1603CHAPTER 204 Enterovirus, Parechovirus, and Reovirus Infections

the onset of symptomatic disease, when virus is present in the stool

and throat. The ingestion of virus-contaminated food or water also

can cause disease. Certain enteroviruses (such as enterovirus 70,

which causes acute hemorrhagic conjunctivitis) can be transmitted by

direct inoculation from the fingers to the eye. Airborne transmission

is important for some viruses that cause respiratory tract disease, such

as coxsackievirus A21. Enteroviruses can be transmitted across the

placenta from mother to fetus, causing severe disease in the newborn.

The transmission of enteroviruses through blood transfusions or insect

bites has not been documented. Nosocomial spread of coxsackievirus

and echovirus has taken place in hospital nurseries. Outbreaks of

enteroviruses correlate with levels of preexisting immunity to specific

serotypes and birth rates.

■ CLINICAL FEATURES

Poliovirus Infection Most infections with poliovirus are asymptomatic. After an incubation period of 3–6 days, ~5% of patients present with a minor illness (abortive poliomyelitis) manifested by fever,

malaise, sore throat, anorexia, myalgias, and headache. This condition

usually resolves in 3 days. About 1% of patients present with aseptic

meningitis (nonparalytic poliomyelitis). Examination of cerebrospinal

fluid (CSF) reveals lymphocytic pleocytosis, a normal glucose level,

and a normal or slightly elevated protein level; CSF polymorphonuclear

leukocytes may be present early. In some patients, especially children,

malaise and fever precede the onset of aseptic meningitis.

PARALYTIC POLIOMYELITIS The least common presentation is that of

paralytic disease. After one or several days, signs of aseptic meningitis

are followed by severe back, neck, and muscle pain and by the rapid

or gradual development of motor weakness. In some cases, the disease

appears to be biphasic, with aseptic meningitis followed first by apparent recovery but then (1–2 days later) by the return of fever and the

development of paralysis; this form is more common among children

than among adults. Weakness is generally asymmetric, is proximal

more than distal, and may involve the legs (most commonly); the arms;

or the abdominal, thoracic, or bulbar muscles. Paralysis develops during the febrile phase of the illness and usually does not progress after

defervescence. Urinary retention also may occur. Examination reveals

weakness, fasciculations, decreased muscle tone, and reduced or absent

reflexes in affected areas. Transient hyperreflexia sometimes precedes

the loss of reflexes. Patients frequently report sensory symptoms, but

objective sensory testing usually yields normal results. Bulbar paralysis

may lead to dysphagia, difficulty in handling secretions, or dysphonia.

Respiratory insufficiency due to aspiration, involvement of the respiratory center in the medulla, or paralysis of the phrenic or intercostal

nerves may develop, and severe medullary involvement may lead to

circulatory collapse. Most patients with paralysis recover some function weeks to months after infection. About two-thirds of patients have

residual neurologic sequelae.

Paralytic disease is more common among older individuals, pregnant women, and persons exercising strenuously or undergoing trauma

at the time of CNS symptoms. Tonsillectomy predisposes to bulbar

poliomyelitis, and IM injections increase the risk of paralysis in the

involved limb(s).

VACCINE-ASSOCIATED POLIOMYELITIS The risk of developing poliomyelitis after oral vaccination is estimated at 1 case per 2.5 million

doses. The risk is ~2000 times higher among immunodeficient persons, especially persons with hypo- or agammaglobulinemia. Before

1997, an average of eight cases of vaccine-associated poliomyelitis

occurred—in both vaccinees and their contacts—in the United States

each year. With the change in recommendations first to a sequential

regimen of inactivated poliovirus vaccine (IPV) and oral poliovirus

vaccine (OPV) in 1997 and then to an all-IPV regimen in 2000, the

number of cases of vaccine-associated polio declined. From 1997 to

1999, six such cases were reported in the United States; no cases have

been reported since 1999.

POSTPOLIO SYNDROME The postpolio syndrome presents as new

onset of weakness, fatigue, fasciculations, and pain with additional

TABLE 204-1 Manifestations Commonly Associated with Enterovirus

Serotypes

MANIFESTATION

SEROTYPE(S) OF INDICATED VIRUS

COXSACKIEVIRUS

ECHOVIRUS (E) AND

ENTEROVIRUS (Ent)

Acute hemorrhagic

conjunctivitis

A24 E70

Aseptic meningitis A2, 4, 7, 9, 10; B1–5 E4, 6, 7, 9, 11, 13, 16, 18,

19, 30, 33; Ent70, 71

Encephalitis A9; B1–5 E3, 4, 6, 7, 9, 11, 18, 25,

30; Ent71

Exanthem A4, 5, 6, 9, 10, 16; B1, 3–5 E4–7, 9, 11, 16–19, 25, 30;

Ent71

Generalized disease of

the newborn

B1–5 E4–7, 9, 11, 14, 16, 18, 19

Hand-foot-and-mouth

disease

A5–7, 9, 10, 16; B1, 2, 5 Ent71

Herpangina A1–10, 16, 22; B1–5 E6, 9, 11, 16, 17, 25, 30;

Ent71

Myocarditis, pericarditis A4, 9, 16; B1–5 E6, 9, 11, 22

Paralysis A4, 7, 9; B1–5 E2–4, 6, 7, 9, 11, 18, 30;

EntD68, 70, 71

Pleurodynia A1, 2, 4, 6, 9, 10, 16; B1–6 E1–3, 6, 7, 9, 11, 12, 14, 16,

19, 24, 25, 30

Pneumonia A9, 16; B1–5 E6, 7, 9, 11, 12, 19, 20, 30;

EntD68, 71

atrophy of the muscle group involved during the initial paralytic disease

20–40 years earlier. The syndrome is more common among women and

with increasing time after acute disease. The onset is usually insidious,

and weakness occasionally extends to muscles that were not involved

during the initial illness. The prognosis is generally good; progression

to further weakness is usually slow, with plateau periods of 1–10 years.

The postpolio syndrome is thought to be due to progressive dysfunction and loss of motor neurons that compensated for the neurons

lost during the original infection and not to persistent or reactivated

poliovirus infection.

Other Enteroviruses An estimated 5–10 million cases of symptomatic disease due to enteroviruses other than poliovirus occur in the

United States each year. Among neonates, enteroviruses are the most

common cause of aseptic meningitis and nonspecific febrile illnesses.

Certain clinical syndromes are more likely to be caused by certain

serotypes (Table 204-1).

NONSPECIFIC FEBRILE ILLNESS (SUMMER GRIPPE) The most common clinical manifestation of enterovirus infection is a nonspecific

febrile illness. After an incubation period of 3–6 days, patients present

with an acute onset of fever, malaise, and headache. Occasional cases

are associated with upper respiratory symptoms, and some cases

include nausea and vomiting. Symptoms often last for 3–4 days, and

most cases resolve in a week. While infections with other respiratory

viruses occur more often from late fall to early spring, febrile illness

due to enteroviruses frequently occurs in the summer and early fall.

