Mumps is an acute contagious disease characterized by nonsuppurative enlargement of one or both salivary glands. Mumps virus mostly causes a mild childhood disease, but in adults complications including meningitis and orchitis are fairly common. More than one-third of all mumps infections are asymptomatic.
Pathogenesis and Pathology
Humans are the only natural hosts for mumps virus. Primary replication occurs in nasal or upper respiratory tract epithelial cells. Viremia then disseminates the virus to the salivary glands and other major organ systems. Involvement of the parotid gland is not an obligatory step in the infectious process.
The incubation period may range from 2 to 4 weeks but is typically about 14–18 days. Virus is shed in the saliva from about 3 days before to 9 days after the onset of salivary gland swelling. About one-third of infected individuals do not exhibit obvious symptoms (inapparent infections) but are equally capable of transmitting infection. It is difficult to control transmission of mumps because of the variable incubation periods, the presence of virus in saliva before clinical symptoms develop, and the large number of asymptomatic but infectious cases.
Mumps is a systemic viral disease with a propensity to replicate in epithelial cells in various visceral organs. Virus frequently infects the kidneys and can be detected in the urine of most patients. Viruria may persist for up to 14 days after the onset of clinical symptoms. The central nervous system is also commonly infected and may be involved in the absence of parotitis.
The clinical features of mumps reflect the pathogenesis of the infection. At least one-third of all mumps infections are subclinical, including the majority of infections in children younger than 2 years. The most characteristic feature of symptomatic cases is swelling of the salivary glands, which occurs in about 50% of patients.
A prodromal period of malaise and anorexia is followed by rapid enlargement of parotid glands as well as other salivary glands. Swelling may be confined to one parotid gland, or one gland may enlarge several days before the other. Gland enlargement is associated with pain.
Central nervous system involvement is common (10–30% of cases). Mumps causes aseptic meningitis and is more common among males than females. Meningoencephalitis usually occurs 5–7 days after inflammation of the salivary glands, but up to half of patients will not have clinical evidence of parotitis. Meningitis is reported in up to 15% of cases and encephalitis in fewer than 0.3%. Cases of mumps meningitis and meningoencephalitis usually resolve without sequelae, although unilateral deafness occurs in about five in 100,000 cases. The mortality rate from mumps encephalitis is about 1%.
The testes and ovaries may be affected, especially after puberty. Around 20–50% of men who are infected with mumps virus develop orchitis (often unilateral). Because of the lack of elasticity of the tunica albuginea, which does not allow the inflamed testis to swell, the complication is extremely painful. Atrophy of the testis may occur as a result of pressure necrosis but only rarely does sterility result. Mumps oophoritis occurs in about 5% of women. Pancreatitis is reported in about 4% of cases.
Immunity is permanent after a single infection. There is only one antigenic type of mumps virus, and it does not exhibit significant antigenic variation (see Table 40-2).
Antibodies to the HN glycoprotein, the F glycoprotein, and the nucleocapsid protein (NP) develop in serum after natural infection. Antibodies to the NP protein appear earliest (3–7 days after the onset of clinical symptoms) but are transient and are usually gone within 6 months. Antibodies to HN antigen develop more slowly (~4 weeks after onset) but persist for years.
Antibodies against the HN antigen correlate well with immunity. Even subclinical infections are thought to generate lifelong immunity. A cell-mediated immune response also develops. Interferon is induced early in mumps infection. In immune individuals, IgA antibodies secreted in the nasopharynx exhibit neutralizing activity.
Passive immunity is transferred from mother to offspring; thus, it is rare to see mumps in infants younger than 6 months.
The diagnosis of typical cases usually can be made on the basis of clinical findings. However, other infectious agents, drugs, and conditions can cause similar symptoms. In cases without parotitis, the laboratory can be helpful in establishing the diagnosis. Tests include detection of viral nucleic acid by RT-PCR, isolation of infectious virus, and serology.
A. Nucleic Acid Detection
RT-PCR is a very sensitive method that can detect mumps genome sequences in clinical samples. It can detect the virus in many clinical samples that have negative results in virus isolation attempts. RT-PCR assays can identify virus strains and provide useful information in epidemiologic studies.
B. Isolation and Identification of Virus
The most appropriate clinical samples for viral isolation are saliva, cerebrospinal fluid, and urine collected within a few days after onset of illness. Virus can be recovered from the urine for up to 2 weeks. Monkey kidney cells are preferred for viral isolation. Samples should be inoculated shortly after collection because mumps virus is thermolabile. For rapid diagnosis, immunofluorescence using mumps-specific antiserum can detect mumps virus antigens as early as 2–3 days after the inoculation of cell cultures in shell vials.
