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Measles

  • Updated 2018 Sep 06 09:27:00 AM: > 5,000 cases of measles (> 1,000 confirmed) reported in Brazil in 2018 as of August 4, leading to level 1 travel watch (CDC Travel Notices 2018 Aug 4) view update
  • Centers for Disease Control/Prevention Advisory Committee on Immunization Practices (CDC/ACIP) 2018 recommended immunization schedules for persons aged 0-18 years (MMWR Morb Mortal Wkly Rep 2018 Feb 9) view update
  • 1,073 cases of measles reported by 15 countries in European Union/European Economic Area in January 2018, with highest number of cases from Greece and France (European Center for Disease Prevention and Control Surveillance Report 2018 Mar) view update

 

 

General Information

Description

Also called

  • rubeola

Epidemiology

Geographic distribution

Incidence/Prevalence

  • incidence decreasing worldwide
  • sporadic epidemics in Americas likely due to importation from endemic countries and lack of vaccination
    • United States
      • no sustained epidemic since measles elimination documented in 2000
      • number of reported cases has increased in recent years
        • 79 cases reported in Minnesota in 2017, of which 90% were unvaccinated and 81% belonged to Somali communities; outbreak declared over as of August 25, 2017 (Minnesota Department of Health 2017 Aug 25)
        • 31 cases reported among detainees and staff members at a United States Immigration and Customs Enforcement detention center in Arizona between May and June 2016 (MMWR Morb Mortal Wkly Rep 2017 May 26;66(20):543 full-text)
        • 7 cases reported in Shelby County, Tennessee, between April and May 2016 in patients aged 7 months to 50 years, with unknown source (MMWR Morb Mortal Wkly Rep 2016 Sep 30;65(38):1039)
        • 188 cases reported in United States in 2015, including a large outbreak linked to an amusement park in California (CDC 2017 July 25)
          • among 159 cases reported between January 4 and April 2, 2015
            • total of 4 outbreaks occurred, with 69.8% of cases linked to California outbreak in December 2014 described below
            • patient ages ranged from 6 weeks to 70 years
              • 16% aged < 12 months
              • 12% aged 1-4 years
              • 17% aged 5-19 years
              • 36% aged 20-39 years
              • 19% aged ≥ 40 years
            • 82.4% had no or unknown vaccination history
            • 96% associated with 10 imported index cases from 10 measles-endemic countries (mostly from Europe and Asia)
            • hospitalization required by 14%
            • mortality 0%
            • Reference - MMWR Morb Mortal Wkly Rep 2015 Apr 17;64(14):373 full-text
          • among 110 cases reported from California as of February 11, 2015
            • patient ages ranged from 6 weeks to 70 years (median 22 years)
            • 88% with no or unknown vaccination history
            • 35% reported to have primary exposure while visiting an amusement park in the state
            • 31% were secondary cases, including 26 household or close contacts
            • Reference - MMWR Morb Mortal Wkly Rep 2015 Feb 20;64(6):153 full-text
        • total of 667 cases reported from 27 states in 2014 (CDC 2017 July 25)
          • 1 large outbreak of 383 confirmed cases occurred between March and July in Ohio, United States
            • 380 case patients (99%) belonged to Amish communities, with additional 3 case patients epidemiologically linked to the Amish
            • median age 15 years
            • 89% of patients were unvaccinated (estimated vaccination rate 14% in affected Amish households, 88% in general Ohio, United States community)
            • crude attack rate of measles 12 cases per 1,000 Amish persons
            • outbreak began with 2 unvaccinated source patients who returned to Ohio, United States after unknowingly becoming infected in the Philippines
            • Reference - N Engl J Med 2016 Oct 6;375(14):1343, editorial can be found in N Engl J Med 2016 Oct 6;375(14):1392
        • 159 cases reported during January 1-August 24, 2013
          • patient ages ranged from 0 days to 61 years
            • 11% < 12 months old
            • 25% aged 1-4 years
            • 36% aged 5-19 years
            • 27% ≥ 20 years old
          • 91% with no or unknown vaccination history
          • 99% associated with 42 imported index cases from 18 measles-endemic countries (50% from Europe)
          • Reference - MMWR Morb Mortal Wkly Rep 2013 Sep 13;62(36):741 full-text, correction can be found in MMWR Morb Mortal Wkly Rep 2013 Sep 20;62(37):774
        • about 60% of patients with measles in United States between 2000 and 2015 reported no history of vaccination
          • based on systematic review of observational studies
          • 1,416 patients with measles in United States between 2000 and 2015 reported in 18 studies
            • 56.8% had no history of measles vaccination
            • 14.1% had history of receiving a measles-containing vaccine
            • 28.5% had unknown or unclear vaccination history
          • of 970 patients with detailed vaccination history in 7 outbreak reports
            • 574 patients (59.2%) were unvaccinated despite being vaccine eligible
            • 405 patients (41.8%) had nonmedical exemptions
          • Reference - JAMA 2016 Mar 15;315(11):1149, correction can be found in JAMA 2016 May 17;315(19):21215, commentary can be found in JAMA 2016 Mar 15;315(11):1115
    • other parts of Americas
      • Canada
        • 1,171 cases reported between 2002 and 2013
          • incidence 0.29 cases per 100,000 persons
          • annual number of cases ranged from 6 to 752 cases
          • median age 14.4 years (range from < 1 to 63 years)
          • 82% had no or unknown vaccination history
          • estimated effective reproductive number 0.86 (average number of secondary cases that arise when one primary case is introduced into an uninfected population)
          • Reference - Open Forum Infect Dis 2015 Apr;2(2):ofv048 full-text
        • among 725 cases reported during Quebec epidemic in 2011
          • patient mean age 15 years (ranging from 3 months to 53 years), with 55.7% aged 12-17 years
          • 85.9% with no or incomplete vaccination history
          • 1 index case returning from Caribbean accounted for transmission in 93.5%
          • other index cases were imported from European countries including France and Pakistan
          • Reference - J Infect Dis 2013 Mar 15;207(6):990
          • correlation reported between rising incidence in Quebec in 2011 with increased measles activity in France and low local immunity (BMC Infect Dis 2015 Aug 18;15(1):341 full-text)
      • Central and South Americas
  • multiple sustained outbreaks reported from measles-endemic regions
    • Europe
      • total of 27,134 cases reported in 2012 and 31,520 cases reported in 2013
        • 96% of cases in 2013 reported from 9 countries including
          • Georgia (24.8%)
          • Turkey (23.5%)
          • Ukraine (10.5%)
          • Netherlands (7.9%)
          • Italy (7%)
          • Russian Federation (6.9%)
          • United Kingdom (6%)
          • Germany (5.6%)
          • Romania (3.4%)
        • Reference - Clin Microbiol Infect 2014 May;20 Suppl 5:12
      • total of 26,074 cases reported from 36 countries in 2011 (as of October 26, 2011)
        • 53.8% reported from France (mostly in older children and young adults with no or unknown vaccination history)
        • other countries with sustained outbreaks included Spain (10.5%), Romania (8.3%), Republic of Macedonia (2.8%), Uzbekistan (1.2%)
        • Reference - MMWR Morb Mortal Wkly Rep 2011 Dec 2;60:1605 full-text
      • total of 12,132 cases reported in 2006-2007
        • 85% reported from 5 countries
          • Romania
          • Germany
          • United Kingdom
          • Switzerland
          • Italy
        • most cases were unvaccinated or incompletely vaccinated children
        • mortality 0.06%
        • of 210 imported cases, 56% came from another European country and 20% from Asia
        • no indigenous cases reported in 9 countries including Bulgaria, Croatia, Cyprus, Finland, Hungary, Iceland, Portugal, Slovakia, and Slovenia
        • Reference - Lancet 2009 Jan 31;373(9661):383, editorial can be found in Lancet 2009 Jan 31;373(9661):356
    • Africa
      • 176,785 confirmed cases of measles were reported in the 46 WHO African Region member states between 2013 and 2016
        • number of reported cases declined 60% from 71,529 in 2013 to 28,279 in 2016
        • largest percentage decreases in incidence occurred in Angola, Namibia, and Togo
        • highest incidences in 2016 reported in Equatorial Guinea, Gabon, and Liberia
        • Reference - MMWR Morb Mortal Wkly Rep 2017 May 5;66(17):436 full-text
    • Asia
      • ongoing sustained epidemics reported from several countries, mostly from China and Philippines
        • based on WHO surveillance data as of February 11, 2015
        • number of suspected or confirmed measles cases reported in 2014
          • 112,483 cases in China
          • 58,010 cases in Philippines
          • 18,597 cases in Vietnam
        • Reference - WHO Measles Surveillance Data 2015 Feb PDF
  • outbreak in Federated States of Micronesia associated with vaccine failure in adults
    • 393 cases of measles reported between February and August, 2014, after 20 years with no reported measles cases
    • about two-thirds of patients were adults aged ≥ 20 years
      • 49% had ≥ 2 doses of measles-containing vaccine
      • 3% known to be unvaccinated
      • 28% had unknown vaccination status
    • among 90 patients known to be unvaccinated, 60% were aged < 12 months and ineligible for routine vaccination
    • Reference - MMWR Morb Mortal Wkly Rep 2015 Oct 2;64(38):1088 full-text

Risk factors

  • risk factors include(1, 2, 3)
    • living in or travel to endemic and epidemic regions
      • endemic regions often have annual seasonal epidemics with cycles of 2-5 years
        • in temperate climates, typically occur in late winter and early spring, partly due to social activities such as congregation of school-aged children
        • in tropics, often occur during rainy seasons when there is also an increase in birth rates
      • measles acquired while traveling most commonly acquired in Asia
        • based on analysis of GeoSentinel Surveillance Network data
        • 94 cases with confirmed measles diagnoses seen in 30 clinics between 2000 and 2014 evaluated
          • patient age range 1-57 years (median 27 years)
          • two-thirds of cases reported after 2010
        • among 89 patients with known region of exposure, Asia was most common exposure region (66%), followed by Africa (17%) and Europe (13%)
        • unclear measles vaccination status in these patients
        • Reference - Clin Infect Dis 2016 Jan 15;62(2):210
    • lack of vaccination
    • persons at high risk for severe illness and complications include(1, 2, 3)
      • infants and children aged < 5 years
      • adults aged > 20 years
      • pregnant women
      • immunocompromised persons, such as those with hematologic malignancies and HIV infection
      • malnutrition, especially vitamin A deficiency

