1611CHAPTER 205 Measles (Rubeola)

encephalitis after treatment with aerosolized and IV ribavirin.

However, the clinical benefits of ribavirin in measles have not been

conclusively demonstrated in clinical trials.

■ COMPLICATIONS

Most complications of measles involve the respiratory tract and include

the effects of measles virus replication itself and secondary bacterial

infections. Acute laryngotracheobronchitis (croup) can occur during

measles and may result in airway obstruction, particularly in young

children. Giant cell pneumonitis due to replication of measles virus

in the lungs can develop in immunocompromised children, including

those with HIV-1 infection. Many children with measles develop diarrhea, which contributes to undernutrition.

Most complications of measles result from secondary bacterial infections of the respiratory tract that are attributable to a state of immune

suppression lasting for several weeks to months, and perhaps even

years, after acute measles. Otitis media and bronchopneumonia are

most common and may be caused by S. pneumoniae, H. influenzae type

b, or staphylococci. Recurrence of fever or failure of fever to subside

with the rash suggests secondary bacterial infection.

Rare but serious complications of measles involve the central nervous system (CNS). Post-measles encephalomyelitis complicates ~1

in 1000 cases, affecting mainly older children and adults. Encephalomyelitis occurs within 2 weeks of rash onset and is characterized by

fever, seizures, and a variety of neurologic abnormalities. The finding

of periventricular demyelination, the induction of immune responses

to myelin basic protein, and the absence of measles virus in the brain

suggest that post-measles encephalomyelitis is an autoimmune disorder triggered by measles virus infection. Other CNS complications that

occur months to years after acute infection are measles inclusion body

encephalitis (MIBE) and subacute sclerosing panencephalitis (SSPE).

In contrast to post-measles encephalomyelitis, MIBE and SSPE are

caused by persistent measles virus infection. MIBE is a rare but fatal

complication that affects individuals with defective cellular immunity

and typically occurs months after infection. SSPE is a slowly progressive disease characterized by seizures and progressive deterioration of

cognitive and motor functions, with death occurring 5–15 years after

measles virus infection. SSPE most often develops in persons infected

with measles virus at <2 years of age.

■ PROGNOSIS

Most persons with measles recover and develop long-term protective

immunity to reinfection. Measles case–fatality proportions vary with

the average age of infection, the nutritional and immunologic status

of the population, measles vaccine coverage, and access to health

care. Among previously vaccinated persons who do become infected,

disease is less severe and mortality rates are significantly lower. In

developed countries, <1 in 1000 children with measles dies. In endemic

areas of sub-Saharan Africa, the measles case–fatality proportion may

be 5–10% or even higher. Measles is a major cause of childhood deaths

in refugee camps and in internally displaced populations, where case–

fatality proportions have been as high as 20–30%.

■ PREVENTION

Passive Immunization Human immunoglobulin given shortly

after exposure can attenuate the clinical course of measles. In immunocompetent persons, administration of immunoglobulin within 72 h

of exposure usually prevents measles virus infection and almost always

prevents clinical measles. Administered up to 6 days after exposure,

immunoglobulin will still prevent or modify the disease. Prophylaxis

with immunoglobulin is recommended for susceptible household and

nosocomial contacts who are at risk of developing severe measles,

particularly children <1 year of age, immunocompromised persons

(including HIV-infected persons previously immunized with live

attenuated measles vaccine), and pregnant women. Except for premature infants, children <6 months of age usually will be partially or completely protected by passively acquired maternal antibody. Infants born

to women with vaccine-induced measles immunity become susceptible

to measles at a younger age than infants born to women with acquired

immunity from natural infection. If measles is diagnosed in a household

member, all unimmunized children in the household should receive

immunoglobulin. The recommended dose is 0.25 mL/kg given intramuscularly. Immunocompromised persons should receive 0.5 mL/kg.

The maximal total dose is 15 mL. IV immunoglobulin contains antibodies to measles virus; the usual dose of 100–400 mg/kg generally

provides adequate prophylaxis for measles exposures occurring as long

as 3 weeks or more after IV immunoglobulin administration.

Active Immunization The first live attenuated measles vaccine

was developed by passage of the Edmonston strain in chick embryo

fibroblasts to produce the Edmonston B virus, which was licensed

in 1963 in the United States. Further passage of Edmonston B virus

produced the more attenuated Schwarz vaccine that currently serves as the

standard in much of the world. The Moraten (“more attenuated Enders”)

strain, which was licensed in 1968 and is used in the United States, is

genetically identical to the Schwarz strain.

Lyophilized measles vaccines are relatively stable, but reconstituted

vaccine rapidly loses potency. Live attenuated measles vaccines are

inactivated by light and heat and lose about half their potency at 20°C

and almost all their potency at 37°C within 1 h after reconstitution.

Therefore, a cold chain must be maintained before and after reconstitution. Antibodies first appear 12–15 days after vaccination, and titers

peak at 1–3 months. Measles vaccines are often combined with other

live attenuated virus vaccines, such as those for mumps and rubella

(MMR) and for mumps, rubella, and varicella (MMR-V).

The recommended age of first vaccination varies from 6 to 15 months

and represents a balance between the optimal age for seroconversion

and the probability of acquiring measles before that age. The proportions of children who develop protective levels of antibody after

measles vaccination approximate 85% at 9 months of age and 95% at

12 months. Common childhood illnesses concomitant with vaccination

may reduce the level of immune response, but such illness is not a valid reason to withhold vaccination. Measles vaccines have been well tolerated and

immunogenic in HIV-1-infected children and adults, although antibody

levels may wane. Because of the potential severity of wild-type measles

virus infection in HIV-1-infected children, routine measles vaccination is

recommended except for those who are severely immunocompromised.

Measles vaccination is contraindicated in individuals with other severe

deficiencies of cellular immunity because of the possibility of disease due to

progressive pulmonary or CNS infection with the vaccine virus.

The duration of vaccine-induced immunity is at least several

decades, if not longer. Rates of secondary vaccine failure 10–15 years

after immunization have been estimated at ~5%, but are probably

lower when vaccination takes place after 12 months of age. Decreasing

antibody concentrations do not necessarily imply a complete loss of

protective immunity: a secondary immune response usually develops

after reexposure to measles virus, with a rapid rise in antibody titers in

the absence of overt clinical disease.

Standard doses of currently licensed measles vaccines are safe

for immunocompetent children and adults. Fever to 39.4°C (103°F)

occurs in ~5% of seronegative vaccine recipients, and 2% of vaccine

recipients develop a transient rash. Mild transient thrombocytopenia

has been reported, with an incidence of ~1 case per 40,000 doses of

MMR vaccine.

Since the publication of a report in 1998 falsely hypothesizing

that MMR vaccine may cause a syndrome of autism and intestinal

inflammation, much public attention has focused on this purported

association. The events that followed publication of this report led

to diminished vaccine coverage in the United Kingdom and provide

important lessons in the misinterpretation of epidemiologic evidence

and the communication of scientific results to the public. The publication that incited the concern was a case series describing 12 children

with a regressive developmental disorder and chronic enterocolitis; 9 of

these children had autism. In 8 of the 12 cases, the parents associated

onset of the developmental delay with MMR vaccination. This simple

temporal association was misinterpreted and misrepresented as a possible causal relationship, first by the lead author of the study and then

1612 PART 5 Infectious Diseases

by elements of the media and the public. Subsequently, many comprehensive reviews and additional epidemiologic studies refuted evidence

of a causal relationship between MMR vaccination and autism.

■ PROSPECTS FOR MEASLES ERADICATION

Progress in global measles control has renewed discussion of measles

eradication. In contrast to poliovirus eradication, the eradication of

measles virus will not entail challenges posed by prolonged shedding

of potentially virulent vaccine viruses and environmental viral reservoirs. However, in comparison with smallpox eradication, higher levels

of population immunity will be necessary to interrupt measles virus

transmission, more highly skilled health care workers will be required

to administer measles vaccines, and containment through case detection and ring vaccination will be more difficult for measles virus

because of infectivity before rash onset. New tools, such as microneedle

patches to deliver measles vaccine, will facilitate mass vaccination campaigns and vaccination of hard-to-reach children such as those residing

in remote rural areas. Despite enormous progress, measles remains a

leading vaccine-preventable cause of childhood mortality worldwide

and continues to cause outbreaks in communities with low vaccination

coverage rates in industrialized nations.

