on 04-May-2025 (Sun)

Measles virus (MV) belongs to the genus Morbillivirus of the family Paramyxoviridae. It is closely related to the viruses causing canine and phocine distemper, rinderpest of cattle, peste des petits ruminants of goats and sheep, and morbilli of certain aquatic animals

Wild-type (WT) MV is pathogenic only for primates.

Initially, before the rash appears, measles can resemble influenza

The disease presents with a nonpruritic rash that begins on the head and face and spreads down the body, with fever and malaise

Clinically, measles may be confused with Kawasaki disease

Measles virus is difficult to culture

Laboratory diagnosis can be made by reverse-transcriptase polymerase chain reaction on just about any body fluid or tissue

Administration of vitamin A once daily by mouth for 2 days should be considered for patients with measles. The mechanism of action of vitamin A is thought to be by immunomodulation

Live-attenuated measles vaccine is administered to healthy children at 12 to 15 months of age and again at age 4 to 6 years.

Passive immunization with immunoglobulin G should be given to high-risk children and adults exposed to measles but having no history of measles

MV is an enveloped, nonsegmented, single-stranded, negative-sense RNA virus. The genome encodes at least eight structural proteins.3

Because the entire genome has been sequenced, it is possible to differentiate between WT MV and vaccine-type virus.

A number of receptors for MV have been described. One is the signaling lymphocyte activation molecule (SLAM; CDw150); WT virus enters mainly using this reeceptor.6,7,8 SLAM is a membrane glycoprotein that is expressed on T and B lymphocytes and antigen-presenting cells, which accounts for its lymphotropism and immunosuppressive effects.

The complement regulatory protein CD46, which is widely distributed in primate tissues, also serves as a receptor for the MV and is particularly used by vaccine type virus.3,9,10

A third receptor, extracellular matrix metalloproteinase inducer (CD147/EMMPRIN), on epithelial cells facilitates transmission by aerosol.11,12 There are also additional receptors for MV.

The H glycoprotein constitutes the antigen that mediates hemagglutination. The hemagglutination inhibition (HI) test, using red blood cells from Old World monkeys, is a historically important serologic test for measuring antibody to MV.

The F glycoprotein causes hemolysis.

Unlike many other paramyxoviruses, neuraminidase is not found on the envelope of MV.13

Genetic and antigenic variations of MV are now recognized; the sequence of genes coding for H and N is the most variable.14

WT MV is rather difficult to propagate in vitro because it is slow growing, and only a limited number of types of cell cultures are permissive for the virus.16

In general, illness caused by MV is milder in monkeys than that in humans.20

It has not been possible to infect small laboratory animals, such as rodents, with WT MV. However, newborn and suckling rodents may be infected with vaccine strains administered by the intracerebral route.21,22

Measles has been recognized as a disease for some 2000 years, but its infectious nature was not recognized until about 150 years ago.

In 1846 Panum23 studied an epidemic of measles in the Faroe Islands and noted that the disease was contagious, that there was an incubation period of about 2 weeks, and that infection appeared to confer lifelong immunity.

Measles is seen in every country in the world. Without a vaccine, epidemics of measles lasting 3 to 4 months could be predicted to occur every 2 to 5 years.

Countries in which measles vaccine is widely used have experienced a marked decrease in the incidence of disease. For example, for many years, 200,000 to 500,000 cases of measles were reported annually in the United States. Since 1963, when the vaccine was licensed, the incidence of measles in the United States has decreased by almost 99%.25,26 This decrease has been especially pronounced since the early 1980s, when state laws requiring proof of immunity to measles for school entry were enacted

Between 2000 and 2007 an average of 63 annual cases were reported.33 Since then, between 2010 and 2017 an average of about 200 cases were reported annually (range, 55–667); 2014 was a banner year, when 667 measles cases were recorded.33a Leaving out 2014, on average 130 measles cases were reported annually in the United States. Most cases occurred in the unvaccinated

In the late 1980s and early 1990s, however, there was an increase in the incidence of measles; this was brought under control by increasing the rate of immunization and by introducing a two-dose schedule of measles vaccine for all children.27,28,29

In the first 6 months of 2008, 131 measles cases were reported to the CDC; 13% were associated with importations from Europe, Asia, and the Middle East. Of these cases, 99 (76%) were epidemiologically or virologically linked to importations. Most of these patients were younger than 20 years, and 91% were unvaccinated or had an unknown vaccination status. Of the unvaccinated individuals, many of whom declined vaccination for philosophic and/or religious reasons, 85% were eligible for vaccination.

