Chapter 39: Important Childhood Viruses

The viruses that cause measles, mumps, rubella, roseola, and slapped cheek syndrome are typically thought of as childhood diseases, although they can cause disease in adults as well. Measles, mumps, and rubella viruses are united as components of the widely used, very successful MMR vaccine. Note that measles and rubella are characterized by a rash, whereas mumps is not. The prominent feature of mumps is parotid gland swelling. Slapped cheek syndrome, as the name implies, is characterized by a rash on the face and is caused by parvovirus B19. Roseola infantum is a childhood disease characterized by high fever and a rash. It is caused by human herpesvirus-6 (HHV-6).

Additional information regarding the clinical aspects of infections caused by the viruses in this chapter is provided in Part IX entitled Infectious Diseases beginning on page 607.

Disease

This virus causes measles, a disease characterized by a maculopapular rash. It occurs primarily in childhood.

Important Properties

The genome of measles virus consists of single-stranded RNA with a negative polarity (Table 39–1). It is an enveloped virus with a helical nucleocapsid. The virus has a single serotype. Humans are the natural host.

Summary of Replicative Cycle

After adsorption to the cell surface via its hemagglutinin, the virus penetrates and uncoats and the virion RNA polymerase transcribes the negative-strand genome into mRNA. Multiple mRNAs are synthesized, each of which is translated into the specific viral proteins; no polyprotein analogous to that synthesized by poliovirus is made. The helical nucleocapsid is assembled, the matrix protein mediates the interaction with the envelope, and the virus is released by budding from the cell membrane.

Transmission & Epidemiology

Measles virus is transmitted via respiratory droplets produced by coughing and sneezing both during the prodromal period and for a few days after the rash appears. Measles occurs worldwide, usually in outbreaks every 2 to 3 years, when the number of susceptible children reaches a high level. The World Health Organization (WHO) estimates there are 7 million cases of measles each year worldwide.

In the year 2000, the Centers for Disease Control and Prevention (CDC) declared that measles is eliminated from the United States. Elimination meant that sustained transmission within the United States no longer occurred. However, cases acquired abroad (imported cases) followed by small outbreaks continue to occur. In 2016, measles was declared eradicated from the Western Hemisphere.

In 2019, a widespread outbreak of measles occurred in the United States. As of this writing, more than 700 cases have occurred in 22 states. It is believed to have originated from an imported case in an unimmunized child.

The attack rate is one of the highest of viral diseases; most children contract the clinical disease on exposure. When this virus is introduced into a population that has not experienced measles, such as the inhabitants of the Hawaiian Islands in the 1800s, devastating epidemics occur. In malnourished children, especially those in developing countries, measles is a much more serious disease than in well-nourished children. Vitamin A deficiency is especially important in this regard, and supplementation of this vitamin greatly reduces the severity of measles. Patients with deficient cell-mediated immunity (e.g., acquired immunodeficiency syndrome [AIDS] patients) have a severe, life-threatening disease when they contract measles.

Pathogenesis & Immunity

After infecting the cells lining the upper respiratory tract, the virus enters the blood and infects reticuloendothelial cells, where it replicates again. It then spreads via the blood to the skin. The rash is caused primarily by cytotoxic T cells attacking the measles virus-infected vascular endothelial cells in the skin. Antibody-mediated vasculitis may also play a role. Shortly after the rash appears, the virus can no longer be recovered and the patient can no longer spread the virus to others. Multinucleated giant cells, which form as a result of the fusion protein in the spikes, are characteristic of the lesions.

Lifelong immunity occurs in individuals who have had the disease. The hemagglutinin on the surface of the virion is the antigen against which neutralizing antibody is directed. Although IgG antibody may play a role in neutralizing the virus during the viremic stage, cell-mediated immunity is more important. The importance of cell-mediated immunity is illustrated by the fact that agammaglobulinemic children have a normal course of disease, are subsequently immune, and are protected by immunization. Maternal antibody passes the placenta, and infants are protected during the first 6 months of life.

Infection with measles virus can transiently depress cell-mediated immunity against other intracellular microorganisms, such as Mycobacterium tuberculosis, leading to a loss of purified protein derivative (PPD) skin test reactivity, reactivation of dormant organisms, and clinical disease. The proposed mechanism for this unusual finding is that when measles virus binds to its receptor (called CD46) on the surface of human macrophages, the production of interleukin-12 (IL-12), which is necessary for cell-mediated immunity to occur, is suppressed. In 2019, it was reported that measles virus infection can cause the loss of preexisting antibodies, perhaps by affecting memory B cells.

