AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Measles has been called the greatest killer of children in history. Despite the availability of an effective vaccine that was developed more than 30 years ago, the measles virus still affects 50 million people annually and causes more than 1 million deaths. The highest incidence of measles and its associated morbidity and mortality is observed in developing countries. However, it still occurs infrequently in the United States and other industrialized nations.

Pathophysiology

The measles virus initially infects the respiratory epithelium and is transmitted via respiratory droplets. It is highly transmissible with an infectivity rate of 76%, even greater than that of varicella. Prior to the measles vaccine, infection with the measles virus was simply considered a part of life.

Instead of replicating in the respiratory epithelium, as was once thought, replication appears to occur in the regional lymph nodes. Replication in regional lymph nodes eventually leads to viremia. Infection of the endothelial cells ensues, causing an enanthem (Koplik spots). Epithelial cells are also infected, leading to the well-known cutaneous eruption of measles.

The measles virus is a single stranded RNA virus of the genus Morbillivirus and family Paramyxoviridae. Measles virus has 2 membrane glycoproteins called hemagglutinin and fusion. Both of these glycoproteins appear to be important for infection with the measles virus. Hemagglutinin appears to be involved with receptor binding and fusion, with fusion of the virus with host cells. Expression of hemagglutinin activates the alternative complement pathway.

The Edmonston strain of the measles virus and vaccines derived from this strain bind to the cell surface protein CD46, also known as membrane cofactor protein. CD46 is a regulator of the complement activation gene and inhibits activation of the alternative complement pathway. Four isoforms of CD46 exist in humans, and all are capable of binding measles virus.

An additional cellular receptor for the measles virus has recently been identified called SLAM (signaling lymphocyte-activation molecule) or CDw150 expressed on some T and B cells. SLAM is capable of binding strains of the measles virus that also bind CD46 (the Edmonston strain) as well as strains that do not bind CD46 such as the KA strain.

Infection with the measles virus leads to a prolonged immunosuppression, which accounts for much of the morbidity and mortality associated with this disease. Cell-mediated immunity decreases, clinically evidenced by the conversion of positive tuberculin skin test results to negative following infection or vaccination. The mechanism of this immunosuppression is being elucidated.

Following infection with the measles virus, a shift from cell-mediated immunity (a TH-1 response) to humoral immunity (a TH-2 response) occurs. Expression of the TH-2 cytokine interleukin (IL)–2 is increased, supporting antibody formation, and TH-1 cytokines IL-2, IL-12, interferon (IFN)–gamma decrease.

IL-12 is a crucial cytokine for the development of cell-mediated immunity. It is necessary for delayed-type hypersensitivity, induces production of IFN-gamma, and plays a role in activation of T cells and natural killer cells. Karp et al¹ found that infection of monocytes, the primary producer of IL-12, with the measles virus via CD46 led to decreased production of this cytokine. Fugier-Vivier et al² found that activated dendritic cells also had a significant decrease in production of IL-12, leading to proliferation of the measles virus and apoptosis of infected dendritic cells and T cells. These findings support the hypothesis that measles virus infection of antigen-presenting cells plays a critical role in the immunosuppression observed following infection with the measles virus.

Primates are the only hosts for measles virus, and no animal model exists that replicates the clinical findings of measles infection typical in children.

Frequency

United States

The US Centers for Disease Control and Prevention (CDC) support strict surveillance of measles both in the United States and abroad. The CDC defines a case of measles as one that is confirmed by (1) serologic laboratory tests, such as enzyme immunoassays for measles IgM antibodies; (2) cases epidemiologically linked to a laboratory confirmed case; or (3) clinically confirmed cases (ie, cases of measles suspected clinically but neither confirmed by serologic laboratory tests nor epidemiologically linked to a laboratory confirmed case). In countries that are trying to eliminate measles, the category of clinically confirmed cases represents a failure of the surveillance system because all cases ideally should be confirmed serologically or epidemiologically linked to a laboratory confirmed case.

According to an epidemiologic report by the CDC in 1999³, the measles virus is no longer indigenous to the United States. Most reported measles cases are importation associated, meaning that they are linked to a strain of the measles virus outside of the United States.

