Version May 2024
INTRODUCTION — Measles is a highly contagious viral illness that occurs worldwide. The infection is characterized by fever, malaise, cough, coryza, and conjunctivitis, followed by exanthem. Following exposure, approximately 90 percent of susceptible individuals will develop measles. The period of contagiousness is estimated to be from five days before the appearance of the rash to four days afterward. The illness may be transmitted in public spaces, even in the absence of person-to-person contact.
Measles virus infection can cause a variety of clinical syndromes, including [1-4]:
●Classic measles infection in immunocompetent individuals
●Modified measles infection in patients with pre-existing but incompletely protective anti-measles antibody
●Atypical measles infection in patients immunized with the killed virus vaccine
●Neurologic syndromes following measles infection, including acute disseminated encephalomyelitis and subacute sclerosing panencephalitis
●Severe measles infection especially in immunocompromised individuals
●Complications of measles including secondary infection, giant cell pneumonia, and measles inclusion body encephalitis
The clinical manifestations, diagnosis, and treatment of measles will be reviewed here. Issues related to epidemiology, transmission, and prevention of measles virus infection are discussed separately. (See "Measles: Epidemiology and transmission" and "Measles, mumps, and rubella immunization in adults" and "Measles, mumps, and rubella immunization in infants, children, and adolescents".)
CLINICAL MANIFESTATIONS
Stages of infection — Classic measles virus infection can be subdivided into the following clinical stages: incubation, prodrome, exanthem, and recovery [3].
●Incubation period – The incubation period for measles is 6 to 21 days (median 13 days) [5]; it begins after 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, which is considered the first viremia [6]. The period of contagiousness is estimated to be from five days before the appearance of rash to four days afterward. Infected individuals are characteristically asymptomatic during the incubation period, although some have been reported to experience transient respiratory symptoms, fever, or rash [7,8].
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 virus 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 usually lasts for two to four days but may persist for as long as eight days [9]; it is defined by the appearance of symptoms that 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 [7]. The respiratory symptoms result from mucosal inflammation from viral infection of epithelial cells. Fever is typically present. Various fever patterns have been described, and fever as high as 40ºC can occur. The prodromal symptoms typically intensify a few days before the exanthem appears [3].
•Enanthem – Approximately 48 hours prior to onset of the exanthem, patients may develop an enanthem characterized by Koplik 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 and picture 2) as well as the hard and soft palate [10]. They have been described as "grains of salt on a red background" [8]. Koplik spots may coalesce and generally last 12 to 72 hours [11]. Koplik spots often begin to slough when the exanthem appears.
It is important to search carefully for Koplik spots in patients with suspected measles, since they can improve the accuracy of clinical diagnosis [12]. However, this enanthem does not appear in all patients with measles.
●Exanthem – The exanthem of measles arises approximately two to four days after onset of fever; it consists of an erythematous, maculopapular, blanching rash, which classically begins on the face and spreads cephalocaudally and centrifugally to involve the neck, upper trunk, lower trunk, and extremities (picture 3A-B). Early on, the lesions are blanching; in the later stages, they are not (picture 3B). The rash may include petechiae; in severe cases, it may appear hemorrhagic [13-15]. In children, the extent of the rash and degree of confluence generally correlate with the severity of the illness. The palms and soles are rarely involved. The cranial to caudal progression of the rash is characteristic of measles but is not pathognomonic [7].
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. Uncommonly, patients with severe measles develop generalized lymphadenopathy and splenomegaly [8].
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 (in patients of White European descent though not patients of African descent) and begins to fade, followed by fine desquamation in the more severely involved areas. The rash usually lasts six to seven days and fades in the order it appeared [6].
●Recovery and immunity – Cough may persist for one to two weeks after measles. The occurrence of fever beyond the third to fourth day of rash suggests a measles-associated complication. (See 'Complications' below.)
Both humoral and cellular measles-specific immunity are important for viral clearance and lasting protective immunity [3]. Children with defects in humoral immunity, such as agammaglobulinemia, generally recover from measles, while individuals with T cell deficiencies often have severe measles infection and high mortality rates [16-18].
Immunity after measles virus infection is thought to be lifelong, although there are rare reports of measles reinfection [19-21]. A measles surveillance program conducted in the mid-1960s, for example, identified measles in a 16-year-old female with a prior history of measles at age 8 [19]. A rise in anti-measles immunoglobulin (Ig)G but not IgM was observed in this individual, suggesting an anamnestic response. (See 'Modified measles' below.)
Measles virus infection is associated with immunosuppression that can persist. (See 'Immune suppression and secondary infection' below.)
