Chapter 10: Viruses of Mumps, Measles, Rubella, and Other Childhood Exanthems

The major viruses described in this chapter are mumps, measles, rubella, and the human parvovirus B19, which are from different virus families and genetically unrelated, but share several common epidemiologic and clinical characteristics, including: (1) worldwide distribution, with a high incidence of infection in nonimmune individuals; (2) humans as sole reservoir of infection; and (3) person-to-person spread primarily by the respiratory (aerosol) route.

The other diseases discussed in this chapter are roseola infantum and rubella-like rashes caused by many different viruses that are mainly common illnesses occurring in early life. Key characteristics of these major viruses are summarized in Table 10–1.

VIROLOGY

Mumps virus is a paramyxovirus, and only one major antigenic type is known. Like fellow members of its genus, it contains a single-stranded, negative-sense RNA genome, and a helical nucleocapsid that is surrounded by a matrix protein followed by a lipid bilayer envelope (see Figure 9–4). Two glycoproteins are expressed on the surface of the envelope; one mediates hemagglutination and neuraminidase (HN) activity, and the other is responsible for viral lipid membrane fusion (F) to the host cell. Similar to other paramyxoviruses, mumps virus initiates infection by attachment of the HN spike to sialic acid on the cell surface, and F protein promotes fusion with the plasma membrane. It replicates in the cytoplasm by using its own RNA-dependent RNA polymerase, and the progeny viruses are released by budding from the plasma membranes. Details about the structure of the virus are described in Chapter 9 and replication of negative sense RNA viruses (paramyxoviruses) are in Chapter 6.

MUMPS INFECTION

EPIDEMIOLOGY

Mumps infection is observed to occur most frequently in the 5- to 15-year age group. Infection is rarely seen in the first year of life. Mumps is transmitted from person-to-person through the respiratory route (aerosol), such as in respiratory viruses. Although approximately 85% of susceptible household contacts acquire infection, approximately 30% to 40% of these contacts do not develop clinical disease. The disease is communicable from approximately 7 days before until 9 days after onset of illness; however, virus has been recovered in urine for up to 14 days after onset. The highest incidence of infection is usually during the late winter and spring months, but it can occur during any season. In the United States, mumps cases range from couple hundred to couple thousand every year. For example, 2612 cases were reported in 2010, 229 cases in 2012, and 5311 infections in 2016.

PATHOGENESIS

After initial entry into the respiratory tract, the virus replicates locally in the respiratory tract epithelium and local lymph nodes. Replication is followed by viremic dissemination to target tissues such as the salivary glands (parotid glands) and central nervous system (CNS). It is also possible that, before development of immune responses, a secondary phase of viremia may result from virus replication in target tissues (eg, initial parotid glands involvement with later spread to other organs). There is painful swelling of one or both parotid glands. Viruria is common, probably as a result of direct spread from the blood into the urine, in addition to active viral replication in the kidney. The tissue response is that of cell necrosis and inflammation, with predominantly mononuclear cell infiltration. In the salivary glands, swelling and desquamation of necrotic epithelial lining cells, accompanied by interstitial inflammation and edema, may be seen within dilated ducts. The pathogenesis, clinical disease, and immune response are summarized in Figure 10–1.

IMMUNITY

As in most viral infections, the early antibody response in mumps is predominantly with immunoglobulin M (IgM), which is switched gradually over several weeks to a specific IgG antibody. The latter persists for a lifetime, but can often be detected only by specific neutralization assays. Immunity is associated with the presence of neutralizing antibody. The role of cellular immune responses has also been investigated and found to contribute both to the pathogenesis of the acute disease and to recovery from infection. After primary infection, immunity to reinfection is, virtually, always permanent.

CLINICAL ASPECTS

MANIFESTATIONS

After an incubation period of 12 to 29 days (average, 16-18 days), the typical case of mumps is characterized by fever and swelling with tenderness of the salivary glands, especially the parotid glands (Figure 10–2). Swelling may be unilateral or bilateral and persists for 7 to 10 days. Several complications can occur, usually within 1 to 3 weeks of onset of illness. All appear to be a direct result of virus spread to other sites and illustrate the extensive tissue tropism of mumps.

The common complications of mumps infection, which can occur without parotitis, include the following:

• Meningitis: Approximately 10% of all infected patients develop meningitis. It is usually mild, but can be confused with bacterial meningitis. In approximately one-third of these cases, associated or preceding evidence of parotitis is absent.

• Encephalitis: Encephalitis is occasionally severe.

• Spinal cord and peripheral nerves are involved, causing transverse myelitis and polyneuritis in rare cases.

• Pancreatitis: Pancreatitis is suggested by upper abdominal pain, nausea, and vomiting.

