Infectious Diseases

Measles Virus (Rubeola)

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Measles is caused by Rubeola virus, which belongs to the Paramyxovirus family.

Measles is an acute systemic viral infection with fever, respiratory involvement and symptoms, and a rash. Measles can cause serious complications and even fatalities. Infection confers lifelong immunity. Measles is highly contagious and vaccine preventable. Until recently, it had become rare in the United States. Parental fear of vaccinating children has led to an increase in susceptibles, a decrease in herd immunity, and a rise in the number of reported cases in the United States.

What is the best treatment?

  • Supportive measures, such as antipyretics and fluids, are used for treatment of measles, because no specific antiviral therapy is available. Antitussives may be used to suppress cough.

  • Bacterial superinfections, such as pneumonia and otitis media, should be treated with appropriate antimicrobials. Prophylactic antibiotics, however, should not be given. Children with measles should be administered Vitamin A once daily for 2 days. Children older than 12 months of age should receive 200,000 IU, infants 6-12 months of age should receive 100,000 IU, and babies less than 6 months old should be given 50,000 IU. For malnourished children with signs of Vitamin A deficiency, a third dose should be given after 2-4 weeks.

  • Although ribavirin intravenously or by aerosol has been used to treat measles, no formal studies have been conducted, so its efficacy against measles is unproven.

  • The safest and most successful approach to measles is prevention. Measles vaccine is usually given as the combination measles, mumps, and rubella (MMR) vaccines. Currently, 2 doses are usually administered, usually at 12-15 months of age (in outbreaks, vaccine can be given after 6 months of age.). The second dose is usually given at the start of school, but can be administered sooner. The minimum interval between doses is 1 month.

  • There are no issues of anti-infective resistance.

How do patients contract this infection, and how do I prevent spread to other patients?

  • Epidemiology

    • Measles is one of the most contagious diseases known; it is spread by the airborne route from respiratory secretions from infected individuals. There is a prodrome, very much like a rhinovirus "cold," with some cough, lasting about 3 days. The prodrome is followed by fever and gradual development of rash. Measles is most contagious just before rash onset and during the first few days after the rash appears. The presence of Koplik spots on the buccal mucosa is pathognomonic of measles. Complications of measles, including pneumonia and encephalitis, occur in roughly 1 per 1000-2000 cases; complications and severe measles are more frequent in immunocompromised patients. More common, less severe complications include otitis media and croup.

    • Measles usually occurs in winter and early spring in countries with temperate climates. The incubation period is 8-12 days, with an average of 10 days.

    • Worldwide, there were for many years 1 million annual deaths from measle, although this has recently decreased; in 2013 146,000 were reported to WHO. Measles is an enormous problem in developing countries, where infections often occur in very young children with immature immune systems, many of whom are also malnourished, which further impairs their immune response to the virus.

    • Live attenuated measles vaccine was licensed in the United States in 1963. Prior to that, an estimated 500,000 annual cases occurred in the United States. In 1991, a two dose schedule in infancy and early childhood was instituted because of the recognition of a vaccine failure rate of about 5% after 1 dose. Between 2000 and 2007, there were less than 100 annual cases in the United States. Measles became no longer endemic in the United States; molecular studies showed all cases to be due to imported measles from Europe, Asia, and the Middle East.

    • Beginning in 2008, an increase in measles began to occur in the United States. Many cases were related to travel in European and Asian countries, where there were many unvaccinated individuals. For a disease as contagious as measles, a very high rate of immunization (about 95%) is required to provide successful herd immunity. The increase in measles therefore was mainly ascribed to the failure of many parents to immunize their healthy infants, mainly from fear that MMR might be a cause of autism. Others refused vaccination, citing philosophical or religious objections. As many of 15 studies worldwide have failed to demonstrate a causal relationship between MMR vaccine and autism.

    • Today, cases of measles are on the increase in the United States, with reported mini-epidemics among unvaccinated and too-young-to-be-vaccinated children. In 2014, a record 667 cases of measles were reported in 27 states, the highest number of cases in many years. Most of the cases were unvaccinated.

    • Largely due to refusal of parents to immunize their children. In 2013, 11 measles outbreaks in the US were reported by the CDC, and in 2014 23 outbreaks were reported. In December 2015 an outbreak began at a large California amusement park, leading to 111 reported measles cases in 7 states, Mexico and Canada. There were no fatalities, but a number of patients were hospitalized.

      The CDC has released data on measles activity in the United States from January May in 2015. (MMWR April 17, 2015 / 64(14);373-376) It seems that in 2016, the incidence of measles in the US has declined, with less than 50 reported cases in the first half of the year, but final figures will not be available until at least next year.