In 2005, the CDC reported that 66 cases of measles were confirmed in the United States. Fifty of these cases were in unvaccinated individuals and 17 were contracted while traveling abroad. A large outbreak in Indiana in 2005 infected 34 people, the largest outbreak since 1999. This outbreak was linked to a young woman who acquired the infection while on a brief trip (2 wk) to Romania. As recently as June 2006, a measles outbreak occurred in Boston, Mass and was linked to a recent immigrant from India. Thirteen cases of measles were confirmed in this outbreak, and they were linked to a common Indian strain of this virus.
 
More concerning was the report of 2 infected individuals who worked at the Christian Science Center in downtown Boston. Many members of this church are unvaccinated, which raised concern that the virus would spread further.

Importation-associated strains of measles may be acquired outside of the United States (internationally imported), have a known chain of transmission from an internationally imported source (epi-linked), or have a genotype that matches a known international strain without a clear chain of transmission or individual source (imported).

The number of non–importation-associated measles cases has significantly decreased since 1995, when 85% of all reported cases of measles in the United States were considered indigenous and not linked to importation. In addition, only 6 measles outbreaks were reported in 1998, the lowest ever recorded. The data collected by the CDC suggest that indigenous measles has been eliminated in the United States. Despite this, cases of measles will continue to arise, as it is not as well controlled in other parts of the world.

International

Cases of measles will continue to arise even in developed nations with a high percentage of vaccinated individuals because of the millions of people still infected worldwide. Vaccination campaigns in many developing nations have fallen short, making measles deaths the most common cause of childhood death from vaccine-preventable disease. In the World Health Report in 2002, the World Health Organization (WHO) reported 30-40 million cases of measles annually, with 745,000 deaths attributable to the virus. In Africa in the 1990s, an estimated 400,000 children died annually from complications related to measles.

Mortality/Morbidity

• The acute child fatality rate in industrialized nations is only 0.1-0.2%, compared with a 2-10% fatality rate in children in the developing world. The larger incidence of measles in developing nations combined with the higher fatality rate contributes to close to 1 million childhood deaths per year.
• Conditions possibly (unproven) associated with measles include multiple sclerosis, osteosclerosis (hearing loss), and some autoimmune disorders.

Race

Infection with measles has no race predilection. Prevalence is linked to inadequate vaccination in developing countries.

Sex

Measles infection has no sex predilection.

Age

Historically, measles is a disease of childhood and continues to affect children in developing countries. In industrialized nations, infection is seen in unvaccinated individuals of any age or those with waned immunity.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Measles was the first exanthem described historically.

• It has an incubation period of 7-14 days (average, 10-11 d).
• It is communicable just before the beginning of the prodromal symptoms, until approximately 4 days following the onset of the exanthem.
• The prodrome develops on day zero following incubation.
• • The prodrome consists of the well-known 3 C's of measles: cough, coryza, and conjunctivitis.
  • Fever and photophobia are also common during this period.
  • These symptoms increase in severity up to 3-4 days prior to the onset of the morbilliform rash.

Physical

• The enanthem (Koplik spots) predate the exanthem by 24-48 hours and last approximately 2-4 days.
• • These blue-white spots, about the size of kosher salt grains, are surrounded by a red halo.
  • They appear on the buccal mucosa opposite the premolar teeth and are pathognomonic for measles.

• The exanthem itself begins on the fourth or fifth day following the onset of symptoms.
• • The rash appears as slightly elevated papules 0.1-1 cm in diameter that begin on the face and behind the ears.
  • Within 24-36 hours following the onset of the rash, it spreads to the entire trunk and the extremities.
  • Initially, the color is dark red and reaches its maximum intensity in approximately 3 days. It slowly fades to a purplish hue and then to yellow-brown lesions with a fine scale over the following 5-10 days.

• The appearance of the signs and symptoms of measles are as follows:
  • Days 0-1: Prodrome begins.

  • Days 2-3: Koplik spots appear.

  • Days 4-5: Morbilliform rash appears.