Clinical variants
Modified measles — Modified measles is an attenuated infection that occurs in individuals with pre-existing measles immunity (either via wild-type disease or vaccination). It is similar to classic measles except the clinical manifestations are generally milder and the incubation period is longer (17 to 21 days) [9,22]. Individuals with modified measles are not highly contagious [23,24].
Individuals with nonprotective immunity to measles can develop modified measles; nonprotective immunity may occur in one of the following ways:
●Transplacental transfer of anti-measles antibody from mother to infant. This antibody is generally cleared by three to nine months of age [7]; clearance is earlier among infants born to vaccinated women than infants born to women with history of natural infection [25]. When antibody titers reach levels that are not considered protective, the infant is at risk for measles infection, but low antibody levels may prevent severe disease.
●Receipt of immunoglobulin.
●Measles vaccination resulting in antibody titers lower than those considered seroprotective [26].
●Prior history of measles [20]. (See 'Stages of infection' above.)
Atypical measles — Atypical measles refers to measles virus infection among individuals immunized with the killed virus vaccine, which was used in the United States between 1963 and 1967; atypical measles is now rare. The killed virus vaccine sensitized the recipient to measles virus antigens without providing full protection [6].
Individuals with atypical measles develop high fever and headache 7 to 14 days after exposure to measles. Atypical measles is characterized by higher and more prolonged fever [27]. A maculopapular rash develops two to three days later, beginning on the extremities (instead of the head as seen with typical measles) and spreading to the trunk. The rash may involve the palms and soles and tends to spare the upper chest, neck, and head [7]. The rash may be vesicular, petechial, purpuric, or urticarial; it may have a hemorrhagic component. The distribution and varied appearance of the rash can make diagnosis difficult.
A dry cough and pleuritic chest pain are often present; pneumonitis can be severe [7]. Chest radiograph typically demonstrates bilateral pulmonary nodules and hilar lymphadenopathy [10]. Atypical measles often results in severe illness; many individuals develop respiratory distress. Some individuals develop peripheral edema, hepatosplenomegaly, and/or neurologic symptoms such as paresthesias or hyperesthesias [7].
Laboratory findings can include elevated serum aminotransferases [10]. Atypical measles is associated with a characteristic antibody pattern: before or at the onset of the exanthem, the titer is usually <1:5 but, by day 10 of illness, the titer is typically ≥1:1280. The height and rapidity of antibody titer rise is much higher than in primary natural measles infection [7].
The pathogenesis of atypical measles is not entirely understood. Studies in macaques have shown that the formalin-inactivated measles vaccine induces low avidity, short-lived antibodies against the hemagglutinin protein but not the fusion protein, allowing cell-to-cell viral spread with no cytotoxic T cell immunity. Upon exposure to wild-type measles, the poorly neutralizing antibodies form complexes with the measles antigen, resulting in immune complex deposition, vasculitis, and pneumonitis [28].
Individuals with atypical measles do not appear to transmit measles virus to others [29].
The differential diagnosis of atypical measles is broad. (See 'Differential diagnosis' below.)
Laboratory findings — Thrombocytopenia, leukopenia, and T cell cytopenia may be observed during measles infection [7]. Chest radiography may demonstrate interstitial pneumonitis [10].
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 [10].
Histologic evaluation of conjunctival, nasopharyngeal, or buccal epithelial cells may demonstrate giant cells with inclusions (picture 4); these cells may also be present in urine [10].
COMPLICATIONS — One or more complications occur in approximately 30 percent of measles cases [6]. Diarrhea is the most common complication [6]; most deaths are due to respiratory tract complications or encephalitis. Otitis media occurs in 5 to 10 percent of cases and is more common in younger individuals. The risk of complications is increased in resource-limited settings, where the case fatality rate is 4 to 10 percent [30].
Groups at increased risk for complications of measles are described below. (See 'Groups at risk for complications' below.)
Immune suppression and secondary infection — Measles virus infection can lead to immune suppression and secondary infections, which are important components of measles-related morbidity and mortality [31,32]. Secondary and coinfections may include bacteremia, pneumonia, gastroenteritis and otitis media [33]. Pathogens involved include viruses (eg, parainfluenza virus and adenovirus), and bacteria (eg, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes) [34]. Tuberculosis reactivation in the setting of recent measles infection has also been described [10,29]. Measles associated immune defects may account for increased mortality for up to three years following infection [35].
Several immune alterations have been associated with measles virus infection, including T cell lymphopenia with depletion of T-dependent areas of lymph nodes and spleen, cutaneous anergy [36], diminished in vitro T cell proliferation with mitogens or alloantigens, and diminished antibody production [17,18,37,38].