■ FURTHER READING

De Swart RL, Moss WJ: The immunological basis for immunization

series: Module 7: Measles. Update 2020. Geneva: World Health

Organization, 2020.

Griffin DE: Measles immunity and immunosuppression. Curr Opin

Virol 46:9, 2020.

Mina MJ et al: Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens. Science 366:599, 2019.

Moss WJ: Measles. Lancet 380:2490, 2017.

Moss WJ et al: Feasibility assessment of measles and rubella eradication. Vaccine 39:3544, 2021.

Phadke VK et al: Vaccine refusal and measles outbreaks in the US.

JAMA 324:1344, 2020.

Strebel PM, Orenstein WA: Measles. N Engl J Med 381:349, 2019.

World Health Organization: Measles vaccines: WHO position

paper—April 2017. Wkly Epidemiol Rec 92:205, 2017.

World Health Organization: Progress towards regional measles

elimination—worldwide, 2000-2019. MMWR Morb Mortal Wkly

Rep 69:1700, 2020.

Rubella was historically viewed as a variant of measles or scarlet

fever. After an epidemic of rubella in Australia in the early 1940s, the

ophthalmologist Norman Gregg noticed the occurrence of congenital

cataracts among infants whose mothers had reported rubella during

early pregnancy, and congenital rubella syndrome (CRS; see “Clinical

Manifestations,” below) was first described. Not until 1962 was a separate viral agent for rubella isolated.

■ ETIOLOGY

Rubella virus is a member of the Matonaviridae family and the only

member of the genus Rubivirus. This single-strand RNA enveloped

virus measures 40–80 nm in diameter. Its core protein is surrounded

by a single-layer lipoprotein envelope with spike-like projections containing two glycoproteins, E1 and E2. There is only one antigenic type

of rubella virus, and humans are its only known reservoir.

206 Rubella (German Measles)

Laura A. Zimmerman, Susan E. Reef

■ PATHOGENESIS AND PATHOLOGY

Although the pathogenesis of postnatal (acquired) rubella has been

well documented, data on pathology are limited because of the mildness of the disease. Rubella virus is spread from person to person

via respiratory droplets. Primary implantation and replication in the

nasopharynx are followed by spread to the lymph nodes. Subsequent

viremia occurs, which in pregnant women often results in infection of

the placenta. Placental virus replication may lead to infection of fetal

organs. The pathology of CRS in the infected fetus is well defined, with

almost all organs found to be infected; however, the pathogenesis of

CRS is only poorly delineated. In tissue, infections with rubella virus

have diverse effects, ranging from no obvious impact to cell destruction.

The hallmark of fetal infection is a chronic infection with persistence

throughout fetal development in utero and for up to 1 year after birth.

Individuals with acquired rubella may shed virus from 7 days

before rash onset to ~5–7 days thereafter. Both clinical and subclinical

infections are considered contagious. Infants with CRS may shed large

quantities of virus from bodily secretions, particularly from the throat

and in the urine, up to 1 year of age. Outbreaks of rubella, including

some in nosocomial settings, have originated with index cases of CRS.

Thus, only individuals immune to rubella virus should have contact

with infants who have CRS or who are congenitally infected with

rubella virus but are not showing signs of CRS.

■ EPIDEMIOLOGY

The largest recent rubella epidemic in the United States took place in

1964–1965, when an estimated 12.5 million cases occurred, resulting in

~20,000 cases of CRS. Since the introduction of the routine rubella vaccination program in the United States in 1969, the number of rubella

cases reported each year has dropped by >99%; the rate of vaccination

coverage with rubella-containing vaccine (RCV) has been >90% among

children 19–35 months old since 1996. In the United States, a goal for

the elimination of rubella and CRS by 2000 was set in 1989. Interruption of endemic transmission of rubella virus was achieved by 2001. In

2004, a panel of experts agreed unanimously that rubella was no longer

an endemic disease in the United States. The criteria used to document

lack of endemic transmission included low disease incidence, high

nationwide rubella antibody seroprevalence, outbreaks that were few

and contained (i.e., small numbers of cases), and lack of endemic virus

transmission (as assessed by genetic sequencing). Although interruption of endemic transmission has been sustained since 2001, rubella

virus importations continue to occur, and cases continue to develop

among susceptible persons. During 2010−2018, 47 cases of rubella

were reported; 70% of these cases were in persons 20−49 years old—an

age group that includes women of childbearing age. During this period,

13 cases of CRS were reported, all from foreign-born mothers. Therefore, health care providers should remain vigilant, considering the possibility of rubella virus infection in adults (especially those emigrating

or returning from countries without rubella control programs) and

recognizing the potential for CRS among their infants.

The Global Vaccine Action Plan 2011−2020 called for the elimination of rubella in five of the six World Health Organization (WHO)

regions by 2020. Although rubella and CRS are no longer endemic in

the WHO Region of the Americas, they remain important public health

problems globally. The number of rubella cases reported worldwide in

2000 was ~700,000; this figure declined to 26,006 in 2018. However, the

number of rubella cases may be underestimated because cases are often

mild, patients may not seek care, cases may not be recognized or may

not be reported, and, in some countries, cases are identified through

measles surveillance systems that are not specific for rubella. Despite a

continued increase in the number of countries with rubella vaccination

programs, 31% of the world’s children remained unvaccinated against

rubella in 2018. In 2010, it was estimated that 105,000 cases of CRS

occurred annually globally.

■ CLINICAL FEATURES

Acquired Rubella Acquired rubella commonly presents with a

generalized maculopapular rash that usually lasts for up to 3 days

(Fig. 206-1), although as many as 50% of cases may be subclinical or

1613CHAPTER 206 Rubella (German Measles)

without rash. When the rash occurs, it is usually mild and may be difficult to detect in persons with darker skin. In younger children, rash

is usually the first sign of illness. However, in older children and adults,

a 1- to 5-day prodrome often precedes the rash and may include lowgrade fever, malaise, and upper respiratory symptoms. The incubation

period is 14 days (range, 12–23 days).

Lymphadenopathy, particularly occipital and postauricular, may

be noted during the second week after exposure. Although acquired

rubella is usually thought of as a benign disease, arthralgia and arthritis

are common in infected adults, particularly women. Thrombocytopenia and encephalitis are less common complications.

Congenital Rubella Syndrome The most serious consequence

of rubella virus infection can develop when a woman becomes infected

during pregnancy, particularly during the first trimester. The resulting

complications may include miscarriage, fetal death, premature delivery,

or live birth with congenital defects. Infants infected with rubella virus in

utero may have myriad physical defects (Table 206-1), which most commonly relate to the eyes, ears, and heart. This constellation of severe birth

defects is known as CRS. In addition to permanent manifestations, there

are a host of transient physical manifestations, including thrombocytopenia with purpura/petechiae (e.g., dermal erythropoiesis, “blueberry

muffin syndrome”). Some infants may be born with congenital rubella

virus infection but have no apparent signs or symptoms of CRS and are

referred to as “infants with congenital rubella virus infection only.”

■ DIAGNOSIS

Acquired Rubella Clinical diagnosis of acquired rubella is difficult because of the mimicry of many illnesses with rashes, the varied

FIGURE 206-1 Mild maculopapular rash of rubella in a child.

TABLE 206-1 Common Transient and Permanent Manifestations in

Infants with Congenital Rubella Syndrome

TRANSIENT MANIFESTATIONS PERMANENT MANIFESTATIONS

Hepatosplenomegaly

Interstitial pneumonitis

Thrombocytopenia with purpura/

petechiae (e.g., dermal erythropoiesis

or “blueberry muffin syndrome”)

Hemolytic anemia

Bony radiolucencies

Intrauterine growth retardation

Adenopathy

Meningoencephalitis

Hearing impairment/deafness

Congenital heart defects (patent

ductus arteriosus, pulmonary arterial

stenosis)

Eye defects (cataracts, cloudy

cornea, microphthalmos, pigmentary

retinopathy, congenital glaucoma)

Microcephaly

Central nervous system sequelae

(mental and motor delay, autism)

clinical presentations, and the high rates of subclinical and mild disease. Illnesses that may be similar to rubella in presentation include

scarlet fever, roseola, toxoplasmosis, fifth disease, measles, Zika, and

illnesses with suboccipital and postauricular lymphadenopathy. Thus,

laboratory documentation of rubella virus infection is considered the

only reliable way to confirm acute disease.