Clinical Findings

After an incubation period of 10 to 14 days, a prodromal phase characterized by fever, conjunctivitis (causing photophobia), running nose, and coughing occurs. Koplik’s spots appear several days before the rash and are virtually diagnostic. They are bright red lesions with a white, central dot that are located on the buccal mucosa (Figure 39–1). A few days later, a maculopapular rash appears on the face and proceeds gradually down the body to the lower extremities, including the palms and soles (Figure 39–2 and Table 39–2). The rash develops a brownish hue several days later.

The complications of measles can be quite severe. Encephalitis occurs at a rate of 1 per 1000 cases of measles. The mortality rate of encephalitis is 10%, and there are permanent sequelae, such as deafness and mental retardation, in 40% of cases. In addition, both primary measles (giant cell) pneumonia and secondary bacterial pneumonia occur. Bacterial otitis media are quite common. Subacute sclerosing panencephalitis (SSPE) is a rare, fatal disease of the central nervous system that occurs several years after measles (see Chapter 44).

Measles in a pregnant woman leads to an increased risk of stillbirth rather than congenital abnormalities. Measles virus infection of the fetus is more severe than rubella virus infection, so the former typically causes fetal death, whereas the latter causes congenital abnormalities.

Atypical measles occurs in some people who were given the killed vaccine and were subsequently infected with measles virus. It is characterized by an atypical rash without Koplik’s spots. Because the killed vaccine has not been used for many years, atypical measles occurs only in adults and is infrequent.

Laboratory Diagnosis

Most diagnoses are made on clinical grounds, but a polymerase chain reaction (PCR) assay for measles virus RNA can be performed in cases that are difficult to diagnose. A greater than fourfold rise in antibody titer to measles virus can also be used.

Treatment

There is no antiviral therapy available.

Prevention

Prevention rests on immunization with the live, attenuated vaccine. The vaccine is effective and causes few side effects. Two doses are recommended. The first dose should be given between 12 and 15 months of age and the second dose at 4 to 6 years of age. It is usually given in combination with rubella and mumps vaccines (MMR vaccine). The vaccine should not be given to children prior to 12 months of age, because maternal antibody in the child can neutralize the virus and reduce the immune response. Because immunity can wane, a booster dose at 4 to 6 years is recommended.

The vaccine contains live virus, so it should not be given to immunocompromised persons or pregnant women. The vaccine has decreased the number of cases of measles greatly in the United States; there were only 138 reported cases of measles in 1997. However, outbreaks still occur among unimmunized individuals (e.g., children in inner cities and in developing countries).

The killed vaccine should not be used. Immune globulin can be used to modify the disease if given to unimmunized individuals early in the incubation period. This is especially necessary if the unimmunized individuals are immunocompromised.

Disease

This virus causes mumps, a disease characterized by salivary gland swelling. It occurs primarily in childhood.

Important Properties

The genome of mumps virus consists of single-stranded RNA with a negative polarity (see Table 39–1). It is an enveloped virus with a helical nucleocapsid. The virus has a single serotype. Humans are the natural host.

Summary of Replicative Cycle

Replication is similar to that of measles virus (see Introduction).

Transmission & Epidemiology

Mumps virus is transmitted via respiratory droplets. Mumps occurs worldwide, with a peak incidence in the winter. About 30% of children have a subclinical (inapparent) infection, which confers immunity. There were only 683 reported cases of mumps in the United States in 1997—a finding attributed to the widespread use of the vaccine. However, in 2006, a resurgence of mumps occurred, with 6584 cases being recorded despite a high (87%) coverage rate for the vaccine.

Pathogenesis & Immunity

The virus infects the upper respiratory tract and then spreads through the blood to infect the salivary glands, especially the parotid gland, testes, ovaries, pancreas, and, in some cases, meninges. Alternatively, the virus may ascend from the buccal mucosa up Stensen’s duct to the parotid gland.

Lifelong immunity occurs in persons who have had the disease. There is a popular misconception that unilateral mumps can be followed by mumps on the other side. Mumps occurs only once; subsequent cases of parotitis can be caused by other viruses such as parainfluenza viruses, by bacteria, and by duct stones. Maternal antibody passes the placenta and provides protection during the first 6 months of life.