Etiology and Pathogenesis

Pathogen

  • measles virus(1, 2, 3)
    • member of Paramyxoviridae family, Morbillivirus genus
    • enveloped, single-stranded, negative-sense RNA virus
    • 19 genotypes, prevalence varies with geography
    • 2 viral membrane proteins mediate host cell entry
      • hemagglutinin (HA) protein is surface antigen responsible for virus attachment to host cell
      • fusion protein plays role in fusion of cell and viral membrane, viral penetration, and hemolysis
    • only 1 antigenic type based on HA
    • no change in vaccine efficacy despite estimated mutation rates ranging from 10-4 to 10-5 per nucleotide per year
  • no genetic mutations detected among 27 strains isolated from measles outbreak following 2010 Olympic Winter Games in Vancouver, Canada (J Infect Dis 2015 Nov 15;212(10):1574, editorial can be found in J Infect Dis 2015 Nov 15;212(10):1529)

Transmission

  • transmitted person-to-person(1, 2,3)
    • mainly via large respiratory droplets
    • less commonly via small aerosol particles
    • virus can live for up to 2 hours in airspace where the infected person coughed or sneezed
  • infectious period lasts from about 4 days before to 4 days after rash onset(1, 2, 3)
    • symptoms of cough, coryza, and sneezing may increase viral shedding
    • immunocompromised patients may shed virus for longer periods
  • attack rate(2)
    • high among children < 12 months old in developing countries
    • secondary attack rate > 90% among unvaccinated persons
  • incubation period(1, 2)
    • 10-12 days to fever onset
    • 14 days (range 7-21 days) to rash onset
  • transmission typically occurs among patients without prior vaccination, but transmission among persons with prior evidence of immunity has also been reported
    • 5 patients developed measles during small outbreak in New York City, New York in 2011
    • index patient had previously received 2 doses of measles-containing vaccine
    • of 88 contacts, 4 secondary patients were confirmed, all of whom had previously received 2 doses of measles-containing vaccine or showed positive measles immunoglobulin G (IgG) antibody
    • Reference - Clin Infect Dis 2014 May;58(9):1205
  • measles viral RNA detected in air specimens and on environmental surfaces in a hospital setting on days 5-8 after rash onset in an unvaccinated young woman with measles (J Infect Dis 2016 Feb 15;213(4):600)
  • transmission in healthcare facilities
    • transmission among healthcare facilities reported in 78 cases in United States between 2001 and 2014, including 29 healthcare workers, of whom 65.5% had presumptive evidence of measles immunity (Clin Infect Dis 2015 Aug 15;61(4):615)
    • laboratory-confirmed measles reported in 8 healthcare workers at single hospital in the Netherlands in 2014 (J Infect Dis 2016 Dec 15;214(12):1980)
  • potential measles transmission during commercial air travel reported in 46-year-old adult who had used same terminal gate with 19-month-old patient in international airport in Unites States, April-May 2014 (MMWR Morb Mortal Wkly Rep 2015 Jun 26;64(24):679 full-text)

Pathogenesis

  • infection occurs in upper respiratory tract epithelium(2)
  • viral replication in upper respiratory tract epithelial cells and lymph nodes leads to primary viremia in about 2-3 days(1, 2)
  • subsequent dissemination to distal reticuloendothelial sites, such as the spleen, leads to secondary viremia about 5-7 days after infection(1, 2)
  • secondary viremia may lead to spread to the respiratory tract and other organs(1, 2)

Immune response

  • cellular immunity critical for viral elimination(1)
    • CD4 and CD8 T cells infiltrate sites of infection at about day 14 following infection (clinically correlates to onset of rash)
      • measles-specific CD8 T cells rapidly activate, expand, and contract
      • CD4 response begins at same time, but activation is prolonged
    • cytokine and chemokine production increases during infection, including
      • interleukin (IL)-8, which increases shortly after infection
      • interferon (IFN) gamma and IL-2, produced by activated type 1 CD4 cells and CD8 T cells during rash
      • IL-4, IL-10, and IL-3, produced by type 2 and regulatory CD4 T cells after rash
    • viral clearance typically accomplished by day 20
    • prolonged disease or death reported in patients with severe T-lymphocyte deficiencies (whereas children with agammaglobulinemia recover)
  • humoral immune response(1)
    • immunoglobulin M (IgM) appears with rash, followed by sustained production of immunoglobulin G (IgG)
    • antibody response important for lifelong immunity to measles, which occurs through exposure to measles virus or vaccine
    • passive transfer of maternal antibodies protects infants against infection
    • postexposure prophylaxis with antimeasles immune globulin protects susceptible persons following potential exposure
  • measles-virus-induced immune suppression(1)
    • immune response to measles virus associated with reduced response to other antigens, including
      • suppression of delayed-type hypersensitivity responses to recall antigens
      • impairment of cellular and humoral responses to new antigens
    • secondary bacterial and viral infections may occur due to immune suppression
      • can be associated with pneumonia or diarrhea
      • responsible for significant portion of measles-related morbidity and mortality

History and Physical

Clinical presentation

Classic measles

  • prodrome begins about 10-12 days after infection and lasts for 2-4 days, with symptoms including(1, 2)
    • fever, may be high - 103-105 degrees F (39-41 degrees C)
    • cough
    • coryza
    • conjunctivitis
    • Koplik spots
      • small blue-white lesions on bright red background of buccal mucosa
      • may appear 1-2 days either before or after rash onset
      • pathognomonic for measles
  • maculopapular rash arises about 2-4 days after fever onset(1, 2)
    • begins on face and head, and proceeds to trunk and extremities
    • may become confluent, particularly on upper body
    • lesions initially blanch with pressure, but no longer do after 3-4 days
    • fine desquamation may occur in severely affected areas
    • typically resolves after 3-6 days in same manner of appearance
    • rash may not occur in immunocompromised patients
  • additional signs and symptoms may include(1, 2)
    • anorexia
    • diarrhea (particularly in infants)
    • generalized lymphadenopathy
  • rare presentations include
  • secondary infections may be evident at time of presentation including(1)
    • otitis media
    • pneumonia

Atypical measles

  • atypical measles(2)
    • occurs only in persons who received inactivated (or killed) measles vaccine
    • infection with wild-type measles virus after vaccination results in signs of hypersensitivity polyserositis
    • signs and symptoms include
      • fever
      • pneumonia
      • pleural effusions
      • edema
      • rash
        • usually maculopapular or petechial
        • may be urticarial, purpuric, or vesicular components
        • appears first on wrists or ankles

History

  • ask about risk factors for measles(1, 2, 3)
    • living in or travel to endemic areas
    • lack of vaccination
    • living in close quarters, such as a college dormitory
  • ask about risk factors for severe disease(1, 2, 3)
    • immunocompromise
    • pregnancy
    • malnutrition

Physical

General physical

  • assess for fever, which may be as high as 103-105 degrees F (39-41 degrees C)(1, 2)

Skin

  • assess for rash(1, 2)
    • may be present on face and head in early course, then spread to trunk and extremities
    • affected areas are often discrete but may become confluent late in course
    • early lesions may blanch with pressure
    • desquamation may be present in severely affected areas

HEENT

  • assess for(1, 2)
    • conjunctivitis (may be early sign)
    • Koplik spots
    • otitis media (may occur as secondary infection)

Chest

  • assess for pneumonia (may be primary due to measles or secondary bacterial infection)(1, 2)

Diagnosis

Making the diagnosis

  • suspect measles in patients with(1)
    • fever
    • maculopapular rash
    • cough, coryza, or conjunctivitis
    • potential exposure, such as history of travel to or residence in endemic or epidemic areas
  • diagnosis can be made clinically and suspected cases should be reported to state or local health department(1, 3)
  • confirmatory diagnostic testing typically coordinated by state or local health department and performed at Centers for Disease Control and Prevention (CDC) Measles Virus Laboratory(3)
  • most commonly used confirmatory tests include
    • antibody testing
      • serum preferred specimen type
        • presence of immunoglobulin M (IgM) is preferred test used to confirm acute infection
        • 4-fold rise in immunoglobulin G (IgG) titers in paired acute and convalescent samples considered diagnostic
      • oral fluid samples may also have high sensitivity for measles virus detection
    • reverse transcriptase-polymerase chain reaction (RT-PCR)
      • oropharyngeal, nasal, or nasopharyngeal swabs are preferred sample types
      • greatest sensitivity on days 1-3 after onset of rash

Differential diagnosis

  • other causes of maculopapular rash, including
    • other viral disease in children
      • rubella
        • prodrome rare in children but may be present in adults
        • about 27% of suspected measles were laboratory confirmed rubella in study of 4,592 serum samples collected from 2010 to 2015 in India (J Med Virol 2016 Oct;88(10):1685)
      • erythema infectiosum (Fifth disease)
        • characterized by initial "slapped cheek" rash
        • secondary erythematous maculopapular rash on the trunk and limbs may appear after a few days
        • nonspecific prodromal illness may precede rash by 2-5 days
      • roseola
        • rash begins on neck or trunk and spreads to extremities
        • rash preceded by high fever lasting 3-4 days
      • Reference - Gershon AA. Measles Virus (Rubeola). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 7th ed. Elsevier Health Sciences; 2009
    • less common infections causing fever and rash
      • enteroviruses (echo virus and coxsackie virus infections)
      • Epstein-Barr virus-associated infectious mononucleosis
      • cytomegalovirus infection
      • Rocky Mountain spotted fever
      • Staphylococcal toxic shock syndrome
      • scarlet fever
      • group A Streptococcus
      • Kawasaki disease
      • acute HIV infection
      • hepatitis B virus (acute serum sickness like reaction to early infection)
  • other causes of morbilliform rash in highly vaccinated populations
    • based on cohort study of 195 children with morbilliform rash and fever in English population with high vaccination coverage
    • no patient had measles or rubella
    • 93 (48%) had laboratory confirmation of infections, including
      • parvovirus B19 in 17%
      • group A Streptococcus in 15%
      • human herpesvirus type 6 in 6%
      • enterovirus in 5%
      • adenovirus in 4%
      • group C Streptococcus in 3%
    • Reference - Arch Dis Child 2002 Sep;87(3):202 full-text

Testing overview

  • most commonly used confirmatory tests include
    • antibody testing
      • serum considered gold standard for antibody testing
        • presence of immunoglobulin M (IgM) is preferred test used to confirm acute infection
        • 4-fold rise in immunoglobulin G (IgG) titers in paired acute and convalescent samples considered diagnostic
      • oral fluid IgM appears to have comparable specificity and only modest reduction in sensitivity
    • reverse transcriptase-polymerase chain reaction (RT-PCR)
      • oropharyngeal, nasal, or nasopharyngeal swabs are preferred sample types
      • greatest sensitivity on days 1-3 after onset of rash
    • viral isolation
      • can be performed on clinical specimens ≤ 7 days of rash onset
      • mainly used for disease surveillance and viral strain identification
  • confirmatory diagnostic testing typically coordinated by state or local health department and performed at Centers for Disease Control and Prevention (CDC) Measles Virus Laboratory(3)
    • instructions for specimen collection and submission for
  • World Health Organization Rubella Lab Manual can be found at WHO 2014 Sep 17 PDF