As an example of the impact on humoral immunity, one study of 77 unvaccinated children found that 11 to 73 percent of the measured array of antibodies to other pathogens was lost following natural measles infection [39]. In another report, genetic sequencing of B cells harvested from patients before and after measles virus infection suggested incomplete restoration of the naive B cell pool; depletion of B memory cells was also identified [40].
Gastrointestinal — Diarrhea is the most common complication; it occurs in approximately 8 percent of cases [6]. Other gastrointestinal complications include gingivostomatitis, gastroenteritis, hepatitis, mesenteric lymphadenitis, and appendicitis. In resource-limited settings, measles-induced stomatitis and diarrhea can lead to diminished nutritional status [7,10].
Pulmonary — Pneumonia is the most common cause of measles-associated death in children; it occurs in approximately 6 percent of cases [6]. Respiratory tract infections occur most frequently among patients <5 years and >20 years of age.
Pulmonary complications of measles virus infection include bronchopneumonia, laryngotracheobronchitis (croup), and bronchiolitis [8,31]. Measles has also been associated with development of bronchiectasis, which can predispose to recurrent respiratory infections [31]. Bacterial superinfection may occur in up to 5 percent of cases.
In one retrospective study of measles deaths in South Africa, 85 percent of cases were attributed to pneumonia (due to viral or bacterial infection) [31]. In a series of 182 cases of measles-associated pneumonia, bacterial pathogens included Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, and Staphylococcus aureus [7,8,41]. 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.
Neurologic — Neurologic complications associated with measles include encephalitis, acute disseminated encephalomyelitis and subacute sclerosing panencephalitis.
Acute measles-induced encephalopathy has been described in the setting of human immunodeficiency virus infection; this manifestation is rare [42].
Encephalitis — Encephalitis occurs in up to 1 per 1000 measles cases. It usually appears within a few days of the rash, typically day 5 (range 1 to 14 days); symptoms may include fever, headache, vomiting, stiff neck, meningeal irritation, drowsiness, convulsions, and coma [6]. Acute measles encephalitis may also occur in the absence of rash [43]. Analysis of cerebrospinal fluid is notable for pleocytosis (predominantly lymphocytes), elevated protein concentration, and normal glucose concentration. Approximately 25 percent of children have neurodevelopmental sequelae; rapidly progressive and fatal disease occurs in about 15 percent of cases [7].
Acute disseminated encephalomyelitis — Acute disseminated encephalomyelitis (ADEM) is a demyelinating disease that occurs in about 1 per 1000 measles cases. ADEM is thought to be a postinfectious autoimmune response; it may be triggered by a number of infectious causes [8,10,44]. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis".)
ADEM presents during the recovery phase of measles, typically within two weeks of the exanthem [10,44,45]. In contrast, subacute sclerosing panencephalitis (SSPE) generally presents years after initial infection. (See 'Subacute sclerosing panencephalitis' below.)
Clinical manifestations of ADEM include fever, headache, neck stiffness, seizures, and mental status changes such as confusion, somnolence, or coma [29,46]. Other manifestations may include ataxia, myoclonus, choreoathetosis, and signs of myelitis, such as paraplegia, quadriplegia, sensory loss, loss of bladder and bowel control, and back pain [46]. 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 following measles infection is associated with a 10 to 20 percent mortality [44]; this is higher than mortality from ADEM due to other causes (up to 7 percent) [47]. Residual neurologic abnormalities are common among survivors, including behavior disorders, cognitive deficits, and epilepsy [44,46].
Subacute sclerosing panencephalitis — SSPE is a fatal, progressive degenerative disease of the central nervous system that usually occurs 7 to 10 years after natural measles virus infection. Its pathogenesis is not well understood but may involve persistent infection with a genetic variant of measles virus within the central nervous system [10,48].
The incidence of SSPE increases when vaccination rates fall [49,50]. Between 1960 and 1974, the risk of SSPE was 8.5 cases per million cases of natural measles infection. Between 1970 and 1980, the risk of SSPE fell to 0.06 cases per million; the decline paralleled the decline of measles cases as a result of vaccination (with a lag time of several years) [49].
Between 1989 and 1991, during a resurgence of measles infection in the United States, the risk of SSPE was estimated to be approximately 200 per million (eg, more than 10-fold higher than the historical estimates); however, due to likely under-reporting of measles cases, the true risk was thought to be about half of this estimate [51]. Subsequently, a study including cases of measles diagnosed in California between 1998 and 2015 noted that the risk of SSPE among children with measles infection who were less than five years of age at the time of the initial infection was approximately 730 per million (1:1367); the risk for development of SSPE among children whose measles infection occurred prior to 12 months of age was approximately 1640 per million (1:609) [52].