  • Day 6: Koplik spots regress.

  • Days 7-8: Rash is most intense.

  • Day 10: Rash begins to resolve.

Causes

See Pathophysiology.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Exanthems usually associated with systemic lymphadenopathy
Brucellosis
Cytomegalovirus
Gianotti-Crosti syndrome
HIV (primary)
Mononucleosis + ampicillin or allopurinol
Kawasaki disease
Rubella (German measles)
Syphilis (congenital, secondary)
Toxoplasmosis
Anticonvulsant hypersensitivity syndrome

Exanthems usually not associated with systemic lymphadenopathy
Drug reaction
Measles
Enterovirus, echovirus, coxsackievirus
Infectious hepatitis
Rat bite fever (Spirillum minus)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The diagnosis of measles is made on a clinical basis and historically does not require a diagnostic workup. Given the rarity of measles in the United States, laboratory confirmation of the disease should be sought. Contact your local public health department and the CDC for any suspected cases of measles.
• • The CDC recommends that a sample of the patient's serum be obtained for measles IgM antibody testing. Although commercial antibody tests are available, any positive results obtained from these tests must be confirmed by the IgM enzyme immunoassay (EIA-IgM) developed by the CDC. This assay has been thoroughly evaluated and is both highly sensitive and highly specific for anti–measles IgM antibodies. The CDC EIA-IgM is the reference test for measles in North America and South America.
  
  
  • Other methods of detecting measles infection have also been developed. A radioimmunoassay technique that detects anti–measles IgM antibodies in oral fluids has been used in the United Kingdom. The CDC is currently trying to develop a similar EIA that can detect IgM antibodies in oral fluids rather than requiring blood samples. In addition to simply detecting measles infection, the particular strain of the measles virus can be identified by genotyping the viral RNA to determine its origin.

Histologic Findings

Skin biopsy of the fully evolved exanthem of measles is not specific, but the findings can be suggestive of the diagnosis. The histologic findings include psoriasiform epidermal hyperplasia, spongiosis, parakeratosis, and occasional dyskeratotic keratinocytes. Multinucleated keratinocytes (Warthin-Finkeldey giant cells) may be seen. A superficial, perivascular lymphocytic infiltrate associated with variable erythrocyte extravasation is present in the dermis. Multinucleated lymphoid cells containing intranuclear and cytoplasmic inclusions may be observed.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treatment for measles generally consists of only supportive care, with particular attention to maintaining good hydration, especially in the developing world. Recently, however, the WHO has also recommended that vitamin A supplementation be given with measles vaccination in the developing world. The impetus behind this recommendation stems from the fact that a precipitous decrease occurs in vitamin A levels, which may already be low in children who are malnourished, at the onset of the exanthem. By giving a bolus of vitamin A with the vaccine, the WHO hopes to attenuate some of the complications (eg, blindness) associated with vitamin A deficiency. Antibiotics are indicated with diagnosed or suspected secondary bacterial infection but are not empirically indicated.

Infected individuals or those suspected to have infection with the live measles virus should be quarantined until they are no longer contagious to prevent spread of the disease to other nonimmunized individuals.

Consultations

• Dermatologist


• Infectious disease specialist

Diet

Vitamin A supplementation has been recommended in developing nations because of the higher rate of blindness following measles infection in malnourished individuals.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Preparation

In the United States, the measles vaccine is given in suite with mumps and rubella. Grown in chick fibroblast cell culture, the vaccine contains neomycin, sorbitol, and gelatin. Measles vaccine is both heat sensitive and light sensitive. Once reconstituted, its potency decreases each hour by 50% at 22-25°C, and it is completely inactivated at 37°C. This characteristic of the measles vaccine is important to consider both in the United States and abroad and may be responsible for decreased effectiveness of vaccine programs in developing countries with hot climates, particularly in areas where refrigeration may not be available. The measles vaccine should be stored at 2-8°C (35.6-46.4°F) and protected from light exposure. Once it has been reconstituted, the vaccine should be discarded after 8 hours.

