Measles (Rubeola)

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PREVENTION AND ERADICATION OF POLIOVIRUS

(See also Chap. 148) 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, the World Health Organization adopted a resolution to eradicate poliomyelitis by the year 2000. From 1988 to 2001, the number of cases worldwide decreased by >99%, with only 496 confirmed cases reported in 2001. Wild-type poliovirus type 2 has not been detected in the world since 1999. The Americas were certified free of indigenous wild-type poliovirus transmission in 1994, the Western Pacific Region in 2000, and the European Region in 2002. However, in 2002, there were 1922 cases of polio, with 1600 cases reported in India. In fact, after the 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 2012, 293 cases of polio were reported (the lowest number ever in a 1-year period); 85% were from Nigeria, Pakistan, and Afghanistan, the only countries where polio remains endemic (Table 228-2). As of November 2013, there had been 390 cases of polio in 2013 compared with 293 cases in 2012. The increase was associated with a marked rise in imported cases, including more than 180 cases in Somalia, more than 10 cases each in Kenya and Syria, and cases in Cameroon and Ethiopia. Also in 2013, wild-type poliovirus was detected in sewage in Israel, prompting a massive vaccination campaign with OPV. As of November 2013, India had not reported a case of polio since January 2011. Polio is a source of concern for unimmunized or partially immunized travelers. Importation of poliovirus accounted for ~50% of cases in 2013. 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.

TABLE 228-2

LABORATORY-CONFIRMED CASES OF POLIOMYELITIS IN 2012

The occurrence of outbreaks of poliomyelitis due to circulating vaccine-derived poliovirus of all three types has been increasing, especially in areas with low vaccination rates. In Egypt, 32 cases of vaccine-derived polio occurred in 1983–1993; in the Dominican Republic and Haiti, 21 cases occurred in 2000–2001; in Indonesia, 46 cases were reported in 2005; in Nigeria, 385 cases occurred in 2005–2012; in the Democratic Republic of the Congo, 64 cases were reported in 2008–2012; in Pakistan, 16 cases occurred in 2012, and at least 30 cases occurred in 2013. These OPV-derived viruses reverted to a more neurovirulent phenotype after undetected circulation (probably for >2 years). The epidemic in Hispaniola was 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 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.

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 vaccine-associated 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. With eradication of wild-type poliovirus type 2, bivalent OPV (types 1 and 3), which was shown to be superior to trivalent OPV, has been the vaccine of choice to eliminate polio and has markedly reduced rates of polio in Nigeria. 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 228-3.

TABLE 228-3

RECOMMENDATIONS FOR POLIOVIRUS VACCINATION OF ADULTS

1. Most adults in the United States have been vaccinated during childhood and are at little risk of exposure to wild-type virus in the United States. Immunization is recommended for those with a higher risk of exposure than the general population, including:

a. travelers to areas where poliovirus is or may be epidemic or endemic;

b. members of communities or population groups with disease caused by wild-type polioviruses;

c. laboratory workers handling specimens that may contain wild-type polioviruses; and

d. health care workers in close contact with patients who may be excreting wild-type polioviruses.

2. Three doses of IPV are recommended for adults who need to be immunized. The second dose should be given 1–2 months after the first dose; the third dose should be given 6–12 months after the second dose.

3. Adults who are at increased risk of exposure to wild-type poliovirus and who have previously completed primary immunization should receive a single dose of IPV. Adults who did not complete primary immunization should receive the remaining required doses of IPV.

Abbreviation: IPV, inactivated poliovirus vaccine.

Source: Modified from Pickering LK, ed. Red Book 2012: Committee on Infectious Diseases, 29th ed.

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 >10 years, that vaccine-derived poliovirus can circulate and cause disease, and that wild-type poliovirus is present in research laboratories.

PARECHOVIRUSES

Human parechoviruses (HPeVs), like enteroviruses, are members of the family Picornaviridae. The 16 serotypes of HPeV commonly cause infections in early childhood. HPeV-1 infections 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, transient paralysis, exanthems, respiratory tract disease, 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.

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.

229	Measles (Rubeola)
	Kaitlin Rainwater-Lovett, William J. Moss

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 between 5 million and 8 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. In the United States, high-level coverage with two doses of measles vaccine eliminated endemic measles virus transmission in 2000. More recently, progress 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.

