Measles

MICROBIOLOGY

• Morbillivirus, a negative sense, single-strand RNA virus of the Paramyxoviridae group.
  • Related to other morbilliviruses infecting animals, including rinderpest virus, peste des petitis ruminants virus, canine distemper virus and dolphin morbillivirus.
• Measles virus (MV), also known as rubeola, is a respiratory agent with subsequent viremia.
• Others in the paramyxovirus family:
  • Human metapneumovirus
  • Hendra virus
  • RSV
  • Parainfluenza
  • Nipah virus, cause of encephalitis.

CLINICAL

• Until routine measles immunization, the rubeola virus was the most common and highly contagious of childhood diseases.
• Remains a worldwide problem with 140,000 measles-related deaths (2018, WHO). Eradication is difficult despite WHO efforts due to difficulties in lower-resource countries, such as maintaining a cold chain for the vaccine.
  
  • U.S. (2024 data): 16 outbreaks, 285 cases in 33 jurisdictions.
    • Outbreaks continue to occur in the U.S. due to an under-immunized population in many locales and imported infections.
    • CDC is updating data weekly due to the Texas outbreak and the outbreak in Ontario, Canada (Feb-Mar 2025, ongoing as of this update).
      • 2/27/25: 164 measles cases were reported by 9 jurisdictions: Alaska, California, Georgia, Kentucky, New Jersey, New Mexico, New York City, Rhode Island, and Texas.
    • In 2019, 1274 individual cases of measles were confirmed in 31 states, the highest number in the U.S. since 1992.
      • Factors driving the persistence of outbreaks include:
        • More travelers who acquire measles overseas and remain infectious upon returning to the U.S. →
        • Further transmission in communities, especially those with higher rates of unvaccinated people.
  • For outbreak reports, see CDC: Measles Cases and Outbreaks.
• Risks:
  
  • Non-immunized or poor response to the vaccine.
    • Most cases in the U.S. are in non-immunized children/adolescents or adults.
    • Exposure risk typically from travelers visiting the U.S. or just returning from visiting overseas in a country with active measles
    • See the WHO map for countries with active cases; most cases (2020, latest data) are seen in Africa (especially DRC), Kazakhstan, and the Philippines; however, many countries report positive cases annually.
• Typical signs and symptoms are fever, coryza, and cough followed by a rash [Fig 1].
  
  • Incubation: typically 10-12 days following exposure; first symptom is high fever and flu-like symptoms, cough and coryza.
  • Koplik spots: appear 2-3d after the onset of symptoms, and occur on the inside of the mouth as tiny, bluish-white spots surrounded by erythema on the buccal mucosa [Fig 2]. It may precede the onset of rash and is pathognomonic of measles.
  • Rash: typically 3-5d after illness onset as a macular rash that begins on the face and spreads downward to become large confluent blotches over the entire body [Fig 3]. Fever may spike and then abate with the onset of rash and the disappearance of viremia.
  • Patients may also experience diarrhea, vomiting, lymphadenopathy, abdominal pain, pharyngitis, splenomegaly, leukopenia, and thrombocytopenia.
• The entire illness lasts up to 10- 14 days. Patients usually become afebrile following the onset of the rash.
  • If fever persists, a secondary bacterial infection is suspected.
• Diagnosis:
  
  • Clinical: usually a clinically based dx based on acute febrile illness, characteristic rash and/or Koplik spots (irregular red spots w/tiny blue-white specks on buccal/lingual mucosa) in a patient with residence or travel within an endemic country or recent exposure to an index or secondary case.
  • Serology: measles EIA
    • IgM is helpful for acute infection. It can be negative before the rash but typically becomes positive at the rash onset.
    • IgG is used to assess immune status.
  • Culture: tissue/secretions may be cultured for viruses and/or identified by IFA.
    • Nasopharyngeal aspirate IFA offers rapid dx.
  • RT-PCR: respiratory or urine samples.
  • In the U.S.: contact the local or state health department first.
    • The CDC Infectious Diseases Laboratories offers diagnostic assistance (culture, PCR): T: 404-639-1156; E-Mail: jrota@cdc.gov
• Secondary complications: otitis media, bronchopneumonia, croup, diarrhea, bronchitis.
  