GENERALIZED DISEASE OF THE NEWBORN Most serious enterovirus

infections in infants develop during the first week of life, although

severe disease can occur up to 3 months of age. Neonates often present with an illness resembling bacterial sepsis, with fever, irritability,

and lethargy. Laboratory abnormalities include leukocytosis with a

left shift, thrombocytopenia, elevated values in liver function tests,

and CSF pleocytosis. The illness can be complicated by myocarditis

and hypotension, fulminant hepatitis and disseminated intravascular

coagulation, meningitis or meningoencephalitis, or pneumonia. It may

be difficult to distinguish neonatal enterovirus infection from bacterial

sepsis, although a history of a recent virus-like illness in the mother

provides a clue.

1604 PART 5 Infectious Diseases

ASEPTIC MENINGITIS AND ENCEPHALITIS In children and young

adults, enteroviruses are the cause of up to 90% of cases of aseptic

meningitis in which an etiologic agent can be identified. Patients

with aseptic meningitis typically present with an acute onset of fever,

chills, headache, photophobia, and pain on eye movement. Nausea

and vomiting also are common. Examination reveals meningismus

without localizing neurologic signs; drowsiness or irritability also may

be apparent. In some cases, a febrile illness may be reported that remits

but returns several days later in conjunction with signs of meningitis.

Other systemic manifestations may provide clues to an enteroviral

cause, including diarrhea, myalgias, rash, pleurodynia, myocarditis,

and herpangina. Examination of the CSF invariably reveals pleocytosis;

the CSF cell count shows a shift from neutrophil to lymphocyte predominance within 1 day of presentation, and the total cell count does

not exceed 1000/μL. The CSF glucose level is usually normal (in contrast to the low CSF glucose level in mumps), with a normal or slightly

elevated protein concentration. Partially treated bacterial meningitis

may be particularly difficult to exclude in some instances. Enteroviral

meningitis is more common in summer and fall in temperate climates,

while viral meningitis of other etiologies is more common in winter

and spring. Symptoms ordinarily resolve within a week, although CSF

abnormalities can persist for several weeks. Enteroviral meningitis is

often more severe in adults than in children. Neurologic sequelae are

rare, and most patients have an excellent prognosis.

Enteroviral encephalitis is much less common than enteroviral aseptic

meningitis. Occasional highly inflammatory cases of enteroviral meningitis may be complicated by a mild form of encephalitis that is recognized on the basis of progressive lethargy, disorientation, and sometimes

seizures. Less commonly, severe primary encephalitis may develop. An

estimated 10–35% of cases of viral encephalitis are due to enteroviruses.

Immunocompetent patients generally have a good prognosis.

Patients with hypogammaglobulinemia, agammaglobulinemia, or

severe combined immunodeficiency may develop chronic meningitis

or encephalitis; about half of these patients have a dermatomyositis-like

syndrome, with peripheral edema, rash, and myositis. They may also

have chronic hepatitis. Patients may develop neurologic disease while

receiving immunoglobulin replacement therapy. Echoviruses (especially echovirus 11) are the most common pathogens in this situation.

Paralytic disease due to enteroviruses other than poliovirus occurs

sporadically and is usually less severe than poliomyelitis. Most cases are

due to enterovirus 70 or 71 or to coxsackievirus A7 or A9. Guillain-Barré

syndrome is also associated with enterovirus infection. While earlier

studies suggested a link between enteroviruses and chronic fatigue syndrome, most recent studies have not demonstrated such an association.

ACUTE FLACCID MYELITIS Patients with acute flaccid myelitis present

with fever or respiratory symptoms and progress within hours to a few

days to flaccid paralysis in one or more limbs. The disease is much

more frequent in children. Less commonly, the disease can affect

cranial nerves and respiratory or bulbar muscles. Like polio and some

other enteroviruses, the disease affects the anterior horn cells in the

spinal cord; gray matter changes can be seen on MRI of the spinal cord.

The CSF shows a lymphocytic pleocytosis and often a mildly elevated

protein. Cases of acute flaccid myelitis have occurred in late summer or

early fall since 2012. Several studies have shown antibodies to enteroviruses in the CSF; antibodies to enterovirus D68 are most frequently

detected. While enterovirus D68 has been detected in respiratory, stool,

and nasopharyngeal samples from patients with acute flaccid myelitis,

the virus has been rarely detected in the CSF. Treatment is supportive,

and most patients have persistent neurologic deficits.

PLEURODYNIA (BORNHOLM DISEASE) Patients with pleurodynia

present with an acute onset of fever and spasms of pleuritic chest or

upper abdominal pain. Chest pain is more common in adults, and

abdominal pain is more common in children. Paroxysms of severe,

knifelike pain usually last 15–30 min and are associated with diaphoresis and tachypnea. Fever peaks within an hour after the onset of paroxysms and subsides when pain resolves. The involved muscles are tender

to palpation, and a pleural rub may be detected. The white blood cell

count and chest x-ray results are usually normal. Most cases are due to

coxsackievirus B and occur during epidemics. Symptoms resolve in a

few days, and recurrences are rare. Treatment includes the administration of nonsteroidal anti-inflammatory agents or the application of heat

to the affected muscles.

MYOCARDITIS AND PERICARDITIS Enteroviruses are estimated to

cause up to one-third of cases of acute myocarditis. Coxsackievirus B

and its RNA have been detected in pericardial fluid and myocardial

tissue in some cases of acute myocarditis and pericarditis. Most cases

of enteroviral myocarditis or pericarditis occur in newborns, adolescents, or young adults. More than two-thirds of patients are male.

Patients often present with an upper respiratory tract infection that is

followed by fever, chest pain, dyspnea, arrhythmias, and occasionally

heart failure. A pericardial friction rub is documented in half of cases,

and the electrocardiogram shows ST-segment elevations or ST- and

T-wave abnormalities. Serum levels of myocardial enzymes are often

elevated. Neonates commonly have severe disease, while older children

and adults recover completely. Up to 10% of cases progress to chronic

dilated cardiomyopathy. Chronic constrictive pericarditis also may be

a sequela.

EXANTHEMS Enterovirus infection is the leading cause of exanthems

in children in the summer and fall. While exanthems are associated

with many enteroviruses, certain types have been linked to specific

syndromes. Echoviruses 9 and 16 have frequently been associated with

exanthem and fever. Rashes may be discrete or confluent, beginning on

the face and spreading to the trunk and extremities. Echovirus 9 is the

most common cause of a rubelliform (discrete) rash. Unlike the rash of

rubella, the enteroviral rash occurs in the summer and is not associated

with lymphadenopathy. Roseola-like rashes develop after defervescence, with macules and papules on the face and trunk. The Boston

exanthem, caused by echovirus 16, is a roseola-like rash. A variety of

other rashes have been associated with enteroviruses, including erythema multiforme (see Fig. A1-24) and vesicular, urticarial, petechial,

bullous, or purpuric lesions. Enanthems also occur, including lesions

that resemble the Koplik’s spots seen with measles (see Fig. A1-2).