Laboratory assessment of rubella virus infection is conducted

by serologic and virologic methods. For acquired rubella, serologic

diagnosis is most common and depends on the demonstration of IgM

antibodies in an acute-phase serum specimen or a fourfold rise in IgG

antibody titer between acute- and convalescent-phase specimens. To

detect a rise in IgG antibody titer indicative of acute disease, the acutephase serum specimen should be collected within 7–10 days after onset

of illness and the convalescent-phase specimen ~14–21 days after the

first specimen. The enzyme-linked immunosorbent assay IgM capture

technique is considered most accurate for serologic diagnosis, but the

indirect IgM assays also are acceptable. After rubella virus infection,

IgM antibody may be detectable for up to 6 weeks. In case of a negative

result for IgM in specimens taken earlier than day 5 after rash onset,

serologic testing should be repeated.

Although uncommon, reinfection with rubella virus is possible, and

IgM antibodies may be present. In this instance, IgG avidity testing is

used in conjunction with IgG testing to distinguish primary rubella

infection from reinfection. The detection of low-avidity antibodies in

a patient’s serum indicates recent infection. The presence of mature

(high-avidity) IgG antibodies most likely indicates an infection occurring

at least 2 months previously. Avidity testing may be particularly useful

in diagnosing rubella in pregnant women and assessing the risk of CRS.

Rubella virus is typically detected in the nasopharynx during the

prodromal period and for as long as 2 weeks after rash onset. However,

since the secretion of virus in individuals with acquired rubella is

maximal just before or up to 4 days after rash onset, this is the optimal

time frame for collecting specimens for virus detection. Rubella is

usually diagnosed by viral RNA detection in a reverse-transcriptase

polymerase chain reaction (RT-PCR) assay; rubella virus isolation can

also be used to diagnose rubella.

Congenital Rubella Syndrome The classic triad of CRS—clinical

manifestations of cataracts, hearing impairment, and heart defects—is

seen in ~10% of infants with CRS. Infants may present with different

combinations of defects depending on when infection occurs during

gestation. Hearing impairment is the most common single defect

of CRS. However, as with acquired rubella, laboratory diagnosis of

congenital infection is highly recommended, particularly because

most features of the clinical presentation are nonspecific and may be

associated with other intrauterine infections. Early diagnosis of CRS

allows the prompt implementation of infection control measures and

facilitates appropriate medical intervention for specific disabilities.

Diagnostic tests used to confirm CRS include serologic assays and

virus detection. In an infant with congenital infection, serum IgM antibodies are normally present for up to 6 months but may be detectable

for up to 1 year after birth. In some instances, IgM may not be detectable until 1 month of age; thus, infants who have symptoms consistent

with CRS but who test negative shortly after birth should be retested

at 1 month. A rubella serum IgG titer persisting beyond the time

expected after passive transfer of maternal IgG antibody (i.e., a rubella

titer that does not decline at the expected rate of a twofold dilution per

month) is another serologic criterion used to confirm CRS.

In congenital infection, rubella virus is detected most commonly

from throat swabs and less commonly from urine and cerebrospinal

fluid. Infants with congenital rubella may excrete virus for up to

1 year, but specimens for virus isolation are most likely to be positive if

obtained within the first 6 months after birth. Rubella virus in infants

with CRS can also be detected by RT-PCR.

Rubella Diagnosis in Pregnant Women In the United States,

screening for rubella IgG antibodies is recommended as part of routine

prenatal care. Pregnant women with a positive IgG antibody serologic

test are considered immune. Susceptible pregnant women should be

vaccinated postpartum.

1614 PART 5 Infectious Diseases

Introduced (Includes partial introduction) to date (170 countries or 88%)

Planned introduction in 2019 (3 countries or 2%)

Not Available, Not Introduced/No Plans (21 countries or 11%)

Not applicable

0 875 1750 3500 Kilometers

FIGURE 206-2 Countries using rubella vaccine in national childhood immunization schedules, 2018. Disclaimer—The boundaries and names shown and the designations

used on this map do not imply the expression or any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory,

city, or area nor of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted or dashed lines on maps represent approximate border lines for which

there may not be full agreement. (From the World Health Organization, WHO, 2019. All rights reserved.)

A susceptible pregnant woman exposed to rubella virus should be

tested for IgM antibodies and, if positive, confirmed by testing for

low-avidity IgG antibodies to determine whether she was infected

during pregnancy. Pregnant women with evidence of acute infection

must be clinically monitored, and gestational age at the time of maternal infection must be determined to assess the possibility of risk to the

fetus. Among women infected with rubella virus during the first 10 weeks

of gestation, the risk of delivering an infant with CRS is 90%. The risk

of birth defects declines with infection later in gestation, and fetal

defects are rarely associated with maternal rubella after the 16th week

of gestation, although sensorineural hearing deficit may occur with

infection as late as 20 weeks. Because of the potential for false-positive

results, rubella IgM antibody testing is not recommended for pregnant

women with no history of illness or contact with a rubella-like illness.

TREATMENT

Rubella

No specific therapy is available for rubella virus infection. Symptombased treatment for various manifestations, such as fever and arthralgia, is appropriate. Immunoglobulin does not prevent rubella virus

infection after exposure and therefore is not recommended as routine

postexposure prophylaxis. Although immunoglobulin may modify

or suppress symptoms, it can create an unwarranted sense of security: infants with congenital rubella have been born to women who

received immunoglobulin shortly after exposure. Administration of

immunoglobulin should be considered only if a pregnant woman who

has been exposed to a person with rubella will not consider termination of the pregnancy under any circumstances. In such cases, IM

administration of 20 mL of immunoglobulin within 72 h of rubella

exposure may reduce—but does not eliminate—the risk of rubella.

■ PREVENTION

After the isolation of rubella virus in the early 1960s and the occurrence of a devastating rubella pandemic in 1964–1965, a vaccine for

rubella was developed and licensed in 1969. The majority of rubellacontaining vaccines (RCVs) used worldwide are combined measles and

rubella (MR) or measles, mumps, and rubella (MMR) formulations.

A tetravalent measles, mumps, rubella, and varicella (MMRV) vaccine is

available but is not widely used. Available rubella-containing vaccines

are live attenuated vaccine virus.

The public health burden of rubella virus infection is measured primarily through the occurrence of CRS cases among women who were infected

during pregnancy. The 1964–1965 rubella epidemic in the United States

resulted in >30,000 infections during pregnancy. CRS occurred in ~20,000

infants born alive, including >11,000 infants who were deaf, >3500 infants

who were blind, and almost 2000 infants with intellectual disability. The

medical cost of this epidemic exceeded $1.5 billion. It has been estimated

that the cost for children with CRS ranges from $11,255 in low-income

countries to $934,000 in high-income countries.

In some countries, there are few data to document the epidemiology

of CRS, but clusters of CRS cases have been reported in developing countries. Before the introduction of routine immunization against rubella in

the United States, the incidence of CRS was 0.1–0.2 case per 1000 live

births during endemic periods and 1–4 cases per 1000 live births during epidemic periods. Where rubella virus is circulating and women of

childbearing age are susceptible, CRS cases will continue to occur.

The most effective method of preventing acquired rubella and CRS

is through vaccination with an RCV. One dose induces seroconversion

in ≥95% of persons ≥1 year of age. Immunity is considered long-term

and is probably lifelong. The most commonly used vaccine globally is

the RA27/3 virus strain. The recommendation for routine rubella vaccination schedules in the United States is a first dose of MMR vaccine

at 12–15 months of age and a second dose at 4–6 years. Other persons

recommended to receive a dose of a rubella-containing vaccine include

adolescents and adults without documented evidence of immunity,

individuals in congregate settings (e.g., college students, military personnel, childcare and health care workers), international travelers, and

susceptible women before and after pregnancy.