In traditional culture systems, cytopathic effects typical of mumps virus consist of cell rounding and giant cell formation. Because not all primary isolates show characteristic syncytial formation, the hemadsorption test may be used to demonstrate the presence of a hemadsorbing agent 1 and 2 weeks after inoculation.
Simple detection of mumps antibody is not adequate to diagnose an infection. Rather, an antibody rise can be demonstrated using paired sera: a fourfold or greater rise in antibody titer is evidence of mumps infection. The ELISA or HI test is commonly used. Antibodies against the HN protein are neutralizing.
ELISA can be designed to detect either mumps-specific IgM antibody or mumps-specific IgG antibody. Mumps IgM is uniformly present early in the illness and seldom persists longer than 60 days. Therefore, demonstration of mumps-specific IgM in serum drawn early in illness strongly suggests recent infection. Heterotypic antibodies induced by parainfluenza virus infections do not cross-react in the mumps IgM ELISA.
Mumps occurs endemically worldwide. Cases appear throughout the year in hot climates and peak in the winter and spring in temperate climates. Mumps is primarily an infection of children, with the highest incidence in children ages 5–9 years. Outbreaks occur where crowding favors dissemination of the virus. In children younger than 5 years, mumps may commonly cause upper respiratory tract infection without parotitis.
Mumps is quite contagious; most susceptible individuals in a household will acquire infection from an infected member. The virus is transmitted by direct contact, airborne droplets, or fomites contaminated with saliva or urine. Closer contact is necessary for transmission of mumps than for transmission of measles or varicella.
About one-third of infections with mumps virus are inapparent. During the course of inapparent infection, the patient can transmit the virus to others. Individuals with subclinical mumps acquire immunity.
The overall mortality rate for mumps is low (one death per 10,000 cases in the United States), mostly caused by encephalitis.
The incidence of mumps and associated complications has declined markedly since introduction of the live-virus vaccine. In 1967, the year mumps vaccine was licensed, there were about 200,000 mumps cases (and 900 patients with encephalitis) in the United States. From 2001 to 2003, there were fewer than 300 mumps cases each year.
In 2006, there was an outbreak of mumps in the United States that resulted in more than 5700 cases. Six states in the Midwest reported 84% of the cases. The outbreak started on a college campus among young adults and spread to all age groups. In 2009, a mumps outbreak occurred in the states of New York and New Jersey in which 88% of those affected had been vaccinated. The SH gene of mumps virus is variable and has allowed classification of known virus strains into 12 genotypes. The viruses that caused the 2006 and 2009 outbreaks in the United States were both identified as belonging in genotype G. A massive mumps epidemic occurred in 2004 in the United Kingdom that caused more than 56,000 cases. It also involved closely related genotype G viruses.
Treatment, Prevention, and Control
There is no specific therapy.
Immunization with attenuated live mumps virus vaccine is the best approach to reducing mumps-associated morbidity and mortality rates. Attempts to minimize viral spread during an outbreak by using isolation procedures are not effective because of the high incidence of asymptomatic cases and the degree of viral shedding before clinical symptoms appear; however, students and health care workers who acquire mumps illness should be excluded from school and work until 5 days after the onset of parotitis.
An effective attenuated live-virus vaccine made in chick embryo cell culture was licensed in the United States in 1967. It produces a subclinical, noncommunicable infection. Mumps vaccine is available in combination with measles and rubella (MMR) live-virus vaccines. Combination live-virus vaccines produce antibodies to each of the viruses in about 78–95% of vaccines. There is no increased risk of aseptic meningitis after MMR vaccination. Other live attenuated mumps virus vaccines have been developed in Japan, Russia, and Switzerland.
Two doses of MMR vaccine are recommended for school entry. Because of the 2006 outbreak of mumps, updated vaccination recommendations for prevention of mumps transmission in settings with high risk for spread of infection were released. Two doses of vaccine should be given to health care workers born before 1957 without evidence of mumps immunity, and a second dose of vaccine should be considered for those who had received only a single dose.
MEASLES (RUBEOLA) VIRUS INFECTIONS
Measles is an acute, highly infectious disease characterized by fever, respiratory symptoms, and a maculopapular rash. Complications are common and may be quite serious. The introduction of an effective live-virus vaccine has dramatically reduced the incidence of this disease in the United States, but measles is still a leading cause of death of young children in many developing countries.