HAND-FOOT-AND-MOUTH DISEASE (FIG. 204-1) After an incubation

period of 4–6 days, patients with hand-foot-and-mouth disease present

with fever, anorexia, and malaise; these manifestations are followed by

the development of sore throat and vesicles (see Fig. A1-22) on the

buccal mucosa and often on the tongue and then by the appearance of

tender vesicular lesions on the dorsum of the hands, sometimes with

involvement of the palms. The vesicles may form bullae and quickly

ulcerate. About one-third of patients also have lesions on the palate,

uvula, or tonsillar pillars, and one-third have a rash on the feet (including the soles) or on the buttocks. Generalized rashes also have been

reported. The disease is highly infectious, with attack rates of close to

100% among young children. The lesions usually resolve in 1 week.

Most cases are due to coxsackievirus A16 or enterovirus 71.

An epidemic of enterovirus 71 infection in Taiwan in 1998 resulted

in thousands of cases of hand-foot-and-mouth disease or herpangina

(see below). Severe complications included CNS disease, myocarditis,

and pulmonary hemorrhage. About 90% of those who died were children ≤5 years old, and death was associated with pulmonary edema

or pulmonary hemorrhage. CNS disease included aseptic meningitis,

flaccid paralysis (similar to that seen in poliomyelitis), and rhombencephalitis with myoclonus and tremor or ataxia. The mean age of

patients with CNS complications was 2.5 years, and MRI in cases with

encephalitis usually showed brainstem lesions. Follow-up of children at

6 months showed persistent dysphagia, cranial nerve palsies, hypoventilation, limb weakness, and atrophy; at 3 years, persistent neurologic

sequelae were documented, with delayed development and impaired

cognitive function.

Yearly epidemics of enterovirus 71 infection have occurred in China

since 2008, with thousands of cases and hundreds of deaths each year.

Infections have been associated with fever, rash, brainstem encephalitis

with myoclonic jerks, and limb trembling; some cases have progressed

to seizures and coma. Lung findings include pulmonary edema and

hemorrhage. While the level of creatine kinase MB is sometimes elevated, myocardial necrosis generally is not found.

1605CHAPTER 204 Enterovirus, Parechovirus, and Reovirus Infections

FIGURE 204-2 Acute hemorrhagic conjunctivitis due to enterovirus 70. (Image

reprinted courtesy of Jerri Ann Jenista, MD.)

A B

C D

FIGURE 204-1 Vesicular eruptions of the hand (A), knee (B), and mouth (C) of a 6-year-old boy with coxsackievirus A6

infection. Several of his fingernails were shed 2 months later (D). (Images reprinted courtesy of Centers for Disease

Control and Prevention/Emerging Infectious Diseases.)

Cyclic epidemics occur every 2–3 years in other Asian countries.

However, the virus circulates at lower rates in the United States, Europe,

and Africa. In the United States, hand-foot-and-mouth disease is most

commonly associated with coxsackievirus A16. Between November

2011 and February 2012, outbreaks of hand-foot-and-mouth disease

due to coxsackievirus A6 occurred in several U.S. states, and 19% of the

affected persons were hospitalized.

HERPANGINA Herpangina is usually caused by coxsackievirus A and

presents as acute-onset fever, sore throat, odynophagia, and grayish-white

papulovesicular lesions on an erythematous base that ulcerate. The

lesions can persist for weeks; are present on the soft palate, anterior

pillars of the tonsils, and uvula; and are concentrated in the posterior

portion of the mouth. In contrast to herpes stomatitis, enteroviral

herpangina is not associated with gingivitis. Acute lymphonodular

pharyngitis associated with coxsackievirus A10 presents as white or

yellow nodules surrounded by erythema in the posterior oropharynx.

The lesions do not ulcerate.

ACUTE HEMORRHAGIC CONJUNCTIVITIS Patients with acute hemorrhagic conjunctivitis present with an acute onset of severe eye pain,

blurred vision, photophobia, and watery discharge from the eye. Examination reveals edema, chemosis, and subconjunctival hemorrhage and often

shows punctate keratitis and conjunctival follicles as well (Fig. 204-2).

Preauricular adenopathy is often found. Epidemics and nosocomial

spread have been associated with enterovirus 70 and coxsackievirus

A24. Outbreaks have been due to coxsackievirus A24 in China and

India (2010), Japan (2011), and Thailand (2014). Systemic symptoms,

including headache and fever, develop in 20% of cases, and recovery is

usually complete in 10 days. The sudden onset and short duration of

the illness help to distinguish acute hemorrhagic conjunctivitis from

other ocular infections, such as those due to adenovirus and Chlamydia

trachomatis. Paralysis has been associated with some cases of acute

hemorrhagic conjunctivitis due to enterovirus 70 during epidemics.

OTHER MANIFESTATIONS Enteroviruses are an infrequent cause of

childhood pneumonia and the common cold. From mid-August 2014

to January 2015, enterovirus D68 infection was confirmed in more

than 1000 persons with mild to severe respiratory illnesses in 49 U.S.

states. Nearly all reported cases were in children, many of whom had

asthma. A prospective study of >300

children showed that prolonged shedding of enteroviruses in the stool was

associated with development of islet cell

autoantibodies and type 1 diabetes. Coxsackievirus B has been isolated at autopsy

from the pancreas of a few children

presenting with type 1 diabetes mellitus; however, most attempts to isolate

the virus have been unsuccessful. Other

diseases that have been associated with

enterovirus infection include parotitis,

bronchitis, bronchiolitis, croup, infectious lymphocytosis, polymyositis, acute

arthritis, and acute nephritis.

■ DIAGNOSIS

Isolation of enterovirus in cell culture

is the traditional diagnostic procedure.

While cultures of stool, nasopharyngeal,

or throat samples from patients with

enterovirus diseases are often positive,

isolation of the virus from these sites

does not prove that it is directly associated with disease because these sites

are frequently colonized for weeks in

patients with subclinical infections. Isolation of virus from the throat is more

likely to be associated with disease than

is isolation from the stool since virus is

shed for shorter periods from the throat. Cultures of CSF, serum, fluid

from body cavities, or tissues are positive less frequently, but a positive

result is indicative of disease caused by enterovirus. In some cases, the

virus is isolated only from the blood or only from the CSF; therefore,

it is important to culture multiple sites. Cultures are more likely to

be positive earlier than later in the course of infection. Most human

enteroviruses can be detected within a week after inoculation of cell

cultures. Cultures may be negative because of the presence of neutralizing antibody, lack of susceptibility of the cells used, or inappropriate

handling of the specimen. Coxsackievirus A may require inoculation

into special cell-culture lines or into suckling mice.

