1967

Measles Virus (Rubeola)

162 Anne A. Gershon

SHORT VIEW SUMMARY

Definition
Measles is a highly contagious viral infection,
usually of childhood.
The disease presents with a nonpruritic
rash that begins on the head and face and
spreads down the body, with fever and
malaise.
Initially, before the rash appears, measles can
resemble influenza.
There is usually accompanying conjunctivitis,
cough, and coryza.
Complications include infections of the
respiratory tract and central nervous system
Microbiology
involvement.
Epidemiology
Measles is very contagious before the rash
Diagnosis
appears, which enhances the chance of spread
before the disease is identified.
Measles is also contagious for a few days
after rash onset.
The virus spreads by droplets and also by the
airborne route.
Widespread vaccination with two vaccine
doses in the Americas has reduced the
incidence of measles so that the virus is no
longer endemic in these regions.
When vaccination rates fall below 95%,
Therapy
measles outbreaks can occur if the virus is
reintroduced into a population.
Immunosuppressed patients are at high risk to
develop severe measles without necessarily
manifesting a rash.
Measles vaccination has been shown to be
unrelated to development of autism.
Prevention
Measles is caused by an RNA virus classified as
a Morbillivirus of the Paramyxoviridae family.
Clinically, measles may be confused with
Kawasaki disease.
Measles virus is difficult to culture.
Diagnosis is usually made clinically, particularly
if Koplik spots on the oral mucosa are observed.
Laboratory diagnosis can be made by
reverse-transcriptase polymerase chain
reaction (RT-PCR) on just about any body fluid
or tissue.
No specific therapy has been proven to be
useful.
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.

Measles, an acute infection caused by the rubeola virus, is highly con-
tagious and usually seen in children. The illness is characterized by
conjunctivitis, cough, coryza, fever, and a maculopapular rash that
begins several days after the initial symptoms appear. There is a char-
acteristic enanthem, Koplik spots, that is specific for measles and that
precedes the onset of rash. Recovery from measles is the rule, but
serious complications of the respiratory tract and central nervous
system (CNS) may occur. Measles in the United States has been largely
controlled since the introduction of live-attenuated measles vaccine in
1963; it remains a serious problem in developing countries, but suc-
cessful efforts are now being carried out for improved control of the
disease.1
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. Although
these viruses are distinct agents, they share certain antigens.2,3 Wild-
type measles virus is pathogenic only for primates.
DESCRIPTION OF THE PATHOGEN
MV is an enveloped, nonsegmented, single-stranded, negative-sense
RNA virus. The genome encodes at least eight structural proteins.3
Morphology
On electron microscopy, measles virions are pleomorphic spheres with
a diameter of 100 to 250nm. Virions consist of an inner nucleocapsid
that is a coiled helix of protein and RNA, and an envelope that bears
two types of short surface projections.3,4 These projections include the
hemagglutinin (H) and the fusion (F) proteins. The molecular weight
of the single-stranded RNA is 4.5kDa. Because the entire genome has
been sequenced, it is possible to differentiate between wild-type
measles virus and vaccine-type virus.
Chemical and Antigenic Composition
Measles virus encodes at least eight structural proteins. These have
letter names and include the following: F, C, H, L (large), M (matrix),
N, P, and V. Three of them, the nucleoprotein (N), the phosphopoly-
merase protein (P), and the large protein (L), are complexed with RNA.
C and V interact with cellular proteins and also play roles in the regula-
tion of transcription and replication of the virus. Three are associated
with the viral envelope: the M protein, a nonglycosylated protein asso-
ciated with the inner lipid bilayer, and the two glycoproteins, H and F.5
The H glycoprotein is involved in attachment of the virus to host cells,
and the F glycoprotein is involved in spread of the virus from one cell
to another. The major receptor for measles virus is the signaling lym-
phocyte activation molecule (SLAM; CDw150); wild-type virus enters
mainly using this reeceptor.6-8 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 measles virus and
is particularly used by vaccine type virus.3,9,10 A third receptor, extracel-
lular matrix metalloproteinase inducer (CD147/EMMPRIN) on epi-
thelial cells facilitates transmission by aerosol.11,12 Multiple receptors
probably enable MV to enter different types of cells during infection.