Clinical Findings

After an incubation period of 18 to 21 days, a prodromal stage of fever, malaise, and anorexia is followed by tender swelling of the salivary glands, either unilateral or bilateral (Figure 39–3). There is a characteristic increase in parotid gland pain when drinking citrus juices. The disease is typically benign and resolves spontaneously within 1 week. A rash does not occur in mumps (see Table 39–2).

Two complications are of significance. One is orchitis in postpubertal males, which, if bilateral, can result in sterility. Postpubertal males have a fibrous tunica albuginea, which resists expansion, thereby causing pressure necrosis of the spermatocytes. Unilateral orchitis, although quite painful, does not lead to sterility. The other complication is meningitis, which is usually benign, self-limited, and without sequelae. Mumps virus, Coxsackie virus, and echovirus are the three most frequent causes of viral (aseptic) meningitis. The widespread use of the vaccine in the United States has led to a marked decrease in the incidence of mumps meningitis.

Laboratory Diagnosis

Most cases of mumps are diagnosed based on clinical features, but a PCR assay for mumps virus RNA is available. Serologic tests, in which there is a greater than fourfold rise in antibody titer to mumps virus, can also be used.

Treatment

There is no antiviral therapy for mumps.

Prevention

Prevention consists of immunization with the live, attenuated vaccine. The vaccine is effective and long-lasting (at least 10 years) and causes few side effects. Two immunizations are recommended, one at 15 months and a booster dose at 4 to 6 years, usually in combination with measles and rubella vaccines. Because it is a live vaccine, it should not be given to immunocompromised persons or pregnant women. Immunoglobulin is not useful for preventing or mitigating mumps orchitis.

In the late 1980s, outbreaks of mumps occurred in both immunized and unimmunized people. This led to the recommendation in 1989 that a second course of the MMR (measles, mumps, rubella) vaccine be administered. The incidence of mumps fell, and outbreaks did not occur until 2006, when 6584 cases occurred, primarily in college-age individuals who, surprisingly, had received two doses of the vaccine. Waning immunity after the second dose and immunization with a different genotype from the genotype that caused the outbreak are suggested explanations.

In 2009, 2010, 2016, 2017, and 2018, at least 2000 cases of mumps were reported in the United States, especially on college campuses. Some of these occurred in individuals who had received two doses of the vaccine. In many individuals, more than 10 years had elapsed since their last MMR immunization, again indicating that waning immunity may play a role. A recommendation for a third mumps immunization is being considered.

Diseases

This virus causes rubella and congenital rubella syndrome. Congenital rubella syndrome is characterized by congenital malformations.

Important Properties

Rubella virus is a member of the togavirus family. It is composed of one piece of single-stranded RNA, an icosahedral nucleocapsid, and a lipoprotein envelope (see Table 39–1). However, unlike the paramyxoviruses, such as measles and mumps viruses, it has a positive-strand RNA and therefore has no virion polymerase. Its surface spikes contain hemagglutinin. The virus has a single serotype. Humans are the natural host.

Summary of Replicative Cycle

Because knowledge of rubella virus replication is incomplete, the following cycle is based on the replication of other togaviruses. After penetration of the cell and uncoating, the plus-strand RNA genome is translated into several nonstructural and structural proteins. Note the difference between togaviruses and poliovirus, which also has a plus-strand RNA genome but translates its RNA into a single large polyprotein, which is subsequently cleaved. One of the nonstructural rubella proteins is an RNA-dependent RNA polymerase, which replicates the genome first by making a minus-strand template and then, from that, plus-strand progeny. Both replication and assembly occur in the cytoplasm, and the envelope is acquired from the outer membrane as the virion exits the cell.

Transmission & Epidemiology

The virus is transmitted via respiratory droplets and from mother to fetus transplacentally. The disease occurs worldwide. In areas where the vaccine is not used, epidemics occur every 6 to 9 years.

In 2005, the CDC declared rubella is eliminated from the United States, and in 2015, rubella was declared eliminated from the Western Hemisphere. The few cases that occur in the United States are acquired outside and imported into this country. Elimination was made possible by the widespread use of the vaccine. As a result, cytomegalovirus is a much more common cause of congenital malformations in the United States than is rubella virus.

Pathogenesis & Immunity

Initial replication of the virus occurs in the nasopharynx and local lymph nodes. From there, it spreads via the blood to the internal organs and skin. The origin of the rash is unclear; it may be due to antigen/antibody-mediated vasculitis.

Natural infection leads to lifelong immunity. Second cases of rubella do not occur; similar rashes are caused by other viruses, such as Coxsackie viruses and echoviruses. Antibody crosses the placenta and protects the newborn.

