ARTICULO MEDICO: PREVENTION AND TREATMENT OF MEASLES

Prevention and treatment of measles
Authors
Jorge L Barinaga, MD, MS
Paul R Skolnik, MD, FACP, FIDSA
Section Editor
Martin S Hirsch, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: May 2013. | This topic last updated: feb 12, 2013.

INTRODUCTION — Measles is a highly contagious viral infection [1]. Mathematical models have estimated that the average number of secondary infections that follow a single introduction of measles into a susceptible population ranges from 12 to 18 [2]. Infection with measles is highly preventable. Control measures for the prevention and spread of measles and treatment modalities for the virus will be reviewed here. The epidemiology, aims for global eradication, clinical manifestations, and diagnosis are discussed separately. (See "Epidemiology and transmission of measles" and "Clinical presentation and diagnosis of measles".)

CONTROLLING SPREAD — Control of outbreaks is of paramount importance in the prevention of measles. The Centers for Disease Control and Prevention (CDC) defines a measles outbreak as “a chain of transmission with three or more confirmed cases” [3]. Suspected cases of measles should be reported immediately to the local or the state health department, and all such reports should be investigated promptly. Control measures should not be delayed while waiting for laboratory confirmation of the diagnosis [4]. (See 'Outbreak control measures' below.)

Case definitions — Several case definitions have been established to standardize the approach to

measles outbreaks [4,5].

· Suspected case — A suspected case is defined as a febrile illness accompanied by rash.

· Clinical case — A clinical case is defined as an illness characterized by cough, coryza, or conjunctivitis, a generalized rash lasting for more than three days, and a temperature > 38.3ºC (>101ºF).

· Probable case — A probable case meets the clinical case definition, but is not linked epidemiologically to a confirmed case and lacks serologic or virologic proof of disease.

· Confirmed case — A confirmed case meets the laboratory criteria for measles (independent of clinical features) or meets the clinical case definition and is epidemiologically linked to a confirmed case.

Outbreak control measures — Prevention of spread in the setting of an outbreak depends upon prompt administration of vaccine to all susceptible persons. All individuals should provide documentation of measles immunity, which includes one of the following (See 'Establishing evidence of measles immunity'below.):

· Birth before the year 1957

· Clinical measles diagnosis by a physician

· Laboratory evidence of immunity

· Documentation of receipt of two doses of live measles virus-containing vaccine from a physician or healthcare facility Individuals unable to produce documentation of measles immunity should be excluded from the outbreak setting until they have complied with vaccination requirements. Those who are exempt from vaccination for medical, religious, or other reasons should be excluded from the outbreak setting for a minimum of three weeks after the onset of rash in the last measles case. Quarantine measures are not otherwise routinely recommended in outbreak control [4].

Schools — Schools are particularly vulnerable to measles outbreaks. In a number of college and secondary school outbreaks in the United States, some individuals who had received one dose of vaccine still developed infection, suggesting that immunity to measles in such individuals can wane. In 1989, the United States adopted a two-dose strategy; revaccination with measles-mumps-rubella (MMR) vaccine is recommended for all children prior to school entry (age four to six years), their siblings, and school personnel who are unable to provide documentation of measles immunity [6]. Furthermore, in order for vaccination to be considered adequate for school outbreaks, two doses of measles vaccine must have been administered after the age of 12 months and separated by at least 28 days.

The Advisory Committee on Immunization Practices (ACIP) also recommends that vaccination efforts be considered at unaffected schools that may be at risk during an outbreak. Those who are properly vaccinated may reenter the school immediately after vaccination [4]. 

Healthcare facilities — In the setting of a measles diagnosis in a healthcare facility, all employees must provide documentation of measles immunity as outlined above [7]. Any employee who cannot produce such documentation must be excluded from work and administered MMR vaccine promptly. The ACIP recommends that vaccination of those born before 1957 who do not have laboratory evidence of measles immunity also be considered, since some individuals with these characteristics have acquired and transmitted measles in the healthcare setting. (See 'Birth before the year 1957' below.)

Susceptible healthcare workers with measles exposure should be vaccinated within 72 hours of exposure. Previous recommendations indicated that if vaccination occurred within 72 hours of exposure, then exclusion from the workplace was not mandatory except in high-risk settings; subsequent guidelines suggest exclusion of all susceptible exposed persons [8]. Any individual who develops a prodromal illness consistent with measles must be excluded from the facility until four days after the appearance of rash; this interval is the period of infectiousness for measles [4].

Isolation is discussed below. (See 'Case isolation' below.)

Outbreaks among infants — Among infants with measles exposure, those aged 6 to 11 months can receive live measles vaccine, although they must be reimmunized at age 12 to 15 months and again prior to school entry. For infants exposed to measles within the household, immunoglobulin administration may be preferable since the risk for acquiring infection is higher than for other types of exposure [4].

Case isolation — When a case of measles is suspected in a healthcare facility, respiratory isolation should be initiated. Specifically, private rooms with negative pressure air ventilation (minimum of six air changes per hour) and the use of masks at all times should be required. Data are insufficient to determine the optimal type of mask or respirator [9]. Susceptible healthcare workers should not enter the room of infected patients. (See 'Healthcare facilities' above.)

The ACIP does not make any specific recommendations about isolation of suspected or confirmed cases of measles in the community. Strict respiratory isolation techniques have been demonstrated to decrease transmission rates in an outbreak situation [10]. Precautions should include respiratory isolation since the transmission of measles virus occurs via aerosol [11].

Use of immune globulin — Intramuscular immune serum globulin can prevent or diminish the severity of disease if administered to susceptible individuals within six days of exposure [4,12]. Administration of immune serum globulin may be especially warranted in exposed individuals for whom the risk of complications of measles is increased, such as pregnant women, individuals less than one year of age, and immunocompromised hosts. Immunocompromised individuals with prior history of vaccination should also receive IG following exposure. Dosing consists of 0.25 mL/kg of body weight to a maximum dose of 15 mL intramuscularly [4,12]. In immunocompromised hosts dosing is 0.5 mL/kg body weight to a maximum dose of 15 mL.

Individuals receiving immune serum globulin should receive live vaccination no earlier than five to six months later, so long as the individual is at least 12 months of age at that time and there is no contraindication to vaccination. The passively-acquired measles antibodies from the immune serum globulin should have been cleared by five to six months. For contacts not belonging to these highrisk groups, the administration of live measles vaccine within 72 hours of the exposure is preferable to immune serum globulin administration.(See 'Contraindications' below.)