Pathogenesis and Pathology
Humans are the only natural hosts for measles virus, although numerous other species, including monkeys, dogs, and mice, can be experimentally infected. The natural history of measles infection is shown in Figure 40-7.
Natural history of measles infection. Viral replication begins in the respiratory epithelium and spreads to monocyte-macrophages, endothelial cells, and epithelial cells in the blood, spleen, lymph nodes, lung, thymus, liver, and skin and to the mucosal surfaces of the gastrointestinal, respiratory, and genitourinary tracts. The virus-specific immune response is detectable when the rash appears. Clearance of virus is approximately coincident with fading of the rash. IgG, immunoglobulin G; IgM, immunoglobulin M; SSPE, subacute sclerosing panencephalitis.
The virus gains access to the human body via the respiratory tract, where it multiplies locally; the infection then spreads to the regional lymphoid tissue, where further multiplication occurs. Primary viremia disseminates the virus, which then replicates in the reticuloendothelial system. Finally, a secondary viremia seeds the epithelial surfaces of the body, including the skin, respiratory tract, and conjunctiva, where focal replication occurs. Measles can replicate in certain lymphocytes, which aids in dissemination throughout the body. Multinucleated giant cells with intranuclear inclusions are seen in lymphoid tissues throughout the body (lymph nodes, tonsils, appendix). The described events occur during the incubation period, which typically lasts 8–15 days but may last up to 3 weeks in adults.
Patients are contagious during the prodromal phase (2–4 days) and the first 2–5 days of rash, when virus is present in tears, nasal and throat secretions, urine, and blood. The characteristic maculopapular rash appears about day 14 just as circulating antibodies become detectable, the viremia disappears, and the fever falls. The rash develops as a result of interaction of immune T cells with virus-infected cells in the small blood vessels and lasts about 1 week. (In patients with defective cell-mediated immunity, no rash develops.)
Involvement of the central nervous system is common in measles (Figure 40-8). Symptomatic encephalitis develops in about one in 1000 cases. Because infectious virus is rarely recovered from the brain, it has been suggested that an autoimmune reaction is the mechanism responsible for this complication. In contrast, progressive measles inclusion body encephalitis may develop in patients with defective cell-mediated immunity. Actively replicating virus is present in the brain in this usually fatal form of disease.
Timing of neurologic complications of measles. Whereas encephalitis occurs in about one of every 1000 cases of measles, subacute sclerosing panencephalitis (SSPE) is a rare late complication that develops in about one of 300,000 cases. MIBE, measles inclusion body encephalitis; PIE, postinfectious encephalomyelitis (also called acute disseminated encephalomyelitis). (Adapted with permission from Griffin DE, Bellini WJ: Measles virus. In Fields BN, Knipe DM, Howley PM [editors-in-chief]. Fields Virology, 3rd ed. Lippincott-Raven, 1996.)
A rare late complication of measles is subacute sclerosing panencephalitis (SSPE). This fatal disease develops years after the initial measles infection and is caused by virus that remains in the body after acute measles infection. Large amounts of measles antigens are present within inclusion bodies in infected brain cells, but only a few virus particles mature. Viral replication is defective owing to lack of production of one or more viral gene products, often the matrix protein.
Infections in nonimmune hosts are almost always symptomatic. Measles has an incubation period of 8–15 days from exposure to the onset of rash.
The prodromal phase is characterized by fever, sneezing, coughing, running nose, redness of the eyes, Koplik spots, and lymphopenia. The cough and coryza reflect an intense inflammatory reaction involving the mucosa of the respiratory tract. The conjunctivitis is commonly associated with photophobia. Koplik spots—pathognomonic for measles—are small, bluish white ulcerations on the buccal mucosa opposite the lower molars. These spots contain giant cells and viral antigens and appear slightly before the rash. The fever and cough persist until the rash appears and then subside within 1–2 days. The rash, which starts on the head and then spreads progressively to the chest, the trunk, and down the limbs, appears as light pink, discrete maculopapules that coalesce to form blotches, becoming brownish in 5–10 days. The fading rash resolves with desquamation. Symptoms are most marked when the rash is at its peak but subside rapidly thereafter.
Modified measles occurs in partially immune persons, such as infants with residual maternal antibody. The incubation period is prolonged, prodromal symptoms are diminished, Koplik spots are usually absent, and the rash is mild.
The most common complication of measles is otitis media (5–9% of cases).