• Orchitis: Orchitis (inflammation of the testes) is estimated to occur in 10% to 20% of infected men, which could be unilateral or bilateral in postpubertal men. Although subsequent sterility is a concern, it appears that this outcome is rare.

• Oophoritis: Oophoritis (inflammation of ovaries) is an unusual, usually benign, inflammation of the ovarian glands.

Other rare and transient complications include myocarditis, nephritis, arthritis, thyroiditis, thrombocytopenic purpura, mastitis, and pneumonia. Most complications resolve without sequelae within 2 to 3 weeks. However, occasional permanent effects have been noted, particularly in severe CNS infection, in which sensorineural hearing loss and other impairment can occur.

DIAGNOSIS

Mumps virus can be readily detected or isolated early in the illness from the saliva, pharynx, and other affected sites, such as the cerebrospinal fluid (CSF). In addition, the urine is an excellent source for virus isolation. Rapid diagnosis can be made by direct detection of viral nucleic acid by reverse transcription-polymerase chain reaction (RT-PCR). Mumps virus grows well in primary monolayer cell cultures derived from monkey kidney, producing syncytial giant cells and viral hemagglutinin. Virus culture is gold standard.

The usual serologic tests are enzyme-linked immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IF) to detect IgM- and IgG-specific antibody responses. Other serologic tests are also available, such as complement fixation, hemagglutination inhibition, and neutralization. Of these, the neutralization test is the most sensitive for detection of immunity to infection.

PREVENTION

There is no specific treatment available for mumps. Since 1967, a live attenuated vaccine that is safe and highly effective has been available. As a result of its routine use, infections in the United States before 2005 were exceedingly rare; however, in late 2005 and into 2006, a large outbreak (greater than 6000 proved or probable cases) developed in Iowa and eight neighboring midwestern states. Most occurred in persons 18 to 25 years of age, many of whom had been previously vaccinated at least once. The mumps strain identified was genotype G, a common strain similar to the one that involved more than 70 000 cases in the United Kingdom from 2004 to 2006. Thus, it has been reemphasized that a two-dose vaccine regimen is essential to ensure adequate immunity. The vaccine is produced by serial propagation of virus in chick embryo cell cultures. Mumps is commonly combined with measles and rubella (MMR) vaccine or measles, rubella, and varicella (chicken pox virus) vaccine (MMRV), and given as a single injection to a child at 12 to 15 months of age. A second dose of MMR or MMRV is recommended at 4 to 6 years of age; those who have missed the second dose should receive it no later than 11 to 12 years of age. A single dose causes seroconversion in approximately 80% of recipients, and it increases only to about 90% after two doses. The vaccine must be given at least 2 to 4 weeks before exposure to be at all effective in postexposure prophylaxis. In approximately 10% of the people who have received the two doses of the vaccine and, probably, partially seroconverted could still be infected with the mumps virus because of living in close contact, such as at schools and colleges. In 2009 to 2010, a mumps outbreak occurred in the northeastern United States, spreading in a camp, followed by spread in schools and household. This infection most likely came through a boy who traveled to the United Kingdom and later joined the camp. In 2010, more than 2000 cases and in 2016 more than 5000 cases of mumps were reported in the United States. In 2015-16, several outbreaks were reported from many university campuses, including the largest outbreaks from Iowa and Illinois campuses that held MMR vaccination campaigns.

VIROLOGY

The measles virus is classified in the paramyxovirus family, genus Morbillivirus. It contains a linear, negative-sense, single-stranded RNA genome surrounded by a helical nucleocapsid protein and a lipid bilayer envelope containing two glycoprotein projections (peplomers), two envelope glycoproteins, namely hemagglutinin (H), that mediates virus adsorption to the cell surfaces, and fusion (F) protein that mediates cell fusion, hemolysis, and viral entry into the cell. On the inside of the envelope surface, there is a matrix (M) protein that plays a key role in viral assembly. The virions also contain the viral RNA polymerase (RNA-dependent RNA polymerase) required for viral RNA transcription and replication. Unlike the mumps virus, the measles virus lacks neuraminidase (N) activity. The receptor for measles virus is CD46 (membrane cofactor protein), a regulator of complement activation. Replication of measles virus is similar to other paramyxoviruses, which is described in Chapter 6 for negative-sense RNA viruses. Only a single serotype restricted to human infection is recognized; however, subtle antigenic and genetic variations among wild-type measles strains do occur. These variations can be determined by sequencing analyses, enabling more precise epidemiologic tracking of outbreaks and their origins. Such ongoing molecular surveillance is also extremely important in determining whether significant antigenic drifts evolve over time.