The H glycoprotein constitutes the antigen that mediates hemaggluti-
nation. The hemagglutination inhibition (HI) test, using red blood cells
from Old World monkeys, is a historically important serologic test
for measuring antibody to measles virus. The F glycoprotein causes
hemolysis. Unlike many other paramyxoviruses, neuraminidase is not
found on the envelope of measles virus.13 Genetic and antigenic varia-
tions of measles virus are now recognized; the sequence of genes
coding for H and N is the most variable.14 Numerous genotypes have
been described.6,8,15,16 Measles virus antigens and their role in human
disease5,17 are discussed later.
1967
 1967.e1
KEYWORDS
autism; encephalitis; maculopapular rash; measles; measles-mumps-
rubella (MMR); pneumonia; reverse-transcriptase polymerase chain

Chapter 162 Measles Virus (Rubeola)

reaction (RT-PCR); subacute sclerosing panencephalitis (SSPE);
vaccination; vitamin A
 1968
Growth of Measles Virus in Tissue
Culture
Measles virus was first successfully isolated in the laboratory by Enders
and Peebles in 1954.18 The virus was initially propagated in primary
Part III Infectious Diseases and Their Etiologic Agents
human renal cells but later was cultivated in cultured simian kidney
cells. Wild-type measles virus 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 Typically, cytopathic effects
produced by measles virus in tissue cultures consist of stellate cells with
increased refractility and, especially on passage, multinucleated syncy-
tial giant cells containing intranuclear inclusions. In the absence of
cytopathic effects, virus replication can also be detected by hemadsorp-
tion of rhesus monkey erythrocytes. Presumptive isolates of measles
virus are identified by typing with monoclonal antibodies by using
immunofluorescence or plaque reduction tests.3,19 Reverse-transcriptase
polymerase chain reaction (RT-PCR) assays for measles virus are also
available (see later).
Host Range
Humans are the only natural host for wild-type measles virus, but
monkeys may also be infected. In general, illness caused by measles
virus is milder in monkeys than that in humans.20 It has not been pos-
sible to infect small laboratory animals, such as rodents, with wild-type
measles virus. However, newborn and suckling rodents may be infected
with vaccine strains administered by the intracerebral route.21,22
EPIDEMIOLOGY
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 immu-
nity. The next major advance in the understanding of measles occurred
in 1954, when Enders and Peebles18 successfully propagated wild-type
measles virus in primary human renal tissue culture cells. This was a
prerequisite for the development of a live-attenuated measles vaccine,
which was licensed for use in the United States in 1963.24
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. The yearly incidence of measles in the
United States reached its first nadir in 1983, when 1497 cases were
reported to the Centers for Disease Control and Prevention (CDC) in
Atlanta. 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.27-29 In 1990, more than
25,000 cases of measles and 89 measles-associated deaths were reported
to the CDC.30 In 1991, however, the number of reported cases dropped
significantly, to 9643.31 Between 1993 and 1996, fewer than 1000
annual cases in the United States were reported to the CDC.32 Between
2000 and 2007, an average of 63 annual cases were reported.33 Using
molecular techniques, it was demonstrated that transmission of indig-
enous measles largely ceased in the United States by 1993. Since that
time, most cases of measles in the United States have resulted from
international importation of measles virus.15
In the first 6 months of 2008, however, 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 epi-
demiologically 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. When vaccination coverage fell to
80% to 85%, measles once again became endemic in the United States.
Although current vaccine coverage in the United States, which is more
than 90%, is sufficient to prevent sustained outbreaks of measles, it is
not sufficient to prevent imported cases, with resultant limited U.S.
spread. In the first 19 weeks of 2011, 118 cases of measles were reported
to the CDC, the highest number of cases during that interval since
1996.34 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 under-
standing on susceptibility in recipients of two doses is called for.
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 the United Nations Childrens Fund, the estimated
deaths globally have been reduced by 60%.6 The largest reduction in
deaths was observed in Africa.35 Measles continues to be a problem in
Europe, where vaccine use may be spotty, and introduction of measles
to the United States by air travel has resulted in measles outbreaks.6,36
Despite the many challenges in controlling measles, however, eventual
elimination of this infection continues to be a goal.