In 2011, moreover, a large epidemic of measles occurred in Quebec, Canada, with 725 reported cases, although 95% of 3-year-old children had been immunized with one dose and 90% with two doses. Among adolescents who contracted measles, 22% had received two doses. Thus, although measles vaccine is highly effective, further understanding on susceptibility in recipients of two doses is of interest

For almost the past 20 years, more than half of all measles cases reported in the United States have occurred in individuals who were unvaccinated.37,38

Measles continues to be a worldwide problem that primarily affects children in developing countries. In 2000 it was estimated that more than 750,000 deaths attributed to measles occurred globally.

With the advent of immunization programs supported by the World Health Organization and United Nations Children’s Fund, the estimated deaths globally was reduced by 79% between 2000 and 2014.39 The largest reduction in deaths was observed in Africa.39

The virus, however, remains infective in droplet form in air for several hours, especially under conditions of low relative humidity. This latter fact may account for the increased incidence of measles in winter.49

Measles is spread by direct contact with droplets from respiratory secretions of infected persons and also by the airborne route.

It is one of the most communicable of the infectious diseases, most infectious during the late prodromal phase of the illness, when cough and coryza are at their peak20; however, the disease is probably contagious from several days before until several days after the onset of rash

MV has been isolated from respiratory secretions of patients with measles only until up to 48 hours after the onset of rash.50

Subacute sclerosing panencephalitis (SSPE) is a chronic, degenerative, fatal neurologic disease that occurs on average 7 years after an attack of measles, particularly in children who had measles before 2 years of age. Possibly it is an autoimmune disease.16

A few children who received measles vaccine and who had no prior history of measles have been observed to develop SSPE. It is thought that these children may have had a subclinical case of measles before receiving the vaccine.

The incidence of SSPE in the United States has declined dramatically since the introduction of measles vaccine.25,54 It is almost invariably caused by WT virus; a single case of inclusion-body encephalitis caused by the vaccine strain was reported in 1999.55

Based on the number of cases of measles in children during 1989–91 and the number of cases of SSPE reported to the CDC after those years, it was estimated that the risk of SSPE after measles is 10 times greater than was originally thought, or 1 per 11,000 cases.

More recent analysis of cases of SSPE in the current vaccine era indicate that this complication of natural measles (even mild or subclinical cases) continues to occur, underscoring the impor- tance of measles vaccine in the US population.57

Patients with SSPE have unusually high measles antibody titers in their serum and their cerebrospinal fluid (CSF).58

SSPE is caused by a persistent infection with a measles-related virus in the CNS that occurs despite a vigorous immune response on the part of the host.

The pathogenesis of SSPE is extremely complex and has been ascribed to a combination of host factors and viral replicative phenomena.

The evidence that multiple sclerosis, Crohn disease, and systemic lupus erythematosus are etiologically linked with MV is much weaker than that for SSPE,68,69,70 and MV infection is probably unrelated to these diseases. A causative role for MV in Paget disease of bone has been raised as a possibility but as yet is unproven.71,72,73,74

MV was thought to infect by invasion of the respiratory epithelium from which it spreads to the local lymph nodes, blood, spleen, lymphatic tissue, lung, thymus, liver, and skin.3,72,73

When MV infects epithelial cells, progeny are released into the airway, and thus the virus can be transmitted to new individuals.11

Studies on volunteers inoculated with live MV have indicated that infection may occur after instillation of virus at any point from the nose to the lower parts of the respiratory tract.71

The major infected cell in the blood is the monocyte.3,77

Infected tissues include the thymus, spleen, lymph nodes, liver, skin, conjunctiva, intestine, bladder, and lung.3,6,11

Infection of the entire respiratory mucosa accounts for the cough and coryza that are classic signs of measles. In addition, measles may directly cause croup, bronchiolitis, and pneumonia.