Identification of the enterovirus serotype is useful primarily for

epidemiologic studies and, with a few exceptions, has little clinical

utility. It is important to identify serious infections with enterovirus

during epidemics and to distinguish the vaccine strain of poliovirus

from the other enteroviruses in the throat or in the feces. Stool and

throat samples for culture as well as acute- and convalescent-phase

serum specimens should be obtained from all patients with suspected

1606 PART 5 Infectious Diseases

TABLE 204-2 Laboratory-Confirmed Cases of Poliomyelitis in 2020

COUNTRY WILD-TYPE POLIO VACCINE-DERIVED POLIO

Pakistan 84 135

Afghanistan 56 308

Chad 0 99

Democratic Republic

of the Congo

0 81

Burkina Faso 0 65

Côte d’Ivoire 0 61

Sudan 0 58

Mali 0 51

South Sudan 0 50

Guinea 0 44

Ethiopia 0 36

Yemen 0 31

Somalia 0 14

Others 0 73a

Total 140 1106

a

Others with <13 cases; Ghana, 12 cases; Sierra Leone, Niger 10 cases each;

Togo, 9 cases; Nigeria, 8 cases; Cameroon, 7 cases; Central African Republic,

4 cases; Angola, Benin, 3 cases each; Madagascar, Congo, 2 cases each; Malaysia,

Philippines, Tajikistan, 1 case each.

poliomyelitis. In the absence of a positive CSF culture, a positive

culture of stool obtained within the first 2 weeks after the onset of

symptoms is most often used to confirm the diagnosis of poliomyelitis. If poliovirus infection is suspected, two or more fecal and throat

swab samples should be obtained at least 1 day apart and cultured

for enterovirus as soon as possible. If poliovirus is isolated, it should

be sent to the CDC for identification as either wild-type or vaccine

virus.

Reverse-transcription polymerase chain reaction (PCR) has been

used to amplify viral nucleic acid from CSF, serum, urine, stool,

conjunctiva, throat swabs, and tissues. A pan-enterovirus PCR assay

can detect all human enteroviruses. With the proper controls, PCR

of the CSF is highly sensitive (70–100%) and specific (>80%) and is

more rapid than culture. PCR of the CSF is less likely to be positive

when patients present ≥3 days after the onset of meningitis or with

enterovirus 71 infection; in these cases, PCR of throat or rectal swabs—

although less specific than PCR of CSF—should be considered.

PCR of serum is also highly sensitive and specific in the diagnosis

of disseminated disease. PCR may be particularly helpful for the diagnosis and follow-up of enterovirus disease in immunodeficient patients

receiving immunoglobulin therapy, whose viral cultures may be negative. Antigen detection is less sensitive than PCR.

Serologic diagnosis of enterovirus infection is limited by the large

number of serotypes and the lack of a common antigen. Demonstration of seroconversion may be useful in rare cases for confirmation

of culture results, but serologic testing is usually limited to epidemiologic studies. Serum should be collected and frozen soon after the

onset of disease and again ~4 weeks later. Measurement of neutralizing titers is the most accurate method for antibody determination;

measurement of complement-fixation titers is usually less sensitive.

Titers of virus-specific IgM are elevated in both acute and chronic

infection.

TREATMENT

Enterovirus Infections

Most enterovirus infections are mild and resolve spontaneously;

however, intensive supportive care may be needed for cardiac,

hepatic, or CNS disease. IV, intrathecal, or intraventricular immunoglobulin has been used with apparent success in some cases

for the treatment of chronic enterovirus meningoencephalitis and

dermatomyositis in patients with hypogammaglobulinemia or

agammaglobulinemia. The disease may stabilize or resolve during

therapy; however, some patients decline inexorably despite therapy.

IV immunoglobulin often prevents severe enterovirus disease in

these patients. IV administration of immunoglobulin with high

titers of antibody to the infecting virus has been used in some

cases of life-threatening infection in neonates, who may not have

maternally acquired antibody. In one trial involving neonates with

enterovirus infections, immunoglobulin containing very high titers

of antibody to the infecting virus reduced rates of viremia; however,

the study was too small to show a substantial clinical benefit. The

level of enteroviral antibodies varies with the immunoglobulin

preparation. A phase 2 trial of pleconaril for neonatal enterovirus

sepsis showed that the time to serum PCR negativity was reduced

and the survival rate increased in newborns who had confirmed

enterovirus infections and were treated with the drug, although

in this small study, the differences did not reach significance; as of

this writing, the drug is not available on a compassionate-use basis.

Pocapavir and vapendavir are also being tested for enterovirus

infections; resistance developed rapidly to OPV in a clinical trial of

the drug. Glucocorticoids are contraindicated.

Good hand-washing practices and the use of gowns and gloves

are important in limiting nosocomial transmission of enteroviruses

during epidemics. Enteric precautions are indicated for 7 days after

the onset of enterovirus infections. Inactivated enterovirus 71 vaccines

have been licensed in China.

■ PREVENTION AND ERADICATION OF

POLIOVIRUS

(See also Chap. 123) After a peak of 57,879 cases of poliomyelitis in

the United States in 1952, the introduction of IPV in 1955 and of OPV

in 1961 ultimately eradicated disease due to wild-type poliovirus in the

Western Hemisphere. Such disease has not been documented in the

United States since 1979, when cases occurred among religious groups

who had declined immunization. In the Western Hemisphere, paralysis

due to wild-type poliovirus was last documented in 1991.

In 1988, when ~350,000 cases of polio occurred in 125 countries, the

World Health Organization adopted a resolution to eradicate poliomyelitis by the year 2000. Wild-type poliovirus type 2 and wild-type poliovirus type 3 were declared eradiated in 2015 and 2019, respectively. The

Americas were certified free of indigenous wild-type poliovirus transmission in 1994, the Western Pacific Region in 2000, the European

Region in 2002, and Southeast Asia in 2014. After a nadir of 496 cases

in 2001, 21 countries that had previously been free of polio reported

cases imported from 6 polio-endemic countries in 2002–2005. By 2006,

polio transmission had been reduced in most of these 21 countries. In

2017, there were 22 cases of wild-type polio, the lowest ever reported

for 1 year—all of these cases were from Pakistan and Afghanistan. In

2020, the number of cases of wild-type polio had risen to 140, all from

the same two countries (Table 204-2). Polio is a source of concern for

unimmunized or partially immunized travelers. While importation of

poliovirus accounted for nearly 50% of cases in 2013 and also occurred

in 2014, it has not been reported recently. Clearly, global eradication

of polio is necessary to eliminate the risk of importation of wild-type

virus. Outbreaks are thought to have been facilitated by suboptimal

rates of vaccination, isolated pockets of unvaccinated children, poor

sanitation and crowding, improper vaccine-storage conditions, and a

reduced level of response to one of the serotypes in the vaccine. While

the global eradication campaign has markedly reduced the number of

cases of endemic polio, doubts have been raised as to whether eradication is a realistic goal, given the large number of asymptomatic infections and the political instability in developing countries.