MEASLES INFECTION

EPIDEMIOLOGY

The highest attack rates of measles have been in children, usually sparing infants less than 6 months of age because of passively acquired antibody. However, a shift in age-specific attack rates to greater involvement of adolescents and young adults was observed in the United States in the 1980s. A marked decline in measles in the United States during the early 1990s may reflect decreased transmission as increased immunization coverage takes effect. However, in developing countries, an estimated one million children still die from this disease each year. Furthermore, measles remains endemic in most countries in the world, including parts of Europe. In 2007 to 2008, large outbreaks of measles were occurring in Switzerland and Israel, resulting in imported cases leading to localized spread within the United States. In the United States, approximately 60 people are reported to have measles each year. In 2011, 222 people were infected with measles, including 40% imported from Europe and Asia involving more than a dozen outbreaks in various communities in the United States. In 2013 and 2014, the United States reported 11 outbreaks (3 outbreaks have more than 20 cases and 1 with 58 cases) and 23 outbreaks (1 outbreak with 383 cases in unvaccinated Amish community in Ohio and many cases brought from Philippines—a total of 667 cases), respectively. In 2015, the United States experienced a large, multistate measles outbreak (188 cases) linked to an amusement park in California, likely from a traveler. In 2016, 16 states in the United States reported total of 70 cases, although lower than previous years. It is believed that many measles cases are seen in unvaccinated people. Thus, continued vigilance is required for all who care for patients.

Epidemics tend to occur during the winter and spring and, increasingly, are limited to one-dose vaccine failures or groups who do not accept immunizations. The infection rate among exposed susceptible subjects in a classroom or household setting is estimated at 85%, and more than 95% of those infected become ill. The period of communicability is estimated to be 3 to 5 days before appearance of the rash to 4 days afterward.

PATHOGENESIS

Measles is transmitted through respiratory inhalation and, after implantation of the virus in the upper respiratory tract, viral replication proceeds in the respiratory mucosal epithelium. The effect within individual respiratory cells is profound. Although measles does not directly restrict host cell metabolism, susceptible cells are damaged or destroyed by virtue of the intense viral replicative activity and the promotion of cell fusion with formation of syncytia. This results in disruption of the cellular cytoskeleton, chromosomal disorganization, and the appearance of inclusion bodies within the nucleus and cytoplasm. Replication is followed by viremic and lymphatic dissemination throughout the host to distant sites, including lymphoid tissues, bone marrow, abdominal viscera, and skin. The virus can be demonstrated in the blood during the first week after illness onset, and viruria persists for up to 4 days after the appearance of rash. Viremia also allows the infection of conjunctiva, urinary tract, small blood vessels, and the CNS. Figure 10–3 summarizes the pathogenesis, clinical disease, and immunity in measles virus infection.

During the viremic phase, measles virus infects T and B lymphocytes, circulating monocytes, and polymorphonuclear leukocytes without producing cytolysis. Profound depression of cell-mediated immunity occurs during the acute phase of illness and persists for several weeks thereafter. This is believed to be a result of virus-induced downregulation of interleukin-12 (IL-12) production by monocytes and macrophages. The effect on B lymphocytes has been shown to suppress immunoglobulin synthesis; in addition, generation of natural killer cell activity appears to be impaired. Moreover, there is evidence that the capability of polymorphonuclear leukocytes to generate oxygen radicals is diminished, perhaps directly by the virus or by activated regulatory T cells. This may further explain the enhanced susceptibility to bacterial superinfections. Virion components can be detected in biopsy specimens of Koplik spots and vascular endothelial cells in the areas of skin rash.

In addition to necrosis and inflammatory changes in the respiratory tract epithelium, several other features of measles virus infection are noteworthy. The skin lesions show vasculitis characterized by vascular dilation, edema, and perivascular mononuclear cell infiltrates. The lymphoid tissues show hyperplastic changes, and large multinucleated reticuloendothelial giant cells are often observed (Warthin-Finkeldey cells). Some of the giant cells contain intracytoplasmic and intranuclear inclusions. Similarly involved giant epithelial cells can be found in a variety of mucosal sites, the respiratory tract, skin, and urinary sediment.

In some patients with measles, an immune-mediated postinfectious encephalitis occurs after the rash. The major findings in measles encephalitis include areas of edema, scattered petechial hemorrhages, perivascular mononuclear cell infiltrates, and necrosis of neurons. In most cases, perivenous demyelination in the CNS is also observed. The pathogenesis is thought to be related to infiltration by cytotoxic (CD8+) T cells, which react with myelin-forming or virus-infected brain cells.

IMMUNITY

Cell-mediated immune responses to other antigens may be acutely depressed during measles infection and persist for several months. There is evidence that measles virus-specific cell-mediated immunity developing early in infection plays a role in mediating some of the features of disease, such as the rash, and is necessary to promote recovery from the illness. Antibodies to the virus appear in the first few days of illness, peak in 2 to 3 weeks, and then persist at low levels. Immunity to reinfection is lifelong and is associated with the presence of neutralizing antibody. In patients with defects in cell-mediated immunity, including those with severe protein-calorie malnutrition, infection is prolonged, tissue involvement is more severe, and complications such as progressive viral pneumonia are common. In addition, use of vitamin A may have some benefits in reducing the severity and complications of measles, especially in malnourished children.

