Measles virus, a member of paramyxovirus family and Morbillivirus genus, is a negative-sense RNA, helical, enveloped virus with H and F spikes, which replicates in the cytoplasm by using viral RNA polymerase. Measles (also known as rubeola or 5-day measles) is transmitted through respiratory inhalation (incubation period 7-18 days) and replicates in respiratory mucosal epithelium infections followed by spread to regional lymph nodes and development of viremia and transportation of virus to all body organs. Measles often produce severe illness in children, associated with fever, cough, coryza, widespread rash, and transient immunosuppression. One to 2 days before the development of rash, Koplik spots (small bluish-yellow spots) appear on the buccal mucosa opposite the molar teeth. Severity of measles includes high fever, delirium, conjunctivitis and photophobia. The virus is one of the most contagious agents among humans. Serious complications include encephalitis, pneumonia, otitis media, mastoiditis, sinusitis and bleeding disorders. Pathogenesis involves infection of immune cells, downregulation of lL-12 and depressed cell-mediated immunity. Skin lesions show vasculitis and presence of viral components in rash. Immune-mediated postinfectious encephalitis may occur in some patients through CD8 T cells infiltration in the CNS. Long-term sequelae, such as blindness, may occur, and, rarely, a few patients develop a slowly fatal condition called subacute sclerosing panencephalitis (SSPE) with onset years after the initial infection. Immunity to reinfection is lifelong associated with the presence of neutralizing antibodies. However, patients with defects in cell-mediated immunity and malnutrition have a prolonged infection with severe complication. An effective live attenuated vaccine is recommended (as part of MMR or MMRV) in the first year of life and a booster between 4 to 6 years of age. In the past several years, cases and outbreaks of measles have been reported in the United States and elsewhere underscoring the importance of surveillance and immunization.
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.
✺ Enveloped, helical, negative-sense, single-stranded RNA virus has hemagglutinin and fusion glycoproteins
✺ Replicates in the cytoplasm by using viral RNA polymerase
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.
Although a childhood disease, infections in young adults are also seen
Dramatic decrease in United States, but importation of infections still a problem
✺ Many recent outbreaks in the United States
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.
Epidemics occur in unimmunized or partially immunized groups
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.
Respiratory cell multiplication disrupts cytoskeleton
Viremia disseminates to multiple sites
Pathogenesis of measles virus infection. After exposure, the virus multiplies in the respiratory tract epithelium (incubation period of 9-11 days, on average) and spreads to regional lymph nodes followed by viremia, which helps the virus to be transported throughout the body. Moreover, the virus is also shed in saliva and excreted in the urine. Koplik spots appear on the tongue before appearance of rash on head, then trunk and other extremities. Humoral immune response plays an important role in clearing the virus from the hosts, with IgM appearing early in infection followed by IgG that persists for a long time. Cell-mediated immunity plays a role in disease progression. Postinfectious encephalitis and bacterial superinfections are major complications of measles virus infection. In some patients, there is a rare persistent infection of the CNS known as subacute sclerosing panencephalitis (SSPE).
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.
T and B lymphocytes and monocytes are infected
Leukocyte function is impaired
✺ IL-12 downregulation leads into depressed cell-mediated immunity
Susceptibility to bacterial superinfections enhanced
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.
Vasculitis, giant cells, and inclusions are seen
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.
Encephalitis lesions are due to cytotoxic T-cell (CD8 T cells) activity
Why is IL-12 downregulation results in severity of measles?
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.
Lifelong immunity associated with neutralizing antibody
✺ Defects in cell-mediated immunity and protein-calorie malnutrition lead to measles severity and complications, including viral pneumonia
✺ Vitamin A may have some benefits
Think ➱ Apply 10-2. Downregulation of IL-12 results in suppression of Th1 cells response and release of antiviral cytokines causing reduced CD8 T cells response to control the infection.
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.
✺ Incubation period is 7 to 18 days (average 9-11 days)
✺ Onset begins with cough, coryza, conjunctivitis, and fever
✺ Koplik spots appear on buccal mucous membranes 1 to 2 days before rash
✺ Rash appears first on head then on trunk and extremities
✺ Maculopapular and semiconfluent rash persists for 3 to 5 days
Oral Koplik spots on day 3 of measles. (Reproduced with permission from Nester EW: Microbiology: A Human Perspective, 6th edition. 2009.)
Measles rash on day 4 of illness. (Reproduced with permission from Nester EW: Microbiology: A Human Perspective, 6th edition. 2009.)
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.
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.
✺ Bacterial superinfection is a common complication
✺ Encephalitis can be severe with 15% mortality and permanent neurologic damage in 25% survivors
Thrombocytopenic purpura and bleeding occur in acute phase
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.
✺ SSPE is a rare, progressive neurologic disease usually occurs 2 to 10 years after measles infection
Neurologic deterioration is progressive in children
Inclusions seen in 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.
Chronic measles virus infection causes SSPE
Incomplete measles virus is present in brain tissue
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.
SSPE incidence declined after introduction of measles vaccine
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.
✺ Rapid diagnosis by RT-PCR in respiratory specimens
✺ IgM detection suggests current or recent infection
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.
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.
Live attenuated vaccine (MMR or MMRV) is highly immunogenic, given in the first year of life and a booster at 4 to 6 years of age
Vaccination is contraindicated in pregnant and immunocompromised individuals
Passive protection is appropriate for immunocompromised
While measles virus entry in replication in respiratory tract mucosa results in a significant IgA response, why does the live, attenuated measles (MMR) vaccine predominantly generates IgG response?