At present, there is minimal published evidence that immunity
induced by measles vaccine wanes significantly with time.28,37-42 The
major reasons why measles has not fully been eliminated from the
United States are failure to immunize all persons who qualify for vac-
cination, primary vaccine failure, and importation of measles to the
United States from other countries.15,36,40-42,43,44 Based on the aforemen-
tioned recent Canadian experience, further studies on the possibility
of waning immunity to measles, even after two doses, seems to be
warranted.
Spread of Infection
The measles virion is very labile; it is sensitive to acid, proteolytic
enzymes, strong light, and drying.3 The virus, however, remains infec-
tive 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.45
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. Measles
virus has been isolated from respiratory secretions of patients with
measles only until up to 48 hours after the onset of rash.46 Airborne
spread of measles in physicians offices47,48 and in a sports complex49
has been observed.
OTHER DISEASES ASSOCIATED
WITH MEASLES VIRUS
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.25,50 It is almost invariably caused
by wild-type virus; a single case of inclusion-body encephalitis caused
by the vaccine strain was reported in 1999.51 Based on the number of
cases of measles in children during 1989 to 1991, 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 origi-
nally thought, or 1 per 11,000 cases. Genotyping revealed that these
SSPE cases were caused by the wild-type measles virus circulating
during those years. It appears therefore that vaccination can prevent
significantly more cases of SSPE than was originally projected.52
Patients with SSPE have unusually high measles antibody titers,
both in their serum and in their cerebrospinal fluid.53 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.
Although a measles-like virus has occasionally been isolated, using
cocultivation techniques, from the brains of patients with SSPE at
autopsy,54,55 the infection is usually characterized by an inability to
produce viral progeny.56 This inability may be a result of defects in the
formation of gene products arising from genomic mutations caused by
errors of RNA replication. Originally, the inability to replicate was
ascribed to failure of the infective virus to produce measles M protein.57
Later, it was realized that this failure was related to mutations of the
gene encoding this protein. Now it is recognized that defects in enve-
lope gene products H and F also occur as a result of other genomic
mutations of the causative virus. Host factors, such as defective cellular
immunity and the ability of specific antibodies to confine the virus to
intracellular multiplication, are also postulated to play a role in the
pathogenesis of SSPE.56-59,60,61 Measles virus RNA was demonstrated by
an in situ RT-PCR assay in neurons, astrocytes, oligodendrocytes, and
vascular endothelial cells in the brain of a patient who died from SSPE.62
The evidence that multiple sclerosis, Crohns disease, and systemic
lupus erythematosus are etiologically linked with measles virus is
much weaker than that for SSPE,63-65 and measles virus infection is
probably unrelated to these diseases. A causative role for measles virus
in Pagets disease of bone has been raised as a possibility but as yet is
unproven.66,67-69
PATHOGENESIS
MV was thought to infect by invasion of the respiratory epithelium
from which it spreads to the local lymph nodes, blood, spleen, lym-
phatic tissue, lung, thymus, liver, and skin.3,67,68 Recent studies in
monkeys, however, have suggested that MV enters lymphoid cells of
the upper respiratory tract by using the SLAM receptor. After replica-
tion in lymphoid cells, MV then invades epithelial cells in organs such
as the respiratory tract, intestine, bladder, and skin. When MV infects
epithelial cells, progeny is released into the airway, and thus the virus
can be transmitted to new individuals.11 Studies on volunteers inocu-
lated with live measles virus have indicated that infection may occur
after instillation of virus at any point from the nose to the lower parts
of the respiratory tract.66
Measles virus has been isolated from the leukocytes of patients with
clinical measles.70 The virus has also been propagated in vitro in human
T and B lymphocytes and in monocytes.71 The major infected cell in
the blood is the monocyte.3,72 Endothelial, epithelial, and dendritic cells
are also infected. 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 sec-
ondary 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.73 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. MV antigen has been demonstrated in the involved
skin and mucous membranes by immunofluorescence assay.73-75 MV
has also been isolated from the rash in its early stages.68 If hypersensi-
tivity is the actual cause of the rash, however, it is probably mediated
by cellular rather than humoral immunity,76 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 (Hechts) pneumonia without a
rash after an exposure to measles or if measles vaccine is given.77,78
1969
IMMUNITY
Immunity to measles after an attack of the disease appears to be life-
long. Rarely, second attacks of measles have been reported after natural
infection. Similarly, after measles vaccination, immunity is of many
Chapter 162 Measles Virus (Rubeola)
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 infec-
tion and provides an immunologic stimulus to antibody formation.