CLINICAL ASPECTS

MANIFESTATIONS

Common synonyms for measles include rubeola, 5-day measles, and hard measles. The incubation period ranges from 7 to 18 days. A typical illness usually begins 9 to 11 days after exposure, with cough, coryza, conjunctivitis, and fever. One to three days after onset, pinpoint gray-white spots surrounded by erythema (grains-of-salt appearance) appear on mucous membranes. This sign, called Koplik spots, is usually most noticeable over the buccal mucosa opposite the molar teeth and persists for 1 to 2 days (Figure 10–4). Within a day of the appearance of Koplik spots, the typical measles rash begins—first on the head, then on the trunk and extremities. The rash is maculopapular and semiconfluent; it persists for 3 to 5 days before fading (Figure 10–5). Fever and severe systemic symptoms gradually diminish as the rash progresses to the extremities. Lymphadenopathy is also common, with particularly noticeable involvement of the cervical nodes.

Measles can be very severe, especially in immunocompromised or malnourished patients. Death can result from overwhelming viral infection of the host, with extensive involvement of the respiratory tract and other viscera. In some developing countries, mortality rates of 15% to 25% have been recorded.

Complications

Bacterial superinfection, the most common complication, occurs in 5% to 15% of all cases. Such infections include acute otitis media, mastoiditis, sinusitis, pneumonia, and sepsis. Clinical signs of encephalitis develop in 1 per 500 to 1000 cases. This condition usually occurs 3 to 14 days after onset of illness and can be extremely severe. The mortality in measles encephalitis is approximately 15%, and permanent neurologic damage among survivors is estimated at 25%. Acute thrombocytopenic purpura may also develop during the acute phase of measles, leading to bleeding episodes. Abdominal pain and acute appendicitis can occur secondary to inflammation and swelling of lymphoid tissue.

Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a rare, progressive neurologic disease of children, which usually begins 2 to 10 years after a measles infection. It is characterized by insidious onset of personality change, poor school performance, progressive intellectual deterioration, development of myoclonic jerks (periodic muscle spasms), and motor dysfunctions, such as spasticity, tremors, loss of coordination, and ocular abnormalities, including blindness. Neurologic and intellectual deterioration generally progresses over 6 to 12 months, with children eventually becoming bedridden and stuporous. Dysfunctions of the autonomic nervous system, such as difficulty with temperature regulation, may develop. Progressive inanition, superinfection, and metabolic imbalances eventually lead to death. Most of the pathologic features of the disease are localized to the CNS and retina. Both the gray matter and the white matter of the brain are involved, the most noteworthy feature being the presence of intranuclear and intracytoplasmic inclusions in oligodendroglial and neuronal cells.

The disease is a result of chronic wild-type measles virus infection of the CNS. Studies have shown that patients have a variety of patterns of missing measles virus structural proteins in brain tissue. Thus, any of several defects in viral gene expression may prevent normal viral assembly, allowing persistence of defective virus at an intracellular site with failure of immune eradication.

Rarely, a similar progressive, degenerative neurologic disorder may be related to persistent rubella virus infection of the CNS. This condition is seen most often in adolescents who have had congenital rubella syndrome. Rubella virus has been isolated from brain tissue in these patients, again using cocultivation techniques.

The incidence of SSPE is approximately 1 per 100 000 measles cases. Its occurrence in the United States has decreased markedly over the last 25 years with the widespread use of live measles vaccine. At present, there is no accepted effective therapy for SSPE.

DIAGNOSIS

The typical measles infection can often be diagnosed on the basis of clinical findings, but laboratory confirmation is necessary. Detection of measles in throat, nasal or nasopharyngeal specimens can be performed by RT-PCR or virus isolation. A rapid diagnosis can be done by employing real time RT-PCR to detect measles viral genome in respiratory specimens and urinary sediments. Virus isolation from the respiratory specimens or urine is usually most productive in the first 5 days of illness. Measles grows on a variety of cell cultures, producing multinucleated giant cells similar to those observed in infected host tissues. Serologic diagnosis, IgM and IgG may involve HI, ELISA, or indirect fluorescent antibody methods.

TREATMENT

No specific therapy is available other than supportive measures and close observation for the development of complications such as bacterial superinfection. Intravenous ribavirin has been suggested for patients with severe measles pneumonia, but no controlled studies have been performed.