Use of OPV, especially in areas with low vaccination rates, has been

associated with vaccine-derived polio due to mutations that result

in restoration of viral fitness and neurovirulence during prolonged

replication in individuals or person-to-person transmission. Vaccinederived polio was recognized in Egypt in 1983–1993, and hundreds

of cases have been reported in many countries, including 385 cases in

Nigeria in 2005–2012. Epidemics have been rapidly terminated after

intensive vaccination with OPV. In 2005, a case of vaccine-derived

polio occurred in an unvaccinated U.S. woman returning from a visit to

1607CHAPTER 204 Enterovirus, Parechovirus, and Reovirus Infections

Central and South America. In the same year, an unvaccinated immunocompromised infant in Minnesota was found to be shedding

vaccine-derived poliovirus; further investigation identified 4 of 22 infants

in the same community who were shedding the virus. All 5 infants were

asymptomatic. These outbreaks emphasize the need for maintaining

high levels of vaccine coverage and continued surveillance for circulating virus. From 2010 to 2014, 60–70 cases of vaccine-derived polio

were reported annually. In 2016, only 5 cases were reported (in Nigeria,

Pakistan, and Laos). However, this number has been increasing each

year, with 1106 cases of vaccine-derived polio in 2020 from 27 countries; about half of these cases were from the Eastern Mediterranean

Region and half were from Africa (Table 204-2). From 2018 to March

2020, 92% of cases of vaccine-derived polio were due to type 2 virus.

Cessation of vaccination with type 2 OPV is believed to be responsible

for this increase in polio type 2. IPV is used in most industrialized

countries and OPV in most developing countries, including those

in which polio still is or recently was endemic. While IM injections

of other vaccines (live or attenuated) can be given concurrently with

OPV, unnecessary IM injections should be avoided during the first

month after OPV vaccination because they increase the risk of vaccineassociated paralysis. Since 1988, an enhanced-potency inactivated

poliovirus vaccine has been available in the United States.

After several doses of OPV alone, the seropositivity rate for individual poliovirus serotypes may still be suboptimal for children in developing countries; one or more supplemental doses of IPV can increase

the rate of seropositivity for these serotypes. Against a given serotype,

monovalent OPV containing only that serotype is more immunogenic

than trivalent vaccine because of a lack of interference from other

serotypes. Given the eradication of wild-type poliovirus type 2 and

the establishment of OPV type 2 as the primary cause of vaccinederived polio, bivalent OPV (types 1 and 3), which had been shown to

be superior to trivalent OPV in inducing antibodies to types 1 and 3,

replaced trivalent OPV vaccine in April 2016. However, outbreaks of

vaccine-derived polio due to polio type 2 have required vaccination

with monovalent OPV type 2. Two modified type 2 OPVs that are

impaired for reversion to neurovirulence were safe and immunogenic

in phase 2 clinical trials. Addition of at least one dose of trivalent IPV

after immunization with bivalent OPV will reduce the risk of vaccinederived polio associated with type 2 virus and enhance immunity

to poliovirus types 1 and 3. Accordingly, in 2016, ~90% of countries

included trivalent IPV in their immunization schedules. As the frequency of wild-type polio declines and reports of polio associated with

circulating vaccine-derived viruses increase, the World Health Organization is investigating whether IPV can be produced from OPV strains

that require less biocontainment, ultimately replacing OPV.

OPV and IPV induce antibodies that persist for at least 5 years. Both

vaccines induce IgG and IgA antibodies. Compared with recipients

of IPV, recipients of OPV shed less virus and less frequently develop

reinfection with wild-type virus after exposure to poliovirus. Although

IPV is safe and efficacious, OPV offers the advantages of ease of administration, lower cost, and induction of intestinal immunity resulting

in a reduction in the risk of community transmission of wild-type

virus. Because of progress toward global eradication of polio and the

continued occurrence of cases of vaccine-associated polio, an all-IPV

regimen was recommended in 2000 for childhood poliovirus vaccination in the United States, with vaccine administration at 2, 4, and

6–18 months and 4–6 years of age. The risk of vaccine-associated polio

should be discussed before OPV is administered. Recommendations

for vaccination of adults are listed in Table 204-3.

There are concerns about discontinuing vaccination in the event

that endemic spread of poliovirus is eliminated. Among the reasons

for these concerns are that poliovirus is shed from some immunocompromised persons for >25 years, that vaccine-derived poliovirus can

circulate and cause disease, and that wild-type poliovirus is present in

research laboratories and vaccine manufacturing facilities. Antivirals

and monoclonal antibodies are in development to reduce or terminate

shedding of poliovirus by long-term virus excretors. Pocapavir was

shown to reduce shedding of OPV type 1 in a clinical trial, but rapid

development of resistance with virus transmission, despite reduced

shedding, indicates that combination therapy with other antivirals and/

or monoclonal antibodies will be needed.

PARECHOVIRUSES

Human parechoviruses (HPeVs), like enteroviruses, are members of

the family Picornaviridae. The 16 serotypes of HPeV commonly cause

infections in early childhood. Infections with HPeV type 1 (HPeV-1)

occur throughout the year, while other parechovirus infections occur

more commonly in summer and fall. Infections with HPeVs present

similarly to those due to enteroviruses and may cause generalized

disease of the newborn, aseptic meningitis, encephalitis, seizures, transient paralysis, exanthems, respiratory tract disease, rash, hepatitis, and

gastroenteritis. While HPeV-1 is the most common serotype and generally causes mild disease, deaths of infants in the United States have

been associated with HPeV-1, HPeV-3, and HPeV-6. HPeVs can be

isolated from the same sites as enteroviruses, including the nasopharynx, stool, and respiratory tract secretions. PCR using pan-enterovirus

primers does not detect HPeVs, and while PCR assays are performed

by the CDC and research laboratories, many commercial laboratories

do not perform the test. Pleconaril is not active against parechoviruses.

REOVIRUSES

Reoviruses are double-stranded RNA viruses encompassing three

serotypes. Serologic studies indicate that most humans are infected

with reoviruses during childhood. Most infections either are asymptomatic or cause mild upper respiratory tract symptoms. Reovirus is

considered a rare cause of mild gastroenteritis or meningitis in infants

and children. Speculation regarding an association of reovirus type 3 with

idiopathic neonatal hepatitis and extrahepatic biliary atresia is based

on an elevated prevalence of antibody to reovirus in some affected

patients and the detection of viral RNA by PCR in hepatobiliary tissues in some studies. New orthoreoviruses have been associated with

human disease—e.g., Melaka and Kampar viruses with fever and acute

respiratory disease in Malaysia and Nelson Bay virus with acute respiratory disease in a traveler from Bali.

■ FURTHER READING

Abedi GR et al: Enterovirus and parechovirus surveillance–United

States, 2014-2016. MMWR Morb Mortal Wkly Rep 67:515, 2018.

Chard AN et al: Progress toward polio eradication-worldwide, January

2018-March 2020. MMWR Morb Mortal Wkly Rep 69:784, 2020.

TABLE 204-3 Recommendations for Poliovirus Vaccination of Adults

1. Most adults in the United States have little risk for exposure to polioviruses,

and most are immune as a result of vaccination during childhood.