Vaccine-related epidemiology

In the preimmunization era, approximately 130 million cases of measles and 7-8 million measles-related deaths occurred around the world each year (child mortality rate, 7%). However, by 1991, 80% of the world's children were immunized by age 1 year, and an estimated 1 million lives are saved annually with immunization. Despite this marked improvement, the WHO estimated that, in 1994, 45 million cases of measles and 1.19 million measles-related deaths still occurred, primarily in the developing world. Before the advent of the vaccine, measles primarily affected preschool-aged and young school-aged children. In the postvaccine era in industrialized nations, the age of children affected by measles has increased. By 1980, 60% of all cases of measles occurred in children older than 10 years. In developing countries, a different trend has been observed. The age of children infected has decreased, likely because the passive immunity from the mother wanes earlier in these countries.

Vaccine schedule

The difference in the age of children at risk for measles in the developed world versus the developing world has led to unique vaccination schedules aimed at serving the needs of these different communities. Although the best time for vaccination is debated, the following schedules are generally used: 2 doses in industrialized nations at age 12-15 months and age 11-12 years and 3 doses in developing countries starting at age 6-9 months, then at age 15 months, and repeated again upon entry into kindergarten.

One of the major complications with giving the vaccine at such an early age in the developing world is that the child may still have circulating antibodies from the mother. These antibodies can bind vaccine antigen prior to stimulating the child's own immune response and result in primary vaccine failure. Once this passive immunity wanes completely, the child has no protection against infection. This complication led health officials to recommend repeating the injection at age 15 months. Nonetheless, infection can occur within this window.

In industrialized nations, this schedule should be changed in some instances. For example, during outbreaks of measles in the United States or if an infant is traveling to an area where measles is endemic, the child should be vaccinated as young as age 6 months and then the regular schedule for industrialized nations should be followed.

Another indication for the vaccine is postexposure prophylaxis. Some evidence suggests that the vaccine may provide protection in susceptible persons exposed to the virus if the vaccine is given within the first 72 hours of known exposure. The measles vaccine, although live, is not communicable. Therefore, vaccination in all persons in contact with individuals who are immunocompromised is important in preventing the spread of natural disease to these patients.

Vaccine efficacy

Antibody titers following vaccination are lower than those following natural disease. However, 93% of children vaccinated at age 12 months and 98% of those vaccinated at age 15 months develop immunity to measles. Furthermore, more than 99% of children who receive 2 doses of the vaccine at least 1 month apart and after 12 months develop an appropriate response. Protective titers can last as long as 16 years.

Drug Category: Vaccines, viral

The greatest advance against measles in the last 30 years has certainly been in prevention rather than treatment. The measles virus was first isolated in 1954 by Enders and Peebles, and the first live-attenuated vaccine, the Edmonston B strain, became available in the mid-to-late 1960s. The Moraten strain is the attenuated measles virus used in the United States today.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• The complications of measles are generally more common and more severe in developing countries. The most common fatal complication of measles is dehydration secondary to diarrhea. Other complications associated with measles include pneumonia, malnutrition, gangrenous stomatitis (noma), vitamin A deficiency (leading to corneal ulceration and blindness), and immunosuppression (increasing children's susceptibility to other diseases).
• • Acute complications include diarrhea, pneumonia, laryngotracheal bronchitis, otitis media, malnutrition, gangrenous stomatitis (noma), vitamin A deficiency (leading to corneal ulceration and blindness), and acute encephalitis.
  • Late complications include immunosuppression and subacute sclerosing panencephalitis.

Patient Education

• For excellent patient education resources, visit eMedicine's Children's Health Center and Bacterial and Viral Infections Center. Also, see eMedicine's patient education articles Measles; Skin Rashes in Children; and Immunization Schedule, Children.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to report suspected cases of measles to local and/or state health departments is a pitfall. All suspected cases of measles should be reported to the local and/or state health departments, and a blood sample from the patient should be obtained for confirmatory testing for measles EIA-IgM antibodies.
• Failure to report any adverse reactions to vaccination is a pitfall. Any adverse reactions to vaccination should be reported to the CDC. A Vaccine Adverse Event Report Form can be obtained by calling 1-800-822-7967.

