AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Measles virus (MV), a negative-sense enveloped RNA virus, is a member of the Morbillivirus genus in the Paramyxoviridae family. Measles is a highly communicable acute disease. It is also known as rubeola and is marked by prodromal fever, cough, coryza, conjunctivitis, and pathognomonic enanthem (ie, Koplik spots), followed by an erythematous maculopapular rash on the third to seventh day. Infection confers life-long immunity.

A generalized immunosuppression that follows acute measles frequently predisposes patients to bacterial otitis media and bronchopneumonia. In approximately 0.1% of cases, measles causes acute encephalitis. Subacute sclerosing panencephalitis (SSPE) is a rare chronic degenerative disease that occurs several years after measles infection. Because of a failure to deliver at least one dose of measles vaccine to all infants in certain industrialized and developing nations, measles remains a common disease in certain regions and continues to account for nearly 50% of the 1.6 million deaths caused each year by vaccine-preventable childhood diseases.

Maternal antibodies play a significant role in protection against infection in infants younger than 1 year and may interfere with live-attenuated measles vaccination. A single dose of measles vaccine administered to a child older than 12 months induces protective immunity in 95% of recipients. Because MV is highly contagious, a 5% susceptible population is sufficient to sustain periodic outbreaks in otherwise highly vaccinated populations. A second dose of vaccine, now recommended for all school-aged children in the United States,¹ induces immunity in about 95% of the 5% who do not respond to the first dose. Slight genotypic variation in recently circulating strains has not affected the protective efficacy of live-attenuated measles vaccines.

Unsubstantiated claims that suggest an association between the measles vaccine and autism have resulted in reduced vaccine use and a recent resurgence of measles in countries where immunization rates have fallen to below the level needed to maintain herd immunity.^{2, 3} Considering that for industrialized countries such as the United States, endemic transmission of measles may be reestablished if measles immunity falls to less than 93-95%, efforts to ensure high immunization rates among people in both developed and developing countries must be sustained.

Vitamin A supplementation during acute measles significantly reduces risks of morbidity and mortality.

Pathophysiology

In temperate areas, the peak incidence of infection occurs during late winter and spring. MV is spread by direct contact via respiratory droplets or, less commonly, by airborne transmission.  Initial infection and viral replication occur locally in tracheal and bronchial epithelial cells. After 2-4 days, MV infects local lymphatic tissues, perhaps carried by pulmonary macrophages. Following the amplification of MV in regional lymph nodes, a predominantly cell-associated viremia disseminates the virus to various organs prior to the appearance of rash.

In individuals with deficiencies in cellular immunity, MV causes a progressive and often fatal giant cell pneumonia. MV infection causes an immunosuppression marked by decreases in delayed-type hypersensitivity, interleukin-12 production, and antigen-specific lymphoproliferative responses that persist for weeks to months after the acute infection. Immunosuppression may predispose individuals to severe bacterial infection, particularly bronchopneumonia, a major cause of measles-related mortality among younger children.

Frequency

United States

The practice of administering 2 doses of live-attenuated measles vaccine to children to prevent school outbreaks of measles was implemented when the vaccine was first licensed in 1963. The immunization program resulted in a decrease of more than 99% in reported incidence. The last major US outbreak (1989-1991) affected more than 55,000 Americans and resulted in 123 deaths. 

Vaccination programs interrupted the transmission of indigenous MV in the United States by 1993 and reduced the incidence of measles to an historic low (<0.5 cases per million persons) by 1997-1999. From 1997-2004, the reported incidence was as low as 37-116 cases per year. Since November 2002, measles has not been considered an endemic disease in the United States. 

Despite the highest recorded immunization rates in history, young children who are not appropriately vaccinated may experience more than a 60-fold increase in risk of disease due to exposure to imported measles cases from countries that have not yet eliminated the disease. In 2006, a total of 49 confirmed cases were reported in United States.