PREVENTION

Highly immunogenic live attenuated measles vaccine is available and is most commonly administered as MMRV. To ensure effective immunization, the vaccine should be administered to infants at 12 to 15 months of age with a second dose at 4 to 6 or 11 to 12 years of age. Immunity induced by the vaccine may be lifelong. Because the vaccine consists of live virus, it should not be administered to immunocompromised patients and is not recommended for pregnant women. Exceptions to these guidelines include susceptible human immunodeficiency virus (HIV)-infected persons. Exposed susceptible patients who are immunologically compromised (including small infants) may be given immune serum globulin intramuscularly. This treatment can modify or prevent disease if given within 6 days of exposure, but protection is transient.

Rubella, commonly known as German measles or 3-day measles, was considered a mild, benign exanthem of childhood until 1941, when the Australian ophthalmologist Sir Norman Gregg described the profound defects that could be induced in the fetus as a result of maternal infection. Since 1962, when the virus was first isolated, knowledge regarding its extreme medical importance and biologic characteristics has increased rapidly.

VIROLOGY

Rubella virus is classified as a member of the togavirus family, Rubivirus genus. It is a simple, icosahedral, enveloped virus, and contains a single-stranded, positive-sense RNA genome. There is a single species of capsid protein, and the lipid bilayer envelope contains two glycoproteins—E1 and E2. E1 interacts with the receptor on the host cell and comprises the principal antigenic determinants or epitopes involved in virus neutralization and hemagglutination. E2 interacts with capsid and E1 to reach the Golgi apparatus for viral assembly. There is only one serotype of rubella; however, some strain variation in virulence and antigenicity has been reported. In addition, there are no extrahuman or animal reservoirs for rubella virus as well as any related animal viruses. There is no serologic cross-reactivity between rubella virus and other members of the togavirus family such as alphaviruses (transmitted via arthropods). The details of viral structure of the togavirus are described in Chapter 16. The virus can agglutinate some types of red blood cells, such as those obtained from 1-day-old chicks and trypsin-treated human type O cells.

Rubella virus enters target cells via receptor-mediated endocytosis. Viral positive-sense RNA is translated to produce viral proteins, including RNA-dependent RNA polymerase. These proteins are required for the synthesis of replicative intermediates, full length genomic RNA, and subgenomic RNA. The subgenomic RNA encodes the structural proteins of the virus, including capsid and envelope proteins. The full-length genomic RNA encodes for nonstructural proteins and RNA polymerase and also serves as genomic RNA for progeny viruses. Virus assembly takes place in either the Golgi complex or cytoplasmic membranes.

RUBELLA INFECTION

EPIDEMOLOGY

While endemic rubella has been eliminated in the United States due to vaccination, it is a serious concern in various parts of the world, including Africa, Asia, and elsewhere. In the United States, most of the rubella cases are imported. Rubella infections are usually observed during the winter and spring months. In contrast to measles, which has a high clinical attack rate among exposed susceptible individuals, only 30% to 60% of rubella-infected susceptible persons develop clinically apparent disease. A major focus of concern is susceptible women of childbearing age, who carry a risk of exposure during pregnancy and transmitting the virus to their babies (congenital infection). Patients with primary acquired rubella infections are contagious from 7 days before to 7 days after the onset of rash; congenitally infected infants may spread the virus to others for 6 months or longer after birth. In the United States, less than a dozen cases of congenital rubella are seen. However, more than 100 000 babies are born with congenital rubella syndrome (CRS) every year worldwide. CRS is the highest in Africa and Southeast Asia where the vaccination is the lowest. The disease is preventable by vaccination.

PATHOGENESIS

In acquired infection, the virus enters the host through the upper respiratory tract, replicates, and then spreads by the bloodstream to distant sites, including lymphoid tissues, skin, and organs. Viremia in these infections has been detected for as long as 8 days before to 2 days after onset of the rash, and virus shedding from the oropharynx can be detected up to 8 days after onset (Figure 10–6). Cellular immune responses and circulating virus–antibody immune complexes are thought to play a role in mediating the inflammatory responses to infection, such as rash and arthritis.

Congenital infection occurs as a result of maternal viremia that leads to placental infection and then transplacental spread to the fetus. The risk of congenital infection correlates with the timing of transmission of the virus to the fetus. If the virus is transmitted to the fetus early in gestation, then the risk of development of congenital rubella syndrome (CRS) is very high. After fetal infection occurs, it persists chronically. Such persistence is probably related to an inability to eliminate the virus by immune or interferon-mediated mechanisms. There is too little inflammatory change in the fetal tissues to explain the pathogenesis of the congenital defects. The possibilities include placental and fetal vasculitis with compromise of fetal oxygenation, chronic viral infection of cells leading to impaired mitosis, cellular necrosis, and induction of chromosomal breakage. Any or all of these factors may operate at a critical stage of organogenesis to induce permanent defects. Viral persistence with circulating virus–antibody immune complexes may evoke inflammatory changes postnatally and produce continuing tissue damage.