General laboratory findings

  • transient lymphopenia may be observed in children with measles
    • based on case-control study
    • 274 children hospitalized with measles in Lusaka, Zambia, were evaluated at entry, discharge, and 1-month follow-up and compared to 96 healthy Zambian children
    • lymphopenia present in patients hospitalized for measles at time of admission, but lymphocyte count was similar to that of control children at discharge
    • CD4/CD8 ratios were decreased at all time points
    • lymphocyte counts lower in girls, in patients with temperatures of > 38.5 degrees C (101.3 degrees F), and in malnourished children
    • Reference - Clin Diagn Lab Immunol 2002 Sep;9(5):994 full-text

Microbiologic testing

Antibody testing

  • immunoglobulin M (IgM) antibodies
    • most commonly used laboratory test
    • IgM levels rise with onset of rash (although may not be detectable until ≥ 4 days after rash onset) and persist for 1-2 months
    • detection of IgM considered diagnostic for acute infection
    • sensitivity varies with timing of sample collection and patient immunization status
    • negative results do not rule out diagnosis in vaccinated patients
      • test may be negative in unvaccinated persons
      • repeat testing should be performed in those with initial negative results within 3 days after rash onset, due to possible false-positive results
    • Reference - (1, 2), Infect Dis Clin North Am 2015 Dec;29(4):725
  • IgG antibodies(1, 2)
    • 4-fold rise in IgG titers in paired acute and convalescent samples considered diagnostic
    • first sample drawn as soon as possible, with second sample drawn 10-30 days later
  • specimen types
    • serum considered gold standard (MMWR Morb Mortal Wkly Rep 2008 Jun 20;57(24):657 full-text)
    • cerebrospinal fluid (CSF), when encephalitis suspected
      • detection of antibodies in the CSF is diagnostic
      • CSF profile showing lymphocytic pleocytosis with elevated protein is supportive
      • diagnosis often made if systemic measles is present in patient with encephalitis
      • Reference - QJM 2015 Mar;108(3):177
    • detection of IgM in oral fluid may be have comparable specificity but slightly lower sensitivity than serum for diagnosis of measles (level 2 [mid-level] evidence)
      • based on diagnostic case-control study
      • 73 children with measles and 44 healthy children had oral fluid and serum (reference standard) evaluated for IgM using enzyme-linked immunosorbent assay (ELISA)
      • oral fluid had sensitivity 92%, specificity 100% for detection of antimeasles IgM
      • Reference - Int J Infect Dis 2010 Nov;14(11):e991 full-text
    • dried blood samples

Reverse transcriptase-polymerase chain reaction (RT-PCR)

  • may be used to confirm measles infection(1)
  • testing can be performed on(1, 3)
    • oropharyngeal swab (preferred)
    • nasal or nasopharyngeal swab (preferred)
    • blood
    • urine
    • conjunctival swab
  • measles viral RNA detected in clinical samples up to 3 months after rash onset
    • based on cohort study
    • 49 children (median age 15 months, range 5-138 months) diagnosed with measles during Zambia outbreak in 1999-2001 evaluated
    • blood, urine, and nasopharyngeal samples collected at median of 100 days (range 65-118) after rash onset were assayed by RT-PCR for viral nucleocapsid and hemagglutinin RNA
    • 18 children (37%) had viral RNA in at least 1 sample, including
      • 18% of 44 blood samples
      • 23% of 30 nasopharyngeal samples
      • 50% of 6 urine samples
    • Reference - J Clin Virol 2007 Aug;39(4):312
  • RT-PCR using oral fluid samples may have higher sensitivity for viral RNA than serum samples > 7 days after rash onset in patients with measles (level 2 [mid-level] evidence)
    • based on diagnostic cohort study without independent reference standard
    • 270 patients with clinical suspicion of measles evaluated for viral RNA using RT-PCR with oral fluid samples and serum, and for antimeasles virus IgM using serum samples
    • reference standard was positive result on any test
    • in 102 confirmed cases with paired oral fluid and serum samples, detection rates of viral RNA
      • 98% using oral fluid
      • 95% using serum
        Detection Rate of Measles Virus-Specific IgM and Measles Virus RNA in Serum or Oral Fluid, Related to Time from Rash Onset:
         Day 0-3 Day 4-7 > Day 7 Unknown
        IgM-positive serum samples82%91%100%85%
        MV RNA-positive serum samples97%98%35%90%
        MV RNA-positive oral fluid samples99%97%100%100%
        Abbreviations: IgM, immunoglobulin M; MV, measles virus.
    • Reference - J Med Virol 2013 Apr;85(4):723 full-text
  • RT-PCR performed on filter paper blood samples had 48% sensitivity in 90 patients with acute measles infection and 100% specificity in 27 patients without measles (J Clin Microbiol 2001 Jan;39(1):270 full-text)

Viral isolation

  • not routinely performed for diagnosis of measles, but critical for measles surveillance and viral strain identification(1, 2)
  • specimens should be collected within 7 days of rash onset(2)
  • instructions for specimen collection can be found at CDC 2015 May 5

Biopsy and pathology

  • biopsy may be needed for complications such as pneumonia
    • findings with pneumonia
      • interstitial pneumonia with multinucleated giant cells along alveolar spaces
      • giant cells typically have eosinophilic viral inclusions in the nucleus or cytoplasm
      • other reported findings include
        • diffuse alveolar damage with hyaline membrane formation
        • reactive alveolar epithelial hyperplasia
        • necrotizing alveolitis
        • proliferation of bronchiolar epithelium with squamous metaplasia
      • atypical findings reported in immunocompetent children range from organizing diffuse alveolar damage to interstitial pneumonia with moderate numbers of giant cells, without viral inclusions
      • Reference - Pediatr Pathol 1992 Nov-Dec;12(6):773

Treatment

Treatment overview

  • supportive care is the mainstay of treatment
  • no specific antiviral therapy available
  • World Health Organization (WHO) recommends vitamin A supplement for all children in developing countries with measles, which has been associated with decreased morbidity and mortality, although mechanism of action is unknown
    • 2 doses given 24 hours apart recommended
    • dosage varies by age
      • 200,000 units/day for children ≥ 12 months old
      • 100,000 units/day for children aged 6-11 months
      • 50,000 units/day for children < 6 months old
      • vitamin A 200,000 units orally once daily for 2 days may reduce mortality in hospitalized children with measles (level 2 [mid-level] evidence)

Medications

Antiviral therapy

  • no specific antiviral therapy available(1)
  • use of nonspecific antiviral or immunomodulatory therapy reported in case series and small trials but efficacy is unclear

Vitamin A

  • World Health Organization (WHO) 2014 recommends vitamin A in children in developing countries with measles, which has been associated with decreased morbidity and mortality
    • mechanism of action is unknown but may be related to increased utilization of vitamin A during measles infection
    • 2 doses given 24 hours apart recommended
    • recommended doses vary by age
      • 200,000 units/day for children ≥ 12 months old
      • 100,000 units/day for children aged 6-11 months
      • 50,000 units/day for children < 6 months old
    • in children with vitamin A deficiency, administration of third dose after 2-4 weeks is recommended
    • Reference - (1), WHO Measles Fact Sheet 2014 Feb, Lancet 1987 May 9;1(8541):1067
  • vitamin A 200,000 units orally once daily for 2 days may reduce mortality in hospitalized children with measles (level 2 [mid-level] evidence)
    • based on Cochrane review limited by clinical heterogeneity
    • systematic review of 8 randomized trials comparing vitamin A orally vs. placebo in 2,574 children < 15 years old with measles
    • trials included patients with varying disease severity and likelihood of underlying vitamin A deficiency
    • no significant reduction in mortality (relative risk [RR] 0.7, 95% CI 0.42-1.15) in overall analysis of 8 trials with 2,574 children
    • vitamin A ≥ 200,000 units once daily for 2 days associated with
      • reduced mortality in analysis of 3 trials with 429 hospitalized children
        • RR 0.4 (95% CI 0.19-0.87, NNT 12-74 with 11% mortality in placebo group)
        • greater reductions reported in subgroup analysis of children < 2 years old (RR 0.21, 95% CI 0.07-0.66, NNT 10-27 assuming 11% mortality in placebo group); no significant difference in subgroup ≥ 2 years old
        • all 3 trials conducted in areas with hospital case fatality rate > 10%
      • reduced incidence of croup (RR 0.53, 95% CI 0.29-0.89) in analysis of 4 trials with 488 patients
      • no significant difference in pneumonia-specific mortality (4 trials), incidence of pneumonia (2 trials), and incidence of diarrhea (2 trials)
    • in subgroup analyses of vitamin A formulations
      • water-based formulation associated with reduced mortality in analysis of 2 trials with 249 patients
        • RR 0.23 (95% CI 0.06-0.89)
        • NNT 13-106 with 8.6% mortality in controls
      • oil-based formulation not associated with reduced mortality in analysis of 3 trials with 674 patients
    • single dose of vitamin A not associated with reduced mortality
    • no trials compared 2 doses vs. single dose
    • no adverse effects reported
    • Reference - Cochrane Database Syst Rev 2005 Oct 19;(4):CD001479 (review updated 2011 Jul 6)
  • no randomized trials identified evaluating vitamin A for prevention of blindness in children with measles without prior clinical signs of vitamin A deficiency

Antibiotics

  • antibiotics are indicated in patients with measles who show clinical symptoms of bacterial superinfection, such as(1)
    • pneumonia
    • otitis media
    • see Acute otitis media (AOM) in children and Community-acquired pneumonia in children for details
  • prophylactic antibiotics may decrease otitis media, tonsillitis, and possibly pneumonia in children and adolescents with measles (level 2 [mid-level] evidence)
    • based on Cochrane review of trials with methodologic and statistical limitations
    • systematic review of 7 randomized or quasi-randomized trials comparing antibiotics vs. placebo or no treatment (control) for prevention of complications in 1,263 patients < 18 years old with clinically diagnosed measles
    • all trials had unclear or inadequate allocation concealment
    • antibiotics included co-trimoxazole, other sulfa antibiotics, penicillins, and tetracyclines
    • prophylactic antibiotics associated with
      • reduced otitis media in analysis of 5 trials with 1,033 patients
        • odds ratio (OR) 0.34 (95% CI 0.16-0.73)
        • NNT 24-77 with otitis media in 5% of control group
      • reduced tonsillitis in analysis of 2 trials with 256 patients
        • OR 0.08 (95% CI 0.01-0.72)
        • NNT 12-43 with tonsillitis in 9% of control group
      • nonsignificant reductions in
        • pneumonia (OR 0.35, 95% CI 0.12-1.01) in analysis of all trials, but results limited by significant heterogeneity
        • conjunctivitis (OR 0.39, 95% CI 0.15-1) in analysis of 2 trials with 212 patients
    • no significant differences between groups in mortality (7 trials with 1,482 patients), diarrhea (4 trials with 776 patients), and croup (1 trial with 130 patients)
    • Reference - Cochrane Database Syst Rev 2013 Aug 14;(8):CD001477
    • DynaMed commentary -- measles-induced immune suppression is associated with increased secondary bacterial infections such as otitis media and pneumonia; while prophylactic antibiotics may reduce rates of infection, it is not routine practice to prescribe