Vaccination with IPV is recommended for those at greater risk for exposure

to polioviruses than the general population:

a. travelers to areas or countries where polio is epidemic or endemic;

b. members of communities or specific population groups with disease

caused by wild-type polioviruses;

c. laboratory workers who handle specimens that might contain polioviruses;

d. health care workers who have close contact with patients who might be

excreting wild-type polioviruses; and

e. unvaccinated adults whose children will be receiving oral poliovirus

vaccine.

2. Adults who are unvaccinated or whose vaccination status is unknown and

who are at increased risk should receive three doses of IPV. Two doses of

IPV should be administered at intervals of 4–8 weeks; a third dose should be

administered 6–12 months after the second.

3. Adults who have had a primary series of polio vaccine and who are at

increased risk should receive another dose of IPV. Currently, data do not

indicate a need for more than a single lifetime booster dose with IPV for

adults. However, adults who will be in a polio-infected or polio-exporting

country for >4 weeks and whose booster dose of polio vaccine was

administered >1 year earlier should receive an additional booster dose of

vaccine before departing for that country.

Abbreviation: IPV, inactivated poliovirus vaccine.

Source: Modified from Centers for Disease Control and Prevention: MMWR

Recomm Rep 46(RR-5):1, 2000; and Wallace et al: MMWR Morb Mortal Wkly Rep

63(27):591, 2014.

1608 PART 5 Infectious Diseases

Macklin GR et al: Evolving epidemiology of poliovirus serotype 2 following withdrawal of the serotype 2 oral poliovirus vaccine. Science

368:401, 2020.

Mckay SL et al: Increase in acute flaccid myelitis—United States, 2018.

Morb Mortal Wkly Rep 67:1273, 2018.

Murphy OC, Pardo CA: Acute flaccid myelitis: A clinical review.

Semin Neurol 40:211, 2020.

Saez-Llorens et al: Safety and immunogenicity of two novel type 2 oral

poliovirus vaccine candidates compared with monovalent type 2 oral

poliovirus vaccine in children and infants: Two clinical trials. Lancet

397:27, 2021.

Schubert RD et al: Pan-viral serology implicates enteroviruses in

acute flaccid myelitis. Nat Med 25:1748; 2019.

■ DEFINITION

Measles is a highly contagious viral disease that is characterized by a

prodromal illness of fever, cough, coryza, and conjunctivitis followed

by the appearance of a generalized maculopapular rash. Before the

widespread use of measles vaccines, it was estimated that measles

caused >2 million deaths worldwide each year.

■ GLOBAL CONSIDERATIONS

Remarkable progress has been made in reducing global measles

incidence and mortality rates through measles vaccination. In the

Americas, intensive vaccination and surveillance efforts—based in

part on the successful Pan American Health Organization strategy of

periodic nationwide measles vaccination campaigns (supplementary

immunization activities, or SIAs)—and high levels of routine measles

vaccine coverage interrupted endemic transmission of measles virus.

The World Health Organization’s (WHO’s) Region of the Americas

was declared to have eliminated measles in September 2016—the first

region in the world to do so. In the United States, high-level coverage

with two doses of measles vaccine eliminated endemic measles virus

transmission in 2000. Progress also has been made in reducing measles

incidence and mortality rates in sub-Saharan Africa and Asia as a consequence of increasing routine measles vaccine coverage and provision

of a second dose of measles vaccine through mass measles vaccination

campaigns and childhood immunization programs. From 2000 to

2019, estimated global measles deaths decreased 62%, from 539,000

(95% confidence interval [CI], 357,200−911,900) to 207,500 (95% CI,

123,100−472,900). Measles vaccination prevented an estimated 25.5

million deaths over this period. However, a global measles resurgence

in 2019 led to the loss of measles elimination status in the Region of the

Americas and threatened elimination in the United States, highlighting

the continual risk. In 2019, the 1282 measles cases reported in the

United States were the highest since 1992.

The Measles and Rubella Initiative, a partnership led by the American

Red Cross, the United Nations Foundation, UNICEF, the U.S. Centers

for Disease Control and Prevention (CDC), and the WHO, is playing

an important role in reducing global measles incidence and mortality

rates. Since its inception in 2001, the Initiative has provided governments and communities in 88 countries with technical and financial

support for routine immunization activities, mass vaccination campaigns, and disease surveillance systems.

■ ETIOLOGY

Measles virus is a spherical, nonsegmented, single-stranded, negativesense RNA virus and a member of the Morbillivirus genus in the family

Paramyxoviridae. Measles was originally a zoonotic infection, arising from animal-to-human transmission of an ancestral morbillivirus

205 Measles (Rubeola)

Kaitlin Rainwater-Lovett, William J. Moss

thousands of years ago, when human populations had attained sufficient

size to sustain virus transmission. Although RNA viruses typically have

high mutation rates, measles virus is considered to be an antigenically

monotypic virus; i.e., the surface proteins responsible for inducing protective immunity have retained their antigenic structure across time and

distance. The public health significance of this stability is that measles

vaccines developed decades ago from a single strain of measles virus

remain protective worldwide. Measles virus is killed by ultraviolet light

and heat, and attenuated measles vaccine viruses retain these characteristics, necessitating a cold chain for vaccine transport and storage.

■ EPIDEMIOLOGY

Measles virus is one of the most highly contagious directly transmitted

pathogens. Outbreaks can occur in populations in which <10% of persons are susceptible. Chains of transmission are common among household contacts, school-age children, and health care workers. There are

no latent or persistent measles virus infections that result in prolonged

contagiousness, nor are there animal reservoirs for the virus. Thus, measles virus can be maintained in human populations only by an unbroken

chain of acute infections, which requires a continuous supply of susceptible individuals. Newborns become susceptible to measles virus infection

when passively acquired maternal antibody is lost; when not vaccinated,

these infants account for the bulk of new susceptible individuals.

Endemic measles has a typical temporal pattern characterized by

yearly seasonal epidemics superimposed on longer epidemic cycles of

2–5 years or more. In temperate climates, annual measles outbreaks

typically occur in the late winter and early spring. These annual outbreaks are probably attributable to social networks facilitating transmission (e.g., congregation of children at school) and environmental

factors favoring the viability and transmission of measles virus. Measles

cases continue to occur during interepidemic periods in large populations, but at low incidence. The longer epidemic cycles occurring every

several years result from the accumulation of susceptible persons over

successive birth cohorts and the subsequent decline in the number of

susceptibles following an outbreak.

Secondary attack rates among susceptible household and institutional contacts generally exceed 90%. The average age at which measles

occurs depends on rates of contact with infected persons, protective

maternal antibody decline, and vaccine coverage. In densely populated urban settings with low-level vaccination coverage, measles is a

disease of infants and young children. The cumulative incidence can

reach 50% by 1 year of age, with a significant proportion of children

acquiring measles before 9 months—the age of routine vaccination in

many countries, in line with the schedule recommended by the WHO’s

Expanded Programme on Immunization. As measles vaccine coverage

increases or population density decreases, the age distribution shifts

toward older children. In such situations, measles cases predominate

in school-age children. Infants and young children, although susceptible if not protected by vaccination, are not exposed to measles virus

at a rate sufficient to cause a heavy disease burden in this age group.