Because of the theoretical risk of transmission of live attenuated

rubella vaccine virus to the developing fetus, women known to be

pregnant should not receive RCV. In addition, pregnancy should be

avoided for 28 days after receipt of RCV. In follow-up studies of ~3000

unknowingly pregnant women who received rubella vaccine, no infant

was born with CRS. Receipt of RCV during pregnancy is not ordinarily

a reason to consider termination of the pregnancy.

In 2018, 168 (87%) of the 194 member countries of the WHO recommend inclusion of RCV in the routine childhood vaccination schedule (Fig. 206-2). Goals for the elimination of rubella and CRS have

1615CHAPTER 207 Mumps

been established in the WHO American, European, Southeast Asian,

and Western Pacific regions. The African and Eastern Mediterranean

regions have not yet set such goals.

■ FURTHER READING

Centers for Disease Control and Prevention: Control and

prevention of rubella: Evaluation and management of suspected outbreaks, rubella in pregnant women, and surveillance for congenital

rubella syndrome. MMWR Morb Mortal Wkly Rep 50:1, 2001.

Centers for Disease Control and Prevention: Notice to readers:

Revised ACIP recommendation for avoiding pregnancy after receiving a rubella-containing vaccine. MMWR Morb Mortal Wkly Rep

50:1117, 2001.

Centers for Disease Control and Prevention: Rubella, in Manual for the Surveillance of Vaccine-Preventable Diseases, 5th ed, SW

Roush et al (eds). Atlanta, Centers for Disease Control and Prevention, 2018, Chapter 14. Available at https://www.cdc.gov/vaccines/

pubs/surv-manual/index.html. Accessed January 1, 2020.

Centers for Disease Control and Prevention: Rubella, in Epidemiology and Prevention of Vaccine Preventable Diseases, 13th ed,

Jennifer Hamborsky et al (eds). Washington, DC, Public Health

Foundation, 2015, Chapter 18. Available at https://www.cdc.gov/

vaccines/pubs/pinkbook/index.html. Accessed December 4, 2017.

Grant GB et al: Progress toward rubella and congenital rubella syndrome control and elimination: Worldwide, 2000–2018. MMWR

Morb Mortal Wkly Rep 68:855, 2019.

Reef S, Plotkin SA: Rubella vaccine, in Vaccines, SA Plotkin and WA

Orenstein (eds). Philadelphia, Saunders, 2018, pp 970–1000.

Thompson K, Odahowski C: The costs and valuation of health

impacts of measles and rubella risk management policies. Risk Anal

36:1357, 2016.

Vynnycky E et al: Using seroprevalence and immunisation coverage

data to estimate the global burden of congenital rubella syndrome,

1996–2010: A systematic review. PLoS One 11:e0149160, 2016.

World Health Organization: Rubella, module 11, in The Immunological Basis for Immunization Series. Geneva, WHO, 2008. Available at

http://www.who.int/immunization/documents/ISBN9789241596848/

en/index.html. Accessed December 4, 2017.

World Health Organization: Rubella vaccines: WHO position

paper. Wkly Epidemiol Rec 86:301, 2011. Available at http://www

.who.int/wer/2011/wer8629.pdf?ua=1. Accessed December 4, 2017.

World Health Organization: Global Vaccine Action Plan

2011– 2020. Geneva, WHO, 2013. Available at http://www.who.int/

immunization/global_vaccine_action_plan/GVAP_doc_2011_2020/

en/. Accessed May 26, 2021.

Mumps is an acute, self-limited, systemic viral illness typically characterized by parotitis or other salivary gland swelling. Although mumps

was once considered a universal childhood disease in the United States,

routine mumps vaccination had led to a >99% reduction in cases by the

early 2000s. However, since 2006, there has been an increase in mumps

cases in this country, the majority among fully vaccinated persons.

Mumps should be suspected in all patients with parotitis or mumps

complications (see “Clinical Manifestations”), regardless of age, vaccination status, or travel history.

■ ETIOLOGIC AGENT

Mumps is an acute viral illness caused by a paramyxovirus from the

Rubulavirus genus in the Paramyxoviridae family. This single-stranded,

negative-sense, enveloped RNA virus is ~15.3 kb in size and encodes

207 Mumps

Jessica Leung, Mariel Marlow

several minor proteins and seven major proteins. Mumps virus is

rapidly inactivated by formalin, ether, chloroform, heat, and ultraviolet light. There is only one mumps virus serotype. One of the seven

major encoded proteins, the small hydrophobic (SH) protein, exhibits

hypervariability among strains; thus, the SH gene nucleotide sequence

is used to genotype the virus for molecular epidemiologic purposes.

The 12 known genotypes of mumps virus are designated by the

letters A to N (except E and M). In the United States, >98% of mumps

virus specimens genotyped from 2015 through 2017 were genotype G.

Most mumps vaccines licensed globally are composed of virus strains

from genotype A, B, or N. The mumps virus strain (Jeryl Lynn) used

in vaccines in the United States is genotype A.

■ EPIDEMIOLOGY

Mumps occurs worldwide and is endemic in many countries. In the

absence of routine vaccination, the incidence of mumps is 100–1000

cases per 100,000 population, with epidemic peaks every 2–5 years.

From 1999 through 2019, on average, >500,000 mumps cases were

reported to the World Health Organization annually; however, global

mumps incidence is challenging to estimate, as few countries routinely

collect data on mumps incidence. Since 2018, mumps vaccine is routinely used in 122 countries. Mumps incidence has been reduced by

97–99% in countries with a routine two-dose measles, mumps, and

rubella (MMR) vaccination schedule and by 87–88% in those with a

one-dose vaccination program. However, since the mid-2000s, large

mumps outbreaks have been reported among populations with high

two-dose MMR coverage in countries with routine mumps immunization programs. Most outbreaks have occurred in settings with intense

or frequent close contact, such as universities, close-knit communities,

and correctional facilities, and most cases have occurred in fully vaccinated persons. Despite these outbreaks, mumps incidence is still much

higher in countries that do not have routine mumps vaccination.

In the United States, prior to licensure of a vaccine for mumps in

1967, >100,000 mumps cases occurred annually. After the implementation of a one-dose mumps vaccination policy in 1977 and a subsequent two-dose policy in 1989, reported mumps cases declined to an

annual average of ~300 by the early 2000s. However, since 2006, there

has been an increase in mumps cases reported in the United States,

with several peak years (Fig. 207-1). During the highest peak in cases,

from January 2016 through June 2017, 150 mumps outbreaks and 9200

outbreak-associated cases were reported in a range of settings and groups,

including schools, universities, athletic teams and facilities, church groups,

workplaces, and large parties and events. While a majority of cases have

occurred in fully vaccinated young adults in association with large university outbreaks, about one-third of cases have affected children or adolescents, most of whom were vaccinated. As of 2020, mumps is endemic

in the United States, and there are no elimination goals for the disease.

Multiple factors are likely involved in being at risk for mumps infection among vaccinated persons. Following vaccination, these factors

include (1) failure to develop an immune response, (2) the development of a low-level immune response that is insufficient for protection,

(3) a decrease in immunity over time (waning immunity) after initial

development of a vaccine-induced immune response, (4) lower levels

of vaccine-induced antibodies to the circulating wild-type virus strains

than to the vaccine virus strain, and (5) a lower frequency of subclinical immunologic boosting due to lack of exposure to wild-type virus

during periods of low disease incidence.

■ PATHOGENESIS

Humans are the only known natural reservoir for mumps virus, which

is transmitted through direct contact with respiratory droplets or saliva

of an infected person. The average incubation period is 16–18 days,

with a range of 12–25 days. A person is most infectious from 2 days

before until 5 days after onset of parotitis or other salivary gland

swelling. However, mumps virus has been detected in saliva as early as

7 days before onset and as late as 9 days after onset of these manifestations. Mumps virus has been isolated from urine and seminal fluid

up to 14 days after onset of parotitis, although no studies have assessed

transmissibility of the virus through these fluids.

1616 PART 5 Infectious Diseases

Mumps can occur in a person who is fully vaccinated, but vaccinated

persons are at a lower risk for mumps and mumps complications.