Complications and Prognosis

Complications

  • up to 40% of patients with measles develop complications(1)
  • increased risk for complications associated with(1, 2)
    • age < 5 years or ≥ 20 years
    • malnutrition
    • immunosuppression
    • pregnancy
  • complications in respiratory tract include(1, 2)
    • pneumonia
      • most common cause of measles-related death
      • may be due to measles virus (giant cell pneumonia)
      • may be due to secondary bacterial infection in setting of measles-induced immunosuppression
    • laryngotracheobronchitis (croup)
    • otitis media
  • other complications include(1, 2)
    • mouth ulcers or stomatitis
    • diarrhea, which may further contribute to malnutrition
    • keratoconjunctivitis
      • common after measles, particularly in children with vitamin A deficiency
      • may result in blindness
  • rare central nervous system (CNS) complications
    • short-term CNS complications
      • primary measles encephalitis
        • caused by viral infection of brain during rash phase of infection
        • incidence about 1-3 per 1,000 patients
        • treatment largely supportive
        • mortality rate 10%-15%
        • permanent neurological damage in 25%
      • acute postmeasles encephalitis (or acute disseminated encephalomyelitis (ADEM))
        • caused by immune-mediated brain inflammation after measles infection
        • incidence about 1 per 1,000 children
        • occurs 2-30 days after infection
        • in addition to typical encephalitis symptoms, patients may have difficulty urinating, disturbed vision, and hyporeflexia
        • difficult to differentiate from primary measles encephalitis (both conditions may be part of overlapping spectrum)
        • corticosteroids primary treatment
        • mortality about 5% in children and 25% in adults
        • one-third of patients may relapse
        • subtle defects in attention, decision-making ability, or behavior may be present in children > 3 years after recovery
    • long-term CNS complications
      • measles inclusion body encephalitis
        • most commonly occurs in immunodeficient children
        • lack of adequate immune response may lead to
          • lack of T-cell-mediated rash with initial infection
          • establishment of persistent infection
        • symptoms arise about 1 year after initial infection or vaccination and may include altered mental status, motor deficits, and seizures
        • cerebrospinal fluid (CSF) analysis is usually normal but may show mild pleocytosis and proteinosis
        • brain biopsy needed for diagnosis and may show
          • glial cell proliferation and focal necrosis
          • perivascular inflammation
          • intranuclear or intracytoplasmic inclusion bodies
          • viral nucleocapsid may be visible on electron microscopy
          • reverse transcriptase-polymerase chain reaction (RT-PCR) or immunohistochemistry can confirm diagnosis
        • treatment supportive but ribavirin has been used in case reports
        • reported mortality about 75% with neurologic sequelae common in survivors
        • measles inclusion body encephalitis in 13-year-old patient who had received stem cell transplantation in case report (Pediatrics 2004 Nov;114(5):e657 full-text)
      • subacute sclerosing panencephalitis (SSPE)
        • incidence
          • 1 per 25,000 measles infections overall
          • 1 per 5,500 infections in children < 1 year old
          • incidence of SSPE 1 in 1,367 children aged < 5 years and 1 in 609 in children aged < 1 year old at time of measles disease among cases reported to the California Department of Public Health between 1998 and 2015 (Clin Infect Dis 2017 Jul 15;65(2):226)
        • hypothesized to arise from failure of viral clearance when infection acquired at early age
        • persistent viral infection leads to symptoms about 6-15 years after initial infection
        • early symptoms may include behavioral changes and cognitive decline
        • motor symptoms, including seizures, may follow weeks to months later
        • ocular involvement, such as necrotizing retinitis, occur in about 50%
        • ultimately coma and death occur about 3 years from symptom onset
        • diagnosis is made by finding of very high measles antibody titers in CSF
        • progressive grey matter, periventricular white matter, and brainstem lesions may be seen on magnetic resonance imaging (MRI)
        • bilateral synchronous sharp waves on electroencephalogram (EEG) support diagnosis
        • death occurs 5-15 years after measles virus infection
        • treatment is supportive but use of nonspecific antiviral therapies and immunomodulatory therapy reported in case series
        • detection of measles viral RNA in postmortem brain tissues from patients with SSPE can be found in case series (J Infect Dis 2005 Nov 15;192(10):1686), editorial can be found in J Infect Dis 2005 Nov 15;192(10):1679
        • detection of measles viral RNA in postmortem brain tissues from 29-year-old pregnant woman with SSPE in case report (Lancet Infect Dis 2016 Mar;16(3):366)
    • Reference - QJM 2015 Mar;108(3):177

Prognosis

Mortality

  • measles-related mortality has been reduced since implementation of measles vaccination
  • case fatality rate(1, 2)
    • highest in young children and adults
    • up to 25% in developing countries
  • most common causes of death(2)
    • pneumonia in children
    • acute encephalitis in adults

Pregnancy

  • measles virus infection during pregnancy associated with increased risk of(2)
    • prematurity
    • spontaneous miscarriage
    • low birth weight
    • birth defects (rarely reported, without measles proven as cause)
  • pregnancy with measles virus infection associated with increased risk of maternal death and fetal loss
    • based on cohort study
    • 55 pregnant women (median age 26 years) with measles during Namibia outbreak in 2009-2011 were matched to 172 pregnant women without measles
      • of patients with known HIV status, 15% of patients without measles and 19% of patients with measles were HIV-positive
      • measles-related complications included diarrhea (in 60%), pneumonia (in 40%), and encephalitis (in 5%)
    • of 42 measles-related pregnancies with known outcomes
      • 25 (60%) had ≥ 1 adverse maternal, fetal, or neonatal outcome
      • 5 women (12%) died
    • compared to pregnancies without measles, pregnancies with measles associated with increased risk of
      • maternal death (adjusted relative risk [RR] 9.6, 95% CI 1.3-70)
      • spontaneous miscarriage (adjusted RR 5.9, 95% CI 1.8-19.7)
      • intrauterine fetal death (adjusted RR 9, 95% CI 1.2-65.5)
      • neonatal low birth weight (adjusted RR 3.5, 95% CI 1.5-8.2)
    • Reference - Clin Infect Dis 2014 Apr;58(8):1086, editorial can be found in Clin Infect Dis 2014 Apr;58(8):1093

Prevention and Screening

Prevention

Postexposure management

  • Centers for Disease Control (CDC) 2013 recommendations for measles postexposure prophylaxis
    • measles/mumps/rubella (MMR) vaccine
      • MMR vaccine recommended for postexposure prophylaxis in vaccine-eligible persons ≥ 12 months old if used within 72 hours of initial exposure
      • may be more effective in limited contact settings such as schools, child care, and medical offices compared to settings with intense, prolonged, close contact, although evidence limited
      • revaccination within 72 hours of exposure may be effective in patients who received 1 vaccine dose before exposure (incomplete vaccine series)
    • human immune globulin (IG)
      • recommended for postexposure prophylaxis if given within 6 days of exposure for following groups
        • infants < 12 months old (IG given intramuscularly preferred, MMR vaccine is an alternative at age 6-12 months)
        • pregnant women without evidence of measles immunity (IVIG preferred)
        • severely immunocompromised persons (IVIG preferred)
      • other nonimmune persons exposed to measles can be given IG, with preference given to persons with intense, prolonged contact
      • IG not recommended for postexposure prophylaxis in persons who have received any measles-containing vaccine after age 12 months, unless severely immunocompromised
      • recommended dose
        • 0.5 mL/kg for IG given intramuscularly
        • 400 mg/kg for IG given IV (IVIG)
      • IG given intramuscularly may have limited efficacy in persons weighing > 30 kg (66.1 lbs) because volume limit for dosing is 15 mL
      • if IG used, patient should subsequently receive vaccination
        • ≥ 6 months after IG given intramuscularly
        • ≥ 8 months after IVIG
    • Reference - CDC summary recommendations on prevention of measles, rubella, congenital rubella syndrome, and mumps (MMWR Recomm Rep 2013 Jun 14;62(RR-04):1 full-text)
  • immune globulin within 7 days of measles exposure in susceptible patients may reduce measles-related mortality and measles cases (level 2 [mid-level] evidence)
    • based on Cochrane review of mostly observational studies
    • systematic review of 3 randomized or quasi-randomized trials and 10 prospective cohort studies evaluating intramuscular injection or IV infusion of immunoglobulins (passive immunization) in 3,925 susceptible patients with exposure to but no symptoms of measles
    • most studies conducted prior to 1950
    • comparing immunoglobulins to no treatment, immunoglobulins associated with
      • reduced measles cases within 7 days of exposure
        • in analysis of 6 studies with 1,575 patients
          • risk ratio (RR) 0.52 (95% CI 0.48-0.57), all studies suggest risk reduction but heterogeneity in magnitude of effect
          • NNT 43-52 with measles in 4.5% of no treatment group, as reported in single 2009 study
          • NNT 2-3 with measles in 76%-100% of no treatment group, as reported in 5 studies conducted prior to 1950
        • all types of blood products studied (gamma globulin, convalescent serum, and adult serum) had significant reduction in measles cases
      • reduced mortality due to measles in analysis of 3 studies with 893 patients
        • RR 0.24 (95% CI 0.13-0.44)
        • NNT 9-13 with mortality due to measles in 14% of no treatment group
      • reduced complications due to measles (otitis media, pneumonia, and encephalitis) in analysis of 3 studies with 832 patients
        • RR 0.18 (95% CI 0.05-0.6)
        • NNT 21-50 with complications due to measles in 5% of no treatment group
    • gamma globulin associated with reduced measles cases compared to serum treatment in analysis of 2 studies with 702 patients
      • RR 0.56 (95% CI 0.46-0.69)
      • NNT 4-7 with measles in 46% of serum group
    • no serious adverse events reported
    • Reference - Cochrane Database Syst Rev 2014 Apr 1;(4):CD010056
  • measles vaccine within 72 hours of measles exposure may be more effective than immune globulin in preventing measles cases in susceptible patients (level 2 [mid-level] evidence)
    • based on limited evidence (2 studies identified in Cochrane Database Syst Rev 2014 Apr 1;(4):CD010056)
    • in nonrandomized trial of 289 patients aged 6-35 months admitted to acute pediatric unit in Rhodesia, Africa (now Zimbabwe) in 1968
      • children did not have measles but were admitted to hospital where measles exposure was common
      • children were consecutively assigned to 1 of 3 groups - measles vaccine 1 dose intramuscularly, human immune globulin 2 mL intramuscularly (repeated every 3 weeks), or no treatment
      • 80 children (28%) were excluded due to loss to follow-up (60 children), death not associated with measles (18 children), or measles diagnosed in first 9 days (2 children)
      • cases of measles between 10 days and within 2 weeks of discharge
        • 2 cases with vaccine (2.9% followed patients, 2% original group)
        • 13 cases with immune globulin (19.1% followed patients, 13.7% original group)
        • 34 cases with no treatment (46.6% followed patients, 34.7% original cohort)
      • Reference - Cent Afr J Med 1972 Jan;18(1):4
    • in cohort of 553 susceptible persons exposed to measles in New South Wales, Australia in 2006
      • susceptible contacts defined as infants aged 6-12 months, children aged 1-4 years with no prior MMR vaccine, and persons > 4 years old without 2 prior MMR vaccine doses who were in same room with case or in same room up to 2 hours later
      • 82 contacts received measles vaccine within 3 days of exposure - 0 developed measles within 3 months
      • 183 contacts received immune globulin within 7 days of exposure - 2 (1.1%) developed measles
      • 288 contacts had no prophylaxis - 13 (4.5%) developed measles
      • Reference - N S W Public Health Bull 2009 May-Jun;20(5-6):81
      • DynaMed commentary -- susceptibility to measles infection likely overestimated based on low rate of measles in contacts with no prophylaxis
  • modified measles may occur after IG given as measles postexposure prophylaxis(2)
    • associated with prolonged incubation period, mild prodrome, and short duration of sparse, discrete rash
    • similar clinical presentation also seen in patients who had received vaccination