As vaccination coverage increases further, the age distribution of cases

may be shifted into adolescence and adulthood; this distribution is

seen in measles outbreaks in the United States and necessitates targeted

measles vaccination programs for these older age groups. Some countries have a bimodal distribution, with measles cases predominantly in

young infants and adults.

Persons with measles are infectious for several days before and after

the onset of rash, when levels of measles virus in blood and body fluids

are highest and when cough, coryza, and sneezing, which facilitate

virus spread, are most severe. The contagiousness of measles before

the onset of recognizable disease hinders the effectiveness of isolation

measures. Viral shedding by children with impaired cell-mediated

immunity can be prolonged.

Medical settings are well-recognized sites of measles virus transmission. Children may present to health care facilities during the prodrome,

when the diagnosis is not obvious although the child is infectious and

is likely to infect susceptible contacts. Health care workers can acquire

measles from infected children and transmit measles virus to others.

Nosocomial transmission can be reduced by maintenance of a high index

1609CHAPTER 205 Measles (Rubeola)

of clinical suspicion, use of appropriate isolation precautions when measles is suspected, administration of measles vaccine to susceptible children

and health care workers, and documentation of health care workers’

immunity to measles (i.e., proof of receipt of two doses of measles vaccine

or detection of antibodies to measles virus).

As efforts at measles control are increasingly successful, public perceptions of the risk of measles as a disease diminish and are replaced

by concerns about possible adverse events associated with measles

vaccine. As a consequence, numerous measles outbreaks have occurred

because of opposition to vaccination on religious or philosophical

grounds or unfounded fears of serious adverse events (see “Active

Immunization,” below, and Chap. 3).

■ PATHOGENESIS

Measles virus is transmitted primarily by respiratory droplets over

short distances and, less commonly, by small-particle aerosols that

remain suspended in the air for long periods. Airborne transmission

appears to be important in certain settings, including schools, physicians’ offices, hospitals, and enclosed public places. The virus can be

transmitted by direct contact with infected secretions but does not

survive for long on fomites.

The incubation period for measles is ~10 days to fever onset and

14 days to rash onset. This period may be shorter in infants and longer (up to 3 weeks) in adults. Infection is initiated when measles virus

is deposited in the respiratory tract, oropharynx, or conjunctivae

(Fig. 205-1A). During the first 2–4 days after infection, measles virus

proliferates locally in the respiratory mucosa, primarily in dendritic

cells and lymphocytes, and spreads to draining lymph nodes. Virus

then enters the bloodstream in infected lymphocytes, producing the

primary viremia that disseminates infection throughout the reticuloendothelial system. Further replication results in secondary viremia

that begins 5–7 days after infection and disseminates measles virus

throughout the body. Replication of measles virus in the target organs,

together with the host’s immune response, is responsible for the signs

and symptoms of measles that occur 8–12 days after infection and

mark the end of the incubation period (Fig. 205-1B).

■ IMMUNE RESPONSES

Host immune responses to measles virus are essential for viral clearance, clinical recovery, and the establishment of long-term immunity

(Fig. 205-1C). Early nonspecific (innate) immune responses during the

prodromal phase include activation of natural killer cells and increased

production of antiviral proteins. The adaptive immune responses

consist of measles virus–specific antibody and cellular responses.

The protective efficacy of antibodies to measles virus is illustrated by

the immunity conferred to infants from passively acquired maternal

antibodies and the protection of exposed, susceptible individuals after

administration of anti–measles virus immunoglobulin. The first measles virus–specific antibodies produced after infection are of the IgM

subtype, with a subsequent switch to predominantly IgG1 and IgG3

isotypes. The IgM antibody response is typically absent following reexposure or revaccination and serves as a marker of primary infection.

The importance of cellular immunity to measles virus is demonstrated by the ability of children with agammaglobulinemia (congenital

inability to produce antibodies) to recover fully from measles and the

contrasting picture for children with severe defects in T lymphocyte

function, who often develop severe or fatal disease (Chap. 351). The

initial predominant TH1 response (characterized by interferon γ) is

essential for viral clearance, and the later TH2 response (characterized

by interleukin 4) promotes the development of measles virus–specific

antibodies that are critical for protection against reinfection.

The duration of protective immunity following wild-type measles

virus infection is generally thought to be lifelong. Immunologic memory to measles virus includes both continued production of measles

virus–specific antibodies and circulation of measles virus–specific

CD4+ and CD8+ T lymphocytes.

However, the intense immune responses induced by measles virus

infection are paradoxically associated with depressed responses to

unrelated (non–measles virus) antigens, which persist for several weeks

Respiratory epithelium

Local lymph nodes

Blood

Spleen

Lymphatic tissue

Lung

Thymus

Liver

Skin

A

B

CVirus titer (pfu) Severity of clinical symptoms

5 10 15 20

5 10 15 20

Days after infection

Days after infection

5 10 15 20

Days after infection

Conjunctivitis

Cough

Fever

Immune response

CD4+ T cells

Immune suppression

CD8+ T cells

IgM

IgG

Rash

Koplik’s

spots

FIGURE 205-1 Measles virus infection: pathogenesis, clinical features, and

immune responses. A. Spread of measles virus, from initial infection of the

respiratory tract through dissemination to the skin. B. Appearance of clinical signs

and symptoms, including Koplik’s spots and rash. C. Antibody and T cell responses

to measles virus. The signs and symptoms of measles arise coincident with the host

immune response. (Reproduced with permission from WJ Moss: Global measles

elimination. Nat Rev Microbiology 4:900, 2006.)

to months beyond resolution of the acute illness. This state of immune

suppression enhances susceptibility to secondary infections with bacteria

and viruses that cause pneumonia and diarrhea and is responsible for a

substantial proportion of measles-related morbidity and deaths. Delayedtype hypersensitivity responses to recall antigens, such as tuberculin,

are suppressed, and cellular and humoral responses to new antigens are

impaired. Reactivation of tuberculosis and remission of autoimmune diseases after measles have been described and are attributed to this period

of immune suppression. Importantly, measles results in depletion of circulating antibodies against previously encountered viruses and bacteria,

impairing immunologic memory. This mechanism may explain why

child morbidity and mortality can be increased for >2 years after measles.

APPROACH TO THE PATIENT

Measles

Clinicians should consider measles in persons presenting with fever

and generalized erythematous rash, particularly when measles virus

is known to be circulating or the patient has a history of travel to

1610 PART 5 Infectious Diseases

endemic areas. Appropriate precautions must be taken to prevent

nosocomial transmission. The diagnosis requires laboratory confirmation except during large outbreaks in which an epidemiologic

link to a confirmed case can be established. Care is largely supportive and consists of the administration of vitamin A and antibiotics (see “Treatment,” below). Complications of measles, including

secondary bacterial infections and encephalitis, may occur after

acute illness and require careful monitoring, particularly in immunocompromised persons.