Mumps infection is asymptomatic in ~20% of unvaccinated patients;

the proportion asymptomatic among vaccinated persons is unknown.

Parotitis can be preceded by several days by a prodrome of low-grade

fever, malaise, myalgia, headache, and anorexia. Parotitis typically lasts

for 5 days (range, 3–7 days); most cases resolve within 10 days. Parotitis

is generally bilateral and may not occur synchronously on both sides;

unilateral involvement occurs in about one-third of cases. Swelling of

the parotid gland is accompanied by tenderness and obliteration of the

space between the earlobe and the angle of the mandible (Figs. 207-2

and 207-3). The patient frequently reports an earache and jaw pain and

finds it difficult to eat, swallow, or talk. The orifice of the parotid duct

is commonly red and swollen. The submaxillary and sublingual glands

are involved less often than the parotid gland and are rarely involved

alone. In ~6% of mumps cases, obstruction of lymphatic drainage

secondary to bilateral salivary gland swelling may lead to presternal

pitting edema, associated often with submandibular adenitis and rarely

with the more life-threatening supraglottic edema.

The most frequent complications of mumps include orchitis, oophoritis, mastitis, pancreatitis, hearing loss, meningitis, and encephalitis.

Complications can occur in the absence of parotitis and are more

Number of mumps cases

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

2018

2019

Year

1000

338

266

270

231

258

314

800

454

404

229

584

1223

1329

2515

1991

2612

6584

6366

6109

2000

3000

4000

5000

6000

7000

0

3780

FIGURE 207-1 Reported mumps cases: United States, 2000–2019. (Source: National Notifiable Diseases Surveillance System, 2000–2019 Annual Tables of Infectious Disease

Data. Atlanta, GA, CDC Division of Health Informatics and Surveillance, 2019. Available at https://www.cdc.gov/nndss/infectious-tables.html.)

Primary mumps virus replication likely occurs in the nasal mucosa

or upper respiratory mucosal epithelium. Given the range of symptoms, it is assumed that, after infection of the respiratory mucosa, the

virus spreads to regional lymph nodes. Mononuclear cells and cells

within regional lymph nodes can become infected; such infection

facilitates the development of viremia, which usually lasts 3–5 days.

Viremia can result in a range of acute inflammatory reactions, most

commonly in the salivary glands (resulting in parotitis) and the testes

(resulting in orchitis). Other sites of virus dissemination include the

kidneys (reflected in the frequency of viruria), the central nervous system (CNS), the pancreas, the heart, the ovaries, the mammary glands,

the perilymphatic fluid within the cochlea, and (during pregnancy)

the fetus.

Little is known about the pathology of mumps since the disease is

rarely fatal. Affected salivary glands contain perivascular and interstitial mononuclear-cell infiltrates and exhibit hemorrhage with prominent edema. Serum and urine amylase levels may be elevated as a result

of inflammation and tissue damage in the parotid gland. Necrosis of

acinar and epithelial duct cells is evident in the salivary glands and in

the germinal epithelium of the seminiferous tubules of the testes. The

virus probably enters cerebrospinal fluid (CSF) through the choroid

plexus or via transiting mononuclear cells during plasma viremia.

Although relevant data are limited, in many cases, mumps

encephalitis appears to be a para- or postinfectious process

(as suggested by perivenous demyelination and perivascular

mononuclear-cell inflammation) rather than the result of a

direct cytotoxic effect caused by viral invasion of the CNS.

However, although rare, primary mumps encephalitis does

occur, as shown by mumps virus isolation from brain tissue.

Infection of the perilymphatic fluid likely develops via retrograde penetration by the virus from the cervical lymph nodes

following viremia, but infection could also occur via the CSF

in cases of mumps CNS infection, given that the perilymph

communicates with the CSF. Virus in the perilymph can result

in infection of the cochlea and damage to the organ of Corti

and the tectorial membrane, leading to transient or permanent

deafness. Evidence of placental and intrauterine spread has

been found in both early and late gestation. Virus frequently

disseminates to the kidneys, but kidney involvement in mumps

is almost always benign.

■ CLINICAL MANIFESTATIONS

While typically presenting with parotitis or other salivary

gland swelling, mumps infection can range from asymptomatic

or nonspecific respiratory symptoms to serious complications.

A B

FIGURE 207-2 The same person before mumps acquisition (A) and on day 3 of acute bilateral

parotitis (B). (Courtesy of patient C.M. From JD Shanley: The resurgence of mumps in young

adults and adolescents. Cleve Clin J Med 74:42, 2007. Reprinted with permission. Copyright ©

2007 Cleveland Clinic Foundation. All rights reserved.)

1617CHAPTER 207 Mumps

common among adults than among children and among males than

among females, likely due to rates of orchitis.

Orchitis (testicular inflammation), usually accompanied by fever,

is the most common complication, developing in up to 30% of unvaccinated and 6% of vaccinated postpubertal males. This complication

is rare in children. Orchitis typically occurs during the first week of

parotitis but can develop up to 6 weeks after parotitis. Both testes are

involved in ~10–30% of cases. The testis is painful and tender and can

be enlarged to several times its normal size. Pain and swelling may

last for 1 week, while tenderness may last for several weeks. Testicular

atrophy develops in ~30–50% of affected testicles. The development of

anti-sperm antibodies, reduced testosterone production, and impaired

sperm mobility through oligospermia, azoospermia, or asthenospermia may lead to temporary sterility or subfertility. However, no

studies have assessed the risk of permanent infertility in men with

mumps orchitis.

Approximately 7% of unvaccinated and ≤1% of vaccinated postpubertal women develop oophoritis, which may be associated with lower

abdominal pain and vomiting. The rate of mastitis in mumps has been

estimated to be as high as 30% among unvaccinated postpubertal

women and as low as ≤1% among vaccinated postpubertal women.

Pancreatitis occurs in ~4% of unvaccinated and <1% of vaccinated

mumps patients. Mumps pancreatitis, which may present as abdominal

pain, is difficult to diagnose because an elevated serum amylase level

can be associated with either parotitis or pancreatitis. However, serum

lipase is elevated in pancreatitis and the presence of both elevated

serum amylase and lipase can help determine if pancreatitis is present

in addition to parotitis. Hearing loss associated with mumps infection

can occur in up to 4% of unvaccinated and <1% of vaccinated mumps

patients. Mumps-related hearing loss is usually sudden in onset, unilateral, and transient and may be associated with vestibular symptoms.

Bilateral and permanent hearing loss are rare.

Mumps virus is highly neurotropic, with subclinical CNS involvement occurring in up to 55% of patients as manifested by CSF pleocytosis. However, symptomatic CNS infection is less common. Aseptic

meningitis occurs in ≤1% of vaccinated patients and up to 10% of

unvaccinated patients and is a self-limited manifestation without significant risk of death or long-term sequelae. Symptoms of aseptic meningitis, including stiff neck, headache, and drowsiness, typically appear

~5 days after parotitis. Encephalitis develops in ≤1% of patients, who

present with high fever, marked changes in the level of consciousness,

seizures, and focal neurologic symptoms. Electroencephalographic

abnormalities may be seen. Permanent sequelae are sometimes identified in survivors, and adult infections more commonly have poor outcomes than do pediatric infections. The mortality rate associated with

mumps encephalitis is ~1.5%. Other CNS problems occasionally associated with mumps include cerebellar ataxia, facial palsy, transverse

myelitis, hydrocephalus, Guillain-Barré syndrome, flaccid paralysis,

and behavioral changes.

Although rare and self-limited, myocarditis and endocardial fibroelastosis may represent severe complications of mumps infection;

however, mumps-associated electrocardiographic abnormalities have

been reported in up to 15% of cases. Other unusual complications

include thyroiditis, nephritis, arthritis, hepatic disease, keratouveitis,

and thrombocytopenic purpura. Abnormal renal function is common,

but severe, life-threatening nephritis is rare.

Mumps infection in pregnant women is generally benign and is not

more severe than in women who are not pregnant. Evidence suggesting

an association between maternal mumps infection and an increased

rate of spontaneous abortion or intrauterine fetal death is inconclusive.