After birth, infants affected with rubella continue to excrete the virus in the throat, urine, and intestinal tract (Figure 10–7). Virus may be isolated from virtually all tissues in the first few weeks of life. Shedding of virus in the throat and urine, which persists for at least 6 months in most cases, has been known to continue for 30 months. Rubella virus has also been isolated from lens tissue removed 3 to 4 years later. These observations underscore the fact that such infants are important reservoirs in perpetuating virus transmission. The prolonged virus shedding is somewhat puzzling; it does not represent a typical example of immunologic tolerance. The affected infants are usually able to produce circulating IgM and IgG antibodies to the virus (Figure 10–7), although antibodies may decrease to undetectable levels after 3 to 4 years. Many infants have evidence of depressed rubella virus-specific cell-mediated immunity during the first year of life.

PATHOLOGY

Because postnatally acquired disease is usually mild, little is known about the pathology of rubella. Mononuclear cell inflammatory changes can be observed in tissues, and viral antigen can be detected in the same sites (eg, skin and synovial fluid). Congenital infections are characterized primarily by the various malformations. Necrosis of tissues such as myocardium and vascular endothelium may also be seen, and quantitative studies suggest a decrease in cell quantity in affected organs. In severe cases, normal calcium deposition in the metaphyses of long bones is delayed, sometimes referred to as a “celery stalk” appearance on a radiograph.

IMMUNITY

After infection with rubella, the serum antibody titer rises, reaching a peak within 2 to 3 weeks of onset (Figure 10–7). Natural infection also results in the production of specific secretory IgA antibodies in the respiratory tract. Immunity to disease is nearly always lifelong; however, reexposure can lead to transient respiratory tract infection, with an anamnestic rise in IgG and secretory IgA antibodies, but without resultant viremia or illness.

CLINICAL ASPECTS

MANIFESTATIONS

Rubella is commonly known as German measles or 3-day measles. The incubation period for acquired infection is 14 to 21 days (average, 16 days). Illness is generally very mild, consisting primarily of low-grade fever, sore throat and other upper respiratory symptoms, and lymphadenopathy, which is most prominent in the posterior cervical and postauricular areas. A macular rash often follows within a day of onset and lasts 1 to 3 days. This rash, which is often quite faint, is usually most prominent over the head, neck, and trunk (Figure 10–8). In addition, petechial lesions may be seen over the soft palate during the acute phase. The most common complication is arthralgia or overt arthritis, which may affect the joints of the fingers, wrists, elbows, knees, and ankles. The joint problems, which occur most frequently in women, rarely last longer than a few days to 3 weeks. Other, rarer complications include thrombocytopenic purpura and encephalitis.

The major significance of rubella is not the acute illness but the risk of fetal damage in pregnant women, particularly when they contract either symptomatic or subclinical primary infection during the first trimester. The risk of fetal malformation and chronic fetal infection, which is estimated to be as high as 80% if infection occurs in the first 2 weeks of gestation, decreases to 6% to 10% by the 14th week. The overall risk during the first trimester is estimated at 20% to 30%.

Clinical manifestations of congenital rubella syndrome vary, but may include any combination of the following major findings: cardiac defects, commonly patent ductus arteriosus and pulmonary valvular stenosis; eye defects such as cataracts, chorioretinitis, glaucoma, coloboma, cloudy cornea, and microphthalmia; sensorineural deafness; enlargement of liver and spleen; thrombocytopenia; and intrauterine growth restriction. There is also appearance of purpura more often on head, neck, and trunk due to extramedullary hematopoiesis, also referred as blueberry muffin. Other findings include CNS defects such as microcephaly, mental retardation, and encephalitis; anemia; transient immunodeficiency; interstitial pneumonia; and intravascular coagulation; hepatitis; rash; and other congenital malformations. Late complications of congenital rubella syndrome have also been described, including an increased risk of diabetes mellitus, chronic thyroiditis, and, occasionally, the development of a progressive subacute panencephalitis in the second decade of life. Some congenitally infected infants may appear entirely normal at birth, and sequelae such as hearing or learning deficits may not become apparent until months later. The spectrum of defects, thus, varies from subtle to severe. Congenital rubella is considered as part of TORCHS (toxoplasma, others, rubella, CMV, herpes, syphilis) in clinical evaluation and screening of congenital infections.

DIAGNOSIS

Because of the rather nonspecific nature of the illness, a diagnosis of rubella cannot be made on clinical grounds alone. More than 30 other viral agents, which are discussed later in this chapter, can produce a similar illness. Confirmation of the diagnosis requires laboratory studies. The virus may be detected by RT-PCR or isolated from respiratory secretions in the acute phase (and from urine, tissues, and feces in congenitally infected infants) by inoculation into a variety of cell cultures. Serologic diagnosis is most commonly used in acquired infections; paired acute and convalescent samples collected 10 to 21 days apart are used. Hemagglutination inhibition, IF, EIA, and other tests are available.