In 2003, the World Health Assembly endorsed a resolution urging member countries to reduce the number of deaths attributed to measles by 50% (compared with 1999 estimates) by the end of 2005. This target was met. Global measles mortality rates were further reduced in 2008; during that year, there were an estimated 164,000 deaths due to measles (uncertainty bounds: 115,000 and 222,000 deaths). These achievements attest to the enormous public-health significance of measles vaccination. However, recent large outbreaks of measles in Europe and Africa illustrate the challenges faced in sustaining measles control: in these outbreaks, measles was imported into countries that had eliminated indigenous transmission of measles virus.

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 World Health Organization (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 more than 80 countries with technical and financial support for routine immunization activities, mass vaccination campaigns, and disease surveillance systems. Through its 2012–2020 Global Measles and Rubella Strategic Plan, the Initiative aims to reduce measles deaths by 95% (compared with year 2000 estimates) by 2015 and to eliminate measles from at least five of the six WHO regions by 2020. As regional goals for measles elimination are set, global measles eradication is likely to become a public health goal in the near future.

ETIOLOGY

Measles virus is a spherical, nonsegmented, single-stranded, negative-sense 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 ~10,000 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 distribution 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 large 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.

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 quarantine 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 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).

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 on epithelial cells in the respiratory tract, oropharynx, or conjunctivae (Fig. 229-1A). During the first 2–4 days after infection, measles virus proliferates locally in the respiratory mucosa and spreads to draining lymph nodes. Virus then enters the bloodstream in infected leukocytes (primarily monocytes), 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 these 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. 229-1B).

FIGURE 229-1 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. (Source: Modified from WJ Moss, DE Griffin: Nat Rev Microbiol 4:900, 2006.)

IMMUNE RESPONSES

Host immune responses to measles virus are essential for viral clearance, clinical recovery, and the establishment of long-term immunity (Fig. 229-1C). 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 IgG4 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. 374). The initial predominant T_H1 response (characterized by interferon γ) is essential for viral clearance, and the later T_H2 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 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. Delayed-type 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.

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 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. 229-1B). 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. 25e-2) develop on the buccal mucosa ~2 days before the rash appears. The characteristic rash of measles (see Fig. 25e-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 (see Fig. 25e-2) 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 to 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 (see Fig. 25e-3), 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. 226). 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 (see Fig. 25e-22).

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. 25e-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 (see Fig. 25e-2) 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-transcriptase 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 wild-type 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 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 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). Postmeasles 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 postmeasles 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 postmeasles 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 die. 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. 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 maximum 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 closely related 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 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 by elements of the media and the public. Subsequently, several 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 aerosol administration of measles vaccines, will facilitate mass vaccination campaigns. 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.

230e	Rubella (German Measles)
	Laura A. Zimmerman, Susan E. Reef

Rubella was historically viewed as a variant of measles or scarlet fever. Not until 1962 was a separate viral agent for rubella isolated. 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 infection during early pregnancy, and congenital rubella syndrome (CRS; see “Clinical Manifestations,” below) was first described.

ETIOLOGY

Rubella virus is a member of the Togaviridae family and the only member of the genus Rubivirus. This single-stranded RNA enveloped virus measures 50–70 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.

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 chronicity, 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 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 has been >90% among children 19–35 months old since 1995 and >95% for kindergarten and first-grade entrants since 1980. In 1989 a goal for the elimination of rubella and CRS in the United States was set, and in 2004 a panel of experts agreed unanimously that rubella was no longer an endemic disease in this country. 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). In the United States, interruption of endemic transmission of rubella virus has been sustained since 2001; in 2012, however, three cases of CRS were reported in infants whose mothers had acquired rubella infection abroad. Thus health care providers should remain vigilant, considering the possibility of rubella infection in patients emigrating or returning from countries without rubella control programs and the accompanying potential for CRS among their infants.

Although rubella and CRS are no longer endemic in the United States, they remain important public health problems globally. The number of rubella cases reported worldwide in 1999 was ~900,000; this figure declined steadily to 94,030 in 2012. However, numbers of rubella cases are substantially underestimated because cases in many countries are identified through measles surveillance systems that are not specific for rubella. In 2010, it was estimated that 103,000 cases of CRS occur globally.