  • Most common in children < 5 yrs, adults > 20 yrs.
  • Many deaths from measles occur in malnourished children, succumbing to pneumonia or diarrhea.
    • In low-resource countries: tuberculosis, viral infections (adenovirus, herpesviruses), and other bacterial infections (S. aureus, Klebsiella, Pseudomonas).
  • Pregnancy: miscarriage, pre-term delivery
  • Direct measles complications are less common
    • Encephalomyelitis: 100/100,000 infections
    • Subacute sclerosing panencephalitis (SSPE): 10/100,000

SITES OF INFECTION

• Mucocutaneous/systemic: characteristic disease progression starts with a prodrome of fever, cough, coryza, and conjunctivitis followed by flat macular rash fusing to form blotches first over the chest/trunk and then to limbs.
• Pulmonary: pneumonitis (giant-cell pneumonia) during primary measles virus infection.
  
  • Atypical measles: now rare or nonexistent, pneumonitis as hallmark w/ hypersensitivity-like reaction in recipients of killed-measles vaccine (given in the 1960s-1970s) exposed to native measles.
• CNS:
  • Acute encephalomyelitis occurs 1:1000 w/ 15% mortality.
    
    • The most frequently seen neurological complication of measles.
    • Two types:
      • Primary acute measles encephalitis
        • Direct viral CNS infection, mortality 10-25%, with 25% suffering permanent neurologic sequelae.
        • May recover MV in CSF.
      • Acute, post-measles encephalitis (immune-mediated)
        • More common than primary measles encephalitis.
        • Frequent symptoms include visual disturbances, difficulty with micturition, and reduced reflexes.
        • Relapses may occur in one-third.
  • Measles inclusion body encephalitis (MIBE)
    
    • Occurs typically in immunodeficient children, ~ 1 year after measles or measles immunization.
    • Native MV >> vaccine strains may cause.
    • CSF is usually normal.
    • High anti-measles IgG in CSF.
    • MV RNA may be detected in brain biopsies.
    • Mortality: 75%
  • Subacute sclerosing panencephalitis (SSPE): very rare, < 1:300,000 cases usually occurring 7-10 years or more after measles.
    
    • Due to defective, persistent measles virions.
    • Progressive brain inflammation leads to gradually progressive cognitive impairment, behavioral disturbances, myoclonus/spasms, seizures, and subsequently, gait abnormalities and speech impairment that result in mutism, a vegetative state before coma and death.
      • Diagnostic findings:
        • MRI: white matter changes in the cerebral cortex and brain stem
        • CSF: elevated measles IgG
        • EEG: characteristic periodic spikes (Rademecker complex)
        • Brain biopsy: eosinophilic inclusion bodies

TREATMENT

OTHER INFORMATION

• Measles had been considered eradicated in the U.S. (2000) as few cases were imported; however, two-plus decades have seen numerous outbreaks in the non-immune that appear to be the consequence of < 90-92% community immunization rates.
• Koplik spots may help differentiate febrile illness (like influenza) as they can be seen in prodrome before the rash.
• HIV, immune suppression, pregnancy, cancer or vitamin A deficiency/malnutrition are all risks for severe measles.
• Measles cases (suspected or confirmed) should be reported promptly to local public health authorities.
• Vaccine immunity may wane, but 95% protection is commonly quoted; however, since 1989, a two-dose vaccine schedule has been used to decrease the risk of infection, with 2-5% who fail to seroconvert after one dose.
  
  • Conversion failure may also be linked to inadequate vaccine refrigeration, leading to potency loss.
  • In mumps outbreaks, the third dose of MMR vaccine is now recommended for those at increased risk.
• Multiple extensive studies have not been able to link the MMR vaccine to autism, asthma, etc. The famous Wakefield Lancet paper that started the fracas has been withdrawn, the researcher’s physician censured, and his medical license pulled.
• Global statistics (WHO):
  • Measles immunization has reduced the number of cases, but there is still substantial morbidity, with 140,000 deaths globally (2018, WHO).
  • Estimated 95% of measles now occur in low-income countries.
  • According to WHO data, global immunization in children receiving at least one dose of measles vaccine has risen to 86% receiving at least one dose (2018) from 72% (2000).