Determination of IgM-specific antibody is, sometimes, useful to ascertain whether an infection occurred in the last several months; it has also been used in the diagnosis of congenital infections. Unfortunately, there are certain pitfalls in interpreting this test. Some individuals (less than 5%) with acquired infections may have persistent elevations of IgM-specific antibodies for 200 days or more afterward, and some congenitally infected infants do not produce detectable IgM-specific antibodies.

TREATMENT AND PREVENTION

Other than supportive measures, there is no specific therapy for either the acquired or the congenital rubella infection.

Since 1969, a live attenuated rubella vaccine has been available for routine immunization either as MMR or MMRV. As a result of the widespread use of the vaccine in the United States, the number of cases of rubella has declined dramatically. From 1990 through 1999, the median number of cases reported annually was only 232. The current vaccine virus—grown in human diploid fibroblast cell cultures (RA 27/3)—has been shown to be highly effective. It causes seroconversion in approximately 95% of recipients. Routine immunization is now recommended for infants after the first year of life and for other individuals with no history of immunization and lack of immunity by serologic testing. Target groups include female adolescents and hospital personnel in high-risk settings. The vaccine is contraindicated in many immunocompromised patients and in pregnancy. To date, more than 200 instances of accidental vaccination of susceptible pregnant women have been reported, with no clinically apparent adverse effects on the fetus. However, it is strongly recommended that immunization be avoided in this setting, and that nonpregnant women avoid conception for at least 3 months after receiving the vaccine.

Parvoviruses are very small (18-26 nm), naked icosahedral capsid virions that contain a linear single-stranded DNA genome. Parvovirus B19 causes disease in humans (children) known as erythema infectiosum, slapped face, or fifth disease. The other parvovirus that infects humans is human bocavirus, believed to cause wheezing and respiratory infections in children. Parvovirus also causes disease in animals, including canine parvovirus and feline panleukopenia virus, which produce severe infections among puppies and kittens, respectively. These do not appear to cross species barriers such as infecting humans. The other parvovirus that is of some interest is adeno-associated virus (AAV) because of its potential in gene therapy. The human parvovirus B19 has been well described, but its origin is not yet known.

Parvovirus B19 encodes three capsid proteins (VP1, VP2, and VP3) that encapsidate a single-stranded DNA molecule into an icosahedral symmetry. VP2 is the major capsid protein that comprises almost 90% of the virion capsid. The virus can be grown in primary cultures of human bone marrow cells, fetal liver cells, hematopoietic progenitor cells generated from peripheral blood, and a megakaryocytic leukemia cell line. The major cellular receptor for the virus is globoside (also known as blood group P antigen, which is commonly found on erythroid progenitors, erythroblasts, megakaryocytes, and endothelial cells). All represent potential targets for disease production. A primary site of replication appears to be the nucleus of an immature cell in the erythrocyte lineage that is mitotically active. Such infected cells then cease to proliferate, resulting in an impairment of normal erythrocyte development. Parvovirus enters the cells after binding to P antigen (globoside) followed by internalization, uncoating, and delivery of single-stranded DNA to the nucleus. The single-stranded DNA genome is converted to double-stranded DNA by host DNA polymerase, which is transcribed by host RNA polymerase to produce viral mRNAs, followed by synthesis of viral proteins. After synthesis of single-stranded DNA genomes by host DNA polymerase, progeny viruses are assembled in the nucleus and released upon cell lysis.

The clinical consequences of this effect on erythrocytes are generally trivial, unless patients are already compromised by a chronic hemolytic process, such as sickle cell disease or thalassemia, in which maximal erythropoiesis is continually needed to counterbalance increased destruction of circulating erythrocytes. Primary infection by parvovirus B19 in such individuals often produces an acute, severe, and sometimes fatal anemia manifested as a rapid fall in red blood cell count and hemoglobin. These patients may present initially with no clinical symptoms other than fever; this is commonly referred to as aplastic crisis. Immunocompromised patients such as those with acquired immunodeficiency syndrome (AIDS), sometimes, have difficulty clearing the virus and develop persistent anemia with reticulocytopenia. Parvovirus B19 has also been occasionally implicated as a cause of persistent bone marrow failure and an acute hemophagocytic syndrome. In addition, it is now recognized as sometimes causing severe, protracted anemia in many settings of immune compromise, including in patients with AIDS, organ transplant recipients, and leukemic patients undergoing chemotherapy. Parvovirus B19 has also been implicated in triggering various forms of autoimmune diseases affecting joints, connective tissues, and small and large vessels both in children and adults. Furthermore, autoimmune neutropenia, thrombocytopenia, and hemolytic anemia are known sequelae of parvovirus B19 infection.