International

Approximately 30 million measles cases are reported annually. Most reported cases are from Africa. In 1998, the cases of measles per 100,000 total population reported to the World Health Organization was 1.6 in the Americas, 8.2 in Europe, 11.1 in the Eastern Mediterranean region, 4.2 in South East Asia, 5.0 in the Western Pacific region, and 61.7 in Africa. Only 187 confirmed cases were reported in the Western Hemisphere (mainly in Venezuela, Mexico, and the United States) in 2006.⁴

Mortality/Morbidity

• Morbidity: Common infectious complications include otitis media, interstitial pneumonitis,⁵ bronchopneumonia, laryngotracheobronchitis (ie, croup), exacerbation of tuberculosis, transient loss of hypersensitivity reaction to tuberculin skin test, encephalomyelitis, and diarrhea. Rare complications include hemorrhagic measles, purpura fulminans, hepatitis, disseminated intravascular coagulation (DIC), and SSPE. Transient hepatitis may occur during an acute infection. Approximately 1 of every 1,000 patients develops acute encephalitis, which often results in permanent brain damage. SSPE, a degenerative CNS disease, can result from a persistent measles infection. SSPE is characterized by the onset of behavioral and intellectual deterioration and seizures years after an acute infection (the mean incubation period for SSPE is approximately 10.8 y).
• Mortality: Measles-related mortality, most often due to respiratory and neurologic complications, occurs in 0.1-0.3% of reported US cases. Worldwide, measles causes approximately 880,000 deaths each year. Measles caused an estimated 345,000 deaths worldwide in 2005. An estimated 85% of these deaths occur in Africa and Southeast Asia. Case-fatality rates are higher among children younger than 5 years. Highest fatality rates are among infants aged 4-12 months and in children who are immunocompromised because of human immunodeficiency virus (HIV) infection or other causes. At the end of 2005, with the partnership of several global organizations, over 217 million children were vaccinated worldwide, reducing the number of deaths by 75% in Africa.⁴

Race

• Measles affects people of all races.

Sex

• Excess mortality following acute measles has been observed among females at all ages, but it is most marked in adolescents and young adults.
• Excessive non–measles-related mortality has also been observed among female recipients of high-titer measles vaccines in Senegal, Guinea Bissau, and Haiti.⁶

Age

Age-specific attack rates may be highest in susceptible infants younger than 12 months, school-aged children, or young adults, depending on local immunization practices and incidence of the disease. Complications such as otitis media, bronchopneumonia, laryngotracheobronchitis (ie, croup), and diarrhea occur more commonly in young children.

CLINICAL

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History

The incubation period from exposure to onset of symptoms ranges from 8-12 days. The prodromal phase is marked by malaise, fever, anorexia, and conjunctivitis, cough, and coryza (the "3 Cs"). The entire course of uncomplicated measles, from late prodrome to resolution of fever and rash, is 7-10 days. Cough may be the final symptom to appear.

Patients are contagious from 1-2 days before onset of symptoms. Healthy children are also contagious during the period from 3-5 days before the appearance of the rash to 4 days after the onset of rash. On the other hand, immunocompromised individuals can be contagious during the duration of the illness.

Physical

• Fever: A temperature often exceeding 104°F (40°C) begins with the prodrome and persists 7-10 days.
• Enanthem: Koplik spots (ie, bluish-gray specks or "grains of sand" on a red base) appear on the buccal mucosa opposite the second molars near the end of the prodrome. It is generally seen 2 days prior to the appearance of the rash and lasts until 2 days after the rash appears (see Media file 1). This enanthem begins to slough as the rash appears. Although this is the pathognomonic enanthem of measles, its absence does not exclude diagnosis.
• Rash: An erythematous and maculopapular rash that becomes confluent begins on the face and then proceeds to the trunk, extremities, palms, and soles; it lasts for about 5 days. Patients appear most ill during the first or second day of the rash. Desquamation and brown staining, which spares the palms and soles, may occur after one week. The rash may be absent in patients with underlying deficiencies in cellular immunity.
• Lymphoid involvement: Generalized lymphadenopathy, mild hepatomegaly, and appendicitis may occur because of generalized involvement of lymphoid tissue.

Causes

• Risk factors for infection
• • Children with immunodeficiency due to HIV or acquired immunodeficiency syndrome (AIDS), leukemia, alkylating agents, or corticosteroid therapy, regardless of immunization status
  • Travel to areas where measles is endemic or contact with travelers to endemic areas
  • Infants who lose passive antibody prior to the age of routine immunization
• Risk factors for severe measles and its complications
• • Malnutrition
  • Underlying immunodeficiency
  • Pregnancy
  • Vitamin A deficiency

DIFFERENTIALS

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WORKUP

Section 5 of 11  

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Lab Studies

Diagnosis is usually determined from the classic clinical picture.