Administration of immune serum globulin should not be used for outbreak control [4].

MEASLES VACCINATION — Measles vaccination has markedly reduced the incidence of easles throughout the developed world. However, measles cases still occur in low-incidence countries via importation by travelers. Therefore, maintenance of immunity is important even in countries with a low incidence of measles, since a single imported case can result in large measles outbreaks in the setting of waning immunity. (See "Epidemiology and transmission of measles".) Measles vaccine is recommended for all children and for certain high-risk adolescents and adults. Factors to be considered when determining the need for measles vaccination include the age of the recipient, the date of administration of the first dose of vaccine (if any), and local measles epidemiology, including the potential risk of exposure, the type of measles vaccine administered previously, contraindications to vaccination, travel plans, and evidence of prior measles infection. (See "Measles-mumps-rubella vaccination in high risk adults".)

The importance of maintenance of immunity was underscored by a Centers for Disease Control and Prevention (CDC) analysis of United States measles cases reported in 2011, which found that the majority of cases could have been prevented by vaccination; 89 percent of 118 measles cases occurred in unvaccinated individuals [13]. Immunization is also important for preventing severe sequelae of measles infection, including subacute sclerosing panencephalitis [14]. (See "Clinical presentation and diagnosis of measles".)

Strategies to update immunizations in foreign-born adults are an important component of a comprehensive vaccine program. This is supported by a serologic study of recently arrived immigrants and refugees to Canada, in which 36 percent of participants were nonimmune to at least one of three vaccine-preventable diseases (eg, measles, mumps, or rubella) [15]. (See "Epidemiology and transmission of measles".)

Types of measles vaccines — The vaccine strain currently in use in the United States is the Enders-Edmonston strain. This live attenuated vaccine was licensed for use in 1968. It is available in combination as a measles-mumps-rubella (MMR) vaccine [5], and as the quadrivalent MMRV vaccine (measles, mumps, rubella, and varicella). Several other vaccines, also derived from attenuated measles virus, are in use in other parts of the world. Previously used measles vaccines include an inactivated Edmonston B strain vaccine distributed in the United States from 1963 to 1967, a live attenuated Edmonston B strain vaccine from 1963 to 1975, and a different live attenuated Schwarz strain vaccine introduced in 1965, which is no longer available in the United States. The inactivated vaccine was associated with severe atypical measles in those exposed to live measles after vaccination.

Management of patients previously vaccinated with prior vaccine types is discussed below. (See 'Prior vaccination with other strains' below.)

MMRV — MMRV vaccine was approved by the United States Food and Drug administration in 2005 for individuals aged 12 months to 12 years. MMRV has comparable immunogenicity to simultaneous MMR and varicella vaccination [16]. In postlicensure studies MMRV was associated with a small increased risk for febrile seizures; this risk was present at the typical age of receipt for the first dose of vaccine, but not at the age of receipt for the second dose [16]. The Advisory Committee on Immunization Practices (ACIP) reviewed the risks and benefits of MMRV compared to simultaneous MMR and varicella vaccineand issued recommendations for use as follows [16,17]:

· For the first dose of measles, mumps, rubella, and varicella vaccines at age 12 to 47 months, either separate MMR and varicella vaccines or MMRV vaccine may be used. Providers considering administration of MMRV vaccine should discuss the benefits and risks of both vaccination options with the parents or caregivers. Unless the parent or caregiver expresses a preference for MMRV vaccine, the CDC recommends that separate MMR and varicella vaccines be administered for the first dose in this age group.

· For the second dose of measles, mumps, rubella, and varicella vaccines at any age (15 months to 12 years) and for the first dose at age ≥48 months, use of MMRV vaccine generally is preferred over separate injections of its equivalent component vaccines (ie, MMR vaccine and varicella vaccine). Considerations should include provider assessment, patient preference, and the potential for adverse events. Provider assessment denotes consideration of “the number of injections, vaccine availability, likelihood of improved coverage, likelihood of patient return, and storage and cost considerations.”

Vaccine effectiveness — In the United States, anti-measles antibody develops in 95 percent of individuals vaccinated at age 12 months, and 98 percent of individuals vaccinated at age 15 months [4]. Measles vaccination usually leads to long-term immunity; more than 90 percent of recipients develop anti-measles antibody if the first dose of the two-dose series is given no sooner than 12 months of age [18]. Waning of immunity after vaccination, known as secondary vaccine failure, has been reported but is relatively rare [4].

In many countries outside the United States, measles vaccination is performed at age nine. Estimates vary for the effectiveness of vaccination at this age; it may be approximately 85 percent [19-23].

General recommendations — For prevention of measles infection in the United States, we agree with the ACIP, which recommends one dose of MMR at age 12 to 15 months, followed by a second dose administered no sooner than 28 days later [4,16,17]. The American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the ACIP all recommend that the second dose of vaccine be given prior to school entry (ages four to six years). (See "Standard immunizations for children and adolescents", section on 'MMR vaccine'.)

In the absence of contraindication, MMR is the vaccine of choice for protection against measles, mumps, and rubella. Doses of MMR and other measles-containing vaccines administered before the first birthday should not be counted when determining the adequacy of measles vaccination [4].

To achieve the goal of administering two doses of MMR to all children from kindergarten to grade 12, the ACIP has recommended that children without evidence of measles immunity not be admitted to school until the first dose of MMR has been administered. The ACIP, AAP, and AAFP all recommend a health maintenance visit for children 11 to 12 years old; this visit can be used to

update vaccinations [4].

International travelers aged 6 to 11 months should have one MMR dose before departure. MMRV is not licensed for children younger than 12 months of age and therefore should not be considered in this setting.

Children who receive a dose of measles vaccine before their first birthday should be revaccinated with two doses of MMR vaccine, the first of which should be administered when the child is aged 12 to 15 months (12 months if the child remains in a high risk area) and the second at least 28 days later [24]. Other international travelers should have documentation of two doses of live measles vaccine.

It is safe to administer most vaccines with MMR during the same visit including [4]:

· Diphtheria toxoid/tetanus toxoid/acellular pertussis vaccine (DTaP) or diphtheria toxoid/tetanus toxoid/whole-cell pertussis vaccine (DTP)

· Haemophilus influenzae type b vaccine (Hib)

· Inactivated polio vaccine (IPV) or oral polio vaccine (OPV) — current recommendations are to use IPV instead of OPV in most countries [25]

· Hepatitis B vaccine

· Varicella vaccine (See 'MMRV' above.)