Infection control

  • Centers for Disease Control and Prevention Healthcare Infection Control Practices Advisory Committee (CDC HICPAC) 2007 guideline for infection control in healthcare settings
    • use airborne precautions when caring for patients with confirmed or suspected measles virus infection (CDC HICPAC Category IA/IC)
      • for at least 4 days after rash onset
      • extended period may be needed in immunocompromised patients
    • patient placement
      • in hospitals and long-term care settings, isolate patient in an airborne infection isolation room (negative pressure room) (CDC HICPAC Category IA/IC)
      • in epidemic settings (CDC HICPAC Category II)
        • consult infection control specialists and
          • group patients together
          • use temporary portable solutions to create negative pressure environment
      • in ambulatory settings, place patient in an airborne infection isolation room if possible or have patient wear mask and remain in examination room until transfer (CDC HICPAC Category IB/IC)
    • restrict contact between unvaccinated healthcare personnel and patients (CDC HICPAC Category IA/IC)
    • personal protective equipment (PPE)
    • provide postexposure management to susceptible persons as soon as possible after potential exposure (CDC HICPAC Category IA)
    • Reference - CDC HICPAC guideline on isolation precautions: preventing transmission of infectious agents in healthcare settings (CDC 2007 PDF)
  • unprotected patient exposure contributing to secondary transmission in 5 healthcare workers despite 4 of whom had presumptive evidence of immunity during outbreak in California, January-April 2014 (Clin Infect Dis 2016 Jan 15;62(2):166)

Immunization

Recommendations

  • World Health Organization (WHO) 2017 position paper on measles vaccines
    • measles vaccination recommended for all susceptible children and adults without contraindications (including history of severe reaction to any vaccine component or any form of severe immunosuppression)
    • measles vaccines may be used interchangeably
    • timing for routine measles containing vaccine (MCV1 first dose and MCV2 second dose)
      • in countries with ongoing transmission in which risk of measles mortality among infants is high
        • give MCV1 at age 9 months
        • give MCV2 at age 15-18 months (minimum interval 4 weeks between MCV1 and MCV2)
      • in countries with low levels of measles transmission and low risk of transmission to infants
        • administer MCV1 at 12 months, at which age seroconversion rates are higher
        • determine optimal age for MCV2 based on programmatic considerations (administration at age 15-18 months ensures early protection and may correspond with other vaccinations)
      • give supplemental dose of MCV to infants from 6 months age
        • during measles outbreak as part of intensified delivery
        • during campaigns in settings with high risk of measles among infants aged < 9 months
        • to internally displaced populations and refugees, and populations in conflict zones
        • to individual infants at high risk of infection
        • to infants traveling to countries with high rates of infection
        • to infants with HIV infection or exposure
      • take every opportunity to vaccinate children
      • screen children for measles vaccination at time of school entry and vaccinate any lacking evidence of receipt of 2 doses with missing doses
    • Reference - Wkly Epidemiol Rec 2017 Apr 28;92(17):205 PDF, also published in Vaccine 2017 Jul 28 early online
  • Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (CDC ACIP) summary recommendations on measles, mumps, and rubella (MMR) vaccine
    • schedule for MMR vaccine during routine childhood vaccination
      • first dose at age 12-15 months
      • second dose at age 4-6 years (may be given earlier but must be ≥ 28 days after first dose)
    • use of quadrivalent MMR-varicella (MMRV) vaccine
      • not recommended for first dose at age 12-47 months, unless parents or caregivers show preference
      • MMRV generally preferred over MMR
        • for second dose at age 15 months to 12 years
        • if first dose at age 4-12 years
      • second dose may be given earlier but must be
        • ≥ 28 days after first dose of MMR
        • ≥ 3 months after first dose of MMRV
      • not approved for patients with HIV
    • adults born in 1957 or later should be given MMR vaccine unless evident immunity to measles, mumps, and rubella
    • vaccination recommended for following groups unless evident immunity to measles, mumps, and rubella
      • students entering school (any post-high school education)
      • health care personnel
      • international travelers ≥ 6 months old
      • nonpregnant women who could become pregnant
      • household members and close contacts of immunocompromised persons
      • persons with HIV infection in absence of severe immunosuppression
        • MMR only
        • absence of severe immunosuppression defined as CD4 ≥ 15% for ≥ 6 months in persons ≤ 5 years old or CD4 ≥ 15% and CD4 count ≥ 200 cells/mm3 for ≥ 6 months for persons > 5 years old
    • contraindications to MMR vaccine
      • history of anaphylactic reaction to neomycin (however, history of contact dermatitis to neomycin is not a contraindication)
      • history of severe allergic reaction to any vaccine component (however, allergy to eggs is not a contraindication)
      • pregnancy
      • immunosuppression
    • precautions for MMR or MMRV vaccine
      • recent receipt of antibody-containing blood product (≤ 11 months)
      • moderate or severe illness without fever
      • history of thrombocytopenia or thrombocytopenic purpura
      • tuberculin testing
        • MMR vaccine may result in temporary depression of tuberculin skin sensitivity (which raises risk of false-negative results)
        • tuberculin testing should be administered either any time before, simultaneously with, or at least 4-6 weeks after administration of MMR or MMRV vaccine
      • personal or family history of seizures (MMRV only)
    • acceptable presumptive evidence of immunity to measles
      • documentation of 2 doses of live measles virus-containing vaccine (1 dose acceptable for preschool-aged children in routine settings, adults not at high risk, or infants aged 6-11 months traveling internationally)
      • laboratory evidence of immunity (unequivocal presence of immunoglobulin in serum)
      • laboratory confirmation of disease
      • born before 1957
    • References - MMWR Morb Mortal Wkly Rep 2018 Feb 9;67(5):156 full-text and MMWR Recomm Rep 2013 Jun 14;62(RR-04):1 full-text
    • see Immunizations in children and adolescents for Recommended Immunization Schedule from Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP)

Efficacy

  • MMR vaccine reported to be effective against measles and mumps in children (level 3 [lacking direct] evidence)
    • based on noncomparative outcomes from Cochrane review
    • systematic review of 5 randomized trials, 1 nonrandomized trial, and 58 observational studies (cohort studies, case series, ecological studies) comparing measles/mumps/rubella (MMR) vaccine to no treatment or placebo in about 14,700,000 healthy children aged up to 18 years
    • 6 MMR vaccines
      • M-M-R by Merck includes Jeryl Lynn strain of mumps
      • Priorix by Glaxo SmithKline Beecham includes mumps strain derived from Jeryl Lynn strain
      • Morupar by Chiron includes Urabe AM 9 strain of mumps
      • Trimovax by Pasteur-Merieux Serums includes Urabe AM 9 strain of mumps
      • Triviraten Berna vaccine includes Rubini strain of mumps
      • Pluserix by Smith-Kline Beecham includes Urabe strain of mumps
    • vaccines had
      • 69%-81% efficacy for preventing clinical mumps
      • > 95% efficacy for preventing clinical measles
    • no included studies evaluated efficacy for preventing rubella
    • Reference - Cochrane Database Syst Rev 2012 Feb 15;(2):CD004407
  • simultaneous vitamin A supplementation may increase antibody response to measles vaccine in children having 1 dose of measles vaccine at age 9 months (level 3 [lacking direct] evidence)
    • based on randomized trial without clinical outcomes
    • 462 children randomized to supplementation with vitamin A 100,000 units vs. placebo at time of vaccination followed until age 18 months
      • 150 infants had 2-dose measles vaccine at ages 6 months and 9 months
      • 312 infants had 1 dose of measles vaccine at 9 months
    • in infants having 2-dose vaccine schedule
      • seroconversion 98%
      • no significant difference in seroconversion or geometric mean titer comparing vitamin A vs. placebo
    • in infants having 1-dose schedule
      • seroconversion 95%
      • geometric mean titer significantly higher in children receiving vitamin A
      • vitamin A effect on plasma antibody concentration stronger in boys
    • Reference - Lancet 1997 Jul 12;350(9071):101
    • increase in protective antibody levels continued through age 6-8 years
      • based on follow-up study of randomized trial above
      • 278 children (aged 6.8-8.2 years) randomized to vitamin A 100,000 units vs. placebo at time of 9-month measles vaccination were evaluated
      • in subgroup analysis of children with protective antibody levels, vitamin A-supplemented children associated with increased protective antibody levels through age 6-8 years (p = 0.09)
      • Reference - Lancet 2002 Apr 13;359(9314):1313
  • efficacy of measles vaccination in HIV-infected children
    • measles vaccination associated with about 60% seroprotection rates in HIV-infected children (level 3 [lacking direct] evidence)
      • based on systematic review without clinical outcomes
      • systematic review of 39 studies evaluating immunogenicity and safety of measles vaccine in > 1,200 children ≤ 15 years old
      • serological response rates following standard titer measles vaccine at age 6 months in 1 study
        • 59% in HIV-infected children
        • 68% in HIV-exposed but uninfected children
        • 62% in HIV-unexposed children
      • HIV-infected children had comparable (about 60%) seropositive rates with vaccination at age 9 months (8 studies) and at age 12 months (10 studies), but studies varied widely (21%-100%)
      • seropositive rates increased to > 90% with vaccination at age 12 months in HIV-exposed but uninfected children (6 studies) and in HIV-unexposed children (2 studies)
      • lower serological response in HIV-infected children compared to HIV-exposed children after vaccination at 12 months (risk ratio [RR] 0.61, 95% CI 0.5-0.73) in analysis of 6 studies
      • Reference - J Infect Dis 2011 Jul;204 Suppl 1:S164
      • DynaMed commentary -- CD4+ T cell counts varied among studies within this systematic review
    • measles revaccination at age 15-27 months increases rate of adequate immunity in HIV-infected children (level 3 [lacking direct] evidence)
      • based on prospective cohort study without clinical outcomes
      • 441 Zambian children were vaccinated for measles at about age 9 months
      • rates of adequate immunity (defined as measles antibody titer ≥ 120 units/L) among 359 children (81%) who were followed 6 months after vaccination
        • 94% among 98 HIV-seronegative children
        • 94% among 211 HIV-seropositive but uninfected children
        • 88% among 50 HIV-infected children
      • rate of adequate immunity among 101 children (23%) who survived and were followed 27 months after vaccination
        • 89% of 71 HIV-uninfected children
        • 50% of 18 HIV-infected children who did not receive supplemental immunization
        • 92% of 12 HIV-infected children who were revaccinated at ages 15-27 months
      • Reference - J Infect Dis 2007 Aug 1;196(3):347

