.
  • Decreasing antibody concentrations do not necessarily imply a complete loss of protective immunity as a secondary immune response usually develops after reexposure to measles virus, with a rapid rise in antibody titers in the absence of overt clinical disease.

9.2 Passive Immunization

  • Human immunoglobulin given shortly after exposure can attenuate the clinical course of measles.
  • In immunocompetent persons, administration of immunoglobulin within 72 h of exposure usually prevents measles virus infection and almost always prevents clinical measles.
  • Administered up to 6 days after exposure, immunoglobulin will still prevent or modify the disease.
  • Prophylaxis with immunoglobulin is recommended for susceptible household and nosocomial contacts who are at risk of developing severe measles, particularly children <1 year of age, immunocompromised persons (including immunocompromised persons living with HIV who were previously immunized with live attenuated measles vaccine), and pregnant women.
  • Except for premature infants, children <6 months of age usually will be partially or completely protected by passively acquired maternal antibody.
  • Infants born to women with vaccine-induced measles immunity become susceptible to measles at a younger age than infants born to women with acquired immunity from natural infection.
  • If measles is diagnosed in a household member, all unimmunized children in the household should receive immunoglobulin.
  • The recommended dose is 0.5 mL/kg given intramuscularly with a maximum total dose of 15 mL.
  • Immunocompromised and pregnant persons should receive 400 mg/kg intravenously.
  • IV immunoglobulin contains antibodies to measles virus, and the usual dose of 100–400 mg/kg generally provides adequate prophylaxis for measles exposures occurring as long as 3 weeks or more after IV immunoglobulin administration.

9.3 Vaccine Details

  • The first live attenuated measles vaccine was developed by passage of the Edmonston strain in chick embryo fibroblasts to produce the Edmonston B virus, which was licensed in 1963 in the United States but was reactogenic.
  • Further passage of Edmonston B virus produced the more attenuated and less reactogenic Schwarz vaccine.
  • The Moraten ("more attenuated Enders") strain, which was licensed in 1968 and is used in the United States, is genetically identical to the Schwarz strain.
  • The Edmonston-Zagreb vaccine, also derived from the Edmonston B strain, is widely used in many countries and was passaged in human diploid cells.
  • Lyophilized measles vaccines are relatively stable, but reconstituted vaccine rapidly loses potency.
  • Live attenuated measles vaccines are inactivated by light and heat and lose about half their potency at 20°C and almost all their potency at 37°C within 1 h after reconstitution.
  • Therefore, a cold chain must be maintained before and after reconstitution.
  • Antibodies first appear 12–15 days after vaccination, and titers peak at 1–3 months.

10. KEY PEARLS & CLINICAL TRAPS

  • Koplik's spots are pathognomonic of measles and appear on the buccal mucosa ~2 days before the rash.
  • Measles virus is antigenically monotypic, meaning vaccines developed decades ago remain protective worldwide.
  • Vitamin A supplementation (200,000 IU/day for 2 days) reduces morbidity and mortality in children with measles.
  • Measles induces a state of immunosuppression lasting weeks to months, increasing susceptibility to secondary bacterial infections.
  • Measles is one of the most highly contagious directly transmitted pathogens, with secondary attack rates exceeding 90%.
  • Measles vaccination is contraindicated in individuals with severe deficiencies of cellular immunity.
  • Secondary vaccine failure rates are estimated at ~5% but are likely lower when vaccination takes place after 12 months of age.
  • Measles case-fatality rate is 0.01–0.1% in developed countries but can be 5–10% or higher in endemic areas.
  • Post-measles encephalomyelitis occurs in ~1 in 1000 cases and is an autoimmune disorder triggered by the infection.
  • Measles vaccination is contraindicated in individuals with other severe deficiencies of cellular immunity because of the possibility of disease due to progressive pulmonary or CNS infection with the vaccine virus.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Measles virus infection: pathogenesis, clinical features, and immune responses

Caption: FIGURE 211-1 Measles virus infection: pathogenesis, clinical features, and immune responses. A. Spread of measles virus, from initial infection of the respiratory tract through dissemination to the skin. B. Appearance of clinical signs and symptoms, including Koplik’s spots and rash. C. Antibody and T-cell responses to measles virus. The signs and symptoms of measles arise coincident with the host immune response. (Reproduced with permission from WJ Moss and DE Griffin: Global measles elimination. Nat Rev Microbiology 4:900, 2006.) — FIGURE 211-1 Measles virus infection: pathogenesis, clinical features, and immune responses. A. Spread of measles virus, from initial infection of the respiratory tract through dissemination to the skin. B. Appearance of clinical signs and symptoms, including Koplik's spots and rash. C. Antibody and T-cell responses to measles virus. The signs and symptoms of measles arise coincident with the host immune response. (Reproduced with permission from WJ Moss and DE Griffin: Global measles elimination. Nat Rev Microbiology 4:900, 2006.)

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.