Live measles and yellow fever vaccines can be administered simultaneously at separate anatomical sites in separate syringes. Limited data exist regarding interactions between MMR and Japanese encephalitis vaccine, meningococcal vaccine, or typhoid vaccine, but a significant interaction is not expected to occur [4].

Approach in high risk areas — In the United States, high risk regions are defined by the ACIP as counties with a large inner-city population, counties with a recent measles outbreak among unvaccinated preschool children, and counties with more than five cases of measles among preschool-aged children during the preceding five years [4]. In such regions, the first dose of measles vaccine should be given at age 12 months rather than 15 months. The benefit of preventing measles cases among children aged 12 to 15 months outweighs the risk of slightly reduced vaccine efficacy at this age. Individuals with inadequate response to the first vaccination are likely to develop sufficient immunity with the second vaccination.

Timing of vaccination — The World Health Organization (WHO) recommends that in highprevalence settings, the first dose of MMR be administered at age nine months (given high risk of transmission), whereas in low-prevalence areas it can be given at 12 months (given higher likelihood of seroconversion as discussed below) [26].

Children are at risk for measles following clearance of transplacentally-acquired maternal antibodies [27-30]. Lower levels of measles antibodies have been observed among vaccinated mothers than mothers who had had natural infection [30]. Maternal antibody levels correlated with neonatal antibody levels at birth (r=0.93), and the median time to loss of immunity was shorter for infants of vaccinated women than for infants of naturally immune women (0.97 months versus 3.78 months, respectively). At six months of age, immunity waned in more than 99 percent of neonates born to vaccinated mothers and 95 percent of neonates born to naturally immune mothers [30]. This suggests that by age six months, children are at risk for becoming infected with measles, and that the number of children at risk may grow as vaccination reduces the number of mothers with natural

immunity [31]. Such observations have led to the suggestion that an early two-dose vaccination program may be beneficial [31-33]. An interim analysis of a randomized trial of measles vaccine at age 4.5 months found that, in a coincidental outbreak, the monthly incidence of measles was 0.7 percent in the early-vaccination group versus 3.1 percent in the control group [31]. The investigators cautioned that the results likely only applied to the measles vaccine used in the study (Edmonston-Zagreb), and an accompanying editorial recommended that early vaccination not replace vaccine doses given at age 9 to 15 months [32].

Other research shows that children vaccinated at a younger age are less likely to respond to measles vaccine. The 2009 World Health Organization (WHO) vaccination guidelines estimate that at age 8 to 9 months, a median 89.6 percent of infants seroconvert after one dose of measles vaccine (interquartile range (IQR): 82 to 95 percent), and at age 11 to 12 months a median 99 percent of infants seroconvert (IQR: 93 to 100 percent). A review on vaccine effectiveness noted that the median effectiveness for a single dose of measles vaccine was higher when given at age older than12 months than at age 9 to 11 months; 92.5 percent (IQR: 85 to 97 percent) versus 84 percent (IQR: 72 to 95 percent), respectively [34]. In addition, among Canadian teenagers who developed measles in spite of two doses of childhood measles vaccine, the susceptibility to measles was twoto fourfold higher among those who received the first dose at age 12 months compared with those who received the at age >15 months [35].

In regions with high prevalence of HIV, rapid waning of measles antibody in HIV-infected children suggests that measles vaccination campaigns may need to be repeated more frequently [36]. In a prospective study of 696 children, antibody titers 27 months after vaccination were detectable less frequently in the HIV-infected group than the HIV-negative group (50 percent versus 89 percent, respectively) [37]. A subset of 12 children with HIV infection incidentally received repeat vaccination; antibody titers were detectable in 92 percent of these children, although the durability of this response was not assessed. (See"Immunizations in HIV-infected patients", section on 'Measles, mumps, and rubella vaccine' and "Clinical presentation and diagnosis of measles".).

Prior vaccination with other strains — Previous vaccination with live attenuated Edmonston B measles vaccine (1963 to 1975) is considered an effective first dose of vaccine if given at age 12 months or older. If indicated, a second dose of MMR vaccine should be administered. All other individuals are considered unvaccinated including: those receiving a further attenuated strain (Schwarz or Moraten), especially if coadministered with IG or a high-titer measles immune globulin (no longer available in the United States); those vaccinated with an unknown strain with or without globulin coadministration; and those receiving inactivated measles vaccine or vaccine of unknown type between 1963 and 1967.

These persons should receive two doses of live vaccine separated by at least 28 days. Those who received inactivated vaccine followed within three months by live vaccine should also be revaccinated with two doses of live vaccine separated by at least 28 days.

Lack of association with autism — Concern has been raised periodically about a possible link between receipt of MMR and autism. Several studies have now been performed which fail to demonstrate any such association. (See "Autism and chronic disease: Little evidence for vaccines as a contributing factor".)

ESTABLISHING EVIDENCE OF MEASLES IMMUNITY — Evidence for measles immunity is important to establish whether subsequent vaccination is needed. The criteria below are accepted by the Advisory Committee on Immunization Practices (ACIP) as presumptive evidence of measles immunity. Nonetheless, transmission of infection can occur even among individuals who meet criteria for presumptive immunity. Local criteria may differ from those listed below.

Birth before the year 1957 — Most individuals born before 1957 have had natural measles infection, given the widespread measles epidemics in the United States before the introduction of measles vaccine. Among hospital workers born before 1957, 5 to 9 percent do not have serologic evidence of immunity to measles [38].

Given the risk of occupational exposure to measles and the risk that healthcare workers with measles may transmit infection to others in a healthcare setting, in a provisional update to its guidelines the Centers for Disease Control and Prevention (CDC) recommend that healthcare facilities consider administration of two doses of measles-mumps-rubella (MMR) vaccine to healthcare workers born prior to 1957 (in the absence of other evidence for measles immunity) [39].

Public health authorities should be contacted to determine local vaccination policies for healthcare workers.

Clinical measles diagnosis — A clinical diagnosis of measles documented by a physician is considered acceptable presumptive evidence for immunity [4,39].

Laboratory evidence of immunity — Anti-measles antibody unequivocally detected by any serologic test is considered evidence for measles immunity. A negative serology should prompt vaccination except in individuals who are pregnant or have other contraindications (See 'Contraindications' below.)