Safety

  • adverse effects appear uncommon after mumps, measles, and rubella (MMR) vaccine (level 2 [mid-level] evidence)
    • based on Cochrane review of observational studies
    • systematic review of 5 randomized trials, 1 nonrandomized trial, and 58 observational studies (cohort studies, case series, ecological studies) comparing MMR vaccine to no treatment or placebo in 14,700,000 healthy children aged up to 18 years
    • 6 MMR vaccines
      • M-M-R by Merck includes Jeryl Lynn strain of mumps
      • Priorix by Glaxo SmithKline Beecham includes mumps strain derived from Jeryl Lynn strain
      • Morupar by Chiron includes Urabe AM 9 strain of mumps
      • Trimovax by Pasteur Merieux Serums includes Urabe AM 9 strain of mumps
      • Triviraten Berna vaccine includes Rubini strain of mumps
      • Pluserix by SmithKline Beecham includes Urabe strain of mumps
    • for aseptic meningitis
      • estimated attributable risk was 1 case per 14,000 doses (Urabe-containing MMR vaccine Pluserix) within 11 weeks after start of vaccination campaign in time-series study with > 450,000 children aged 1-11 years
      • 22-71 cases during observation period before vaccination vs. 48-108 within 11 weeks after start of vaccination campaign (vaccine containing Leningrad-Zagreb mumps strains) in 2-center time-series study with > 1,000,000 children
      • association not significant in cohort and self-controlled case series studies using vaccines containing Jeryl Lynn mumps strains
    • for febrile seizures, estimated absolute risk attributed to MMR vaccine was 1.56 per 1,000 children in 1 cohort study with 537,171 children aged 3 months to 5 years, with highest risk within 2 weeks post vaccination (vaccine contained Moraten measles, Jeryl Lynn mumps, and Wistar RA 27/3 rubella strains) (JAMA 2004 Jul 21;292(3):351)
    • for acute immune thrombocytopenic purpura
      • estimated attributable risk was 1 case/25,000 doses within 6 weeks after vaccination in 1 case-control study with 139 children; no significant difference between groups from 7 to 26 weeks post vaccination
      • estimated attributable risk was 1 case/40,000 doses in 1 self-controlled case-series study with 63 children aged 12-23 months
      • 3.6% of cases vs. 1.4% of controls received MMR vaccine within 6 weeks before hospitalization in case-control study with 2,311 patients aged 1 month to 18 years
    • MMR vaccine not likely associated with autism, asthma, leukemia, hay fever, type 1 diabetes, gait disturbance, Crohn disease, demyelinating diseases, infection, or encephalitis
    • Reference - Cochrane Database Syst Rev 2012 Feb 15;(2):CD004407
  • adverse events appear uncommon in children receiving MMR vaccine
    • based on randomized crossover trial
    • 1,162 twins aged 14-83 months randomized to measles/mumps/rubella (MMR) vaccine vs. placebo with alternate intervention given after 3 weeks
    • vaccine-attributable events occurred in 6%, including fever ≥ 38.5 degrees C (101.3 degrees F), rash, arthralgia, conjunctivitis, staying in bed, drowsiness, and irritability
    • Reference - Pediatrics 2000 Nov;106(5):e62
  • 3,175 adverse events reported in adults after MMR vaccination from 2003 to 2013
    • based on retrospective cohort study
    • 3,175 adverse events (5% classified as serious) in adults after MMR vaccination reported to Vaccine Adverse Event Reporting System between January 2003 and July 2013
    • 50.4% received MMR vaccine alone, most commonly coadministered vaccines in remaining 49.6% were varicella, Tdap, and hepatitis B
    • most common adverse events reported included pyrexia in 19%, rash in 17%, pain in 13%, and arthralgia in 13%
    • 7 deaths reported, only 1 of which directly attributed to vaccine-related cause (disseminated vaccine strain varicella in patient on immunosuppression)
    • Reference - Clin Infect Dis 2015 May 15;60(10):e58
  • adverse events appear uncommon in children receiving combined MMR-varicella vaccine or separate MMR and varicella vaccine
    • based on retrospective cohort study
    • children aged 12-23 months who received 123,200 doses of combined MMR-varicella vaccine and 584,987 doses of separate MMR and varicella (MMR + V) between 2000 and 2012 were evaluated for risk of vaccine-attributable adverse events
    • no significant differences in any adverse event comparing MMRV vs. MMR + V
      Adverse Event Comparison:
      Adverse Event Cases per 100,000 MMRV DosesCases per 100,000 MMR + V Doses
      Anaphylaxis immediately after vaccination1.680.85
      Acute disseminated encephalomyelitis 1-42 days after vaccination00.17
      ITP 1-42 days after vaccination (defined as 2 platelet counts ≤ 150,000 within 7 days)8.4112.16
      ITP 1-42 days after vaccination (defined as 2 platelet counts ≤ 50,000 within 7 days)5.895.73
      Ataxia 1-42 days after vaccination115.26102.51
      Arthritis/arthralgia 1-42 days after vaccination0.840.52
      Meningitis/encephalitis 1-42 days after vaccination1.681.56
      Kawasaki disease 1-56 days after vaccination5.95.42
      Abbreviations: ITP, immune thrombocytopenia purpura; MMRV, measles, mumps, and rubella combined with varicella vaccine; MMR+V, measles, mumps, and rubella vaccine and separate varicella vaccine.
    • compared to outcomes observed 57-180 days after vaccination (no significant differences between MMRV and MMR+V)
      • increased risk of ITP (2 platelet counts ≤ 50,000 within 7 days) 14-28 days after vaccination with
        • MMRV (odds ratio [OR] 11.3, 95% CI 1.9-68.2)
        • MMR + V (OR 10, 95% CI 4.5-22.5)
      • reduced risk of ataxia 1-42 days after vaccination with
        • MMRV (OR 0.7, 95% CI 0.5-0.95)
        • MMR + V (OR 0.81, 95% CI 0.7-0.93)
    • Reference - Pediatrics 2015 Feb;135(2):e321
  • risk of febrile seizures
    • diphtheria, tetanus, and pertussis (DTP) and MMR vaccinations associated with increased risk for febrile seizure, but low risk for epilepsy
      • based on retrospective cohort study
      • 679,942 children who had 340,386 vaccinations with diphtheria, tetanus, and pertussis (DTP) and 137,457 vaccinations with MMR were evaluated
      • 2,281 children had possible first seizure during study
      • 1,094 children (48%) with possible first seizure were randomly selected for chart review
      • 716 children (65% of random sample) had confirmed first seizure and were included in analysis
      • risk of febrile seizure ≤ 30 days after vaccine
        • for DTP using whole-cell pertussis vaccine
          • relative risk (RR) 5.7 (95% CI 1.98-16.42) on day of vaccination
          • not significantly increased after day of vaccination
        • for MMR vaccine
          • RR 2.83 (95% CI 1.44-5.55) 8-14 days after vaccination
          • not significantly increased on day of vaccination, at 1-7 days after vaccination, or > 14 days after vaccination
      • no child with vaccine-associated febrile seizure had subsequent afebrile seizure or diagnosis of epilepsy during up to 7 years of follow-up
      • Reference - N Engl J Med 2001 Aug 30;345(9):656 full-text
    • febrile seizures might be more common after first-dose vaccination with combined MMR-varicella vaccine than separate MMR and varicella vaccines (level 2 [mid-level] evidence)
      • based on retrospective cohort study
      • 277,774 children aged 12-23 months had first-dose vaccination with combined MMR-varicella (MMRV) vaccine or same-day administration of separate MMR and varicella (MMR+V) vaccines between 2006 and 2012 and were followed for 42 days
      • incidence of seizures within 7-10 days of vaccination, 5.8 seizures per 10,000 doses of MMRV vs. 2.2 seizures per 10,000 of MMR+V (relative risk 1.99, 95% CI 1.3-3.05)
      • no significant differences in risk of seizures within 7-10 days in subgroup analysis of children at either high risk or low risk
      • Reference - CMAJ 2014 Aug 5;186(11):824 full-text, editorial can be found in CMAJ 2014 Aug 5;186(11):812
    • risk of fever and seizure may be higher following measles vaccination in children > 16 months old
      • based on retrospective cohort study
      • 840,348 children aged 12-23 months who had measles-containing vaccine between 2001 and 2011 were evaluated
      • increased risk of complications within 7-10 days after immunization
        • increased risk of seizure
          • relative risk (RR) 6.5 (95% CI 5.3-8.1) among children aged 16-23 months
          • RR 3.4 (95% CI 3-3.9) among children aged 12-15 months
        • increased risk of fever
          • RR 5.9 (95% CI 5.4-6.5) among children aged 16-23 months
          • RR 4.4 (95% CI 4.3-4.6) among children aged 12-15 months
      • Reference - JAMA Pediatr 2013 Dec;167(12):1111, editorial can be found in JAMA Pediatr 2013 Dec;167(12):1097, commentary can be found in J Pediatr 2014 Mar;164(3):674, Am Fam Physician 2014 May 15;89(10):786
  • fever, diarrhea, and rash may be more common after first dose of MMR vaccine than after second dose (level 2 [mid-level] evidence)
    • based on prospective cohort study
    • 1,800 children evaluated for fever, diarrhea, and rash during 2 weeks before vs. 2 weeks after measles/mumps/rubella (MMR) vaccine
    • in 535 toddlers ages 12-24 months
      • estimated net 18% increase in fever, diarrhea, and rash after MMR vaccine (NNH 6)
      • median onset 5-10 days postvaccination, duration 2-5 days
    • no increases observed in 633 kindergartners ages 4-6 years or 632 middle school students aged 10-12 years
    • Reference - Pediatrics 2006 Oct;118(4):1422
  • measles vaccination does not appear to be associated with allergic disease in children (level 2 [mid-level] evidence)
    • based on post hoc analysis of cross-sectional study
    • 14,893 children aged 5-13 years in 5 European countries were evaluated for allergy risk factors
    • 12,540 with known vaccination and measles infection status included in analysis
    • 27% provided blood samples
    • atopic sensitization defined as elevated allergen-specific serum immunoglobulin E level
      Allergic Disease and Atopic Sensitization by Measles Infection and Vaccination Status:
       No Infection
      No Vaccination
      (Reference)
      No Infection
      Had Vaccination
      Had Infection
      No Vaccination
      Had Infection
      Had Vaccination
      Asthma8%9%9%7%
      Atopic eczema11%10%11%9%
      Rhinoconjunctivitis4%5% (p < 0.05)4% 3%
      Atopic sensitization35%29%33%28% (p < 0.05)
    • Reference - Pediatrics 2009 Mar;123(3):771 full-text