In general, patients with SSPE are ≤20 years and become ill 7 to 10 years after natural measles infection [51]. Measles infection at an early age is a risk factor for SSPE; about half of patients with SSPE had measles before the age of two years [53]. The risk of SSPE after measles immunization is thought to be lower than after natural measles infection; according to the United States Centers for Disease Control and Prevention, the risk of SSPE following vaccination is ≤1/12 the risk of SSPE following infection [7,49].
It is controversial whether vaccination can cause SSPE. In one review evaluating the effect of measles vaccination on the epidemiology of SSPE, SSPE was eliminated once wild-type virus was eliminated; even among patients with measles that was thought to be vaccine-induced, wild-type virus was isolated by biopsy [54].
SSPE has been divided into the following stages [48,53]:
●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 [55].
The rate of progression is variable. Stabilization at one stage for a period of time can occur, though patients tend to progress from one stage to the next [56]. Some patients have a remitting and relapsing course. Seizures can occur in any of the stages.
The serum anti-measles antibody concentration is elevated, and cerebrospinal fluid analysis shows elevated protein concentration and detectable anti-measles antibody [7,10].
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 [57-59]. Each complex is followed by a relatively flat pattern [58]. These EEG findings are characteristic of SSPE and may be pathognomonic [48,58]. The EEG may also be abnormal in the other stages of SSPE [48].
Computed tomography of the brain may demonstrate atrophy and scarring [48]. Magnetic resonance imaging of the brain may be normal. In one report (18)F-fluorodeoxyglucose positron emission tomography and magnetic resonance spectroscopy revealed substantial functional abnormalities [60]; 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 SSPE underscores the importance of measles vaccination, not only for prevention of measles but also for prevention of the severe neurologic sequelae that can ensue.
Other complications — Ocular complications of measles include keratitis (a common cause of blindness) and corneal ulceration [7,10,61].
Cardiac complications of measles include myocarditis and pericarditis.
GROUPS AT RISK FOR COMPLICATIONS — Groups at increased risk for complications of measles include immunocompromised patients, pregnant women, individuals with vitamin A deficiency or poor nutritional status, and individuals at the extremes of age [7,29,62-64].
Immunocompromised patients — Patients with defects in cell-mediated immunity (eg, AIDS, lymphoma or other malignancies, and those receiving T cell-suppressive medications) are at risk for severe, progressive measles virus infection [62].
The clinical presentation of measles in immunocompromised hosts may be atypical [62]. Exanthem may be absent, evanescent, or severe and desquamative; purpura has also been described. Therefore, a high level of suspicion should be present when an immunocompromised host presents with pneumonia or encephalitis, particularly after measles exposure and despite history of previous immunization [62,65,66].
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 infection or after a vague prodromal illness that may not include an exanthem [7]. In patients without a rash, lung biopsy may be required to make the diagnosis (picture 4).
●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 [10].
Children with human immunodeficiency virus (HIV) infection may present with measles at an earlier age than HIV-uninfected children (11 versus 15 months) [67,68].
Measles virus infection may have a transient suppressive effect on HIV replication [69,70]; it has been hypothesized that measles infection results in immune activation with factors that are suppressive to HIV viral replication. In a study of 93 HIV-infected children hospitalized with measles, the median plasma HIV ribonucleic acid (RNA) level was lower than the median plasma HIV RNA level among HIV-infected children without acute illness (5339 versus 228,454 copies/mL); median levels rose to 60,121 at discharge and 387,148 copies/mL at one month follow-up, respectively [69].
Serology may not be useful for diagnosis of measles in immunocompromised patients because of deficient antibody synthesis [29]. 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 during pregnancy is associated with increased risk for serious maternal and fetal complications [71-75]. In one study including 55 pregnant women with measles in Namibia, measles-related complications included diarrhea (60 percent), pneumonia (40 percent), and encephalitis (5 percent) [75]. Of the 42 pregnancies with known outcomes, 60 percent had at least one adverse maternal, fetal, or neonatal outcome, and 12 percent of women died. Risk for low birthweight, spontaneous abortion, intrauterine fetal death, and maternal death was significantly increased. Another study noted an increased incidence of premature birth [72].
Maternal measles virus infection at the time of delivery is not always associated with neonatal infection. Congenital measles (defined by the appearance of measles rash within 10 days of birth) and postnatally acquired measles (defined as appearance of measles rash within 14 to 30 days of birth) are associated with a spectrum of illnesses ranging from mild to severe disease [73].