Screening in non-outbreak situations is most effective when follow up is assured (eg, hiring of new healthcare workers). If follow-up for reporting results and administering vaccine is not possible, screening should not be performed. Screening is not advised during an outbreak situation; vaccination should be administered.

Documentation of vaccination — Only written documentation of vaccination is considered valid; a self report or parent report of measles vaccination is inadequate. The definitions of adequate measles vaccination differ by group.

· Students in kindergarten through twelfth grade should have documentation of receipt of two doses of vaccine.

· One dose of vaccine administered on or after the first birthday is considered adequate immunization for preschool-aged children, and for persons who (1) are considered at low risk for measles infection; (2) were born 1957 or later; (3) are eighteen or over. Adults at high risk for measles infection and transmission include international travelers, persons attending colleges and other post-high school educational institutions, and persons who work at healthcare facilities.

· Students at post high school educational institutions (including colleges, universities, vocational schools, and technical schools) and persons working in healthcare facilities (including volunteers, students, non-medical workers, part time workers, and persons without patient care responsibilities) should have documentation of two doses of live measles vaccine, preferably with MMR, separated by at least 28 days.

· International travelers aged 6 to 11 months should have documentation of one MMR dose before departure. Children who receive a dose of measles vaccine before their first birthday should be revaccinated with two doses of MMR vaccine, the first of which should be administered when the child is aged 12 to 15 months (12 months if the child remains in a high risk area) and the second at least 28 days later [24]. Other international travelers should have documentation of two doses of live measles vaccine.

CONTRAINDICATIONS — Contraindications to measles vaccination are summarized below. In the setting of measles exposure, individuals with contraindications to vaccination should receive immune globulin [4]. (See 'Use of immune globulin' above.)

Pregnancy — There is a theoretical risk of birth defects among children born to mothers who receive live measles or measles-mumps-rubella (MMR) vaccine during pregnancy. Thus, the vaccine is considered contraindicated in pregnant women. Women of childbearing age should be counseled to avoid pregnancy for 30 days after vaccination [4].

Immunocompromised patients — Live measles vaccine or MMR should be used with caution in severely immunocompromised individuals. Issues related to immunizations in patients with immune suppression due to various causes are discussed separately. (See "Immunizations in HIV-infected patients", section on 'Measles, mumps, and rubella vaccine' and "Immunizations in patients with cancer", section on 'Measles, mumps, and rubella vaccines' and"Immunizations after hematopoietic cell transplantation", section on 'Measles, mumps, and rubella' and "Immunizations in solid organ transplant candidates and recipients", section on 'Measles, mumps, and rubella'.). MMR or live measles vaccination should be postponed in patients receiving prednisone (>2 mg/kg or 20 mg daily or every other day for more than 14 days). Vaccine should not be administered until at least one month after the cessation of treatment.

Close contacts of immunocompromised patients should receive routine measles vaccination; secondary transmission associated with vaccination has not been reported [40].

Thrombocytopenia — Individuals with a history of thrombocytopenia are at increased risk of developing significant thrombocytopenia after MMR vaccination [4]. However, the benefits of primary vaccination usually outweigh the risks. It may be prudent to avoid a second dose of MMR in individuals with history of thrombocytopenia within six weeks of initial vaccination [4].

Recent blood products or immunoglobulin — Vaccine efficacy is diminished significantly by prior passive administration of antibody. Vaccination should be delayed for 3 to 11 months after antibody administration; the length of time varies depending upon the amount of antibody in the preparation.

The interval is six months for those who have received packed red blood cells (unwashed) or whole

blood, and seven months for plasma/platelet preparations [4].

Allergy — A history of anaphylaxis after ingestion of gelatin is associated with an increased risk of anaphylaxis from the MMR or measles vaccine [4]. This history should warrant a skin test for gelatin allergy. Individuals with anaphylaxis (not contact dermatitis) due to neomycin also should not receive these vaccines because they contain a small amount of this antibiotic. In contrast, a history of anaphylaxis after egg ingestion is not a contraindication to measles immunization. (See "Allergic reactions to vaccines".)

Concurrent illness — Vaccination should be delayed in persons with moderate to severe febrile illnesses until resolution of the acute phase of the illness, as long as the vaccine is not being administered for an exposure [4]. However, mild febrile or nonfebrile illnesses do not mandate delay of vaccination.

ADVERSE EVENTS — A variety of adverse reactions have been reported following measles and

measles-mumps-rubella (MMR) vaccine administration [24]. Transient fever (39.4ºC or higher occurring one to two weeks after vaccination) develops in 5 to 15 percent of vaccinees. Transient rash occurs in approximately 5 percent. Most hypersensitivity reactions to the vaccine are minor.

Anaphylaxis can occur, but is extremely rare. Epinephrine should be available for use at any site that administers the vaccine.

Thrombocytopenia has been observed in prospective studies (1 case in 25,000 to 40,000 vaccine doses) [4]. In general, it is transient and occurs within two months of the receipt of vaccine, most commonly at two to three weeks. The risk may be higher in individuals who experienced thrombocytopenia following previous vaccination with MMR. (See 'Thrombocytopenia' above.)

Administration of MMR has been associated with febrile seizures, anaphylaxis, and measles inclusion body encephalitis in immunodeficient individuals [41]. The incidence of vaccine associated seizures has been estimated to be 1 in 3000 MMR doses [4], but is increased in vaccinees with a history of seizures or with a family history in first degree relatives. Most are simple febrile seizures.

In most cases, the benefits of vaccination outweigh the risk of seizures. The incidence of anaphylaxis is unknown but is estimated by the Centers for Disease Control and Prevention (CDC)

to be less than one per every one million MMR doses distributed [4].

TREATMENT OF MEASLES INFECTION — The treatment of measles is largely supportive; there is a role for vitamin A in certain settings, discussed below [42,43]. The World Health Organization (WHO) has published a comprehensive guide to the treatment of measles [44]. Supportive therapy includes antipyretics, fluids, and treatment of bacterial superinfections, such as bacterial pneumonia and otitis. Treatment of other complications, such as seizures and respiratory failure, may also be necessary. (See "Clinical presentation and diagnosis of measles".)