Basis for recommendation

1. Hübschen JM, Gouandjika-Vasilache I, Dina J. Measles. Lancet. 2022;399(10325):678-690.  [PMID:35093206]

   Comment: The review article includes diagnostic issues, management and issues regarding immunization and needs yet to be realized.
   

2. Strebel PM, Orenstein WA. Measles. N Engl J Med. 2019;381(4):349-357.  [PMID:31184814]

   Comment: A comprehensive review also addresses measles (MMR) vaccine safety and efficacy.
   

3. Moss WJ. Measles. Lancet. 2017;390(10111):2490-2502.  [PMID:28673424]

   Comment: A thorough review includes clinical principles, pathogenesis, immunity, and prevention/eradication discussion.
   

4. McLean HQ, Fiebelkorn AP, Temte JL, et al. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013;62(RR-04):1-34.  [PMID:23760231]

   Comment: Report summarizes all recommendations since 1998. New recommendations in this version include:
   
   1) For acceptable evidence of immunity, removing documentation of physician diagnosed disease as an acceptable criterion for evidence of immunity for measles and mumps, and including laboratory confirmation of disease as a criterion for acceptable evidence of immunity for measles, rubella, and mumps.
   
   2) For persons with human immunodeficiency virus (HIV) infection, expanding recommendations for vaccination to all persons aged ≥12 months with HIV infection who do not have evidence of current severe immunosuppression; recommending revaccination of persons with perinatal HIV infection who were vaccinated before establishment of effective antiretroviral therapy (ART) with 2 appropriately spaced doses of MMR vaccine once effective ART has been established; and changing the recommended timing of the 2 doses of MMR vaccine for HIV-infected persons to age 12 through 15 months and 4 through 6 years.
   
   3) For measles postexposure prophylaxis, expanding recommendations for use of immune globulin administered intramuscularly (IGIM) to include infants aged birth to 6 months exposed to measles; increasing the recommended dose of IGIM for immunocompetent persons; and recommending use of immune globulin administered intravenously (IGIV) for severely immunocompromised persons and pregnant women without evidence of measles immunity who are exposed to measles.
   

References

5. Brady AM, El-Badry E, Padron-Regalado E, et al. Serosurveillance for Measles and Rubella. Vaccines (Basel). 2024;12(7).  [PMID:39066453]

   Comment: Ten-year look (2014-2024) of published studies of < 20% publish titers as part of their protocol. Another caveat when looking at such data is that there is considerable heterogeneity of assays which make comparisons challenging.
   

6. Krow-Lucal E, Marin M, Shepersky L, et al. Measles, Mumps, Rubella Vaccine (PRIORIX): Recommendations of the Advisory Committee on Immunization Practices - United States, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(46):1465-1470.  [PMID:36395065]

   Comment: A new formulation of the MMR vaccine is available and can be used interchangeably with the existing vaccine; therefore, previous ACIP recommendations are unchanged.
   

7. Lo Vecchio A, Krzysztofiak A, Montagnani C, et al. Complications and risk factors for severe outcome in children with measles. Arch Dis Child. 2020;105(9):896-899.  [PMID:30636224]

   Comment: Somewhat surprisingly, this study from Italy did not find an age relationship but rather CRP as a risk factor for complications. This may well contrast with what is seen in children in low-resource settings, especially if malnourished.
   

8. Choisy M, Trinh ST, Nguyen TND, et al. Sero-Prevalence Surveillance to Predict Vaccine-Preventable Disease Outbreaks; A Lesson from the 2014 Measles Epidemic in Northern Vietnam. Open Forum Infect Dis. 2019;6(3):ofz030.  [PMID:30863786]

   Comment: The study used banked sera from Vietnamese cohorts suggesting that routine serosurviellance in populations may help understand when to institute preventative immunization measures beyond the routine to prevent outbreaks.
   

9. Marin M, Marlow M, Moore KL, et al. Recommendation of the Advisory Committee on Immunization Practices for Use of a Third Dose of Mumps Virus-Containing Vaccine in Persons at Increased Risk for Mumps During an Outbreak. MMWR Morb Mortal Wkly Rep. 2018;67(1):33-38.  [PMID:29324728]

   Comment: Although this notice is directed at mumps, a third dose of MMR is advocated for people at risk/exposure with outbreaks.
   