    • A death from measles in the United States, was reported July 2, 2015, the first in many years.

    • Measles cases today are mostly ascribed to reluctance of some parents to vaccinate their children for fear of harm from the vaccine, and importations of measles cases from other countries where vaccination is not practiced.

  • Infection control issues

    • Measles in hospitalized patients requires strict isolation with proper hand-washing, gowns, masks, and gloves. Hospitalized patients should be in a negative pressure room, if possible. Airborne transmission precautions are indicated until 4 days after rash onset in otherwise healthy patients and for the duration of illness in the immunocompromised. The incubation period is 8-12 days after exposure. Measles cases should be reported to the local Department of Health.

    • Vaccination of healthy children is highly recommended and, in most states, is required for entry into daycare and/or school. Two doses are administered at 1 year and 4-6 years of age, usually as MMR or the varicella vaccine-containing MMRV. Although MMRV is not licensed for individuals older than 13 years of age, MMR can be administered to adolescents and adults. Second doses of measles-containing vaccines should be at least 1 month apart. Healthy child or adult susceptibles should also be immunized. Exposure to measles in the unvaccinated is not a contraindication to immunization; control of epidemics in schools or other institutions is by immunization. During an outbreak, infants as young as 6 months of age can be vaccinated; such children should eventually receive a total of three doses of measles vaccine. Health care workers should be required to demonstrate proof of measles immunity before being hired.

    • Adverse events after measles vaccine include fever up to 39.4°C in 5-15% of those vaccinated, occurring between 1 and 2 weeks after MMR. Transient measles-like rash occurs in 5% of those vaccinated. Transient thrombocytopenia and anaphylaxis occur rarely. Measles vaccine considered to be extremely safe.

What host factors protect against this infection?

  • Although pre-formed antibodies are useful for passive immunization and play a significant role in preventing recurrent infections, cellular immunity appears more important in host defense against measles than humoral immunity. In general, CD4 T-cells help to control the virus by secretion of cytokines, whereas CD 8 T-cells directly eliminate cells infected with measles virus. Some CD4 T-cells are also cytotoxic for measles virus infected cells.

  • Unvaccinated patients at high risk to develop severe measles include infants younger than 6 months of age and immunocompromised individuals, such as those with congenital or acquired defects in cellular immunity, as well as children being treated for malignant disease or following transplantation. Such individuals should receive passive immunization after a recognized exposure. Exposed HIV-infected children should receive passive immunization whether or not they were immunized.

  • Passive immunization is accomplished with Immune Globulin (IG) within 6 days after exposure. The dose is 0.25 mL/kg IM (immunocompromised children require double that dose); the maximum dose is 15 mL. Passive immunization is not required for healthy household members who have received at least 1 dose of vaccine. For patients who receive intravenous immune globulin (IGIV) regularly, IG is not given unless it is more than 3 weeks since the IVIG was administered.

What are the clinical manifestations of infection with this organism?

  • Measles disease is the main manifestation of infection with rubeola virus. Patients with the prodrome of measles have non-specific respiratory symptoms for about 3 days. Koplik spots appear during and following this prodrome. In the next phase, patients complain of influenza-like symptoms, such as fever, cough, conjunctivitis, and coryza. After a few more days, the typical maculopapular, erythematous, non-pruritic rash begins on the head and face and progresses down the body. Rash first appears behind the ears and on the hairline. The rash, which blanches on pressure, appears last on the extremities, including the palms and soles. The rash may become confluent, especially on the face and neck. It clears first on the face and then on the body. Involved skin may desquamate (except on the palms and soles) during the healing phase. The rash lasts about 5 days; the patient usually feels worst on the first or second day after rash onset.

  • Differentiation between measles and Kawasaki disease in children may be difficult, but it is clinically important because there is a specific treatment for Kawasaki disease (IV immunoglobulin). Children with Kawasaki disease are usually young (<2 years of age), have fever longer than 5 days, do not have Koplik's spots, are often of Asian heritage, usually have a history of measles immunization, have swollen hands and feet, and often have prominent cervical lymph nodes.

  • Because the rash of measles is immunologically mediated, immunocompromised patients, including those with HIV infection, may have measles with no rash and may present with unexplained encephalitis. Immunocompromised patients may also have poor antibody responses to measles. When measles is suspected in such a patient, RT-PCR on body fluids or tissues becomes extremely important to rule in the diagnosis of measles.