Vitamin A — The benefit of vitamin A for treatment of measles was suggested in 1932 [45]. The mechanism of action is not known; it may correct a viral-induced state of hyporetinemia. The WHO and UNICEF recommend that vitamin A (100,000 to 200,000 IU orally) be administered to all children with measles in areas where vitamin A deficiency is prevalent or where the mortality from measles exceeds one percent [24]. This dose recommendation is lower than the 400,000 IU dose (200,000 IU given on successive days) used in the trials below [46,47]:

· In one randomized trial including 180 Tanzanian children hospitalized with measles, mortality was reduced in patients treated with vitamin A (7 versus 13 percent); statistical significance was observed in the subgroup of patients under the age of two years [46].

· In another randomized trial including 189 South African children hospitalized with measles complications, including pneumonia, diarrhea, and croup, vitamin A was beneficial with respect to recovery time from pneumonia (mean of 6 versus 12 days), diarrhea (mean of 5 versus 8 days), incidence of croup (13 versus 27 cases), hospital stay (mean 10 versus 14 days), and overall mortality (2 versus 10 deaths) [47]. The risk of death or a major complication in the control group was twice that of the treated group. Among 156 infected patients in the study, 143 were found to have markedly depressed serum retinol levels.

A Cochrane review of randomized trials on the use of vitamin A for measles concluded that there was no overall significant reduction in mortality with vitamin A therapy for children with measles, but there was evidence that two doses were associated with a reduced risk of mortality and pneumoniaspecific mortality in children under the age of two years [48].

The use of vitamin A for treatment of measles in developed countries has not been evaluated in a clinical trial. The American Academy of Pediatrics recommends that vitamin A supplementation be considered for children with measles in developed countries in the following circumstances [49]:

· Children (6 months to 12 years) hospitalized with measles or its complications (eg, croup, pneumonia, or diarrhea).

· Children (older than six months of age) with measles and any of the following risk factors: immunodeficiency, ophthalmologic evidence of vitamin A deficiency, impaired intestinal absorption, moderate to severe malnutrition, and recent immigration from areas where high mortality rates from measles have been observed.

The recommended regimens for vitamin A supplementation are:

· Children 6 to 12 months — 100,000 IU (50,000 IU/mL) as a single oral dose.

· Children older than 12 months — 200,000 IU (50,000 IU/mL) as a single oral dose.

· For children with ophthalmologic evidence of vitamin A deficiency, repeat doses should be administered on day 2 and day 28.

Ribavirin — Measles virus is susceptible to ribavirin in vitro; there have been no randomized controlled trials to assess its clinical benefit [24]. Data on use of ribavirin are limited to case reports.

In one case report of three HIV-infected children with measles who received aerosolized ribavirin, two of the three survived initially, but died within the subsequent three months [50]. Another case series reported a favorable outcome in five of six adults with severe measles pneumonitis who received intravenous ribavirin. Those who recovered received the drug on day two to day five of illness; the patient who died of progressive respiratory failure received the drug on day 22 of infection [51]

ARTICULO MEDICO: PRESENTACION CLINICA Y DIAGNOSTICO DE SARAMPION(Clinical presentation and diagnosis of measles)

CLINICAL PRESENTATION AND DIAGNOSIS OF MEASLES
Authors
Jorge L Barinaga, MD, MS
Paul R Skolnik, MD, FACP, FIDSA
Section Editors
Martin S Hirsch, MD
Sheldon L Kaplan, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2013. | This topic last updated: jun 17, 2010.

INTRODUCTION — Measles virus is a member of the family Paramyxoviridae, genus Morbillivirus. Measles virus infection can cause a variety of clinical syndromes, including [1]:

· Classic measles infection in immunocompetent patients

· Modified measles in patients with preexisting, but incompletely protective, anti-measles antibody

· Atypical measles in patients immunized with the killed virus vaccine

· Neurologic syndromes following measles infection, including acute disseminated encephalomyelitis (ADEM) and subacute sclerosing panencephalitis (SSPE)

· Severe measles

· Complications of measles including secondary infection, giant cell pneumonia, and measles inclusion body encephalitis.

Despite high community vaccination coverage, measles outbreaks can occur among undervaccinated children [2,3]. The clinical manifestations and diagnosis of classic measles, variant presentations, and unusual neurologic complications will be reviewed here. The epidemiology, transmission, treatment, and prevention of measles are discussed separately. (See "Epidemiology and transmission of measles" and "Prevention and treatment of measles".)

CLINICAL MANIFESTATIONS

Stages of infection — Classic measles infection can be subdivided into the following clinical stages: incubation, prodrome, exanthem, and recovery [4].

· Incubation period — The incubation period begins after measles virus entry via the respiratory mucosa or conjunctivae. The virus replicates locally, spreads to regional lymphatic tissues, and is then thought to disseminate to other reticuloendothelial sites via the bloodstream. The incubation period of measles is usually 10 days with a range generally of 8 to 10 days [5].

Infected individuals are characteristically asymptomatic during the incubation period, although some have been reported to experience transient respiratory symptoms, fever, or morbilliform rash [6,7].

The dissemination of measles virus due to viremia, with associated infection of endothelial, epithelial, monocyte, and macrophage cells, may explain the variety of clinical manifestations and complications that can occur with measles infection. A second viremia occurs several days after the first, coinciding with the appearance of symptoms signaling the beginning of the prodromal phase.

· Prodrome — The prodrome phase is defined by the appearance of symptoms which typically include fever, malaise, and anorexia, followed by conjunctivitis, coryza, and cough. The severity of conjunctivitis is variable and may also be accompanied by lacrimation or photophobia [6]. The respiratory symptoms are due to mucosal inflammation from viral infection of epithelial cells. Fever is typically present; the pattern may be variable. Various fever patterns have been described; fever  is high as 40ºC can occur. The prodrome usually lasts for two to three days but may persist for as long as eight days [5].

Patients may develop an enanthem known as Koplik's spots; these are 1 to 3 mm whitish, grayish, or bluish elevations with an erythematous base, typically seen on the buccal mucosa opposite the molar teeth, though they can spread to cover the buccal and labial mucosa (picture 1) as well as the hard and soft palate [8]. They have been described as "grains of salt on a red background" [7]. Koplik's spots subsequently may coalesce and generally last 12 to 72 hours [4].

Koplik¨s spots

It is important to search carefully for Koplik's spots in patients with suspected measles, since they are considered pathognomonic for measles infection and occur approximately 48 hours before the characteristic exanthem. However, this enanthem does not appear in all patients with measles.