10. Guerra FM, Crowcroft NS, Friedman L, et al. Waning of measles maternal antibody in infants in measles elimination settings - A systematic literature review. Vaccine. 2018;36(10):1248-1255.  [PMID:29398276]

    Comment: Eight studies of antibody levels in cord blood and then followed in infants suggest that insufficient maternal immunization is present in some infants well before customary immunization age.
    

11. Orenstein WA, Hinman A, Nkowane B, et al. Measles and Rubella Global Strategic Plan 2012-2020 midterm review. Vaccine. 2018;36 Suppl 1:A1-A34.  [PMID:29307367]

    Comment: Update with barriers including children infected with HIV, cold-chain issues for the vaccine, high contagiousness and dynamic travel, the fact that much MV eradication has been tied to polio elimination, and those grant dollars (Gates, others) may decline soon. The potential breakthrough would be a new vaccine delivery system that does not require refrigeration and can immunize effectively at younger ages safely.
    

12. Hall V, Banerjee E, Kenyon C, et al. Measles Outbreak - Minnesota April-May 2017. MMWR Morb Mortal Wkly Rep. 2017;66(27):713-717.  [PMID:28704350]

    Comment: Report of cases traced to unvaccinated people (65 total cases), many in a Somali-American community with the misunderstanding that autism was tied to MMR immunization. Though multiple studies have shown no such link, this linkage remains factual in some communities.
    

13. Wendorf KA, Winter K, Zipprich J, et al. Subacute Sclerosing Panencephalitis: The Devastating Measles Complication That Might Be More Common Than Previously Estimated. Clin Infect Dis. 2017;65(2):226-232.  [PMID:28387784]

    Comment: Report from California of 17 SSPE cases, particularly in unvaccinated children who acquired native infection in infancy. The median age of diagnosis = is 12 years, with a latency period estimated at 9.5 years (range 2.5 to 34 years). Authors argue not to allow infants, especially before immunization travel to regions endemic for measles or consider early immunization during months 6-11.
    

14. Liko J, Guzman-Cottrill JA, Cieslak PR. Notes from the Field: Subacute Sclerosing Panencephalitis Death - Oregon, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(1):10-1.  [PMID:26765654]

    Comment: Fourteen-year-old succumbed to SSPE who was thought to have been vaccinated at age 8 mos in the Phillipines (probably too young to engender good immunity) and acquired native measles at age 1 year. Thought to be an extraordinarily rare complicated (due to defective structural protein in the virus), analysis of SSPE among persons who had measles during the 1989–1991 U.S. measles resurgence indicated an incidence of 4–11 SSPE cases per 100,000 measles cases, approximately 10 times higher than earlier estimates.
    

15. Fisher DL, Defres S, Solomon T. Measles-induced encephalitis. QJM. 2015;108(3):177-82.  [PMID:24865261]

    Comment: Helpful survey article reviewing the four major types of encephalitis related to the measles virus.
    

16. Clemmons NS, Gastanaduy PA, Fiebelkorn AP, et al. Measles - United States, January 4-April 2, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(14):373-6.  [PMID:25879894]

    Comment: Imported cases continue to trigger outbreaks in the US, especially in populations where parents have not immunized their children at reasonably high rates, such as California. Over 80% of US-based measles cases are in those unvaccinated or with unknown vaccination status. Four outbreaks were described this year, but 70% accounted for one more significant outbreak. These circumstances certainly highlight why continued immunization rates should be high and universal.
    

17. Perry RT, Murray JS, Gacic-Dobo M, et al. Progress toward regional measles elimination - worldwide, 2000-2014. MMWR Morb Mortal Wkly Rep. 2015;64(44):1246-51.  [PMID:26562349]

    Comment: Measles cases globally are slowly decreasing, but challenging to reach eradication goals. Currently, 63% of countries have > 90% vaccine coverage.
    