Coverage

  • global vaccine coverage
    • vaccine coverage among children aged 1 year in 2014
      WHO Region Percentage Coverage with MCV1 Percentage Coverage with MCV2
      African73% 11%
      Americas92% 51%
      Eastern Mediterranean77%66%
      European94%84%
      South-East Asia 84%59%
      South-East Asia (excluding India)85%78%
      India 84% 51%
      Western Pacific97%93%
      Total85%56%
      Abbreviation: MCV1 or MCV2, measles-containing vaccine; WHO, World Health Organization.
    • 56% of children who did not receive first dose were from 6 countries
      • India
      • Nigeria
      • Pakistan
      • Ethiopia
      • Indonesia
      • Democratic Republic of Congo
    • Reference - MMWR Morb Mortal Wkly Rep 2015 Nov 13;64(44):1246 full-text
  • coverage in United States

Risk of autism

  • no correlation found between autism spectrum disorders (ASD) and use of measles, mumps and rubella (MMR) vaccine - original article retracted and subsequent studies found no association with MMR vaccination
    • 1998 article reporting association between autism and MMR vaccine RETRACTED
      • retraction due to several incorrect elements (including false claims that children were consecutively referred and investigators approved by local ethics committee) (Lancet 2010 Feb 6;375(9713):445)
      • original article was study of 12 children and reported autism as an incidental behavioral disorder associated with MMR vaccine in 9 children (Lancet 1998 Feb 28;351(9103):637)
    • subsequent studies found no association with MMR
      • MMR vaccination not associated with increased risk of autism spectrum disorders in children (level 2 [mid-level] evidence)
        • based on observational studies in Cochrane review
        • systematic review of 58 observational studies (cohort studies, case series, ecological studies), 5 randomized trials, and 1 nonrandomized trial comparing measles/mumps/rubella (MMR) vaccine to no treatment or placebo in about 14,700,000 healthy children aged up to 18 years
        • 8 observational studies evaluated association between MMR vaccination and autism spectrum disorders in children
        • no association between MMR vaccination and
          • risk of autism spectrum disorders
            • in 1 cohort study (risk ratio 0.92, 95% CI 0.68-1.24) with 537,303 children in Denmark
            • in 1 time-series study with 31,426 children in Japan
          • risk of pervasive developmental disorders
            • in 1 case-control study (odds ratio [OR] 0.86, 95% CI 0.68-1.09) with 5,763 children in United Kingdom
            • in 1 time-series study with 27,749 children in Canada
          • risk of regressive autism
            • in 1 cohort study (OR 0.74, 95% CI 0.35-1.52) with 186 children in Japan
            • in 1 cohort study with 195 children in United Kingdom
        • no significant difference in age at first vaccination in 1 case-control study with 2,448 children in United States
        • Reference - Cochrane Database Syst Rev 2012 Feb 15;(2):CD004407
      • MMR vaccination not associated with increased risk of autism spectrum disorders in children with older siblings with or without autism spectrum disorders (level 2 [mid-level] evidence)
        • based on retrospective cohort study
        • 95,727 children born from 2001 to 2007 to families with older siblings were assessed
        • 2% had older sibling with autism spectrum disorder (ASD), 98% had no older siblings with ASD
        • 1% diagnosed with ASD overall
        • ASD diagnosed in 6.9% of children with older siblings with ASD vs. 0.9% of children with no older siblings with ASD (p < 0.001)
        • MMR vaccination rate (≥ 1 dose)
          • 73% at 2 years and 86% at 5 years in children with older sibling with ASD
          • 84% at 2 years and 92% at 5 years in children with no older siblings with ASD
        • in children with older sibling with ASD, no significant differences in rates of ASD diagnosis comparing no MMR vaccination to
          • 1 dose MMR by age 2 years
          • 1 dose MMR by age 3 years
          • 1 dose MMR by age 4 years
          • 1 dose MMR by age 5 years
          • 2 doses MMR by age 5 years
        • similar results in children with no older siblings with ASD
        • Reference - JAMA 2015 Apr 21;313(15):1534, correction can be found in JAMA 2016 Jan 12;315(2):204, editorial can be found in JAMA 2015 Apr 21;313(15):1518
      • no association between MMR vaccination and risk of autism (odds ratio 1.1, 95% CI 0.64-1.9) in 189 children with autism spectrum disorders matched to 224 controls (Vaccine 2012 Jun 13;30(28):4292)
    • Institute of Medicine Immunization Safety Review Committee favors rejection of causal link (Stratton, K, Gable A, Shetty P, McCormick M, eds. Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism 2001. Washington, DC: National Academies Press; 2001)
    • American Academy of Pediatrics list of studies examining vaccine safety and effectiveness, including examination of putative link between MMR and autism, and thimerosal and autism, can be found at AAP 2013 Apr PDF

Timing of vaccination

  • measles vaccination at 4.5 months associated with reduced infant morbidities and hospitalization rates before 9 months, but vaccination at 9 months associated with higher antibody levels and similar clinical outcomes after 9 months (level 2 [mid-level] evidence)
    • based on multiple analyses of randomized trial without blinding
    • children in Guinea-Bissau were initially randomized into 1 of 3 groups
      • 2 doses of Edmonston-Zagreb vaccine at ages 4.5 months and 9 months
      • 1 dose of Schwarz vaccine at age 9 months
      • 1 dose of Edmonston-Zagreb at age 9 months
    • children receiving first dose of vaccine at 9 months further randomized to 1 dose of Edmonston-Zagreb vaccine vs. placebo at 18 months
    • outcomes at < 9 months of age
      • measles vaccination at age 4.5 months associated with reduced infant morbidities and hospitalization rate at 9 months compared to vaccination at 9 months (level 2 [mid-level] evidence)
        • based on randomized trial without blinding
        • 6,417 children were randomized as described above
        • at 9 months, administration of vaccine at 4.5 months associated with reduced hospital admission (hazard rate ratio [RR] 0.7, 95% CI 0.52-0.95)
          • for measles infection (hazard RR 0, 95% CI 0-0.24)
          • for respiratory infection (hazard RR 0.37, 95% CI 0.16-0.89)
        • Reference - J Infect Dis 2014 Jun 1;209(11):1731 full-text
      • early measles vaccination using the Edmonston-Zagreb vaccine associated with reduced rate of measles and hospital admission during measles outbreak (level 2 [mid-level] evidence)
        • based on interim analysis of randomized trial
        • 1,333 children (median age 4.8 months) randomized as described above
        • measles outbreak occurred during study, 96 children developed measles
        • 85 of 96 children with confirmed measles were analyzed
        • comparing children vaccinated at 4.5 months vs. children due to be vaccinated at 9 months
          • monthly incidence of measles 0.7% vs. 3.1% (p < 0.05, NNT 42)
          • hospital admission for measles in 0 vs. 14 children (statistics not reported)
          • measles cases 1.8% vs. 8.6%
          • death attributable to measles in 0 vs. 7 children (statistics not reported)
          • measurable antibody titer at age 9 months in 92% vs. 9% (relative risk 9.81, 95% CI 7.2-13.3)
          • protective antibody levels at age 9 months in 77% vs. 5% (relative risk 14.9, 95% CI 9.7-22.7)
        • NNT to prevent 1 case of measles between ages 4.5 and 9 months during measles outbreak was 7.2
        • no significant differences in overall mortality
        • Reference - BMJ 2008 Jul 24;337:a661 full-text, editorial can be found in BMJ 2008 Jul 24;337:a406
    • outcomes at > 9 months old
      • measles vaccination at age 9 months appears to induce higher protective measles antibody levels at 24 months in children compared to 2-dose vaccination at ages 4.5 and 9 months (level 3 [lacking direct] evidence)
        • based on randomized trial without clinical outcomes
        • 850 children randomized as described above
        • among children receiving 2 doses of vaccine at ages 4.5 and 9 months, protective antibody levels detected in
          • 25% of 435 samples at 4.5 months
          • 77% of 408 samples at 9 months
          • 97% of 337 samples at 24 months
        • among children receiving vaccine at age 9 months with or without second dose at age 18 months, 99% of 314 samples at 24 months had protective antibody levels
        • compared to vaccination at ages 4.5 and 9 months, vaccination at 9 months associated with higher protective antibody levels at 24 months (p = 0.0001)
        • Reference - J Infect Dis 2014 Sep 1;210(5):693
      • measles vaccine given at 4.5 months and 9 months may not reduce mortality compared to single dose of measles vaccine given at 9 months (level 2 [mid-level] evidence)
        • based on randomized trial with high loss to follow-up
        • 6,648 children aged 4.5 months randomized as described above
        • 80% received vitamin A supplementation at birth
        • 29% lost to follow-up or excluded by 36 months
        • no significant difference in mortality from age 4.5 to 36 months among groups
        • 2-dose vaccine associated with lower mortality in children without vitamin A supplementation at birth vs. both single-dose vaccines
        • Reference - BMJ 2010 Nov 30;341:c6495 full-text
  • first dose of 2-dose measles vaccine given at age 12 months associated with increased risk of measles compared to first dose given at age ≥ 15 months
    • based on cohort study
    • 110 school children with measles during 2011 outbreak in Quebec, Canada evaluated
    • attack rates 82% among unvaccinated patients and 4.8% among fully vaccinated patients
    • in subgroup analysis of 2-dose recipients, increased risk of measles associated with first vaccine dose given at age 12 months compared to age ≥ 15 months (relative risk 4.35, 95% CI 1.05-18.1)
    • Reference - Clin Infect Dis 2012 Aug;55(3):394, editorial can be found in Clin Infect Dis 2012 Aug;55(3):403
  • presence of maternal measles antibody at time of vaccination associated with improved survival in children receiving measles vaccine (level 2 [mid-level] evidence)
    • based on meta-analysis with subgroup analysis
    • meta-analysis of 2 randomized trials evaluating 2-dose schedule with measles vaccine given at age 4-6 months and age 9 months in 750 children
    • both trials measured antibody levels before early measles vaccination
    • in subgroup analysis of children receiving first dose at age 4-6 months, presence of maternal measles antibody associated with lower mortality between 4 and 6 months and 5 years (mortality rate ratio 0.22, 95% CI 0.07-0.64)
    • Reference - Clin Infect Dis 2014 Aug 15;59(4):484 full-text
  • early vaccination appears safe in children aged 6-14 months (level 2 [mid-level] evidence)
    • based on cohort study
    • parents of 962 infants aged 6-14 months who had early measles/mumps/rubella vaccine due to a measles outbreak in the Netherlands completed a questionnaire on adverse events
    • 36.4% of infants had systemic adverse events (p = 0.0004 for difference between age groups)
      • 32% of infants aged 6-8 months
      • 45% of infants aged 9-11 months
      • 43% of infants aged 12-14 months
    • 6.1% of infants had local adverse events (p = 0.08 for difference between age groups)
      • 5% of infants aged 6-8 months
      • 7% of infants aged 9-11 months
      • 10% of infants aged 12-14 months
    • Reference - J Infect Dis 2016 May 1;213(9):1466 full-text