However, latent measles virus has not been demonstrated in humans
or in experimental animals. An alternative explanation for the persis-
tence 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.79 Cellular immunity to MV probably also plays a
role in the prevention of recurrent measles because patients with agam-
maglobulinemia do not have multiple attacks of measles. A cell-
mediated response to measles antigen in the absence of detectable
measles antibody was reported in two physicians in whom no disease
developed despite repeated exposures to measles.80 Therefore, when
humoral antibodies to measles are absent or of low titer, cellular immu-
nity to the virus may protect against subsequent illness. Cellular immu-
nity to MV in peripheral blood of persons with a history of measles
has been shown by in vitro lymphocyte stimulation after exposure to
measles antigen81 and by demonstration of measles-specific class I and
II cytotoxic T cells.82-84 A complex interplay of cellular immunity and
cytokines occurs before, during, and after measles infection in healthy
persons.6,85
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 tubercu-
lin.3,86 Effects of vaccine on the immune system that resemble the
effects of naturally occurring measles have also been described.87
CLINICAL MANIFESTATIONS
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. 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.88 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 enan-
them 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. 162-1). During the healing phase, the involved areas (except
palms and soles) may desquamate. The rash is erythematous and mac-
ulopapular; 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.
Complications
The most common complications of measles involve the respiratory
tract and CNS. Involvement of the respiratory tract is part of the virus
infection itself. In addition, bacterial superinfection may occur in any
area of the respiratory tract, including the middle ear. Superinfection
may be secondary to local tissue damage inflicted by the virus and
 1970
Part III Infectious Diseases and Their Etiologic Agents
FIGURE 162-1 Typical rash on a patient with measles. (From Kremer
JR, Muller CP. Measles in Europethere is room for improvement. Lancet.
2009;373:356-358.)
depression of cellular immunity. Pneumonia accompanying measles
may be caused by direct viral invasion of the lungs or by bacterial
superinfection.89 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.90,91
Encephalitis after measles in normal hosts may be acute or chronic
(e.g., SSPE). 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,92 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.
MV has been isolated from the brains of several persons dying of
measles encephalitis.93-96 However, virus isolation is uncommon and
usually requires special virologic techniques such as cocultivation. It is
hypothesized that acute measles encephalitis is caused by hypersensi-
tivity to virus in brain tissue. Both viral and host antigens are present
on the surface of measles-infected cells in vitro.97 Therefore, hypersen-
sitivity may be directed against viral and host (brain) antigens, which
accounts for the encephalitic symptoms. Demyelination, vascular
cuffing, gliosis, and infiltration of fat-laden macrophages near blood
vessel walls are noted in brain tissue from patients with measles
encephalitis.3 In a laboratory study of serum and cerebrospinal fluid
from 19 patients with postinfectious measles encephalitis, similarities
between experimental allergic encephalomyelitis (e.g., immune
responses to myelin basic protein, early destruction of myelin) were
demonstrated in about 50%. There was no evidence of intrathecal
synthesis of antibody against measles virus, which suggests that immu-
nopathology, rather than viral multiplication, is involved in the patho-
genesis of measles encephalitis.98
Transient hepatitis has also been reported during acute measles.99
Special Considerations
Modified Measles
An extremely mild form of measles has been observed in persons with
some degree of passive immunity to the virus. This includes some
babies younger than 1 year who have passively acquired maternal anti-
body to measles virus and some susceptible persons who received
immune globulin after an exposure to measles. The symptoms of
modified measles are variable, and certain classic symptoms, such as
the prodromal period, conjunctivitis, Koplik spots, and rash may be
absent. The incubation period may be prolonged. At times, the infec-
tion is subclinical and, with a great degree of passively acquired immu-
nity, may be prevented completely.79
Atypical Measles
The syndrome of atypical measles has been described in persons who
received killed measles vaccine (or killed vaccine, followed soon after-
ward by live vaccine) and who, several years later, were exposed to
wild-type measles virus.100,101 Initially, these patients have an undetect-
able or a very low measles antibody titer. They then develop unusual
manifestations of measles, followed by the appearance of extremely
high measles antibody titers (e.g., 1:100,000) in their serum.102 After
a prodrome of fever and pain for 1 to 2 days, the rash appears. Unlike
classic measles, it begins peripherally and may be urticarial, maculo-
papular, hemorrhagic, vesicular, or some combination of these types.