• Confirmation of measles virus (MV) infection
• • The MV sandwich-capture immunoglobulin M (IgM) antibody assay is the quickest method to confirm acute measles. Because IgM may not be detectable during the first 2 days of rash, obtain blood for measles-specific IgM on the third day of the rash or on any subsequent day up to one month after onset to avoid a false-negative IgM result. Among persons with confirmed measles infection, the seropositivity rate for first samples is about 77% when collected within 72 hours; the rate rises to 100% when collected 4-11 days after rash onset.⁷ Although the measles serum IgM level remains positive 30-60 days after the illness in most individuals, the IgM titer may become undetectable in some subjects at 4 weeks after rash onset. The assay is offered through many local health departments and through the Centers for Disease Control and Prevention (CDC).
  • Laboratories can confirm measles by demonstrating more than a 4-fold rise in immunoglobulin G (IgG) antibodies between acute and convalescent sera. IgG antibodies may be detectable 4 days after the onset of the rash, although most cases have detectable IgG antibodies by about a week after rash onset. Thus, take specimens on the seventh day after rash onset and repeat 10-14 days later to confirm the case as soon as possible. Patients with SSPE have unusually high titers of measles antibody in their serum and cerebrospinal fluid. The earliest confirmation of measles using IgG antibodies takes about 3 weeks from the onset of illness, a delay too long to permit implementation of effective control measures.
  • MV can be isolated from nasopharyngeal swabs. Viral genotyping in a reference laboratory may determine whether an isolate is endemic or imported. In immunocompromised patients, who may have poor antibody responses that preclude serologic confirmation of measles, virus isolation from infected tissue or identification of measles antigen by immunofluorescence may be the only method to confirm the diagnosis.
• Other diagnostic tests
• • A leukopenia with a relative lymphocytosis occurs in the late stages of viremia.
  • Elevated hepatic transaminase levels may be detected in patients with MV hepatitis.

Imaging Studies

• Perform chest radiography if bacterial pneumonia is suspected. The frequent occurrence of measles pneumonia, even in uncomplicated cases, limits the predictive value of chest radiography for bacterial bronchopneumonia.

Other Tests

• Perform a lumbar puncture if encephalitis is suspected. 
• Cerebrospinal fluid examination reveals the following:
• • Increased protein
  • Normal glucose
  • Mild pleocytosis with a predominance of lymphocytes

Histologic Findings

• Lymphoid multinucleated giant cells (£100 nm in diameter) can be identified in biopsies of Koplik spots, in dermal or epithelial rashes, and in lung or lymphoid tissue.
• Brain biopsies of patients with measles encephalitis can reveal demyelination, vascular cuffing, gliosis, and infiltration of fat-laden macrophages near blood vessel walls.

TREATMENT

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Medical Care

• Treatment is essentially supportive.
• Vitamin A supplements have been associated with reduction in morbidity and mortality and are recommended in the following children:
• • Those who live in developing countries or in areas of impoverishment in developed countries
  • Children aged 6-24 months who are hospitalized for measles-related complications
  • Those with immunodeficiency
  • Those with evidence of an ophthalmologic complication due to vitamin A deficiency
  • Children with malnutrition
  • Children with impaired intestinal absorption
  • Those who have recent emigrated from an area with high mortality rates due to measles
• Consider antibiotic or ribavirin (experimental) administration if evidence suggests otitis media or bacterial pneumonia.
• To prevent or modify measles in exposed susceptible individuals, consider administering measles virus (MV) vaccine or human immunoglobulin (Ig). The morbidity rate is high in children younger than 1 year; therefore, Ig is recommended in these patients.
• The MV vaccine is routinely administered as measles-mumps-rubella (MMR) in two doses.
• • The first dose is given to healthy individuals on or after age 1 year.
  • The second dose is given upon school entry, usually at age 4-6 years.
• Ig is given to the following individuals:
• • Those with immunocompromise
  • Infants aged 6 months to 1 year
  • Infants younger than 6 months who are born to mother without measles immunity
  • Pregnant women

Consultations

Consult public health or infectious disease specialists for recommendations and guidelines for diagnostic confirmation of cases and prophylaxis of susceptible contacts.

Diet

Consider vitamin A supplementation.

MEDICATION

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Drug Category: Vitamins

Vitamin A treatment for children with measles in developing countries has been associated with a marked reduction in morbidity and mortality. The World Health Organization recommends vitamin A administration to all children with measles in communities where vitamin A deficiency is a recognized problem and where the measles virus (MV)-related mortality rate exceeds 1%. Of note, low serum concentrations of vitamin A are found in children with severe measles in the United States. Thus, consider supplemental vitamin A in patients aged 6 months to 2 years who are hospitalized with measles and its complications (eg, croup, pneumonia, diarrhea).