Uncommonly, patients with severe measles develop generalized lymphadenopathy and splenomegaly [7].

· Exanthem — The exanthem of measles is a maculopapular, blanching rash beginning on the face and spreading cephalocaudally and centrifugally to involve the neck, upper trunk, lower trunk, and extremities (picture 2A-B). 

Measles exanthem

The lesions may become confluent, especially in areas such as the face, where the rash develops first (picture 2B). 

The rash may also have some petechiae; in severe cases it may appear hemorrhagic [9-11]. In general, the extent and degree of confluence of the rash correlates with the severity of the illness in  children. The palms and soles are rarely involved. The cranial to caudal progression of the rash is characteristic of measles but is not pathognomonic [6]. 

Other characteristic findings during the exanthematous phase include lymphadenopathy, high fever (peaking two to three days after appearance of rash), pronounced respiratory signs including pharyngitis, and nonpurulent conjunctivitis. Koplik's spots often begin to slough when the exanthem appears.

Clinical improvement typically ensues within 48 hours of the appearance of the rash. After three to four days the rash darkens to a brownish color and begins to fade, followed by fine desquamation. The rash usually lasts six to seven days.

· Recovery and immunity — Cough may persist for one to two weeks after measles infection. The occurrence of fever beyond the third to fourth day of rash suggests a measles-associated complication (see 'Complications' below).

Immunity after measles infection is thought to be lifelong, although there are rare reports of measles reinfection [12,13]. A measles surveillance program conducted in mid 1960s, for example, identified measles in a 16-year old female with a prior history of measles at age 8. A rise in anti-measles IgG but not IgM was noted, suggesting an anamnestic response [12].

(See 'Modified measles' below.) Measles infection can cause transient immunosuppression due to suppression of T-cell responses [8]. Anergy may be present before the appearance of the exanthem and for several weeks after measles infection [8,14]. This is exemplified by reports of tuberculosis reactivation in the setting of recent measles infection [8,15].

Clinical variants

Modified measles — Modified measles is an attenuated measles infection that occurs in patients with preexisting but incompletely protective anti-measles antibody. It is similar to classic measles except the clinical manifestations are generally milder and the incubation period is longer (17 to 21 days) [5]. Individuals with partial immunity to measles can develop modified measles; partial immunity may occur in one of the following ways:

· Transplacental transfer of partially protective anti-measles antibody from mother to infant; this antibody is generally cleared by age nine months [6].

· Receipt of intravenous immunoglobulin

· Measles vaccination with incomplete antibody response

· Prior history of measles [13] (see 'Stages of infection' above)

Atypical measles — Atypical measles occurred in patients immunized with the killed virus vaccine subsequently exposed to wildtype measles virus. Since the killed virus vaccine was used in the United States between 1963 and 1967, atypical measles is now rare. The majority of cases have occurred in recipients of the killed virus vaccine, but there are also reports in recipients of the attenuated live virus vaccine.

Patients with atypical measles develop high fever and headache 7 to 14 days after exposure to measles. A dry cough and pleuritic chest pain are often present [6]. Chest x-ray typically demonstrates bilateral pulmonary nodular and hilar lymphadenopathy [8]. A maculopapular rash develops two to three days later, beginning on the extremities and spreading to the trunk. The rash may involve the palms and soles and tends to spare the upper chest, neck, and head [6]. The rash may be vesicular, petechial, purpuric, or urticarial. The distribution and varied appearance of the rash can make diagnosis difficult. Atypical measles often causes severe illness; many patients develop respiratory distress. Some patients develop peripheral edema, hepatosplenomegaly,and/or neurologic symptoms such as paresthesias or hyperesthesia [6]. Laboratory findings can include elevated serum aminotransferases [8].

Atypical measles is associated with a characteristic antibody pattern: before or at the onset of the exanthem, the titer is usually before or at the onset of the exanthem, the titer is usually less than 1:5, but by day 10 of illness the titer is typically greater than1:1280. The height and rapidity of antibody titer rise is much higher than in primary natural measles infection.

The differential diagnosis of atypical measles is broad and includes infection with varicella-zoster virus, Mycoplasma pneumoniae, Rocky Mountain spotted fever, scarlet fever, meningococcemia, Henoch-Schönlein purpura (IgA vasculitis), drug eruption, or toxic shock syndrome [6,8,15].

Patients with atypical measles do not appear to transmit measles to others [15].

Differential diagnosis — The differential diagnosis of measles depends on the clinical stage.

During the prodromal period measles can resemble the common cold, except that fever is typically present and more pronounced with measles infection [6]. The prodrome can be confused with common respiratory viruses of childhood, such as rhinoviruses, parainfluenza, influenza, adenovirus, and respiratory syncytial virus infections, and, in returning travelers, with the prodrome of Dengue fever. Koplik's spots can be mistaken for Fordyce spots (tiny yellow-white granules sometimes found on the buccal or lip mucosa due to benign ectopic sebaceous glands) [16]. Unlike Koplik's spots, Fordyce spots do not occur on an erythematous mucosal background [6]. Once an exanthem has appeared, alternative diagnoses to consider include Mycoplasma pneumoniae, HHV-6 infection, rubella, Rocky Mountain spotted fever, infectious mononucleosis, scarlet fever, Kawasaki disease, toxic shock syndrome, dengue, and drug eruption [6,8,17]. Measles can usually be distinguished clinically from rubella, erythema infectiosum (parvovirus B19 infection), roseola, and enteroviral infection by the characteristic progression of the measles rash, its subsequent brownish coloration, its blanching on pressure, and clinical history and other physical findings (especially coryza and conjunctivitis) [6,7].

Laboratory findings — Leukopenia, T-cell cytopenia, and thrombocytopenia may be observed during measles infection [6]. 

Chest radiography may demonstrate interstitial pneumonitis [8].

Biopsy samples of lymphoid tissues before the appearance of the exanthem may demonstrate reticuloendothelial giant cells.

Histologic analysis of enanthem or exanthem and cytologic examination of nasal secretions may also demonstrate epithelial giant cells [8].

COMPLICATIONS — The risk of measles associated complications is increased in developing countries, where the case fatality rate is 4 to 10 percent [18]. Most fatalities are due to respiratory tract complications or encephalitis. Groups at increased risk for complications of measles include immunocompromised hosts, pregnant women, and individuals with vitamin A deficiency or poor nutritional status, and individuals at the extremes of age [6,15,19-21]. (See 'Groups at risk for complications' below.)