DIAGNOSIS — The diagnosis of measles should be considered in a patient presenting with a febrile rash illness and clinically compatible symptoms (eg, cough, coryza, and conjunctivitis), especially in the setting of recent exposure to an individual with a febrile rash illness or travel to an area of high measles prevalence, particularly in the absence of measles immunity. Patients being evaluated for measles should be isolated.
The diagnosis of measles virus infection is usually made based on at least one of the following: positive serologic test for serum measles IgM antibody, significant rise in measles IgG antibody between acute and convalescent titers, isolation of measles virus in culture, or detection of measles virus RNA by reverse transcription polymerase chain reaction (RT-PCR). The approach to diagnosis differs depending on the regional prevalence of measles:
●Low measles prevalence (high measles vaccine coverage) – In regions of low measles prevalence, cases of suspected or confirmed measles should be reported to the local health authorities, who can provide guidance on specimen collection for diagnosis as well as infection control interventions. In general, it is useful to obtain three samples from patients with suspected measles infection: a serum sample for measles IgM, a throat or nasopharyngeal swab for viral culture, and a urine sample for viral culture. RT-PCR is useful where available. In the setting of diagnostic uncertainty, the diagnosis may be confirmed by evaluation of paired acute and convalescent sera for anti-measles virus IgG; at least fourfold increase in anti-measles antibody titer is indicative of infection [76,77].
●High measles prevalence (low measles vaccine coverage) – In regions of high measles prevalence, the World Health Organization advocates use of serum IgM as the standard test to confirm a diagnosis of measles. However, the anti-measles virus IgM assay should be interpreted with caution, as false-positive and false-negative results have been reported [10,76]. In one study, at least some false-positive results were found to result from human parvovirus B19 IgM [78].
Serology (anti-measles IgM) is the most common laboratory method used for diagnosis of measles virus infection. The detection of measles virus-specific IgM in serum or oral fluid is diagnostic of acute infection, although false positives may rarely occur and the sensitivity of individual assays varies [6,79]. Anti-measles IgM is generally detectable three days after the appearance of the exanthem; it may be undetectable on the day the exanthem appears [76]. IgM is usually undetectable approximately 30 days after the exanthem. Anti-measles IgG is generally undetectable up to 7 days after rash onset but subsequently peaks about 14 days after the exanthem appears [76].
Measles virus RNA can be detected in heparinized blood, nasopharyngeal aspirates, throat swabs, and urine by real time reverse transcription polymerase chain reaction (rRT–PCR) and conventional, endpoint RT-PCR [80]. Viral RNA is usually present for approximately three days after rash onset.
Culturing virus from peripheral blood mononuclear cells, respiratory secretions, conjunctival swabs, or urine can also establish the diagnosis of measles [10]. Measles virus has been isolated from nasopharyngeal secretions during the prodromal phase [7]. However, culture of the virus requires special facilities. Viral isolates are important for molecular epidemiologic surveillance and can be performed in state public health laboratories or the United States Centers for Disease Control and Prevention.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of measles depends on the clinical stage.
Dengue fever may be mistaken for measles during the prodromal period or after the appearance of exanthem and should be considered in the setting of relevant epidemiologic exposure. Dengue may be diagnosed via serologic testing. (See "Dengue virus infection: Clinical manifestations and diagnosis".)
During the prodromal period, the differential diagnosis includes:
●Common respiratory viruses of childhood – These include rhinoviruses, parainfluenza, influenza, adenovirus, and respiratory syncytial virus infections. Fever due to measles infection is typically more pronounced than fever due to other respiratory viruses; these may be distinguished via nasal swab for polymerase chain reaction [7]. (See "The common cold in children: Clinical features and diagnosis".)
●Fordyce spots – Koplik spots can be mistaken for Fordyce spots (tiny yellow-white granules sometimes found on the buccal or lip mucosa resulting from benign ectopic sebaceous glands) [81]. Unlike Koplik spots, Fordyce spots do not occur on an erythematous mucosal background [7]. (See "Oral lesions".)
Once an exanthem has appeared, the differential diagnosis includes (table 1) [7,10,29,82]:
●Viral causes of rash in children – These include varicella, roseola (human herpesvirus 6 infection), erythema infectiosum (parvovirus B19 infection), enterovirus (hand-foot-and-mouth disease), and rubella. Measles can usually be distinguished clinically by the characteristic progression of the rash, its subsequent brownish coloration, blanching on pressure, and other clinical manifestations (especially coryza and conjunctivitis) [7,8]. (See "Roseola infantum (exanthem subitum)" and "Clinical manifestations and diagnosis of parvovirus B19 infection" and "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention" and "Rubella".)