Also recommend vitamin A supplementation for children who have any of the following:

• Immunodeficiency
• Clinical evidence of vitamin A deficiency (eg, ophthalmologic complications)
• Moderate-to-severe malnutrition, including eating disorders 
• Impaired intestinal absorption
• Recent emigration from an area with high mortality rates due to measles

Drug Category: Antivirals

MV is susceptible to ribavirin in vitro. Although ribavirin (either IV or aerosolized) has been used to treat severely affected and immunocompromised adults with acute measles or SSPE⁸ (IV plus intrathecal high-dose interferon-alfa), no controlled trials have been conducted; ribavirin is not approved by the Food and Drug Administration (FDA) for this indication, and such use should be considered experimental.

Drug Category: Vaccines

These agents are available in the United States with attenuated rubella and mumps viruses as the MMR vaccine. For information regarding vaccines and immunization schedules, see the CDC Web site.

Claims that suggest an association between measles vaccine and pervasive developmental or other neurologic disorders have not been substantiated.³ Vaccines are used for universal immunization of children older than 12 months in the United States or in children at age 9 months in developing countries with high endemicity. In the United States, a second dose can be administered as soon as 2 months later but is generally administered at age 4-6 years. All adults born after 1957 should receive a second dose of MMR unless they are documented as seropositive for measles IgG antibody by enzyme immunoassay (EIA).

If administered within 72 hours of exposure to measles-naive individuals, MMR may prevent or attenuate disease. In a susceptible household contact, consider Ig instead.

In the United States, 48 states and the District of Columbia require a second dose of measles vaccine for school enrollment. Rates of seroconversion average 85% after a single dose at age 9 months (the recommended strategy for routine immunization in developing countries), 95% after a single dose at 12 months, 98% after a single dose at age 15 months, and greater than 99% after 2 doses administered after age 12 months.

The American Academy of Pediatrics suggests an interval of at least 5-6 months after intramuscular Ig (IGIM) is administered before administering the measles vaccine.⁹

Drug Category: Immunoglobulins

Human Ig prevents or modifies measles in susceptible individuals if administered within 6 days of exposure. 

FOLLOW-UP

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Further Inpatient Care

• Hospitalization may be indicated for treatment of complications (eg, bacterial superinfection, pneumonia, dehydration, croup).

In/Out Patient Meds

• Perform timely contact tracing and institute prophylaxis or immunization, if indicated

Deterrence/Prevention

• Prevention requires vaccination with live-attenuated measles vaccine (per routine) or earlier immunization (ie, no younger than age 6 mo) during epidemics.
• Human Ig prevents or modifies disease in susceptible contacts if administered within 6 days of exposure.

Complications

• Common infectious complications include otitis media, interstitial pneumonitis, bronchopneumonia, laryngotracheobronchitis (ie, croup), exacerbation of tuberculosis, transient loss of hypersensitivity reaction to tuberculin skin test, encephalomyelitis, and diarrhea.
• Rare complications include hemorrhagic measles, purpura fulminans, hepatitis, DIC, and SSPE. Transient hepatitis may occur during an acute infection. Approximately 1 of every 1,000 patients develops acute encephalitis, which often results in permanent brain damage. SSPE, a degenerative CNS disease, can result from a persistent measles infection. SSPE is characterized by the onset of behavioral and intellectual deterioration and seizures years after an acute infection (the mean incubation period for SSPE is approximately 10.8 y).

Prognosis

• Most children recover uneventfully. High case-fatality rates may be observed among children who are malnourished or immunodeficient, particularly in developing nations. Overall, case-fatality rate in the United States has been less than 0.1%.