18. Centers for Disease Control and Prevention (CDC). Notes from the field: measles outbreak among members of a religious community - Brooklyn, New York, March-June 2013. MMWR Morb Mortal Wkly Rep. 2013;62(36):752-3.  [PMID:24025758]

    Comment: The story of intentionally non-immunized 17yr who acquired measles in the UK led to the largest outbreak in the US since 2000 with 58 cases. Over 3500 contacts had to be assessed receiving post-exposure MMR or IVIG. This points to two key facts: the highly infectious nature without protective immunity and the significant costs driven by a single case.
    

19. Rafat C, Klouche K, Ricard JD, et al. Severe Measles Infection: The Spectrum of Disease in 36 Critically Ill Adult Patients. Medicine (Baltimore). 2013;92(5):257-272.  [PMID:23982057]

    Comment: Review from France, where recent measles outbreaks have been more common. In this case series, none of the patients had received two doses of MMR--hence at risk. Measles pneumonitis was the primary driver of ICU care, although the viral infection had protean manifestations. Post-infectious encephalomyelitis is also seen, but less commonly.
    

20. Keegan R, Dabbagh A, Strebel PM, et al. Comparing measles with previous eradication programs: enabling and constraining factors. J Infect Dis. 2011;204 Suppl 1:S54-61.  [PMID:21666211]

    Comment: Attempts at eradicating measles have not been achieved; authors review that success likely lies in societal factors in a few endemic countries compared to biological factors. Current estimates place costs of measles eradication at $5-8 billion, but factors such as concurrent polio eradication, anti-vaccine lobbyists, civil wars/terrorism and lack of perceived problems in industrialized countries as reasons slowing or preventing progress.
    

21. Scott P, Moss WJ, Gilani Z, et al. Measles vaccination in HIV-infected children: systematic review and meta-analysis of safety and immunogenicity. J Infect Dis. 2011;204 Suppl 1:S164-78.  [PMID:21666158]

    Comment: Immunization appears generally safe in HIV-infected children upon review of 39 studies, but authors cite the data as limited.
    

22. Martins CL, Garly ML, Balé C, et al. Protective efficacy of standard Edmonston-Zagreb measles vaccination in infants aged 4.5 months: interim analysis of a randomised clinical trial. BMJ. 2008;337:a661.  [PMID:18653640]

    Comment: Safety and efficacy of immunization as early as 4 and 1/2 months compared to the usual approach at 9 months during a measles outbreak in Guinea-Bissau. Infants had 92% seroconversion, and only 0.7% of immunized infants at this earlier timeframe developed measles. There was a trend toward lower mortality, but this was not significant.
    

23. Greenaway C, Dongier P, Boivin JF, et al. Susceptibility to measles, mumps, and rubella in newly arrived adult immigrants and refugees. Ann Intern Med. 2007;146(1):20-4.  [PMID:17200218]

    Comment: Immigrants to Canada, found that about one-third (36%) were non-immune to either measles, mumps or rubella.
    

24. Tierney LM, Wang KC. Images in clinical medicine. Koplik's spots. N Engl J Med. 2006;354(7):740.  [PMID:16481641]

    Comment: View of Koplik spots.
    

25. Parker AA, Staggs W, Dayan GH, et al. Implications of a 2005 measles outbreak in Indiana for sustained elimination of measles in the United States. N Engl J Med. 2006;355(5):447-55.  [PMID:16885548]

    Comment: A large outbreak of measles in the US was attributed to a case imported from Romania that spread in a population of children in whom routine vaccination was refused. The epidemic reinforces the need to maintain high rates of immunization.
    Rating: Important
    

26. Dine MS, Hutchins SS, Thomas A, et al. Persistence of vaccine-induced antibody to measles 26-33 years after vaccination. J Infect Dis. 2004;189 Suppl 1:S123-30.  [PMID:15106101]

    Comment: Addressing concerns about the longevity of measles immunization protection, 56 participants (77% were 2-dose recipients) all had antibodies detected by the plaque reduction neutralization (PRN) antibody assay an average of 26-33 years after the first or second dose of measles vaccine; 92% had a PRN titer considered protective (>1:120). These data support routine two-dose immunization.
    Rating: Important
    

27. van den Hof S, Conyn-van Spaendonck MA, van Steenbergen JE. Measles epidemic in the Netherlands, 1999-2000. J Infect Dis. 2002;186(10):1483-6.  [PMID:12404165]