●Group A Streptococcus infection – Manifestations of group A Streptococcus (GAS) that resemble measles include scarlet fever and toxic shock syndrome. Scarlet fever is diagnosed based on clinical manifestations including rash (coarse, sandpaper-like, erythematous, blanching) in association with pharyngitis; toxic shock syndrome is based on isolation of GAS from a normally sterile site (or for a probable case, if GAS is isolated from a nonsterile site), together with hypotension and organ system dysfunction. (See "Complications of streptococcal tonsillopharyngitis", section on 'Scarlet fever' and "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".)
●Drug eruption – An exanthematous drug eruption can resemble the rash associated with measles; it may be distinguished based on history of recent drug exposure and resolution of the rash after drug withdrawal. (See "Exanthematous (maculopapular) drug eruption".)
●Meningococcemia – Clinical manifestations of meningococcemia may include petechial rash in association with fever, nausea, vomiting, headache, altered mental status, and hemodynamic instability. The diagnosis is established via culture. (See "Clinical manifestations of meningococcal infection".)
●Rocky Mountain spotted fever – Clinical manifestations of Rocky Mountain spotted fever include fever, headache, and maculopapular rash in the setting of tick exposure; the rash typically begins on the extremities and subsequently spreads to the trunk. The diagnosis is established via serology or skin biopsy. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)
●Infectious mononucleosis – Typical features of infectious mononucleosis include fever, pharyngitis, adenopathy, and fatigue. A generalized rash (maculopapular, urticarial, or petechial) is occasionally seen; a maculopapular rash often occurs following administration of certain antibiotics (eg, amoxicillin). (See "Infectious mononucleosis".)
●Mycoplasma pneumoniae – Clinical manifestations of M. pneumoniae infection include respiratory tract infection, which may occur in association with a mild erythematous maculopapular or vesicular rash. The diagnosis can be difficult to establish and most treatment is empiric. (See "Mycoplasma pneumoniae infection in adults".)
●Immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]) – Clinical manifestations of IgAV (HSP) include palpable purpura, arthritis, abdominal pain, and renal disease. The diagnosis is based on clinical manifestations and/or biopsy. (See "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis".)
●Kawasaki disease – Clinical manifestations of Kawasaki disease include fever and mucocutaneous involvement including conjunctivitis, erythema of the lips and oral mucosa, rash, and cervical lymphadenopathy. The diagnosis is based on clinical criteria (table 2). (See "Kawasaki disease: Clinical features and diagnosis".)
●Multisystem inflammatory syndrome in children (MIS-C) – This condition occurs following infection or exposure to COVID-19 and causes fever, abdominal pain, rash, and conjunctivitis. The diagnosis is based on clinical criteria. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)
TREATMENT — The treatment of measles is supportive; there is no specific antiviral therapy approved for treatment of measles. There is a role for vitamin A in certain settings, discussed below. Supportive therapy includes antipyretics, fluids, and treatment of bacterial superinfections, such as bacterial pneumonia and otitis media. Treatment of other complications, such as seizures and respiratory failure, may also be necessary.
Antibiotic prophylaxis during measles epidemics may prevent complications; further study is needed [83,84].
Vitamin A — Vitamin A deficiency contributes to delayed recovery and to risk of complications associated with measles infection. In addition, vitamin A levels fall during measles; in children with underlying vitamin A deficiency, measles can result in xerophthalmia, a spectrum of eye disease [1,3]. Xerophthalmia is characterized by pathologic dryness of the conjunctiva and cornea, caused by inadequate function of the lacrimal glands, and is manifested by Bitot spots (picture 5) (areas of abnormal squamous cell proliferation and keratinization of the conjunctiva), progressing to corneal xerosis (dryness) and keratomalacia (softening) (picture 6). (See "Overview of vitamin A", section on 'Clinical manifestations'.)
Vitamin A supplementation may be beneficial for reducing measles severity and risk of complications. Some data suggest that administration of vitamin A to children <2 years of age with measles may be associated with reduced mortality [85,86].
In one review including eight randomized trials and more than 2500 children with measles (including six studies in Africa, one study in Japan, and one study in England), vitamin A supplementation did not reduce mortality; however, among three studies including approximately 300 children <2 years and who received two doses of vitamin A (200,000 international units administered once daily for two consecutive days), lower mortality was observed (1.9 versus 10.7 percent) [86].