Clinical Findings

Rubella

Rubella is a milder, shorter disease than measles. After an incubation period of 14 to 21 days, a brief prodromal period with fever and malaise is followed by a maculopapular rash, which starts on the face and progresses downward to involve the extremities (Figure 39–4 and Table 39–2). Posterior auricular lymphadenopathy is characteristic. The rash typically lasts 3 days. When rubella occurs in adults, especially women, polyarthritis caused by immune complexes often occurs.

Congenital Rubella Syndrome

The significance of rubella virus is not as a cause of mild childhood disease but as a teratogen. When a nonimmune pregnant woman is infected during the first trimester, especially the first month, significant congenital malformations can occur as a result of maternal viremia and fetal infection (see Table 39–2). The increased rate of abnormalities during the early weeks of pregnancy is attributed to the very sensitive organ development that occurs at that time. The malformations are widespread and involve primarily the heart (e.g., patent ductus arteriosus), the eyes (e.g., cataracts), and the brain (e.g., deafness and mental retardation).

In addition, some children infected in utero can continue to excrete rubella virus for months after birth, which is a significant public health hazard because the virus can be transmitted to pregnant women. Some congenital shedders are asymptomatic and without malformations and hence can be diagnosed only if the virus is isolated. Congenitally infected infants also have significant IgM titers and persistent IgG titers long after maternal antibody has disappeared.

Laboratory Diagnosis

A laboratory diagnosis of rubella virus infection in either adult or newborn specimens or in amniotic fluid can be made by detecting the RNA of the virus by using a PCR-based assay.

The diagnosis can also be made by observing a fourfold or greater rise in antibody titer between acute-phase and convalescent-phase sera or by observing the presence of IgM antibody in a single acute-phase serum sample.

In a pregnant woman, the presence of IgM antibody indicates recent infection, whereas a 1:8 or greater titer of IgG antibody indicates immunity and consequent protection of the fetus. If recent infection has occurred, an amniocentesis can reveal whether there is rubella virus in the amniotic fluid, which indicates definite fetal infection.

Treatment

There is no antiviral therapy.

Prevention

Prevention involves immunization with the live, attenuated vaccine. The vaccine is effective and long-lasting (at least 10 years) and causes few side effects, except for transient arthralgias in some women. It is given subcutaneously to children at 15 months of age (usually in combination with measles and mumps vaccine) and to unimmunized young adult women if they are not pregnant and will use contraception for the next 3 months. There is no evidence that the vaccine virus causes malformations. Because it is a live vaccine, it should not be given to immunocompromised patients or to pregnant women.

The vaccine has caused a significant reduction in the incidence of both rubella and congenital rubella syndrome. It induces some respiratory IgA, thereby interrupting the spread of virulent virus by nasal carriage.

Immune serum globulins (IGs) can be given to pregnant women in the first trimester who have been exposed to a known case of rubella and for whom termination of the pregnancy is not an option. The main problems with giving IG are that there are instances in which it fails to prevent fetal infection and that it may confuse the interpretation of serologic tests. If termination of the pregnancy is an option, it is recommended to attempt to determine whether the mother and fetus have been infected as described in the preceding “Laboratory Diagnosis” section.

To protect pregnant women from exposure to rubella virus, many hospitals require their personnel to demonstrate immunity, either by serologic testing or by proof of immunization.

Diseases

Parvovirus B19 causes erythema infectiosum (slapped cheek syndrome, fifth disease), aplastic anemia (especially in patients with sickle cell anemia), and fetal infections, including hydrops fetalis.

Important Properties

Parvovirus B19 is a very small (22-nm) nonenveloped virus with a single-stranded DNA genome (see Table 39–1). The genome is negative-strand DNA, but there is no virion polymerase. The capsid has icosahedral symmetry. There is one serotype.

Summary of Replicative Cycle

After adsorption to its host cell receptor (blood group P antigen), the virion penetrates and moves to the nucleus, where replication occurs. The single-stranded genome DNA has “hairpin” loops at both of its ends that provide double-stranded areas for the cellular DNA polymerase to initiate the synthesis of the progeny genomes. The viral mRNA is synthesized by cellular RNA polymerase from the double-stranded DNA intermediate. The progeny virions are assembled in the nucleus. B19 virus replicates only when a cell is in S phase, which explains why the virus replicates in red cell precursors but not in mature red cells.