Pneumonia caused by secondary bacterial infection is the most common life-threatening complication of measles. This occurs in fewer than 10% of cases in developed countries but is much more frequent (20–80%) in developing countries. Pulmonary complications account for more than 90% of measles-related deaths. Viral pneumonia develops in 3–15% of adults with measles, but fatalities in this instance are rare.
Giant cell pneumonia is a serious complication in children and adults with deficiencies in cell-mediated immunity. It is believed to be caused by unrestrained viral replication and has a high fatality rate.
Complications involving the central nervous system are the most serious. About 50% of children with regular measles register electroencephalographic changes. Acute encephalitis occurs in about one in 1000 cases. There is no apparent correlation between the severity of the measles and the appearance of neurologic complications. Postinfectious encephalomyelitis (acute disseminated encephalomyelitis) is an autoimmune disease associated with an immune response to myelin basic protein. The mortality rate in encephalitis associated with measles is about 10–20%. The majority of survivors have neurologic sequelae.
SSPE, the rare late complication of measles infection, occurs with an incidence of about one in 10,000 to one in 100,000 cases. The disease begins insidiously 5–15 years after a case of measles; it is characterized by progressive mental deterioration, involuntary movements, muscular rigidity, and coma. It is usually fatal within 1–3 years after onset. Patients with SSPE exhibit high titers of measles antibody in cerebrospinal fluid and serum and defective measles virus in brain cells. With the widespread use of measles vaccine, SSPE has become less common.
There is only one antigenic type of measles virus (see Table 40-2). Infection confers lifelong immunity. Most so-called second attacks represent errors in diagnosis of either the initial or the second illness.
The presence of humoral antibodies indicates immunity. Protective immunity is attributed to neutralizing antibodies against the H protein. However, cellular immunity appears to be essential for clearing the virus and for long-lasting protection. Patients with immunoglobulin deficiencies recover from measles and resist reinfection, but patients with cellular immune deficiencies do very poorly when they acquire measles infections. The role of mucosal immunity in resistance to infections is unclear.
Measles immune responses are involved in disease pathogenesis. Local inflammation causes the prodromal symptoms, and specific cell-mediated immunity plays a role in development of the rash.
Measles infection causes immune suppression—most importantly in the cell-mediated arm of the immune system—but is observed to affect all components. This is related to the serious secondary infections and may persist for months after measles infection.
Typical measles is reliably diagnosed on clinical grounds; laboratory diagnosis may be necessary in cases of modified or atypical measles.
A. Antigen and Nucleic Acid Detection
Measles antigens can be detected directly in epithelial cells from respiratory secretions, the nasopharynx, conjunctiva, and urine. Antibodies to the nucleoprotein are useful because that is the most abundant viral protein in infected cells.
Detection of viral RNA by RT-PCR is a sensitive method that can be applied to a variety of clinical samples for measles diagnosis.
B. Isolation and Identification of Virus
Nasopharyngeal and conjunctival swabs, blood samples, respiratory secretions, and urine collected from a patient during the febrile period are appropriate sources for viral isolation. Monkey or human kidney cells or a lymphoblastoid cell line (B95-a) are optimal for isolation attempts. Measles virus grows slowly; typical cytopathic effects (multinucleated giant cells containing both intranuclear and intracytoplasmic inclusion bodies) take 7–10 days to develop (see Figure 40-5). Shell vial culture tests can be completed in 2–3 days using fluorescent antibody staining to detect measles antigens in the inoculated cultures. However, virus isolation is technically difficult.
Serologic confirmation of measles infection depends on a fourfold rise in antibody titer between acute-phase and convalescent-phase sera or on demonstration of measles-specific IgM antibody in a single serum specimen drawn between 1 and 2 weeks after the onset of rash. ELISA, HI, and neutralization tests all may be used to measure measles antibodies, although ELISA is the most practical method.
Dried blood spots and oral fluids appear to be useful alternatives to serum for detection of measles antibody in areas where serum samples are difficult to collect and handle.
The major part of the immune response is directed against the viral nucleoprotein. Patients with SSPE display an exaggerated antibody response, with titers 10- to 100-fold higher than those seen in typical convalescent sera.
The key epidemiologic features of measles are as follows: The virus is highly contagious, there is a single serotype, there is no animal reservoir, inapparent infections are rare, and infection confers lifelong immunity. Prevalence and age incidence of measles are related to population density, economic and environmental factors, and the use of an effective live-virus vaccine.