  • Although measles in pregnancy does not cause congenital abnormalities, the disease may be more severe in pregnant women, especially in the last trimester, than in women who are not pregnant. Maternal measles early in pregnancy may result in fetal loss. In general, as with many so called childhood infections, measles is more severe in adults than in children. Measles in newborn infants of women with measles at delivery may also be a severe illness.

  • Possibly because measles virus induces a period of immunosuppression, tuberculosis may be aggravated in patients with measles. A positive tuberculin test in a patient with measles may revert to negative for a month or so after recovery from measles,

  • In addition to Kawasaki syndrome, other illnesses included in the differential diagnosis of measles include rubella; scarlet fever; roseola; infectious mononucleosis; infections with rickettsiae, enteroviruses, and adenoviruses; Parvovirus B19; meningococcal infection; toxic shock syndrome; mycoplasma infections; and drug eruptions.

  • There is no definitive evidence to implicate measles in Crohn's disease, systemic lupus erythematosis (SLE), multiple sclerosis, or Paget's disease of bone.

What common complications are associated with infection with this pathogen?

  • The complication of acute encephalitis occurs in 1/1000-2000 measles patients. Symptoms of encephalitis usually develop during the first week after rash onset. Abnormal electroencephalograms may occur in 50% of essentially asymptomatic children during measles convalescence, suggesting, however, that measles infection of the brain is not uncommon. Measles encephalitis ranges from mild to severe. Survivors frequently have neurologic sequelae. Because measles encephalitis is thought to result from infection of the central nervous system (CNS), steroids are not recommended for its treatment.

  • Pneumonia and otitis media accompanying measles may be due to primary viral infection or bacterial superinfection. It appears that measles virus suppresses cell-mediated immune responses, which may explain why secondary bacterial infections occur. In addition, neutropenia may accompany measles. Pneumonia is a common reason for death in infants who contract measles. In teenagers dying of measles, the cause is likely due to encephalitis.

  • Bacterial superinfections of the respiratory tract are common complications and can usually be treated successfully with appropriate antimicrobials.

  • A rare fatal complication, subacute sclerosing panencephalitis (SSPE), with an incubation period as long as 10 years, occurs mainly in children who had measles when they were younger than 2 years of age. These children present with gradual onset of behavioral and intellectual deterioration, with seizures, eventually progressing to coma and death. There is no treatment. The pathogenesis is thought to be from a persistent measles-related virus infection in the brain despite a vigorous immune response to the virus. The incidence of SSPE in the United States declined dramatically after the widespread use of measles vaccine, but increased after the increased number of cases in the early 1990s. There is only 1 case on record of SSPE caused by the vaccine-type virus. Most cases of SSPE in the United States today are seen in children who immigrated to the United States from countries where measles vaccine is not used. SSPE can be diagnosed by unusually high levels of measles antibodies in cerebrospinal fluid (CSF) and serum.

  • Rarely, myocarditis and pericarditis, as well as thrombocytopenic purpura, occur during measles.

  • In immunocompromised patients, two severe complications of measles are giant cell (primary) pneumonia and measles encephalitis. This form of encephalitis appears somewhat between acute encephalitis in non-immunocompromised patients and SSPE. The incubation period is variable; encephalitis may occur as long as 6 months after measles onset. Seizures are often the presenting symptom. Other manifestations include paralysis, coma, and slurred speech; the outcome is usually fatal within weeks to a few months.

  • Atypical measles is an unusual form of the infection that usually appears in adults who received the inactivated ("killed") measles vaccine as children. Use of this vaccine was discontinued in 1968. This vaccine did not induce long-term immunity to measles but did provide partial immunity manifested as hypersensitivity to the virus when the person vaccinated was exposed to natural measles.

  • In atypical measles, the rash begins on the extremities and progresses towards the trunk. The rash may itch and also have a vesicular component. Nodular pneumonia may be seen, along with hepatosplenomegaly, neurological symptoms, such as weakness and paresthesias, and high fever. Koplik spots are rare. These patients are not contagious to others. Antibody titers are usually quite high, which suggests this diagnosis. The illness may be prolonged but is self-limited. Fatalities are exceedingly rare.

How should I identify the organism?

  • Measles can often be diagnosed clinically, especially if Koplik spots are noted. White or bluish Koplik spots first appear on the mucosa opposite the lower molar teeth and, with time, spread to the entire buccal mucosa.