■ CLINICAL MANIFESTATIONS

In most persons, the signs and symptoms of measles are highly characteristic (Fig. 205-1B). Fever and malaise beginning ~10 days after exposure

are followed by cough, coryza, and conjunctivitis. These signs and

symptoms increase in severity over 4 days. Koplik’s spots (see Fig. A1-2)

develop on the buccal mucosa ~2 days before the rash appears. The

characteristic rash of measles (see Fig. A1-3) begins 2 weeks after

infection, when the clinical manifestations are most severe, and signal

the host’s immune response to the replicating virus. Headache, abdominal pain, vomiting, diarrhea, and myalgia may be present.

Koplik’s spots are pathognomonic of measles and consist of bluish

white dots ~1 mm in diameter surrounded by erythema. The lesions

appear first on the buccal mucosa opposite the lower molars but rapidly

increase in number and may involve the entire buccal mucosa. They

fade with the onset of rash.

The rash of measles begins as erythematous macules behind the

ears and on the neck and hairline. The rash progresses to involve the

face, trunk, and arms, with involvement of the legs and feet by the end

of the second day. Areas of confluent rash appear on the trunk and

extremities, and petechiae may be present. The rash fades slowly in

the same order of progression as it appeared, usually beginning on the

third or fourth day after onset. Resolution of the rash may be followed

by desquamation, particularly in undernourished children.

Because the characteristic rash of measles is a consequence of the

cellular immune response, it may not develop in persons with impaired

cellular immunity (e.g., those with AIDS; Chap. 202). These persons

have a high case–fatality rate and frequently develop giant cell pneumonitis caused by measles virus. T lymphocyte defects due to causes

other than HIV-1 infection (e.g., cancer chemotherapy) also are associated with increased severity of measles.

A severe atypical measles syndrome was observed in recipients of a

formalin-inactivated measles vaccine (used in the United States from

1963 to 1967 and in Canada until 1970) who were subsequently exposed

to wild-type measles virus. The atypical rash began on the palms and

soles and spread centripetally to the proximal extremities and trunk,

sparing the face. The rash was initially erythematous and maculopapular

but frequently progressed to vesicular, petechial, or purpuric lesions.

■ DIFFERENTIAL DIAGNOSIS

The differential diagnosis of measles includes other causes of fever, rash,

and conjunctivitis, including rubella, Kawasaki disease, infectious mononucleosis, roseola, scarlet fever, Rocky Mountain spotted fever, enterovirus or adenovirus infection, and drug sensitivity. Rubella is a milder

illness without cough and with distinctive lymphadenopathy. The rash

of roseola (exanthem subitum) (see Fig. A1-5) appears after fever has

subsided. The atypical lymphocytosis in infectious mononucleosis contrasts with the leukopenia commonly observed in children with measles.

■ DIAGNOSIS

Measles is readily diagnosed on clinical grounds by clinicians familiar with the disease, particularly during outbreaks. Koplik’s spots are

especially helpful because they appear early and are pathognomonic.

Clinical diagnosis is more difficult (1) during the prodromal illness; (2)

when the rash is attenuated by passively acquired antibodies or prior

immunization; (3) when the rash is absent or delayed in immunocompromised children or severely undernourished children with impaired

cellular immunity; and (4) in regions where the incidence of measles

is low and other pathogens are responsible for the majority of illnesses

with fever and rash. The CDC case definition for measles requires (1) a

generalized maculopapular rash of at least 3 days’ duration; (2) fever of

at least 38.3°C (101°F); and (3) cough, coryza, or conjunctivitis.

Serology is the most common method of laboratory diagnosis. The

detection of measles virus–specific IgM in a single specimen of serum

or oral fluid is considered diagnostic of acute infection, as is a fourfold or greater increase in measles virus–specific IgG antibody levels

between acute- and convalescent-phase serum specimens. Primary

infection in the immunocompetent host results in antibodies that

are detectable within 1–3 days of rash onset and reach peak levels in

2–4 weeks. Measles virus–specific IgM antibodies may not be detectable until 4–5 days or more after rash onset and usually fall to undetectable levels within 4–8 weeks of rash onset.

Several methods for measurement of antibodies to measles virus are

available. Neutralization tests are sensitive and specific, and the results

are highly correlated with protective immunity; however, these tests

require propagation of measles virus in cell culture and thus are expensive and laborious. Commercially available enzyme immunoassays are

most frequently used. Measles can also be diagnosed by isolation of

the virus in cell culture from respiratory secretions, nasopharyngeal

or conjunctival swabs, blood, or urine. Direct detection of giant cells

in respiratory secretions, urine, or tissue obtained by biopsy provides

another method of diagnosis.

For detection of measles virus RNA by reverse-transcription polymerase chain reaction amplification of RNA extracted from clinical

specimens, primers targeted to highly conserved regions of measles

virus genes are used. Extremely sensitive and specific, this assay may

also permit identification and characterization of measles virus genotypes for molecular epidemiologic studies and can distinguish wildtype from vaccine virus strains.

TREATMENT

Measles

There is no specific antiviral therapy for measles. Treatment consists

of general supportive measures, such as hydration and administration of antipyretic agents. Because secondary bacterial infections

are a major cause of morbidity and death attributable to measles,

effective case management involves prompt antibiotic treatment for

patients who have clinical evidence of bacterial infection, including

pneumonia and otitis media. Streptococcus pneumoniae and Haemophilus influenzae type b are common causes of bacterial pneumonia

following measles; vaccines against these pathogens probably lower

the incidence of secondary bacterial infections following measles.

Vitamin A is effective for the treatment of measles and can

markedly reduce rates of morbidity and mortality. The WHO

recommends administration of once-daily doses of 200,000 IU of

vitamin A for 2 consecutive days to all children with measles who

are ≥12 months of age. Lower doses are recommended for younger

children: 100,000 IU per day for children 6–12 months of age and

50,000 IU per day for children <6 months old. A third dose is recommended 2–4 weeks later for children with evidence of vitamin A

deficiency. While such deficiency is not a widely recognized problem in the United States, many American children with measles

do, in fact, have low serum levels of vitamin A, and these children

experience increased measles-associated morbidity. The Committee

on Infectious Diseases of the American Academy of Pediatrics

recommends that the administration of two consecutive daily doses

of vitamin A be considered for children who are hospitalized with

measles and its complications as well as for children with measles

who are immunodeficient; who have ophthalmologic evidence of

vitamin A deficiency, impaired intestinal absorption, or moderate

to severe malnutrition; or who have recently immigrated from areas

with high measles mortality rates. Parenteral and oral formulations

of vitamin A are available.

Anecdotal reports have described the recovery of previously

healthy pregnant and immunocompromised patients with measles

pneumonia and of immunocompromised patients with measles