Patient Education

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

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to diagnose measles or its complications

Special Concerns

• Because the transmission of indigenous measles has been interrupted in the United States and all recent US epidemics have been linked to imported cases, immediately reporting any suspected case of measles to a local or state health department is imperative, as is obtaining serum for IgM antibody testing as soon as possible (ie, on or after the third day of rash).
• Airborne precautions are indicated for hospitalized children during the period of communicability (ie, 3-5 d before appearance of rash to 4 d after the rash develops in healthy children and for the duration of illness in patients who are immunocompromised). Susceptible health care workers should be excused from work from the fifth to the 21st day after exposure.
• A syndrome called atypical measles has been described in individuals who were infected with wild measles virus (MV) several years after immunization with a killed measles vaccine (a vaccine used in the United States from 1963-1967). The disease tends to be more prolonged and severe than regular measles and is marked by a prolonged high fever, pneumonitis, and a rash that begins peripherally and may be urticarial, maculopapular, hemorrhagic, and/or vesicular. The assumed pathogenesis is hypersensitivity to MV in a partially immune host. Laboratory tests reveal a very low measles antibody titer early in the course of the disease, followed soon thereafter by the appearance of an extremely high measles IgG antibody titer (eg, 1:1,000,000) in the serum.

MULTIMEDIA

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Media file 1:  Koplik spots in measles. Photograph courtesy of the World Health Organization (WHO).
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Media file 2:  Child with measles. Photograph courtesy of the Centers for Disease Control and Prevention (CDC).
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REFERENCES

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1. Centers for Disease Control and Prevention. Immunization Schedules. CDC Recommended Vaccine Schedule. Available at http://www.cdc.gov/vaccines/recs/schedules/default.htm. Accessed December 18, 2007.
2. Meissner HC, Strebel PM, Orenstein WA. Measles vaccines and the potential for worldwide eradication of measles. Pediatrics. 2004;114(4):1065-9. [Medline]. [Full Text].
3. Smeeth L, Cook C, Fombonne E, et al. MMR vaccination and pervasive developmental disorders: a case-control study. Lancet. 2004;11-17;364(9438):963-9. [Medline].
4. Centers for Disease Control and Prevention. Program in brief: Measles Mortality Reduction and Regional Global Measles Elimination. CDC Measles. Available at http://www.cdc.gov/vaccines/about/pibs/downloads/global-measles-elim.pdf. Accessed 2007.
5. Forni AL, Schluger NW, Roberts RB. Severe measles pneumonitis in adults: evaluation of clinical characteristics and therapy with intravenous. Clin Infect Dis Sep. 1994;19(3):454-62. [Medline].
6. Garenne M. Sex differences in measles mortality: a world review. Int J Epidemiol. Jun 1994;23(3):632-42. [Medline].
7. Helfand RF, Heath JL, Anderson LJ, et al. Diagnosis of measles with an IgM capture EIA: the optimal timing of specimen collection after rash onset. J Infect Dis. Jan 1997;175(1):195-9. [Medline].
8. Hosoya M, Shigeta S, Mori S, et al. High-dose intravenous ribavirin therapy for subacute sclerosing panencephalitis. Antimicrob Agents Chemother. Mar 2001;45(3):943-5. [Medline].
9. American Academy of Pediatrics. Measles. In: Pickering LK, ed. Red Book: Report of the Committee on Infectious Disease. Elk Grove, Ill: AAP; 2006:441-52.
10. Centers for Disease Control and Prevention. Global measles control and regional elimination, 1998-1999. MMWR Morb Mortal Wkly Rep. Dec 17 1999;48(49):1124-30. [Medline].
11. Centers for Disease Control and Prevention. Measles--United States, 1999. MMWR Morb Mortal Wkly Rep. Jun 30 2000;49(25):557-60. [Medline].
12. Centers for Disease Control and Prevention. Progress toward global measles control and elimination, 1990-1996. MMWR Morb Mortal Wkly Rep. Sep 26 1997;46(38):893-7. [Medline].
13. Centers for Disease Control and Prevention. Strategies for reducing global measles mortality. Wkly Epidemiol Rec. Dec 15 2000;75(50):411-6. [Medline].
14. Gershon AA. Measles virus (rubeola). In: Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. Philadelphia, Pa: Churchill Livingstone; 1995:1519-26.
15. Griffin DE, Bellini WJ. Measles virus. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology. 3^rd ed. Philadelphia, Pa: Lippincott; 1996.
16. Griffin, DE. Billeter M, ed. Measles Virus. New York, NY: Springer-Verlag; 1995:117-34.
17. Perry RT, Mmiro F, Ndugwa C, Semba RD. Measles infection in HIV-infected African infants. Ann N Y Acad Sci. Nov 2000;918:377-80. [Medline].
18. Shah BR, Laude TA. Measles. In: Atlas of Pediatric Clincal Diagnosis. WB Saunders Co; 2000:59-61.

Article Last Updated: Jan 17, 2008