Erythema Infectiosum

Erythema infectiosum (also referred to as fifth disease or academy rash) is a more common disease that is clearly attributable to parvovirus B19. The virus is primarily transmitted by the respiratory route. In addition, it can be transmitted through blood or blood products as well as from mother to child. After an incubation period of 4 to 12 days, a mild illness appears, characterized by fever, malaise, headache, myalgia, and itching in varying degrees. A confluent, indurated rash appears on the face, giving a “slapped-cheek” appearance. The rash spreads in 1 or 2 days to other areas, particularly exposed surfaces such as the arms and legs, where it is usually macular and reticular (lace-like). During the acute phase, generalized lymphadenopathy or splenomegaly may be seen, together with a mild leukopenia and anemia.

The illness of erythema infectiosum lasts 1 to 2 weeks, but rash may recur for periods of 2 to 4 weeks thereafter, exacerbated by heat, sunlight, exercise, and emotional stress. Arthralgia sometimes persists or recurs for weeks to months, particularly in adolescent or adult females. Overt arthritis or vasculitis have also been reported in some individuals. Serious complications such as hepatitis, thrombocytopenia, nephritis, or encephalitis are rare. However, like rubella, active transplacental transmission of parvovirus B19 can occur during primary infections in the first 20 weeks of pregnancy, sometimes resulting in stillbirth of fetuses that are profoundly anemic. The progress can be so severe that hypoxic damage to the heart, liver, and other tissues leads to extensive edema (hydrops fetalis). The frequency of such adverse outcomes is as yet undetermined.

It is important to be aware that erythema infectiosum is extremely variable in its clinical manifestations; even the “classic” presentation can be mimicked by other agents, such as rubella and echoviruses. Before a firm diagnosis is made on clinical grounds, especially during outbreaks, it is wise to exclude the possibility of atypical rubella infection.

Epidemiologic evidence suggests that spread of the virus is primarily by the respiratory route, and high transmission rates occur in households. Outbreaks tend to be small and localized, particularly during the spring months, with the highest rates among children and young adults. Seroepidemiologic studies have demonstrated evidence of past infection in 30% to 60% of adults. Viremia usually lasts 7 to 12 days but can persist for months in some individuals. It can be detected by specific DNA probe or PCR methods. Alternatively, the presence of IgM-specific antibody late in the acute phase or during convalescence strongly supports the diagnosis.

There is currently no definitive treatment for erythema infectiosum. Commercial immune globulins with antibodies to parvovirus B19 have been used with salutary effects and reduction of serum viral DNA in some patients with refractory infection in a setting of immunodeficiency.

Currently, a recombinant parvovirus B19 virus-like particle vaccine (VLP) is under study, which could potentially benefit groups especially at risk because of chronic hemolytic disease, immunodeficiency, or seronegative pregnancies (to prevent hydrops fetalis), and perhaps even benefit children with acute anemia due to malaria, in whom the hematologic effects may be more profound if there is parvovirus B19 coinfection.

Roseola infantum is a common illness observed in infants and children 6 months to 4 years of age. Its alternative name, exanthem subitum, means “sudden” rash. Roseola has more than one cause: the most common is human herpesvirus type 6 (HHV-6) and, less frequently, human herpesvirus type 7 (HHV-7). HHV-6 and HHV-7 are members of the Roseolovirus genus of herpesvirus family (see Chapter 14). HHV-6 is classified into two groups; HHV-6A and HHV-6B. HHV-6B is a major cause of roseola infantum, whereas HHV-6A is not clearly associated with any disease. Several other agents, including adenoviruses, coxsackieviruses, and echoviruses, have occasionally been noted to cause similar manifestations. The illness is characterized by abrupt onset of high fever, sometimes accompanied by brief, generalized convulsions (seizures) and leukopenia. After 3 to 5 days, the fever diminishes rapidly, followed in a few hours by a faint, transient, macular rash.

In addition to erythema infectiosum, diseases caused by numerous other agents can mimic rubella. These include at least 17 echoviruses, 9 coxsackieviruses, several adenoviral serotypes, arboviruses (such as dengue, West Nile virus, Zika virus), Epstein-Barr virus, Cytomegalovirus, scarlet fever, and toxic drug eruptions. Because of the wide variety of diagnostic possibilities, it is not possible to diagnose or rule out rubella confidently on clinical grounds alone. Therefore, a specific diagnosis requires specific laboratory studies. Because rubella is an infection with such significant impact on the fetus, serologic study to rule out the possibility is mandatory if the diagnosis is suspected during early pregnancy—both in the woman and potentially infective contacts.