In resource-rich settings, data on use of vitamin A for treatment of measles are limited; one study including 108 inpatient children in Italy did not observe a benefit to vitamin A administration [87].
For children with severe measles, we suggest administration of vitamin A; this approach is in alignment with the United States Centers for Disease Control and Prevention, which favors administration of vitamin A to children hospitalized with severe measles [2]. In addition, for children in resource-limited settings with measles (regardless of severity), we suggest administration of vitamin A; this approach is in alignment with the World Health Organization guidance, which favors administration of vitamin A for children with acute measles [1].
Dosing of vitamin A consists of oral administration once daily for two days, as follows [1,2]:
●Infants <6 months of age − 50,000 international units
●Infants 6 to 11 months of age − 100,000 international units
●Children ≥12 months − 200,000 international units
For children with clinical signs and symptoms of severe vitamin A deficiency (such as xerophthalmia, keratitis, keratoconjunctivitis, corneal ulceration, or Bitot spots), a third dose of vitamin A should be administered four to six weeks later [1]. (See "Overview of vitamin A", section on 'Deficiency'.)
Ribavirin — Given the risk of measles-associated mortality among individuals in certain risk groups, we agree with some experts who favor use of ribavirin for treatment of measles pneumonia in patients <12 months, patients ≥12 months with pneumonia requiring ventilatory support, and immunosuppressed patients. Ribavirin dosing consists of 15 to 20 mg/kg per day orally in two divided doses. The optimal duration of therapy is not known; a duration of five to seven days may be reasonable, guided by the patient's clinical status (respiratory symptoms and chest radiograph findings).
Measles virus is susceptible to ribavirin in vitro; data on clinical use of ribavirin are extremely limited [88-92]. In one trial including 100 children with measles treated with supportive care (with or without ribavirin), those who received ribavirin had a shorter duration of fever and constitutional symptoms [88]. In another report including six adults with severe measles pneumonitis treated with intravenous ribavirin, the five patients treated on day 2 to 5 of illness recovered; the patient treated on day 22 of illness did not recover [90].
Investigational therapies — Agents for treatment subacute sclerosing panencephalitis (SSPE) have been evaluated with the goal of stabilization and delay of progression; these agents remain investigational.
Isoprinosine (inosine pranobex) has in vitro activity against mRNA viruses; it is administered orally and generally well tolerated. In one study including 98 individuals with SSPE, the probability of survival among treated patients at 2, 4, 6, and 8 years from onset of SSPE was 78, 69, 65, and 61 percent, compared with 38, 20, 14, and 8 percent in a composite control group [93].
Interferon-alpha or beta has antiviral activity; it may be delivered both intrathecally and intravenously. Some data suggest transient survival benefit [94]. However, in one study including 67 individuals with SSPE, there was no difference in survival among patients treated with combination therapy (intraventricular interferon-alpha and isoprinosine) or isoprinosine monotherapy (35 percent); however, survival among the treated patients was higher than the historical control group (which reported spontaneous improvement in 5 to 10 percent of cases) [95].
PREVENTION
Measles, mumps, and rubella vaccination — Vaccination has led to interruption of measles virus transmission in the developed world and affords protection to unvaccinated individuals via herd immunity. To disrupt broad transmission, herd immunity must be maintained above 85 to 95 percent [96].
Issues related to vaccination for prevention of measles are discussed further separately. (See "Measles, mumps, and rubella immunization in adults" and "Measles, mumps, and rubella immunization in infants, children, and adolescents".)
Infection control — In the inpatient setting, airborne transmission precautions are indicated for four days after the onset of rash in otherwise healthy patients and for the duration of illness in immunocompromised patients [97]. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Airborne precautions'.)
Susceptible individuals should not enter the room of patients with suspected or confirmed measles. Exposed susceptible individuals should be excluded from work from day 5 through day 21 after exposure. If the case is confirmed, even those who were vaccinated within 72 hours should be excluded.
In the outpatient setting, patients with febrile rash illness should be escorted to a separate waiting area or placed immediately in a private room, preferably at negative pressure relative to other patient care areas. Both patients and staff should wear appropriate masks/respirators (masks for patients to prevent generation of droplets, and respirators for staff to filter airborne particles, regardless of immunity status) [98]. If not admitted, patients should be told to remain in isolation at home through four days after rash onset. Measles virus can remain suspended in the air for up to two hours; therefore, the room occupied by a suspect case should not be used for two hours after the patient's departure.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Measles".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Measles (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Syndrome and incubation period − Measles is a highly contagious viral illness that occurs worldwide. The infection is characterized by fever, malaise, cough, coryza, and conjunctivitis, followed by exanthem. Following exposure, approximately 90 percent of susceptible individuals develop measles. The period of contagiousness is estimated to be from five days before the appearance of the rash to four days afterward. The illness may be transmitted in public spaces, even in the absence of person-to-person contact. Patients being evaluated for measles should be isolated. (See 'Introduction' above.)