Damage to the respiratory tract from edema and loss of cilia may predispose to secondary bacterial invasion, resulting in complications such as otitis media and pneumonia.20

Within a few days after generalized involvement of the respiratory tract has occurred, Koplik spots appear; subsequently rash develops. Both manifestations are believed to result from similar pathologic mechanisms. On microscopic examination of skin and mucous mem- branes, multinucleate giant cells and other similar histologic changes are observed in the epidermis and oral epithelium.78

The appearance of the measles rash coincides temporally with the appearance of serum antibody and the termination of communicability of the disease. Therefore it has been postulated that the skin and mucous membrane manifestations of measles actually represent hypersensitivity of the host to the virus

If hypersensitivity is the actual cause of the rash, however, it is probably mediated by cellular rather than humoral immunity,81 and therefore patients with agammaglobulinemia who contract measles develop a rash. Patients with deficiencies in cell-mediated immunity, on the other hand, may develop measles giant cell (Hecht) pneumonia without a rash after an exposure to measles or if measles vaccine is given.82,83

Similarly, after measles vaccination, immunity is of many years’ duration and probably lifelong in most persons.25

How measles antibody persists for years after infection is not understood. One possible explanation is that the virus becomes latent after acute infection and provides an immunologic stimulus to antibody formation. However, latent MV has not been demonstrated in humans or in experimental animals. An alternative explanation for the persistence of measles antibody is that reexposure to the virus results in persistent antigenic stimulation

Reinfection with measles can occur and is almost always asymptomatic, even though a boost in antibody titer can be detected.84

Therefore, when humoral antibodies to measles are absent or of low titer, cellular immunity to the virus may protect against subsequent illness.

During infection, CD8 and CD4 T cells are activated and probably participate in the clearance of virus and the development of rash. During recovery, suppression of cell-mediated responses occurs, with elevation of suppressive cytokines such as interleukin-4, which may be responsible for depressed delayed-type hypersensitivity to tuberculin.3,91

The incubation period of measles is 10 to 14 days; it is often somewhat longer in adults than in children.

A prodromal phase lasting several days begins after the incubation period. It is manifested by malaise, fever, anorexia, conjunctivitis, and respiratory symptoms, such as cough and coryza, and may resemble a severe upper respiratory tract infection.

Measles has also been clinically confused with Kawasaki disease, especially in infants and young children. Other diseases that may mimic measles include rubella, meningococcemia, scarlet fever, toxic shock syndrome, human herpesvirus 6 and 7 infections, and parvovirus B19

Toward the end of the prodrome, just before the appearance of the rash, Koplik spots appear

Koplik spots are pathognomonic of measles. First noted by Koplik in 1896, they consist of bluish gray specks on a red base.93 They have been likened to grains of sand and, without examination of the buccal mucosa in good light, may be overlooked. Most often they appear on the mucosa opposite the second molars. However, in severe cases, the entire mucous membrane of the mouth may be involved. This enanthem persists for several days and begins to slough as the rash appears

The rash of measles usually begins on the face and proceeds down the body to involve the extremities last, including the palms and soles (Fig. 160.1). During the healing phase, the involved areas (except palms and soles) may desquamate.

The rash is erythematous and maculopapular; as it progresses, it becomes confluent, especially on the face and the neck. The rash usually lasts about 5 days and starts to clear first on the skin that was initially involved.

The patient with measles is usually most ill during the first or second day of the rash.

Several days after the appearance of the rash, the fever abates and the patient begins to feel better.

The entire uncomplicated illness from late prodrome to resolution of the fever and rash lasts 7 to 10 days; cough may be the last symptom to disappear.