Special Concerns

• Complications in pregnancy include premature delivery, fetal loss, and increased risk of maternal death.


• No apparent association exists between MMR (measles, mumps, and rubella) vaccination and autism or other autistic disorders.


• No well-established association exists between MMR vaccination and the incidence of inflammatory bowel disease.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Karp CL, Wysocka M, Wahl LM, Ahearn JM, Cuomo PJ, Sherry B, et al. Mechanism of suppression of cell-mediated immunity by measles virus. Science. Jul 12 1996;273(5272):228-31. [Medline].
2. Fugier-Vivier I, Servet-Delprat C, Rivailler P, Rissoan MC, Liu YJ, Rabourdin-Combe C. Measles virus suppresses cell-mediated immunity by interfering with the survival and functions of dendritic and T cells. J Exp Med. Sep 15 1997;186(6):813-23. [Medline].
3. Centers for Disease Control and Prevention. Epidemiology of measles--United States, 1998. MMWR Morb Mortal Wkly Rep. Sep 3 1999;48(34):749-53. [Medline]. [Full Text].
4. Borrow P, Oldstone MB. Measles virus-mononuclear cell interactions. Curr Top Microbiol Immunol. 1995;191:85-100. [Medline].
5. Centers for Disease Control and Prevention. Advances in global measles control and elimination: summary of the 1997 international meeting. MMWR Recomm Rep. Jul 24 1998;47(RR-11):1-23. [Medline]. [Full Text].
6. Clements CJ, Cutts FT. The epidemiology of measles: thirty years of vaccination. Curr Top Microbiol Immunol. 1995;191:13-33. [Medline].
7. Dörig RE, Marcil A, Chopra A, Richardson CD. The human CD46 molecule is a receptor for measles virus (Edmonston strain). Cell. Oct 22 1993;75(2):295-305. [Medline].
8. Feigen RD, Cherry JD, eds. Prevention of infectious diseases. In: Textbook of Pediatric Infectious Diseases. 4^th ed. Philadelphia, Pa: WB Saunders; 1998:2742-44.
9. Feigen RD, Cherry JD, eds. Measles. In: Textbook of Pediatric Infectious Diseases. Philadelphia, Pa: WB Saunders; 1992:1595.
10. Griffin DE. Immune responses during measles virus infection. Curr Top Microbiol Immunol. 1995;191:117-34. [Medline].
11. Habif TP. Exanthems and drug eruptions. In: Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 3^rd ed. Philadelphia, Pa: Mosby; 1996:409-12.
12. Horikami SM, Moyer SA. Structure, transcription, and replication of measles virus. Curr Top Microbiol Immunol. 1995;191:35-50. [Medline].
13. Katz M. Clinical spectrum of measles. Curr Top Microbiol Immunol. 1995;191:1-12. [Medline].
14. Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J, Thorsen P, et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med. Nov 7 2002;347(19):1477-82. [Medline].
15. Manchester M, Liszewski MK, Atkinson JP, Oldstone MB. Multiple isoforms of CD46 (membrane cofactor protein) serve as receptors for measles virus. Proc Natl Acad Sci U S A. Mar 15 1994;91(6):2161-5. [Medline].
16. Naniche D, Varior-Krishnan G, Cervoni F, Wild TF, Rossi B, Rabourdin-Combe C, et al. Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus. J Virol. Oct 1993;67(10):6025-32. [Medline].
17. Norrby E. The paradigms of measles vaccinology. Curr Top Microbiol Immunol. 1995;191:167-80. [Medline].
18. Rima BK, Earle JA, Baczko K, Rota PA, Bellini WJ. Measles virus strain variations. Curr Top Microbiol Immunol. 1995;191:65-83. [Medline].
19. Smith S. Two more cases of measles are confirmed. Boston Globe. June 15, 2006.
20. Tatsuo H, Ono N, Tanaka K, Yanagi Y. SLAM (CDw150) is a cellular receptor for measles virus. Nature. Aug 24 2000;406(6798):893-7. [Medline].

Article Last Updated: May 18, 2007