●Stages of infection − Classic measles infection in immunocompetent patients consists of the following clinical stages: incubation, prodrome, exanthem, and recovery. (See 'Stages of infection' above.)
•Incubation – The incubation is 6 to 21 days (median 13 days).
•Prodrome – A two- to four-day prodrome phase is characterized by fever, malaise, and anorexia, followed by conjunctivitis, coryza, and cough. If present, Koplik spots (picture 1), an enanthem considered pathognomonic for measles infection, typically occurs approximately 48 hours prior to the exanthem.
•Exanthem – The characteristic exanthem arises approximately two to four day after onset of fever; it consists of a red maculopapular rash, which classically begins on the face and head and spreads downward (picture 3A-B). Early on, the lesions are blanching; in later stages, they are not. The rash resolves in five to six days, fading in the order it appeared.
•Recovery – Cough may persist for one two weeks after measles. The occurrence of fever beyond the third to fourth day of rash suggests a measles-associated complication.
●Clinical variants − Clinical variants include modified measles and atypical measles. Modified measles occurs in patients with preexisting but incompletely protective anti-measles antibody. Atypical measles occurs in patients immunized with the killed virus vaccine administered between 1963 and 1967 in the United States who are subsequently exposed to wild-type measles virus. (See 'Clinical variants' above.)
●Diagnosis − The diagnosis of measles should be considered in a patient presenting with a febrile rash illness and clinically compatible symptoms. The approach to diagnosis differs depending on the regional prevalence of measles. (See 'Diagnosis' above.)
•In regions of low measles prevalence, cases of suspected or confirmed measles should be reported to the local health authorities, who provide guidance on specimen collection for diagnosis as well as infection control interventions. In general, it is useful to obtain three samples from patients with suspected measles infection: a serum sample for measles immunoglobulin (Ig)M, a throat or nasopharyngeal swab for viral culture, and a urine sample for viral culture. In the setting of diagnostic uncertainty, the diagnosis may be confirmed by evaluation of paired acute and convalescent sera for anti-measles virus IgG; at least fourfold increase in anti-measles antibody titer is indicative of infection.
•In countries with high measles prevalence, the World Health Organization uses serum IgM as the standard test to confirm the diagnosis of measles. However, the anti-measles IgM assay should be interpreted with caution as false-positive and false-negative results have been reported.
●Complications
•Complications of measles include secondary infections such as diarrhea and pneumonia. Complications of measles among immunocompromised individuals include giant cell pneumonia and measles inclusion body encephalitis. Acute primary measles encephalitis is another rare complication. Groups at increased risk for complications of measles include immunocompromised hosts, pregnant women, individuals with vitamin A deficiency or poor nutritional status, and individuals at the extremes of age. (See 'Complications' above and 'Groups at risk for complications' above.)
•Neurologic syndromes following measles virus infection include acute disseminated encephalomyelitis (ADEM) and subacute sclerosing panencephalitis (SSPE). ADEM is a demyelinating disease that presents during the recovery phase of measles infection and is thought to be caused by a postinfectious autoimmune response. SSPE is a progressive degenerative disease of the central nervous system that generally occurs 7 to 10 years after natural measles infection; its pathogenesis may involve persistent infection with a genetic variant of measles virus within the central nervous system. (See 'Acute disseminated encephalomyelitis' above and 'Subacute sclerosing panencephalitis' above.)
●Treatment − The treatment of measles is largely supportive; in some cases, vitamin A and/or ribavirin may be beneficial.
•Supportive care − Supportive therapy includes antipyretics, fluids, and treatment of bacterial superinfections and other complications.
•Role of vitamin A − For children with severe measles, we suggest administration of vitamin A (Grade 2C). In addition, for children in resource-limited settings with measles (regardless of severity), we suggest administration of vitamin A (Grade 2C). Dosing is summarized above. (See 'Vitamin A' above.)
•Role of ribavirin − For patients <12 months with measles pneumonia, patients ≥12 months with measles pneumonia requiring ventilatory support, and immunosuppressed patients with measles, we suggest treatment with ribavirin (Grade 2C). Dosing is summarized above. (See 'Ribavirin' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jorge L Barinaga, MD, MS, and Paul R Skolnik, MD, FACP, FIDSA, who contributed to an earlier version of this topic review.
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