The most common complications of measles involve the respiratory tract and CNS

Superinfection may be secondary to local tissue damage inflicted by the virus and depression of cellular immunity.

Pneumonia accompanying measles may be caused by direct viral invasion of the lungs or by bacterial superinfection.94

Radiographic evidence of pneumonia is common, even during apparently uncomplicated measles.20

In infants who die of measles, pneumonia accounts for about 60% of deaths, whereas in children 10 to 14 years of age, death is more often observed to be from complications of acute encephalitis.95,96

Acute measles encephalitis manifests with a resurgence of fever during convalescence and frequently with headaches, seizures, and changes in the state of consciousness.

Up to 50% of patients with measles but no symptoms that suggest cerebral involvement may have abnormalities detected by electroencephalography,97 so it is believed that viral invasion of the CNS is a common feature of measles. However, only 1 in 1000 to 2000 patients with measles develops clinical signs of encephalitis.

Measles encephalitis ranges from mild to severe, and a high proportion of patients who recover are left with neurologic sequelae

It is hypothesized that acute measles encephalitis is caused by hyper- sensitivity to virus in brain tissue. Both viral and host antigens are present on the surface of measles-infected cells in vitro.102 Therefore hypersensitivity may be directed against viral and host (brain) antigens, which accounts for the encephalitic symptoms.

In patients with measles reported to the CDC in 1991, the incidence of complications was higher in those older than 20 years than in children.30

In a series of 3220 young adult military recruits with measles between 1976 and 1979, about 3% developed pneumonia requiring hospitalization. Bacterial superinfection of the respiratory tract occurred in 30%, and 17% had evidence of bronchospasm. In addition, 31% had laboratory evidence of hepatitis, 29% had otitis media, and 25% had sinusitis.129

Measles has long been regarded as an illness of childhood. When it occurs in adults, it is often a more severe illness.

It seems prudent to defer measles vaccination in persons with known tuberculosis until antituberculosis therapy is underway.

It has long been thought that tuberculosis is aggravated in persons who contract natural measles, presumably because of a depression of cell- mediated immunity by MV.3 For example, the tuberculin test has been reported to become negative for about 1 month after measles or measles vaccination.20

Severe measles may occur in those with compromised or deficient cellular immunity, such as those being treated for malignant disease, after transplantation, and in individuals with acquired immunodeficiency syndrome (AIDS) or any form of congenital immunodeficiency.82,115–117

In a report of measles cases occurring in immunocompromised patients in 1989–90, combined with some recorded in the literature, the case-fatality rate for severe measles in children and young adults was calculated to be 70% in 40 oncology patients and 40% in 11 patients infected with the human immunodeficiency virus (HIV).118 Of the oncology patients, 40% had no rash, 58% had pneumonitis, and 20% had encephalitis. Of the HIV-infected patients, 27% had no rash, and 82% had pneumonia.

Should immunocompromised patients be inadvertently exposed to measles, they may develop giant cell pneumonia without evidence of a rash.82,115,118 In such cases the clinical diagnosis of measles may be difficult or impossible to establish. Because these children may also have poor antibody responses, virus isolation from infected tissue (or identification of measles antigen by immunofluorescence) may be the only means of diagnosis.

Malnourished children, especially in developing countries, have also been reported to develop severe measles. This may be related to poor cell-mediated immune responses resulting from malnutrition.121 Intense exposure to the virus because of crowding may also play a role in the severity of measles in developing countries.122,123

Immunocompromised patients with no history of clinical measles who are exposed to the infection should be passively immunized with immune globulin, even if they have previously been immunized (see later)

Pregnant Women and Their Offspring Rubeola during pregnancy, in contrast to German measles (rubella), is not known to cause congenital anomalies of the fetus.124

However, measles in pregnancy has been associated with spontaneous abortion and premature delivery.20

Measles in the offspring of mothers with measles ranges from mild to severe.126,127 It is therefore recommended that infants born to women with active measles be passively immunized with immune globulin at birth