Transmission & Epidemiology

B19 virus is transmitted primarily by the respiratory route; transplacental transmission also occurs. Blood donated for transfusions also can transmit the virus. B19 virus infection occurs worldwide, and about half the people in the United States older than 18 years of age have antibodies to the virus. Humans are the natural reservoir; animals are not a source of human infection.

Pathogenesis & Immunity

B19 virus infects primarily two types of cells: red blood cell precursors (erythroblasts) in the bone marrow, which accounts for the aplastic anemia, and endothelial cells in the blood vessels, which accounts, in part, for the rash associated with erythema infectiosum. Immune complexes composed of virus and IgM or IgG also contribute to the pathogenesis of the rash and to the arthritis that is seen in some adults infected with B19 virus. Infection provides lifelong immunity against reinfection.

Hydrops fetalis manifests as massive edema of the fetus. This is secondary to congestive heart failure precipitated by severe anemia caused by the death of parvovirus B19-infected erythroblasts in the fetus.

Clinical Findings

There are five important clinical presentations.

Erythema Infectiosum (Slapped Cheek Syndrome, Fifth Disease)

This is a mild disease, primarily of childhood, characterized by a bright red rash that is most prominent on the cheeks (Figure 39–5), accompanied by low-grade fever, runny nose (coryza), and sore throat. A “lacy,” less intense, erythematous rash appears on the body. The symptoms resolve in about 1 week.

The disease in children is also called fifth disease. The four other macular or maculopapular rash diseases of childhood are measles, rubella, scarlet fever, and roseola.

Aplastic Anemia

Children with chronic anemia, such as sickle cell anemia, thalassemia, and spherocytosis, can have transient but severe aplastic anemia (aplastic crisis) when infected with B19 virus. People with normal red blood cells do not have clinically apparent anemia, although their red blood cell precursors are infected.

Fetal Infections

If a woman is infected with B19 virus during the first or second trimester of pregnancy, the virus may cross the placenta and infect the fetus. Infection during the first trimester is associated with fetal death, whereas infection during the second trimester leads to hydrops fetalis (see Table 39–2). Third-trimester infections do not result in important clinical findings. B19 virus is not a common cause of congenital abnormalities, probably because the fetus dies when infected early in pregnancy.

Arthritis

Parvovirus B19 infection in adults, especially women, can cause arthritis mainly involving the small joints of the hands and feet bilaterally. It resembles rheumatoid arthritis. Other viral infections that cause an immune complex-related arthritis include hepatitis B and rubella.

Chronic B19 Infection

People with immunodeficiencies, especially HIV-infected, chemotherapy, or transplant patients, can have chronic anemia, leukopenia, or thrombocytopenia as a result of chronic B19 infection.

Laboratory Diagnosis

Fifth disease and aplastic anemia are usually diagnosed by detecting IgM antibodies to parvovirus B19. Fetal infection can be determined by PCR analysis of amniotic fluid to detect the DNA of parvovirus B19. In immunocompromised patients, antibodies may not be detectable; therefore, viral DNA in the blood can be assayed by PCR methods.

Treatment & Prevention

There is no specific treatment of B19 infection. Pooled immune globulins may have a beneficial effect on chronic B19 infection in patients with immunodeficiencies. There is no vaccine or chemoprophylaxis.

HHV-6 is the cause of roseola infantum (also known as exanthem subitum). Roseola is a common disease in young children characterized by the sudden onset of a high fever that lasts for a few days. When the fever abates, a transient macular or maculopapular erythematous rash on the face and trunk is often seen (Figure 39–6). Most cases occur in children who are 6 months to 3 years of age. In immunocompetent children, recovery without sequelae typically occurs. HHV-6 is found worldwide, and up to 80% of people are seropositive.

HHV-6 is lymphotropic and infects both T and B cells. It remains latent within these cells but can reactivate in immunocompromised patients and cause pneumonia, encephalitis, or hepatitis. It is one of the most common causes of encephalitis in patients who have received a stem-cell transplant. Many virologic and clinical features of HHV-6 are similar to those of cytomegalovirus, another member of the herpesvirus family. There are two serotypes of HHV-6 called HHV-6A and HHV-6B. HHV-6B is the major cause of roseola.

The laboratory diagnosis can be made by either PCR assay to detect viral DNA or by finding a fourfold or greater rise in antibody titer in the convalescent serum specimen compared to the titer in the acute specimen. There is no antiviral drug needed for roseola in immunocompetent children. Ganciclovir can be used in immunocompromised patients with serious disease. There is no vaccine.