CLINICAL FEATURES

Acquired Rubella Acquired rubella commonly presents with a generalized maculopapular rash that usually lasts for up to 3 days (Fig. 230e-1), although as many as 50% of cases may be subclinical or without rash. When it occurs, the rash is usually mild and may be difficult to detect in persons with darker skin. In 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 low-grade fever, malaise, and upper respiratory symptoms. The incubation period is 14 days (range, 12–23 days).

FIGURE 230e-1 Mild maculopapular rash of rubella in a child.

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 230e-1), which most commonly relate to the eyes, ears, and heart. This constellation of severe birth defects is known as congenital rubella syndrome. 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 infection only.”

TABLE 230e-1

COMMON TRANSIENT AND PERMANENT MANIFESTATIONS IN INFANTS WITH CONGENITAL RUBELLA SYNDROME

DIAGNOSIS

Acquired Rubella Clinical diagnosis of acquired rubella is difficult because of the mimicry of many illnesses with rashes, the varied 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, 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 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. The enzyme-linked immunosorbent assay IgM capture technique is considered most accurate for serologic diagnosis, but the indirect IgM assay also is 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. To detect a rise in IgG antibody titer indicative of acute disease, the acute-phase 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.

IgG avidity testing is used in conjunction with IgG testing. Low-avidity antibodies indicate recent infection. Mature (high-avidity) IgG antibodies most likely indicate an infection occurring at least 2 months previously. This test helps distinguish primary infection from reinfection. Avidity testing may be particularly useful in diagnosing rubella in pregnant women and assessing the risk of CRS.

Rubella virus can be isolated from the blood and nasopharynx during the prodromal period and for as long as 2 weeks after rash onset. However, as 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 viral cultures. Rubella can also be diagnosed by viral RNA detection in a reverse-transcriptase polymerase chain reaction (RT-PCR) assay.

Congenital Rubella Syndrome A clinical diagnosis of CRS is reasonable when an infant presents with a combination of cataracts, hearing impairment, and heart defects; this pattern 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 facilitates appropriate medical intervention for specific disabilities and prompts implementation of infection control measures.

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 isolated 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.

A susceptible pregnant woman exposed to rubella virus should be tested for IgM antibodies and/or a fourfold rise in IgG antibody titer between acute- and convalescent-phase serum specimens 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. Of women infected with rubella virus during the first 11 weeks of gestation, up to 90% deliver an infant with CRS; for maternal infection during the first 20 weeks of pregnancy, the CRS rate is 20%.

TREATMENT

RUBELLA

No specific therapy is available for rubella virus infection. Symptom-based 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 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 pandemic, a vaccine for rubella was developed and licensed in 1969. Currently, the majority of rubella-containing 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.

The public health burden of rubella infection is measured primarily through the resulting CRS cases. The 1964–1965 rubella epidemic in the United States encompassed >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 who were mentally retarded. The cost of this epidemic exceeded $1.5 billion. In 1983, the cost per child with CRS was estimated at $200,000.

In most countries, there is little documented evidence to illuminate the epidemiology of CRS. Clusters of CRS cases have been reported in developing countries. Before the introduction of an immunization program, the incidence of CRS is 0.1–0.2 per 1000 live births during endemic periods and 1–4 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 current recommendation for routine rubella vaccination 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. Target groups for rubella vaccine include children ≥1 year of age, adolescents and adults without documented evidence of immunity, individuals in congregate settings (e.g., college students, military personnel, child care and health care workers), 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 an RCV. In addition, pregnancy should be avoided for 28 days after receipt of an RCV. In follow-up studies of 680 unknowingly pregnant women who received rubella vaccine, no infant was born with CRS. Receipt of an RCV during pregnancy is not ordinarily a reason to consider termination of the pregnancy.

As of 2012, 134 (69%) of the 194 member countries of the World Health Organization recommended inclusion of an RCV in the routine childhood vaccination schedule (Fig. 230e-2). Goals for control or elimination of rubella and CRS have been established in the American Region, the European Region, the South-East Asia Region, and the Western Pacific Region. The other two regions (Eastern Mediterranean and African) have not yet set such goals.

FIGURE 230e-2 Countries using rubella vaccine in their national immunization schedule, 2012. (From the World Health Organization.)

231e	Mumps
	Steven A. Rubin, Kathryn M. Carbone