The disease may be misdiagnosed as varicella, Rocky Mountain spotted
fever, Henoch-Schnlein purpura, drug eruption, or toxic shock syn-
drome. The patient has a high fever, edema of the extremities, intersti-
tial pulmonary infiltrates, hepatitis and, on occasion, a pleural effusion.
The disease tends to be severe with a somewhat more prolonged course
than regular measles. At least one fatality has been reported. No spe-
cific therapy is available. Measles virus has not been isolated from these
patients, and they do not appear to transmit measles to others.101
The pathogenesis of this syndrome is believed to be one of hyper-
sensitivity to MV in a partially immune host. Whether cell-mediated
or humoral immune mechanisms, or both, are involved remains con-
troversial.101,103,104 One hypothesis concerning pathogenesis is that
killed measles vaccine lacks the antigen that stimulates the immunity
that prevents entry of measles virus into cells, thereby allowing measles
infection to occur, despite the partial immunity derived from killed
vaccine.105,106 In an animal model, the low avidity of measles antibodies
induced by the inactivated vaccine fails to neutralize the wild-type
virus, leading to deposition of immune complexes, vasculitis, and
pneumonitis.3
Recurrences of atypical measles have not been reported. Therefore,
those who received killed measles vaccine (or killed vaccine, followed
soon afterward by live vaccine) in the past may be reimmunized with
live measles vaccine. It is important that persons who have received
killed vaccine be made aware, however, that severe local reactions can
follow an injection of live vaccine.107,108 Usually, the reaction consists
of tenderness and erythema around the injection site. However, severe
local edema and high fever may also occur. Immunization with live
vaccine should be strongly considered because the associated risk is
lower than the risk of being exposed to the wild-type virus.109 Because
killed measles vaccine was not used after 1967, atypical measles is now
extremely rare.
Immunocompromised Patients
Severe measles may occur in those with compromised or deficient cel-
lular 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.77,110-112
In a report of measles cases occurring in immunocompromised
patients in 1989 to 1990, combined with some recorded in the litera-
ture, 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).113 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 pneu-
monia without evidence of a rash.77,110,113 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 immuno-
fluorescence) may be the only means of diagnosis. A chronic form of
encephalitis resembling SSPE, often with a concomitant pneumonia,
has also been reported in those with deficient cellular immunity.58,59
This entity has been classified as subacute measles encephalitis and

may be confirmed by the presence of measles RNA or infectious virus
in brain tissue.114 Even in the era of molecular diagnostic techniques,
however, this diagnosis may be difficult to establish, particularly if the
person had no history of clinical measles in the past.115 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.116 Intense exposure to
the virus because of crowding may also play a role in the severity of
measles in developing countries.117,118
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.119 However,
measles in pregnancy has been associated with spontaneous abortion
and premature delivery.20 Measles can be severe in pregnancy. From
1988 to 1991, when there was a resurgence of measles in the United
States, a number of pregnant women developed measles. Of 13 such
women hospitalized in Houston, 54% had respiratory complications
requiring admission to the intensive care unit, and one died.120 These
women were thought to have primary measles pneumonia. Measles in
the offspring of mothers with measles ranges from mild to severe.121,122
It is therefore recommended that infants born to women with active
measles be passively immunized with immune globulin at birth.