  • In the laboratory, the diagnosis can be made by virus isolation, performed using peripheral blood mononuclear cells (PBMC), nasal washings, broncholavage samples, or available tissues in the instance of fatalities. For virus isolation, primary human or monkey kidney cells are mainly used. It is also possible to demonstrate measles antigens or RNA in infected tissues. Multinucleated giant cells in PBMC or other tissues or secretions stained with Wright's stain or hematoxylin and eosin reveal Warthin-Finkeldey cells, which are pathognomonic of measles. These cells are the result of cell fusion. Multinucleated giant cells may originate from lymphoid (classical Warthin-Finkeldey cells) or epithelial cells.

  • Because virus isolation is difficult and expensive, it has been largely supplanted by polymerase chain reaction (PCR) for diagnosis. PCR for measles virus is commercially available and is also performed by many local health departments. Detection of measles virus RNA by RT-PCR is thought to be highly sensitive and specific, although studies of sensitivity and specificity are not yet available. Measles RNA may be persistent for long periods of time in certain tissues and may not necessarily indicate replication of the virus. Nucleotide sequencing that can differentiate between vaccine and wild type virus is available through local health departments.

  • The presence of IgM antibodies to measles virus in a single blood specimen is considered diagnostic. IgM may not be detectable until well into the development of the rash, so two determinations may be necessary if the first is negative and measles is still suspected. Measles IgM persists for about 1 month after rash onset. A four-fold increase in IgG antibody titer in acute and convalescent blood specimens is diagnostic of measles.

How does this organism cause disease?

  • Measles virus enters the body at the respiratory tract using the signaling lymphocyte activation molecule (SLAM) receptor and is thought to multiply first in lymphoid cells. Attenuated measles vaccine strains also utilize another cellular receptor, CD46. The virus then invades epithelial cells in many organs, as well as the respiratory tract. In the respiratory tract, progeny is released into the airway, enabling transmission of the virus to others by the airborne route. Infection of the respiratory tract sets the stage for cough, coryza, croup, bronchiolitis, otitis media, and pneumonia. Damage to the respiratory tract, such as loss of cilia and immunosuppression and neutropenia caused by the virus, may predispose to severe complications, such as pneumonia. Secondary bacterial infection is also facilitated by these transient abnormalities in host defense.

  • Measles virus spreads to many organs via lymphocytes and monocytes by cell-associated viremia. The virus multiplies in lymphoid organs and tissues, such as thymus, spleen, lymph nodes, and tonsils, as well as the skin, lung, gastrointestinal tract, and liver tissues. The hallmark of infection is the multinucleated giant cell. The onset of clinical disease corresponds to activation of adaptive immune responses, with activation, as well as immunosuppression, which probably accounts for the many infectious complications of measles.

  • Presumably, many of the symptoms are the result of tissue destruction, such as cilia, by the virus directly and also possibly due to cytokine release.

  • Measles vaccine has been exonerated as causal of autism by numerous studies, as well as the recently published Report of the Institute of Medicine "Adverse Effects of Vaccines: Evidence and Causality."

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

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McHale, P, Keenan, A, Ghebrehewet, S. "Reasons for measles cases not being vaccinated with MMR: investigation into parents' and carers' views following a large measles outbreak". Epidemiology and infection. vol. 144. 2016. pp. 870-875.

"Measles—United States, January—May 20, 2011". MMWR. vol. 60. 2011. pp. 666-8.

Parker, AA, Staggs, W, Dayan, GH. "Implications of a 2005 measles outbreak in Indiana for sustained elimination of measles in the United States". N Engl J Med. vol. 355. 2006. pp. 447-55.

Parker Fiebelkorn, A, Redd, SB, Gallagher, K. "Measles in the United States during the postelimination era". J Infect Dis. vol. 202. 2010. pp. 1520-8.

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Schuchat, A, Fiebelkorn, AP, Bellini, W. "Measles in the United States since the Millennium Perils and Progress in the Postelimination Era". Microbiology spectrum 4 2016.

Smith, PJ, Marcuse, EK, Seward, JF, Zhao, Z, Orenstein, WA. "Children and Adolescents Unvaccinated Against Measles: Geographic Clustering, Parents' Beliefs, and Missed Opportunities". Public health reports. vol. 130. 2015. pp. 485-504.

Sotir, MJ. "Measles in the 21st Century, a Continuing Preventable Risk to Travelers: Data From the GeoSentinel Global Network". Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. vol. 62. 2016. pp. 210-212.

Sugerman, DE, Barskey, AE, Delea, MG. "Measles outbreak in a highly vaccinated population, San Diego, 2008: role of the intentionally undervaccinated". Pediatrics. vol. 125. 2010. pp. 747-55.

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(Measles Cases and Outbreaks January 1 to May 16, 2014.)

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