Both mumps reinfection after natural infection and recurrent

infection (in which parotid gland swelling resolves and then, weeks to

months later, develops on the same or the other side) can occur. In the

past, mumps reinfection was thought to be rare, but more recent data

have suggested that it may be more common than previously thought.

Death due to mumps is exceedingly rare.

■ DIFFERENTIAL DIAGNOSIS

Mumps is the only cause of parotitis outbreaks, although an increase

in parotitis cases may also result from increased influenza activity—

specifically, infection with influenza A virus subtype H3N2. Other

infectious causes of parotitis include parainfluenza virus types 1–3,

Epstein-Barr virus, human herpesviruses 6A and 6B, herpes simplex

viruses types 1 and 2, coxsackievirus A, adenovirus, parvovirus B19,

echovirus, lymphocytic choriomeningitis virus, and HIV. Laboratory

testing for sporadic parotitis cases caused by these infectious pathogens

can help rule out mumps.

Parotitis can also develop in the setting of sarcoidosis, Sjögren’s

syndrome, Mikulicz’s syndrome, Parinaud’s oculoglandular syndrome,

uremia, diabetes mellitus, laundry starch ingestion, malnutrition, cirrhosis, and some drug treatments. Unilateral parotitis can be caused

by ductal obstruction, cysts, and tumors. In the absence of parotitis or

other salivary gland enlargement, symptoms of other visceral-organ

and/or CNS involvement may predominate, and a laboratory diagnosis

is required. Other entities should be considered when manifestations

consistent with mumps appear in organs other than the parotid. For

example, testicular torsion may produce a painful scrotal mass resembling that seen in mumps orchitis. Orchitis can also be caused by bacterial infections in the prostate and urinary tract, sexually transmitted

diseases such as chlamydia and gonorrhea, and other viral infections

such as those with coxsackievirus, varicella, echovirus, and cytomegalovirus. Oophoritis can also be caused by sexually transmitted diseases

such as chlamydia and gonorrhea. A number of viruses (e.g., enteroviruses) can cause aseptic meningitis that is clinically indistinguishable

from that due to mumps virus.

■ LABORATORY DIAGNOSIS

If mumps is suspected, infection is confirmed by virologic methods,

but serologic testing can aid in diagnosis. Especially in vaccinated

patients, a negative virologic or serologic result in a person with clinical

signs of mumps does not rule out mumps infection.

Virologic methods for confirming mumps include reverse transcription polymerase chain reaction (RT-PCR) and viral culture. RT-PCR is

preferred because of its sensitivity, specificity, and timeliness. Mumps

virus and viral RNA can be detected in blood, saliva, urine, and CSF.

Buccal or oral swabs provide the best specimens for virus detection.

The parotid gland should be massaged for 30 s prior to collection of

the buccal/oral swab sample. As maximal viral shedding occurs within

5 days after symptom onset, specimens for mumps virologic testing

ideally should be collected as close to parotitis onset as possible. The

diagnostic yield of urine specimens increases over time up to 10 days

after parotitis onset, but buccal specimens are more likely than urine

specimens to result in virus detection at any time point.

Serologic methods that can aid in the diagnosis of mumps include

detection of mumps-specific IgM antibodies or a fourfold rise between

acute- and convalescent-phase IgG antibodies. In unvaccinated persons,

IgM antibody is usually detectable within 5 days after onset, reaches

a maximal level a week after onset, and remains elevated for weeks or

Parotid

gland

Sternocleidomastoid muscle

Ear-gland

axis

Parotid

gland

(enlarged)

Ear-gland

axis

FIGURE 207-3 Schematic drawings of a normal parotid gland (left) and a parotid

gland infected with mumps virus (right). An enlarged cervical lymph node is usually

posterior to the imaginary line. (Reproduced with permission from A Gershon et al:

Krugman’s Infectious Diseases of Children, 11th ed. Philadelphia, Elsevier, 2004.)

1618 PART 5 Infectious Diseases

months. Failure to detect mumps IgM in vaccinated patients is very

common, as the IgM response is often undetectable, transient, or delayed

in these individuals. Collection of specimens >3 days after onset may

improve IgM detection. Use of IgG testing is generally not recommended,

as IgG titers in vaccinated or previously infected patients may already be

elevated at the time of acute-phase specimen collection, such that a fourfold rise is not detected in the convalescent-phase specimen.

TREATMENT

Mumps

Mumps is generally a benign, self-resolving illness. Therapy for

parotitis and other clinical manifestations is symptom based and

supportive. The administration of analgesics and the application

of warm or cold compresses to the parotid area may be helpful.

Testicular pain may be minimized by the local application of cold

compresses and gentle support for the scrotum. Anesthetic blocks

also may be used. Neither the administration of glucocorticoids nor

incision of the tunica albuginea is of proven value in severe orchitis.

Mumps immune globulin is not recommended for postexposure

prophylaxis or treatment.

■ PREVENTION

Vaccination is the best prevention measure against mumps. Mumps

vaccine is commonly included as part of the combination MMR vaccine or the combination measles–mumps–rubella–varicella (MMRV)

vaccine. All mumps vaccines currently on the market are live attenuated virus vaccines. Strains used in mumps vaccines have included Jeryl

Lynn, RIT-4385, Urabe Am9, Rubini, Leningrad-3 and LeningradZagreb; Urabe- and Rubini-containing vaccines are no longer available.

The Jeryl Lynn strain is the only strain used in mumps vaccines in the

United States since 1967.

In the United States, children are recommended to receive the first

MMR dose at 12—15 months of age and the second dose at 4—6 years.

Adequate vaccination against mumps is defined as two doses of MMR

for school-aged children (i.e., grades K–12) and for adults at high risk

(i.e., health care workers, international travelers, and students at post–

high school educational institutions) and one dose for preschool-aged

children and adults not at high risk. During an outbreak, a second dose

should be considered for children aged 1—4 years and adults who have

received one dose. In 2017, after an increase in cases among persons

with two MMR doses and a study demonstrating added benefit of a

third MMR vaccine dose for individual protection, a third dose was

recommended for use during outbreaks. The third dose of MMR vaccine is intended for groups whom public health authorities identify as

at increased risk of acquiring mumps during an outbreak; public health

authorities will inform providers of these groups at increased risk. As

the duration of protection provided by a third dose of MMR vaccine is

unknown and may be short term (<1 year), there is no recommendation for a routine third dose.

The effectiveness of MMR vaccine (in which the mumps component is based on the Jeryl Lynn strain) is estimated to be 80% (range,

49–92%) for one dose and 88% (range, 32–95%) for two doses. The

effectiveness of the mumps component is lower than that of the

measles component (two-dose effectiveness of 97%) and the rubella

component (one-dose effectiveness of 97%). Incremental vaccine

effectiveness of a third MMR dose—compared with two doses—during

outbreaks is estimated at 78% (range, 61–88%).

In general, most recipients of mumps vaccine will seroconvert after

vaccination and will have detectable antibodies to mumps virus; however, antibody levels start to decline soon after vaccination. Vaccineinduced neutralizing antibodies to wild-type strains may be lower in

titer and may decline more rapidly than antibodies to the vaccine strain

(Jeryl Lynn). However, most young adults given two vaccine doses in

childhood appear to retain memory B cells.

Mumps vaccines are generally very safe. Urabe and Leningrad-Zagreb

mumps strain vaccines have been associated with a slightly increased

risk of aseptic meningitis, but there is no evidence of this risk for Jeryl

Lynn mumps strain vaccines. There is a twofold greater risk of febrile

seizures among children 12–23 months of age after receipt of the first

dose of MMRV vaccine than after the first dose of MMR vaccine, with

or without simultaneous varicella vaccination; this risk has not been

found among vaccinated children 4–6 years of age.

There is no known immune correlate of protection for mumps; a

positive IgG titer indicates only that a person has been exposed to

mumps virus through either vaccination or natural infection and does

not predict protection against infection. Therefore, all close contacts of

a mumps patient should be advised to self-monitor for mumps symptoms for 25 days after their last exposure. Further, IgG titers should

not be used to infer immunity in close contacts as it may indicate acute

infection rather than immunity. MMR vaccine has not been shown to

prevent illness or alter clinical severity in persons already infected with

mumps virus and is not recommended as postexposure prophylaxis for

immediate close contacts of mumps patients.