Persons with Tuberculosis
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 It seems prudent to defer measles vaccination in
persons with known tuberculosis until antituberculosis therapy is
underway. In geographic areas and populations where tuberculosis is
rare, it is not mandatory to perform a tuberculin test on an infant
before administering measles vaccine.123
Occurrence in Adults
Measles has long been regarded as an illness of childhood. When it
occurs in adults, it is often a more severe illness. 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.124 In patients
with measles reported to the CDC in 1991, the incidence of complica-
tions was higher in those older than 20 years than in children.30
DIAGNOSIS
Classic measles with cough, coryza, conjunctivitis, Koplik spots, and a
maculopapular rash beginning on the face is easily diagnosed clinically.
Often, there is a striking leukopenia, perhaps related to the infection
and death of leukocytes. A laboratory diagnosis of measles is helpful
when the clinician is unfamiliar with the illness because of the decline
in cases of clinical measles since the introduction of measles vaccine. A
laboratory diagnosis may also be helpful in cases of possible atypical
measles, or when unexplained pneumonia or encephalitis occurs in an
immunocompromised patient. The differential diagnosis of measles
includes rubella, Kawasaki syndrome, scarlet fever, roseola, infectious
mononucleosis and rickettsial, enteroviral, and adenoviral infections.
Measles may be diagnosed in the laboratory by virus isolation,
identification of measles antigen or RNA in infected tissues, or dem-
onstration of a significant serologic response to MV. Virus isolation is
technically difficult, and facilities for isolation are not always available.
It is particularly useful, however, for patients with fatal pneumonia and
patients with an immunodeficiency, in whom an antibody response
may be minimal. Immunofluorescent examination of cells from nasal
exudates or from urinary sediment for the presence of measles antigen
may be useful for rapid diagnosis of measles.119,125 A sensitive RT-PCR
1971
amplification method to demonstrate measles virus RNA is available,
and nucleotide sequencing can be used for precise characterization of
diagnostic specimens.16,126
A commonly used laboratory diagnostic method is the serologic
Chapter 162 Measles Virus (Rubeola)
response to the virus. A fourfold or greater increase in measles anti-
body titer in acute and convalescent serum specimens is considered
diagnostic for measles. SSPE may be diagnosed by the demonstration
of high measles antibody titers in serum and cerebrospinal fluid in the
presence of a compatible illness.125 A number of methods are available
for measuring antibodies to measles, usually through hospital or state
health department laboratories. Neutralization, which requires propa-
gation of the virus in vitro, is technically difficult and infrequently
used. Complement fixation lacks sensitivity and is rarely used. The HI
test is not used frequently today because it has been supplanted by the
enzyme-linked immunosorbent assay (ELISA), for which many diag-
nostic kits are commercially available.
The ELISA is sensitive and simple to perform and is now widely
used.127,128 This assay can also be adapted to detect specific immuno-
globulin M (IgM) antibody129 and is therefore useful for the diagnosis
of acute measles on one serum sample. False-negative and false-
positive results, however, may occur with this assay. Measles IgM per-
sists for as long as 1 month after disease onset. Antibody tests that use
capillary blood collected on filter paper from finger- or heel-stick
specimens have been described and are used by some state health
department laboratories.130
PREVENTION
Since the use of live measles vaccine, methods to prevent measles have
changed dramatically. Prevention today is ideally carried out long
before an anticipated exposure to measles by the administration of live
vaccine during the early part of the second year of life. However, there
are rare occasions when passive immunization against measles with
immune globulin must be used.
Included in the group of persons for whom passive immunization
is recommended are those who are at high risk for developing severe
or fatal measles, are susceptible, and/or have been exposed to the infec-
tion. This includes children with malignant disease, particularly if
they are receiving chemotherapy, radiotherapy, or both, and children
with significant deficits in cell-mediated immunity, including patients
with AIDS. Babies younger than 1 year (including newborns whose
mothers have measles) are also at increased risk after an exposure to
measles. Because measles has been reported even after vaccination in
HIV-infected children, it has been recommended that they also be
passively immunized with immune globulin after a recognized expo-
sure.112,113,123,131 To be effective, passive immunization must be given
within 6 days after an exposure; administration after 6 days would not
be expected to influence the course of the disease.