Since measles is a disseminated infection, involvement of multiple organ systems can occur.

Pulmonary — Respiratory tract infections occur most frequently among patients younger than 5 years and older tah 20 years. Pulmonary involvement of measles infection may consist of bronchopneumonia, laryngotracheobronchitis (croup) or bronchiolitis [7,22]. Otitis media occurs in 5 to 10 percent of cases. Measles has also been associated with development of bronchiectasis, which can predispose to recurrent respiratory infections [22]. Bacterial superinfection may occur in up to 5 percent of children.

In one retrospective study of measles fatalities in South Africa, 85 percent of deaths were attributed to viral or bacterial infections of the lung [22]. In a series of 182 cases of measles-associated  pneumonia, 89 percent occurred in association with typical measles infection; bacterial pathogens included Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, and Staphylococcus aureus [6,7,23]. Coinfection with other viruses was also documented, especially parainfluenza (25 percent of patients) and adenovirus (19 percent of patients), but also with cytomegalovirus, enterovirus, influenza, and respiratory syncytial virus.

Antibiotic prophylaxis during a measles epidemic may prevent secondary complications; further study is needed [24,25].

Neurologic

Encephalitis — Encephalitis occurs in up to 1 per 1000 measles cases, usually appearing within a few days of the rash. It is associated with a CSF pleocytosis (predominantly lymphocytes), increased protein levels, and normal glucose. Most children recover from encephalitis; approximately 25 percent have neurodevelopmental sequelae, and about 15 percent may have a rapidly progressive and fatal disease [6].

Acute disseminated encephalomyelitis — Acute disseminated encephalomyelitis (ADEM) is a demyelinating disease that presents during the recovery phase of measles infection, typically within two weeks of the exanthem [8,26]. ADEM is also known as postinfectious or postvaccination encephalomyelitis. In contrast, subacute sclerosing panencephalitis (SSPE) presents years after initial infection. (See 'Subacute sclerosing panencephalitis' below.) ADEM is thought to be caused by a postinfectious autoimmune response, rather than active measles infection of the central nervous system [8,26]. Consistent with this hypothesis is the observation that measles virus has only rarely been isolated from the brains of patients with ADEM [7,8]. (See "Acute disseminated encephalomyelitis in children: Pathogenesis, clinical features, and diagnosis".) The major manifestations of ADEM include fever, headache, neck stiffness, seizures, and mental status changes such as confusion, somnolence, or coma [15,27]. Other findings may include ataxia, myoclonus, choreoathetosis, and signs of myelitis, such as paraplegia, quadriplegia, sensory loss, loss of bladder and bowel control, and, in patients with myelitis, back pain [27]. Analysis of cerebrospinal fluid generally demonstrates a lymphocytic pleocytosis and elevated protein concentration. (See "Viral encephalitis in adults", section on 'Viral versus postinfectious encephalitis'). ADEM is associated with a 10 to 20 percent mortality [26]. Survivors frequently have residual neurologic abnormalities including behavior disorders, mental retardation, and epilepsy [26,27].

Subacute sclerosing panencephalitis — Subacute sclerosing panencephalitis (SSPE) is a fatal, progressive degenerative disease of the central nervous system that occurs 7 to 10 years after natural measles infection. Its pathogenesis is not well understood but may involve persistent infection with a genetic variant of measles virus within the central nervous system [8,28]. During 1960-1974 the estimated incidence of SSPE was 8.5 cases per one million cases of measles. Between 1970 and 1980, the number of cases of SSPE fell to 0.06 cases per million population; the decline paralleled the decline of measles cases, with a lag time of several years [29]. However, data derived from the resurgence of measles infection in the United States between 1989 to 1991 suggest that the risk of SSPE may be 10-fold higher than originally estimated, based on followup study of cases of biopsyproven SSPE [30]. In general, patients with SSPE are ≤20 years and become ill 7 to 10 years after natural measles infection [30]. Measles infection at an early age is a risk factor for SSPE; about half of patients with SSPE had measles before the age of 2 years [31]. The risk of SSPE after measles immunization is thought to be lower than after natural measles infection; according to the CDC, the risk of SSPE following vaccination is ≤ one-twelfth the risk of SSPE following infection [6,29].

SSPE has been divided into the following stages [28,31]:

· Stage I — Stage I consists of insidious development of neurologic symptoms such as personality changes, lethargy, difficulty in school, and strange behavior. Stage I may last from weeks to years.

· Stage II — Stage II is characterized by myoclonus, worsening dementia and long tract motor or sensory disease. The patient eventually develops a highly characteristic form of myoclonus in which massive myoclonic jerks occur approximately every 5 to 10 seconds. Stage II usually lasts 3 to 12 months.

· Stages III and IV — Stages III and IV are characterized by further neurologic deterioration with eventual flaccidity or decorticate rigidity and symptoms and signs of autonomic dysfunction. Myoclonus is absent. Stage IV is a vegetative state.

Death usually occurs during Stage IV but is possible in any of the stages. [32]. The rate of progression can be variable. Stabilization at one stage for a period of time can occur, though in general patients tend to progress from one stage to the next. Some patients have a remitting and relapsing course. Seizures can occur in any of the stages.

Electroencephalogram (EEG) during stage II may demonstrate bursts of high-voltage complexes (300 to 1500 microvolts) of two- to three-per-second delta waves (slow waves) and sharp waves. These complexes last 0.5 to 3 seconds and occur every 3 to 20 seconds [33-35]. Each complex is followed by a relatively flat pattern [34]. These EEG findings are characteristic of SSPE and may be pathognomonic [28,34]. The EEG may be abnormal in the other stages of SSPE as well [28].

Computed tomography of the head may show atrophy and scarring [28]. The serum anti-measles antibody concentration is elevated, and cerebrospinal fluid analysis shows elevated protein concentration and detectable anti-measles antibody [6,8]. Brain MR images may be normal, but in one report (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) and magnetic resonance spectroscopy (MRS) revealed substantial functional abnormalities [36]. Thus, these could be useful techniques for the early detection of SSPE and for assessing the specific brain areas affected in the early stages of SSPE when MRI findings are likely to be normal.

The relentless and fatal course of this complication underscores the importance of measles vaccination, not only for prevention of measles but also for prevention of the severe neurologic sequelae that can ensue. (See "Prevention and treatment of measles".)

