martes, 11 de junio de 2013


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
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".)

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].
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]. 

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