Transmission occurs predominantly via the respiratory route (by inhalation of large droplets of infected secretions). Fomites do not appear to play a significant role in transmission. Hematogenous transplacental transmission can occur when measles occurs during pregnancy.
A continuous supply of susceptible individuals is required for the virus to persist in a community. A population size approaching 500,000 is necessary to sustain measles as an endemic disease; in smaller communities, the virus disappears until it is reintroduced from the outside after a critical number of nonimmune persons accumulates.
Measles is endemic throughout the world. In general, epidemics recur regularly every 2–3 years. A population’s state of immunity is the determining factor; the disease will flare up when there is an accumulation of susceptible children. The severity of an epidemic is a function of the number of susceptible individuals. When the disease is introduced into isolated communities where it has not been endemic, an epidemic builds rapidly and attack rates are almost 100%. All age groups develop clinical measles, and the mortality rate may be as high as 25%.
In industrialized countries, measles occurs in 5- to 10-year-old children; in developing countries, it commonly infects children younger than 5 years. Measles rarely causes death in healthy people in developed countries. However, in malnourished children in developing countries where adequate medical care is unavailable, measles is a leading cause of infant mortality. Those with immunologic disorders, such as advanced human immunodeficiency virus infections, are at risk of severe or fatal measles. The World Health Organization estimated in 2005 that there were 30–40 million measles cases and 530,000 deaths annually worldwide. Measles is a major global cause of mortality among children younger than 5 years, and measles deaths occur disproportionately in Africa and Southeast Asia.
The World Health Organization and the United Nations International Children’s Emergency Fund established a plan in 2005 to reduce measles mortality through immunization activities and better clinical care of cases. Between 2000 and 2008, the numbers of measles cases and of measles deaths were estimated to be reduced by more than 75%.
Measles cases occur throughout the year in temperate climates. Epidemics tend to occur in late winter and early spring.
There were 540 measles cases in the United States from 1997 to 2001, 67% of which were linked to imports (persons infected outside the United States). Over an 8-year period (1996–2004), 117 passengers with imported measles cases were considered infectious while traveling by aircraft. Despite the highly infectious nature of the virus, only four secondary-spread cases were identified.
Measles was declared eliminated from the United States in 2000. However, imported cases have caused multiple outbreaks, particularly in communities declining measles vaccination. Typically measles causes about 50–100 cases annually, but over 600 cases were reported in 2014, with 23 outbreaks. To sustain elimination of measles transmission, vaccine coverage rates need to exceed 90%. Since the first dose of vaccine is given at 12–15 months, infants less than 1 year are at particular risk for severe complications in communities with low measles vaccine coverage.
Treatment, Prevention, and Control
Vitamin A treatment in developing countries has decreased mortality and morbidity. Measles virus is susceptible in vitro to inhibition by ribavirin, but clinical benefits have not been proved.
A highly effective and safe attenuated live measles virus vaccine has been available since 1963. Measles vaccine is available in monovalent form and in combination with live attenuated rubella vaccine (MR), live attenuated rubella and mumps vaccines (MMR), and live attenuated varicella vaccine (MMRV). Measles vaccines are derived from the Edmonston strain of measles virus and protect against all wild measles viruses. However, because of failure to vaccinate children and because of infrequent cases of vaccine failure, measles has not been eliminated from the world, but it has been eliminated from the United States.
Mild clinical reactions (fever or mild rash) occur in 2–5% of vaccines, but there is little or no virus excretion and no transmission. Immunosuppression occurs as with measles, but it is transient and clinically insignificant. Antibody titers tend to be lower than after natural infection, but studies have shown that vaccine-induced antibodies persist for up to 33 years, indicating that immunity is probably lifelong.
It is recommended that all children, health care workers, and international travelers be vaccinated. Contraindications to vaccination include pregnancy, allergy to eggs or neomycin, immune compromise (except that caused by infection with human immunodeficiency virus), and recent administration of immunoglobulin.
The use of killed measles virus vaccine was discontinued by 1970; certain vaccines became sensitized and developed severe atypical measles when infected with wild virus.
Quarantine is not effective as a control measure because transmission of measles occurs during the prodromal phase.
Rinderpest, the world’s most devastating disease of cattle, was caused by rinderpest virus, a relative of measles virus. In 2010, rinderpest was declared to be eradicated from the earth after a successful global effort launched in 1994. This represented the first animal disease (and the second disease in human history after smallpox) to be eradicated worldwide. It was accomplished by widespread vaccination programs and long-term monitoring of cattle and wildlife.