For a healthy infant younger than 1 year who has been exposed to
measles, the modifying dose of immune globulin is 0.25mL/kg intra-
muscularly (IM). An infant passively immunized in this fashion should
be given live measles vaccine at the age of 15 months.123 For immuno-
compromised exposed children, a larger dose of immune globulin is
required. These children should be given immune globulin, 0.5mg/kg
IM, with a maximum of 15mL.
Active immunization against measles was developed in the early
1960s. Live and killed measles vaccines were licensed for use in the
United States in 1963. Killed vaccine was withdrawn from the market
in 1967, after the recognition of atypical measles in recipients of this
vaccine. The first marketed live measles vaccine was the Edmonston B
strain. This vaccine was associated with a fairly high incidence of
moderately severe side reactions, such as rash and fever, and it was
therefore often administered along with a dose of immune globulin.
Subsequently, more attenuated vaccines were developed from the
Edmonston strain.132 Because the incidence of vaccine reactions is low
with these vaccines, immune globulin is no longer given along with
measles vaccine.
In 1976, it was recommended that all healthy children be given live
measles vaccine at 15 months. At present, it is recommended that
children be immunized between the ages of 12 and 15 months (usually
given as measles-mumps-rubella [MMR] vaccine or measles-mumps-
rubella-varicella [MMRV] vaccine).123 A second dose is recommended
 1972
later in childhood.109,123 Properly administered measles vaccine has
been associated with persistence of immunity to measles for many
years.132-135 In one study, although measles HI antibodies were no
longer detectable in some subjects, antibodies were demonstrated by
Part III Infectious Diseases and Their Etiologic Agents
have been treated for malignant disease may be given measles vaccine
3 months after they complete their course of therapy.123 High-risk
children, such as those described, may be given monovalent measles
vaccine or MMR, but they should not be given MMRV vaccine, which

neutralization, and revaccination was associated with a classic booster
antibody response.133 The estimated rate of secondary immune failure
was calculated as less than 0.2%. In the general population, 95% of
properly immunized children can be expected to respond serologically
to measles vaccine. MMRV has been licensed for use in healthy chil-
dren (not adults) in the United States and in many other countries.
After two doses, this vaccine provides an adequate immune response
to all four viral antigens with a single injection (see Chapter 321).136
Vaccination is not usually recommended for infants younger than
12 months because the induction of immunity may be suppressed by
residual transplacentally acquired antibodies. In situations in which the
incidence of natural measles before the age of 1 year is high, live measles
vaccine may be given at 6 to 9 months of age but should be routinely
followed by additional doses.42 Measles antibody titers are lower in
women vaccinated as children than in women who have had natural
measles, and the offspring of vaccinated women often lose transplacen-
tally acquired measles antibodies before they are 1 year old.137,138 There-
fore, vaccination can be routinely given as early as 12 months of age
because most women in their childbearing years today were vaccinated
as children. For individuals who were passively immunized after an
exposure to measles, vaccination should not be performed for 5 months
after a dose of 0.25mL/kg or 6 months after a dose of 0.50mL/kg.123
Transient fever and rash develop about 1 week after vaccination in 5%
to 15% of children. In a 1986 study of 1162 twins who were given either
MMR or placebo, there were side effects (fever, irritability, drowsiness,
conjunctivitis) in 0.5% to 4%.139 Symptoms of CNS dysfunction after
measles vaccine are exceedingly rare.140 Because measles may be severe
in adults, immunization of adults who were not vaccinated previously,
who have no history of measles, and who were born after 1956 is rec-
ommended by the CDC.109 A 1986 Chicago study of hospital employ-
ees, however, indicated that only 1 of 266 (0.03%) was susceptible to
measles; about one third were born after 1957.141
A number of reasons for apparent primary vaccine failures of
measles vaccine have been proposed.25 These include improper storage
of vaccine at temperatures exceeding 4 C, failure to use the proper
diluent for the lyophilized vaccine, exposure of the vaccine to light or
heat, and vaccination in the presence of low levels of passive antibody.