Eye manifestations — Measles-induced keratitis (a common cause of blindness) and corneal ulceration have been described [6,8,37].

Other — Other neurologic complications associated with measles include acute measles-induced encephalopathy, described in the setting of human immunodeficiency virus (HIV) infection; this manifestation is rare [38].

Gastrointestinal — Gastrointestinal complications include gingivostomatitis, diarrhea, gastroenteritis, hepatitis, mesenteric lymphadenitis and appendicitis. In developing countries, measles-induced stomatitis and diarrhea can lead to worsening of nutritional status [6,8].

Cardiac — Cardiac complications of measles include myocarditis and pericarditis.

Immunosuppression — Measles infection can lead to systemic immune suppression and severe secondary infections, especially in the developing world [22,39,40]. These effects are caused by direct infection of T cells by measles virus and by infection of dendritic cells, impairing their important antigenpresenting/accessory function in T cell activation.

GROUPS AT RISK FOR COMPLICATIONS — Groups at increased risk for complications of measles include immunocompromised hosts, pregnant women, and individuals with vitamin A deficiency or poor nutritional status, and individuals at the extremes of age [6,15,19-21].

Immunocompromised patients — Patients with defects in cell-mediated immunity (AIDS, lymphoma or other malignancies) are at risk for severe, progressive measles virus infection [19].

Children with HIV infection may present with measles at an earlier age than HIV-seronegative patients (10 versus 15 months) [41,42]. In addition, measles infection may have a transient suppressive effect on HIV replication [43,44]. In a study of 33 HIVinfected children hospitalized with measles, median plasma HIV RNA levels rose from 5339 at admission to 60,121 copies/mL at

discharge; high levels of viremia persisted at one month follow-up [43].

The degree of infant protection against measles via placental transfer of maternal measles antibodies depends on maternal antibody titer [45-47]. The risk of acquiring measles before nine months of age is higher among infants born to HIV-seropositive women than those born to HIV-seronegative women [45]. In a study of 747 paired maternal-cord serum samples (91 from HIVinfected and 656 from HIV-uninfected mothers), infants born to HIV-infected mothers were more likely to be seronegative for measles; seropositive infants had 35 percent lower levels of measles antibodies compared with infants born to HIV-uninfected mothers [46].

Manifestations — The clinical presentation of measles in immunocompromised hosts may be atypical [19]. Exanthem may be absent, evanescent, or severe and desquamative; purpura has also been described. Some unique measles-associated manifestations have been described in immunocompromised patients; these include giant cell pneumonia and measles inclusion body encephalitis.

· Giant cell pneumonia is characterized by multinucleated giant cells in lung tissue. It can develop in immunocompromised patients after classic measles or after a vague prodromal illness that may not include an exanthem [6]. In patients without a rash, lung biopsy may be required to make the diagnosis (picture 3).

Picture 3

Medium power view of a lung biopsy from a patient with measles pneumonia shows a nodular pattern with acute and chronic inflammation withn areas of necrosis and fibrosis. Multinucleated giant cell with inclusions(arrows) are also shown (hematoxilin-eosin-500X)

· Measles inclusion body encephalitis (MIBE) is characterized by histopathologic evidence of inclusions in neurons and glial cells. Patients present one to six months after exposure to measles with seizures, mental status changes, and myoclonus. MIBE may sometimes present in conjunction with giant cell pneumonia. The pathogenesis of this disorder is uncertain [8].

Diagnosis — Serologic analysis to diagnose measles in immunocompromised patients may not be useful because of deficient antibody synthesis [15]. In these cases, alternative diagnostic approaches should be taken, as described below. Biopsy of involved tissues may be necessary for a definitive diagnosis. (See 'Diagnosis' below.)

Pregnant women — Measles in pregnancy was rare in the prevaccine era, probably because of immunity following natural measles infection when the mothers themselves were children. Measles during pregnancy may increase the risk for serious maternal and fetal complications. In one study of 13 peripartum women, measles infection was complicated by pneumonitis and/or hepatitis in nine women; four of the patients with pneumonitis had an adverse fetal outcome, and there was one maternal death [48]. The incidence of premature births was increased in one study of women who had measles while pregnant compared with matched controls [49]. Measles may also lead to spontaneous abortion [50,51].

A review of the teratogenicity of measles virus concluded that "[t]he teratogenic potential of gestational measles for the fetus has been neither proved nor refuted," and "if there is any increased risk of malformations from gestational measles, this risk appears to be small" [50]. Investigation of a measles epidemic in 1951 found no clear evidence of teratogenicity, increased pathogenicity in the mother, or altered sequelae during pregnancy or birth; however, case finding and follow-up were not complete [20].

Maternal measles virus infection at the time of delivery does not necessarily lead to measles in the neonate. Congenital measles (defined by the appearance of the measles rash within 10 days of birth) and postnatally-acquired measles (appearance of the rash 14 to 30 days of birth) have been associated with a spectrum of illnesses ranging from mild to severe disease [50].

DIAGNOSIS — In countries with very low measles prevalence, diagnosis should consist of evaluation of paired acute and convalescent sera for anti-measles IgM and IgG; at least fourfold increase in anti-measles antibody titer is indicative of infection [52,53].

Anti-measles IgM is generally detectable three days after the appearance of the exanthem; it may be undetectable on the day the exanthem appears [52]. It is usually undetectable approximately 30 days after the exanthem. Anti-measles IgG is generally undetectable up to seven days after rash onset [52], but subsequently peaks about 14 days after the exanthem appears.

In countries with high measles prevalence, the World Health Organization (WHO) uses serum IgM as the standard test to confirm the diagnosis of measles [52,54]. However, the anti-measles IgM assay should be interpreted with caution as false positive and false negative results have been reported [8,52]. In one study, at least some false positive results were found to result from human parvovirus B19 IgM [55].

Histologic evaluation of conjunctival, nasopharyngeal, or buccal epithelial cells may demonstrate giant cells with inclusions (picture 3); these cells may also be present in urine [8].

The diagnosis of measles can also be made by culturing the virus from peripheral blood mononuclear cells, respiratory secretions, conjunctival swabs, or urine [8]. Measles virus has been isolated from nasopharyngeal secretions during the prodromal phase [6]. However, culture of the virus is difficult, requires special facilities, and is not performed frequently. In the United States, a case of suspected or confirmed measles should be reported to the local health authorities; even one case is considered an outbreak [56].