Route of vaccination

  • first-dose measles vaccine administered via aerosol inhalation may not be as effective as subcutaneous injection for induction of immune response in children (level 2 [mid-level] evidence)
    • based on randomized noninferiority trial with high loss to follow-up
    • 2,004 children aged 9-11 months eligible for first dose of measles vaccine in India were randomized to single dose of vaccine via aerosol inhalation vs. subcutaneous injection and followed for 91 days
    • 1,560 (77.8%) patients completed study and had evaluable outcome data included in analysis
    • noninferiority defined as lower bound of 95% CI for treatment difference > -5%
    • comparing aerosol vs. subcutaneous administration
      • measles seropositive rate 85.4% vs. 94.6% (95% CI -12.2 to -6.3, noninferiority not met)
      • seroconversion rate 83.4% vs. 93.2% (95% CI -13.1 to -6.7, noninferiority not met)
      • coryza in 44% vs. 38.7% (p = 0.02, NNH 18)
    • no significant differences between groups in incidence of other common adverse events including fever, cough, and diarrhea
    • no serious vaccine-related adverse events reported in either group
    • Reference - N Engl J Med 2015 Apr 16;372(16):1519 full-text, commentary can be found in BMJ 2015 Apr 15;350:h2006

Parent education

  • web-based educational interventions to promote MMR vaccination do not appear to increase parental intent to vaccinate their children (level 3 [lacking direct] evidence)
    • based on nonclinical outcome from randomized trial with possible selection bias
    • 4,462 adult parents from online panel were asked to complete interview
    • 1,759 parents (39.4% of those sampled) with available interview data were randomized to 1 of 5 web-based interventions
      • text explaining lack of evidence that measles, mumps, and rubella virus (MMR) vaccine causes autism (autism correction)
      • text describing dangers of the diseases prevented by MMR (disease risks)
      • images of children who have diseases prevented by MMR vaccine (disease images)
      • story regarding infant who almost died of measles (disease narrative)
      • text about costs and benefits of bird feeding (control)
    • vaccine promotion interventions adapted from public health authority messaging materials
    • compared to control, autism correction intervention associated with decreased parental intent to vaccinate future child with MMR vaccine
      • adjusted odds ratio 0.52 (95% CI 0.32-0.84)
      • significant difference confined to parents least favorable to vaccination at baseline in subgroup analysis
    • no other significant differences between any intervention vs. control for parental intent to vaccinate with MMR vaccine
    • Reference - Pediatrics 2014 Apr;133(4):e835 full-text, commentary can be found in Indian Pediatr 2014 Jun;51(6):491
    • DynaMed commentary -- parents choosing to participate in survey may have stronger views on perceived risk of childhood vaccination and may be more likely to have negative views compared to overall population
  • information emphasizing direct benefits of MMR vaccination to children rather than benefits to society may increase parental intent to vaccinate their children (level 3 [lacking direct] evidence)
    • based on nonclinical outcome from randomized trial without nationally representative sample
    • 802 parents of infants < 12 months old were randomized to 1 of 4 online MMR vaccine messages
      • Centers for Disease Control and Prevention Vaccine Information Statement (VIS) (standard information describing MMR and MMR vaccine)
      • VIS and information emphasizing benefits of MMR vaccination directly to children receiving the vaccine
      • VIS and information emphasizing benefits to society at large
      • VIS and information emphasizing benefits to both children and society
    • parental intentions to vaccinate their children were scored on scale ranging from 0 (extremely unlikely) to 100 (extremely likely)
    • compared to VIS alone (mean intention 86.3)
      • mean intention 91.6 with additional information emphasizing benefits directly to children receiving the vaccine (p = 0.01)
      • mean intention 86.4 with additional information emphasizing benefits to society (not significant)
      • mean intention 90.8 with additional information emphasizing benefits to both children and society (p = 0.03)
    • persons sociodemographically different than survey recipients may have differences in vaccine acceptability
    • Reference - Pediatrics 2014 Sep;134(3):e675 full-text

Guidelines and Resources

Guidelines

United States guidelines

  • Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (CDC ACIP) 2013 summary recommendations on prevention of measles, rubella, congenital rubella syndrome, and mumps can be found in MMWR Recomm Rep 2013 Jun 14;62(RR-04):1 full-text, correction can be found in MMWR Recomm Rep 2015 Mar 13;64(9):259
  • Centers for Disease Control and Prevention Healthcare Infection Control Practices Advisory Committee (CDC HICPAC) 2007 guideline on isolation precautions: preventing transmission of infectious agents in healthcare settings can be found at CDC 2007 PDF
  • Infectious Diseases Society of America (IDSA) 2013 clinical practice guideline on vaccination of immunocompromised host can be found in Clin Infect Dis 2014 Feb;58(3):e44 full-text, correction can be found in Clin Infect Dis 2014 Jul 1;59(1):144
  • American Academy of Pediatrics Committee on Infectious Diseases 2015 Red Book chapter on measles can be found at Red Book Online

United Kingdom guidelines

Australian and New Zealand guidelines

  • Communicable Diseases Network Australia (CDNA) 2015 guideline on measles can be found at CDNA 2015 May 7

Review articles

Additional resources

Patient Information

ICD-9/ICD-10 Codes

ICD-9 codes

  • 055.0 postmeasles encephalitis
  • 055.1 postmeasles pneumonia
  • 055.2 postmeasles otitis media
  • 055.7 measles with other specified complications
    • 055.71 measles keratoconjunctivitis
    • 055.79 measles with other specified complications
  • 055.8 measles with unspecified complication
  • 055.9 measles without mention of complication
  • V04.2 need for prophylactic vaccination and inoculation against measles alone

ICD-10 codes

  • B05 measles
    • B05.0 measles complicated by encephalitis [also use code G05.1 encephalitis, myelitis and encephalomyelitis in viral diseases classified elsewhere]
    • B05.1 measles complicated by meningitis [also use code G02.0 meningitis in viral diseases classified elsewhere]
    • B05.2 measles complicated by pneumonia [also use code J17.1 pneumonia in viral diseases classified elsewhere]
    • B05.3 measles complicated by otitis media [also use code H67.1 otitis media in viral diseases classified elsewhere]
    • B05.4 measles with intestinal complications
    • B05.8 measles with other complications [for example H19.2 keratitis and keratoconjunctivitis in other infectious and parasitic diseases classified elsewhere]
    • B05.9 measles without complication
  • Z24.4 need for immunization against measles alone

References

General references used

Recommendation grading systems used

  • Centers for Disease Control and Prevention Healthcare Infection Control Practices Advisory Committee (CDC HICPAC) categories for recommendations
    • Category 1A - strongly recommended for implementation and strongly supported by well-designed experimental, clinical, or epidemiologic studies
    • Category 1B - strongly recommended for implementation and supported by some experimental, clinical, or epidemiologic studies
    • Category 1C - required for implementation, as mandated by federal and/or state regulation or standard
    • Category II - suggested for implementation and supported by suggestive clinical or epidemiologic studies or theoretical rationale
    • No recommendation - unresolved issue; practices for which insufficient evidence or no consensus regarding efficacy exists
    • Reference - CDC HICPAC 2007 guideline on isolation precautions: preventing transmission of infectious agents in healthcare settings (CDC 2007 PDF)
  • Infectious Diseases Society of America (IDSA) grades of recommendation
    • strength of recommendation
      • Strong recommendation - desirable effects clearly outweigh undesirable effects, or vice versa
      • Weak recommendation - desirable effects closely balanced with undesirable effects, or (with low- or very low-quality evidence) uncertainty in estimates of desirable effects, harms, and burden so they may be closely balanced
    • quality of evidence
      • High-quality evidence - consistent evidence from well-performed randomized controlled trials (RCTs) or exceptionally strong evidence from unbiased observational studies
      • Moderate-quality evidence - evidence from RCTs with important limitations (inconsistent results, methodologic flaws, indirect, or imprecise) or exceptionally strong evidence from unbiased observational studies
      • Low-quality evidence - evidence for ≥ 1 critical outcome from observational studies, RCTs with serious flaws, or indirect evidence
      • Very low-quality evidence - evidence for ≥ 1 critical outcome from unsystematic clinical observations or very indirect evidence

DynaMed editorial process

  • DynaMed topics are created and maintained by the DynaMed Editorial Team and Process.
  • All editorial team members and reviewers have declared that they have no financial or other competing interests related to this topic, unless otherwise indicated.
  • DynaMed provides Practice-Changing DynaMed Updates, with support from our partners, McMaster University and F1000.

Special acknowledgements

  • Anne Neilan, MD, MPH (Assistant in Pediatrics and Medicine, Massachusetts General Hospital; Instructor, Harvard Medical School; Massachusetts, United States)
  • Dr. Neilan declares no relevant financial conflicts of interest.
  • Amir Qaseem, MD, PhD, MHA, FACP (Vice President of Clinical Policy, American College of Physicians; Pennsylvania, United States; President Emeritus, Guidelines International Network (GIN); Germany)
  • Dr. Qaseem declares no relevant financial conflicts of interest.
  • Vito Iacoviello, MD, FIDSA (Deputy Editor of Infectious Diseases, Immunology, and Rheumatology; Assistant Professor of Medicine, Harvard Medical School; Chief of the Division of Infectious Diseases, Mount Auburn Hospital; Massachusetts, United States)
  • Dr. Iacoviello declares no relevant financial conflicts of interest.
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