Acknowledgment

The authors acknowledge and thank Dr. Steve Rubin, the author of the

previous edition of this chapter.

■ FURTHER READING

Marin M et al: Recommendation of the Advisory Committee on

Immunization Practices for use of a third dose of mumps virus–

containing vaccine in persons at increased risk for mumps during an

outbreak. MMWR Morb Mortal Wkly Rep 67:33, 2018.

Masarani M et al: Mumps orchitis. J R Soc Med 99:573, 2006.

Mcclean HQ et al: Prevention of measles, rubella, congenital rubella

syndrome, and mumps, 2013: Summary recommendations of the

Advisory Committee on Immunization Practices (ACIP). MMWR

Recomm Rep 62(RR-04):1, 2013.

Rota JS et al: Comparison of the sensitivity of laboratory diagnostic

methods from a well-characterized outbreak of mumps in New York

City in 2009. Clin Vaccine Immunol 20:391, 2013.

Rubin S et al: Molecular biology, pathogenesis and pathology of

mumps virus. J Pathol 235:242, 2015.

World Health Organization: WHO immunological basis for immunization series. Module 16: Mumps update 2020. Available at https://apps.

who.int/iris/bitstream/handle/10665/338004/9789240017504-eng.pdf.

RABIES

Rabies is a rapidly progressive, acute infectious disease of the central

nervous system (CNS) in humans and animals that is caused by infection with rabies virus. The infection is normally transmitted from animal vectors via a bite exposure. Rabies has encephalitic and paralytic

forms that progress to death.

■ ETIOLOGIC AGENT

Rabies virus is a member of the family Rhabdoviridae. Two genera in

this family, Lyssavirus and Vesiculovirus, contain species that cause

human disease. Rabies virus is a lyssavirus that infects a broad range of

mammals and causes serious neurologic disease when transmitted to

humans. This single-strand RNA virus has a nonsegmented, negativesense (antisense) genome that consists of 11,932 nucleotides and

encodes 5 proteins: nucleocapsid protein, phosphoprotein, matrix protein, glycoprotein, and a large polymerase protein. Rabies virus variants, which can be characterized by distinctive nucleotide sequences,

are associated with specific animal reservoirs. Six other non–rabies

virus species in the Lyssavirus genus have been reported to cause a

208 Rabies and Other

Rhabdovirus Infections

Alan C. Jackson

1619CHAPTER 208 Rabies and Other Rhabdovirus Infections

clinical picture similar to rabies. Vesicular stomatitis virus, a vesiculovirus, causes vesiculation and ulceration in cattle, horses, and other

animals and causes a self-limited, mild, systemic illness in humans (see

“Other Rhabdoviruses,” below).

■ EPIDEMIOLOGY

Rabies is a zoonotic infection that occurs in a variety of mammals

throughout the world except in Antarctica and on some islands. Rabies

virus is usually transmitted to humans by the bite of an infected animal.

Worldwide, endemic canine rabies is estimated to cause 59,000 human

deaths annually. Most of these deaths occur in Asia and Africa, with

rural populations and children disproportionally affected. Thus, in many

resource-poor and resource-limited countries, canine rabies continues

to be a threat to humans. However, in Latin America, rabies control

efforts in dogs have been quite successful in recent years. Endemic

canine rabies has been eliminated from the United States and most

other resource-rich countries. Rabies is endemic in wildlife species,

and a variety of animal reservoirs have been identified in different

countries of the world (Fig. 208-1). Surveillance data from 2019 identified 4690 confirmed animal cases of rabies in the United States and Puerto

Rico. Only 8.2% of these cases were in domestic animals, including 245

cases in cats, 66 in dogs, and 39 in cattle. In North American wildlife

reservoirs, including bats, raccoons, skunks, and foxes, the infection is

endemic, with involvement of one or more rabies virus variants in each

reservoir species (Fig. 208-2). “Spillover” of rabies to other wildlife

species and to domestic animals occurs. Bat rabies virus variants are

present in every state except Hawaii and are responsible for most indigenously acquired human rabies cases in the United States. Raccoon

rabies is endemic along the entire eastern coast of the United States.

Skunk rabies is present in the midwestern states, with another focus in

California. Rabies in foxes occurs in New Mexico, Arizona, and Alaska.

In the United States there were two human rabies deaths in 2017, three

in 2018, and none in 2019.

In Canada and Europe, epizootics of rabies in red foxes have been

well controlled with the use of baits containing rabies vaccine. A similar approach, along with additional measures, is used in Canada to

control incursions of raccoon rabies from the United States.

Rabies virus variants isolated from humans or other mammalian

species can be identified by reverse-transcription polymerase chain

reaction (RT-PCR) amplification and sequencing or by characterization with monoclonal antibodies. These techniques are helpful in

human cases with no known history of exposure. Worldwide, most

human rabies is transmitted from dogs in countries with endemic

canine rabies and dog-to-dog transmission, and human cases can be

FIGURE 208-1 Distribution of global rabies vectors. (Courtesy of the Centers for Disease Control and Prevention.)

FIGURE 208-2 Distribution of the major rabies virus variants among wild terrestrial

reservoirs in the United States and Puerto Rico, 2015-2019. Darker shading indicates

counties with confirmed animal rabies cases in the past 5 years; lighter shading

represents counties bordering enzootic counties without animal rabies cases that

did not satisfy criteria for adequate surveillance. Small nonenzootic areas with no

rabies cases reported in the past 15 years are shaded if they are in the vicinity of

known-enzootic counties and do not satisfy criteria for adequate surveillance. ARC

FX, Arctic fox rabies virus variant (RVV); AZ FX, Arizona fox RVV; CA SK, California

skunk RVV; MG, Dog-mongoose RVV; NC SK, North central skunk RVV; RC, Eastern

raccoon RVV; SC SK, South central skunk RVV. (X Ma et al: Rabies surveillance in the

United States during 2019. J Am Vet Med Assoc 258:1205, 2021.)

imported by travelers returning from these regions. In North America,

indigenously acquired human disease is usually associated with transmission from bats; there may be no known history of bat bite or other

bat exposure in these cases. Most human cases are due to a bat rabies

virus variant associated with silver-haired and tricolored bats. These

are small bats whose bite may not be recognized, and the virus has

adapted for replication at skin temperature and in cell types that are

present in the skin.

Transmission from nonbite exposures is relatively uncommon.

Aerosols generated in the laboratory or in caves containing millions of

Brazilian free-tail bats have rarely caused human rabies. Transmission

has resulted from corneal transplantation and also from solid-organ

transplantation and a vascular conduit (for a liver transplant) from

1620 PART 5 Infectious Diseases

Eye

Salivary

glands

Dorsal root

ganglion

Spinal

cord

Brain

Infection of brain

neurons with

neuronal

dysfunction

6

Centrifugal spread along

nerves to salivary glands,

skin, cornea, and

other organs

7

Virus binds to nicotinic

acetylcholine receptors at

neuromuscular junction

3

Replication in motor

neurons of the spinal

cord and local dorsal

root ganglia and

rapid ascent to brain

5

1 Virus inoculated

Viral replication

in muscle

2

Virus travels within

axons in peripheral

nerves via retrograde

fast axonal transport

4

Sensory nerves

to skin

Skeletal

muscle

FIGURE 208-3 Schematic representation of events in rabies pathogenesis following peripheral inoculation of

rabies virus by an animal bite. (Reproduced with permission from AC Jackson: Rabies: Scientific basis of the

disease and its management, 3rd ed. Oxford, UK, Elsevier Academic Press, 2013.)

undiagnosed donors with rabies in Texas, Florida, Germany, Kuwait,

and China. Human-to-human transmission is extremely rare, although

hypothetical concern about transmission to health care workers has

prompted the implementation of barrier techniques to prevent exposures from patients with rabies.