The latter may occur if infants are immunized at 12 months of age or
younger, if children are vaccinated 1 or 2 months after receiving an
injection of immune globulin, if the more attenuated vaccines are given
with immune globulin, or if live measles vaccine is administered soon
after killed measles vaccine. No deleterious effects have been associated
with measles revaccination. Although it is probably unusual, sustained
transmission of measles has been reported in secondary schools, even
when 95% of the students were immune and more than 99% were
immunized.142,143
Live measles vaccine is contraindicated in persons with deficits in
cell-mediated immunity and in pregnant women. Fatal measles in chil-
dren with AIDS has been reported.131,144 Although the potential risks
of measles vaccine in these children are unknown, they are less than
the disease itself. It is currently recommended that children with
known asymptomatic HIV infection receive measles vaccine after the
age of 12 months.111,123 The use of measles vaccine should also be con-
sidered for children with known HIV infection who manifest symp-
toms if their CD4 T-cell levels are relatively well preserved, especially
if they live in locations where there may be transmission of measles,
such as certain inner city areas.123 One case of fatal measles pneumonia
resulting from vaccine virus in an HIV-infected vaccinated young adult
has been described after a second dose of vaccine.112,145 Children who
contains a significantly higher dose of the varicella component. No
safety data for MMRV in high-risk children are available.146
Serious hypersensitivity reactions to measles vaccine in persons
allergic to egg protein have been reported. Persons with a history of
anaphylactic reactions after the ingestion of eggs should be vaccinated
only with extreme caution.147,148
Susceptible persons who are exposed to measles, with the exception
of young infants, pregnant women, and immunocompromised persons,
may be given live measles vaccine to prevent disease, as an alternative
to immune globulin. If the vaccine is given shortly after exposure,
clinical cases of measles may be prevented because clinical manifesta-
tions associated with measles vaccine occur in about 7 days, compared
with an incubation period of 10 days for clinical measles.20
An experimental measles vaccine, a derivative of the original
Edmonston B vaccine strain termed Edmonston-Zagreb vaccine,
administered at a dose 10 to 100 times higher than usual, proved to be
immunogenic in 4- to 6-month-old infants.149 Despite its short-term
safety, however, the rate of mortality from causes other than measles
in these vaccinees in Senegal was significantly higher than that in
children who received standard vaccine.150 Therefore, this vaccine is no
longer in use.
The possibility that an abnormal immune reaction to vaccine-type
measles virus in MMR vaccine might cause autism in young children
was raised in 1998 by Wakefield and co-workers.151 This idea was never
accepted by the vast majority of the scientific community, and 10 of
the original 13 authors of the paper eventually withdrew their names
from the article in retraction of its content, in part because of conflict
of interest by Wakefield.152 After extensive review, numerous national
committees, including the Institute of Medicine, concluded that there
is no evidence to support this hypothesis.153-155 A recent case-control
study involving three independent laboratories failed to identify an
association between autism and measles RNA in the gut or exposure
to MMR vaccine.156 Additional other recent scientific studies have
failed to identify an association between MMR vaccine and subsequent
development of autism.157-161 In the United Kingdom, where there has
been extensive adverse publicity about MMR, the incidence of measles
has increased as a result of suboptimal vaccination rates.162
THERAPY
Patients with measles should be given supportive therapy, such as
antipyretics and fluids as indicated. Bacterial superinfection should be
promptly treated with appropriate antimicrobials, but prophylactic
antibiotics to prevent superinfection are of no known value and are
therefore not recommended.
Vitamin A, 200,000IU administered orally to children once daily
for 2 days, has been reported to decrease the severity of measles, espe-
cially in those with vitamin A deficiency (see Chapter 50).163-165 Chil-
dren 6 months to 1 year old should receive 100,000IU for 2 days.
Children younger than 6 months old should receive 50,000 IU for 2
days. Children with clinical signs and symptoms of vitamin A defi-
ciency should receive an age-specific dose (a third dose) 2 to 4 weeks
later. Side effects include transient vomiting and headache.166 This
treatment has also been recommended for consideration in the United
States for children with measles who are immunodeficient, have mal-
absorption, or are malnourished.123 Administration of vitamin A has
been reported to reduce seroconversion in vaccinees and should there-
fore be avoided at or after immunization.167 The efficacy of ribavirin
administered intravenously or by aerosol for treatment of severe
measles is unproven.120,131,168

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