    Comment: A large outbreak in an industrialized country, with 3292 reported cases, 94% of affected patients were unvaccinated. Only 1 patient had received 2 doses of the vaccine. Three patients died, and 16% had complications. Herd immunity outside unvaccinated clusters was high enough to prevent further transmission. This jives with a measles-associated mortality rate in the United States, generally quoted as 0.3%. By contrast, in some developing countries, the mortality rate of measles is as high as 10%
    

28. Centers for Disease Control and Prevention (CDC). Measles outbreak among internationally adopted children arriving in the United States, February-March 2001. MMWR Morb Mortal Wkly Rep. 2002;51(49):1115-6.  [PMID:12530709]

    Comment: Report of case of child aged 10 months adopted from orphanage A in China who was taken to a Texas hospital with fever, conjunctivitis, coryza, Koplik spots, and a maculopapular rash. Measles was confirmed by serologic testing. Public health authorities in Texas notified CDC, which then collaborated with health officials in other states to contact recently adopted children from China and their adoptive families. Contact investigations that identified 14 U.S. measles cases. Most cases in the US arise from importation.
    

29. Forni AL, Schluger NW, Roberts RB. Severe measles pneumonitis in adults: evaluation of clinical characteristics and therapy with intravenous ribavirin. Clin Infect Dis. 1994;19(3):454-62.  [PMID:7811865]

    Comment: Small series from Cornell of six patients with severe measles pneumonitis. One patient died. However, the other five were thought to significantly improve respiratory status with the early administration of parenteral ribavirin.
    Rating: Important
    

30. Sprauer MA, Markowitz LE, Nicholson JK, et al. Response of human immunodeficiency virus-infected adults to measles-rubella vaccination. J Acquir Immune Defic Syndr (1988). 1993;6(9):1013-6.  [PMID:8340890]

    Comment: Report of one HIV-infected adult who developed fever, rash, coryza and conjunctivitis 12 days after measles immunization. A retrospective survey by the New York City Department of Health found no complications following measles immunization of HIV-infected children.
    

31. American Academy of Pediatrics Committee on Infectious Diseases: Vitamin A treatment of measles. Pediatrics. 1993;91(5):1014-5.  [PMID:8474793]

    Comment: Guidelines based on studies suggesting treatment for very sick children or those suffering from malnutrition, immunodeficiency, or complications of infection, all do better with measles infection. Note that a high dose of Vitamin A may cause temporary headaches or nausea.
    

32. Kaplan LJ, Daum RS, Smaron M, et al. Severe measles in immunocompromised patients. JAMA. 1992;267(9):1237-41.  [PMID:1538561]

    Comment: The disease is more severe in patients with HIV, cancer or immunosuppression. The characteristic rash may be absent (27-40%) and hence delay diagnosis consideration. These patients commonly have fever and pneumonitis (58-80%) as the most common features. Giant-cell (Hecht’s Giant Cell) pneumonia with syncytia may be tip-off with culture or IFA confirming since antibody production may not be reliable in this patient population.
    

33. Rahmathullah L, Underwood BA, Thulasiraj RD, et al. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. N Engl J Med. 1990;323(14):929-35.  [PMID:2205798]

    Comment: A large study suggested that prevention of vitamin A deficiency decreased mortality, probably by reducing diarrheal and pulmonary disease due to childhood illnesses such as measles.
    

34. Gremillion DH, Crawford GE. Measles pneumonia in young adults. An analysis of 106 cases. Am J Med. 1981;71(4):539-42.  [PMID:7282741]

    Comment: Atypical measles occurred in recipients of the formalin-inactivated measles vaccine [1963-1967] and subsequently exposed to wild-type measles virus. Sx severity is worse in atypical measles. Instead of starting at the head and spreading down the body, the rash of atypical measles spreads centripetally, not only maculopapular but also hemorrhagic, vesicular, or urticarial. Coryza, conjunctivitis, and Koplik spots were unusual in atypical measles. However, interstitial pneumonia is a prominent feature of atypical measles, pleural effusions, extremity edema, hepatitis, and hyperesthesia. Has been confused with RMSF.
    

Media

Measles rash

Source: CDC

Koplik spots

Source: CDC

Measles d3 rash

Source: CDC