■ PATHOGENESIS

The incubation period of rabies (defined as the interval between

exposure and the onset of clinical disease) is usually 20–90 days, but

in rare cases is either as short as a few days or >1 year. During most

of the incubation period, rabies virus is thought to be present at or

close to the site of inoculation (Fig. 208-3). In muscles, the virus is

known to bind to nicotinic acetylcholine receptors on postsynaptic

membranes at neuromuscular junctions, but the exact details of viral

entry into the skin and SC tissues have not yet been clarified. Rabies

virus spreads centripetally along peripheral nerves toward the spinal

cord or brainstem via retrograde fast axonal transport (rate, up to ~250

mm/d), with delays at intervals of ~12 h at each synapse. Once the virus

enters the CNS, it rapidly disseminates to other regions of the CNS via

fast axonal transport along neuroanatomic connections. Neurons are

prominently infected in rabies; infection of astrocytes is unusual. After

CNS infection becomes established, there is centrifugal spread along

sensory and autonomic nerves to other tissues, including the salivary

glands, heart, adrenal glands, and skin. Rabies virus replicates in acinar

cells of the salivary glands and is secreted in the saliva of rabid animals

that serve as vectors of the disease. There is no well-documented evidence for hematogenous spread of rabies virus.

Pathologic studies show mild inflammatory changes in the CNS in

rabies, with mononuclear inflammatory infiltration in the leptomeninges, perivascular regions, and parenchyma, including microglial

nodules called Babes nodules. Degenerative neuronal changes usually

are not prominent, and there is little evidence of neuronal death;

neuronophagia is observed occasionally. The pathologic changes are

surprisingly mild in light of the clinical severity and fatal outcome of the

disease. The most characteristic pathologic finding in rabies is the Negri

body (Fig. 208-4). Negri bodies are eosinophilic cytoplasmic inclusions

in brain neurons that are composed of rabies virus proteins and viral

RNA. These inclusions occur in a minority of infected neurons, are

commonly observed in Purkinje cells of the cerebellum and in pyramidal neurons of the hippocampus, and are less frequently seen in cortical

and brainstem neurons. Negri bodies are not observed in all cases of

rabies. The lack of prominent degenerative neuronal changes has led to

the concept that neuronal dysfunction—rather

than neuronal death—is responsible for clinical disease in rabies. The basis for behavioral

changes, including the aggressive behavior of

rabid animals, is not well understood but may

be related to infection of serotonergic neurons

in the brainstem.

■ CLINICAL MANIFESTATIONS

For rabies prevention, the emphasis must be on

postexposure prophylaxis (PEP) initiated after a

recognized exposure and before any symptoms

or signs develop. Rabies should usually be suspected on the basis of the clinical presentation

with or without a history of an exposure. The

disease generally presents as atypical encephalitis with relative preservation of consciousness.

Rabies may be difficult to recognize late in the

clinical course when progression to coma has

occurred. A minority of patients (~20%) present

with acute flaccid paralysis. There are prodromal, acute neurologic, and comatose phases

that usually progress to death despite aggressive

therapy (Table 208-1).

Prodromal Features The clinical features

of rabies begin with nonspecific prodromal

manifestations, including fever, malaise, headache, nausea, and vomiting. Anxiety or agitation

also may occur. The earliest specific neurologic

symptoms of rabies include paresthesias, pain,

or pruritus near the site of the exposure, one

or more of which occur in 50–80% of patients

and strongly suggest rabies. The wound has

usually healed by this point, and these symptoms probably reflect infection with associated

inflammatory changes in local dorsal root or

cranial sensory ganglia.

Encephalitic Rabies Two acute neurologic

forms of rabies are seen in humans: the encephalitic (furious) form in 80% and the paralytic

form in 20%. Some of the manifestations of

encephalitic rabies, including fever, confusion,

hallucinations, combativeness, and seizures,

may be seen in other viral encephalitides as

well. Autonomic dysfunction is common in

rabies and may result in hypersalivation, gooseflesh, cardiac arrhythmia, and priapism. In

1621CHAPTER 208 Rabies and Other Rhabdovirus Infections

FIGURE 208-4 Three large Negri bodies in the cytoplasm of a cerebellar Purkinje

cell from an 8-year-old boy who died of rabies after being bitten by a rabid dog in

Mexico. (Reproduced with permission from AC Jackson, E Lopez-Corella. N Engl J

Med 335:568, 1996; © Massachusetts Medical Society.) FIGURE 208-5 Hydrophobic spasm of inspiratory muscles associated with terror

in a patient with encephalitic (furious) rabies who is attempting to swallow water.

(Copyright DA Warrell, Oxford, UK; with permission.)

TABLE 208-1 Clinical Stages of Rabies

STAGE TYPICAL DURATION SYMPTOMS AND SIGNS

Incubation period 20–90 days None

Prodrome 2–10 days Fever, malaise, anorexia, nausea,

vomiting; paresthesias, pain, or

pruritus at the wound site

Acute Neurologic Disease

Encephalitic (80%) 2–7 days Anxiety, agitation, hyperactivity,

bizarre behavior, hallucinations,

autonomic dysfunction,

hydrophobia

Paralytic (20%) 2–10 days Flaccid paralysis in limb(s)

progressing to quadriparesis with

facial paralysis

Coma, deatha 0–14 days

a

Recovery is rare.

Source: Adapted from MAW Hattwick: Rabies virus, in Principles and Practice of

Infectious Diseases, GL Mandell et al (eds). New York, Wiley, 1979.

encephalitic rabies, episodes of hyperexcitability are typically followed

by periods of complete lucidity that become shorter as the disease

progresses. Rabies encephalitis is distinguished by early brainstem

involvement, which results in the classic features of hydrophobia

(involuntary, painful contraction of the diaphragm and accessory

respiratory, laryngeal, and pharyngeal muscles in response to swallowing liquids) (Fig. 208-5) and aerophobia (the same features caused by

stimulation from a draft of air). These symptoms are probably due to

dysfunction of infected brainstem neurons that normally inhibit inspiratory neurons near the nucleus ambiguus, resulting in exaggerated

defense reflexes that protect the respiratory tract. The combination

of hypersalivation and pharyngeal dysfunction is responsible for the

classic appearance of “foaming at the mouth.” Brainstem dysfunction

progresses rapidly, and coma—followed within days by death—is the

rule unless the course is prolonged by supportive measures. With such

measures, late complications can include cardiac and/or respiratory

failure, disturbances of water balance (syndrome of inappropriate

antidiuretic hormone secretion or diabetes insipidus), noncardiogenic

pulmonary edema, and gastrointestinal hemorrhage. Cardiac arrhythmias may be due to dysfunction affecting vital centers in the brainstem

or autonomic pathways or to myocarditis. Multiple-organ failure is common in patients treated aggressively in critical care units.

Paralytic Rabies About 20% of patients have paralytic rabies

in which muscle weakness predominates and cardinal features of

encephalitic rabies (hyperexcitability, hydrophobia, and aerophobia)

are lacking. There is early and prominent flaccid muscle weakness,

often beginning in the bitten extremity and spreading to produce

quadriparesis and facial weakness. Sphincter involvement is common,

sensory involvement is usually mild, and these cases are commonly

misdiagnosed as Guillain-Barré syndrome. Patients with paralytic

rabies generally survive a few days longer than those with encephalitic

rabies, but multiple-organ failure nevertheless ensues.

■ LABORATORY INVESTIGATIONS

Most routine laboratory tests in rabies yield normal results or show

nonspecific abnormalities. Complete blood counts are usually normal.

Examination of cerebrospinal fluid (CSF) often reveals mild mononuclear-cell pleocytosis with a mildly elevated protein level. Severe pleocytosis (>1000 white cells/μL) is unusual and should prompt a search

for an alternative diagnosis. Imaging is usually performed to exclude

other diagnostic possibilities. CT head scans are usually normal in

rabies. MRI brain scans may show signal abnormalities in the brainstem or other gray-matter areas, but these findings are variable and

nonspecific. Electroencephalograms typically show only nonspecific

abnormalities. Of course, important tests in suspected cases of rabies

include those that may identify an alternative, potentially treatable

diagnosis (see “Differential Diagnosis,” below).

■ DIAGNOSIS

In North America, a diagnosis of rabies often is not considered until

relatively late in the clinical course, even with a typical clinical presentation. This diagnosis should be considered in patients presenting with

acute atypical encephalitis or acute flaccid paralysis, including those