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Fig. 28-4 Pathogenesis of measles (From C. A. Mims and D. O White, "Viral Pathogenesis and Immunology " BlackwelJ, Oxford, 1984 )

inflamed conjunctivae. It seems likely that immune responses contribute to the respiratory damage, malaise, and fever, which appear at this stage and get steadily worse until the rash appears. Mucosal foci ulcerate on about the eleventh day, to produce the characteristic Koplik's spots in the mouth. By the fourteenth day, just as circulating antibodies become detectable, the characteristic maculopapular rash appears and the fever falls. This skin rash is due in large part to cell-mediated immune responses to viral antigens (type IV hypersensitivity; see Chapter 9). Measles decreases the resistance of the respiratory epithelium to secondary bacterial infection, hence pneumonia, sinusitis, or otitis media may supervene. In immunocompromised patients, especially those with impaired cell-mediated immunity, giant cell pneumonia may occur, sometimes several months after the acute infection and often with fatal consequences. Measles also provides the classic example of increased severity of a disease due to the effects of malnutrition, as discussed in Chapter 7

Sometimes central nervous system disease occurs, usually after infection in visceral organs has come to an end. Three syndromes have been recognized. Acute postinfectious measles encephalitis is rare in children less than 2 years of age but occurs in about 1 in 1000 cases of measles in older children, with a case-fatality rate of 15%, and is the principal reason for vaccination against measles in the First World. II develops during the first week after the onset of the rash, with a sudden onset and recurrence of fever. There is little or no production of virus in the brain; however, myelin basic protein is found in the cerebrospinal fluid (CSF), and patients' T lymphocytes are often reactive to myelin. The pathogenesis appears to involve autoimmune demyelina-tion (see Chapter 9). In contrast, subacute measles encephalitis occurs only in immunocompromised children, usually within 6 months of the rash; it may be rapidly progressive and is attributable to failure to eliminate virus-infected cells because of the lack of cytotoxic T cells. Finally, subacute sclerosing panen-

Days cephalitis (SSPE) occurs years after the acute disease; it too is always fatal, arid is characterized by very slow replication and spread of measles virus in the brain. Although it is difficult to isolate measles virus from the brain of a patient with SSPE, some neurons contain very large accumulations of measles virus nucleocapsids; sequencing of the viral genome reveals numerous mutations in the M gene and to a lesser extent in other genes. The pathogenesis of SSPE was discussed in Chapter 10.

In the less developed countries of Africa and South America the case-fatality rate of measles is of the order of 3-6%, sometimes higher; this is several hundred times that in developed nations. Factors associated with the increased severity of measles in developing countries include young age at the time of infection, lower socioeconomic status, crowding, concomitant diarrhea, malnutrition (including vitamin A deficiency), lack of access to health care, and underlying immunodeficiency from a variety of causes. In addition to the direct mortality caused by measles, increased overall mortality rates are found in children who have had measles during the previous 9 months compared with children who have not.

Essentially all primary measles infections give rise to clinically manifest disease. The resulting immunity is effectively lifelong; second attacks of measles are virtually unknown, even in totally isolated isiartd communities where subclinical boosts to immunity cannot have occurred for decades (see Chapter 14). As these data suggest, there is only one serotype of measles virus; although a small number of amino acid substitutions are demonstrable in the H protein over the years they do not appear to be sufficient to provide variants with significant selective advantage in a naturally infected population. Although adoptive transfer of neutralizing antibodies against either the H or F glycoprotein confers excellent short-term protection against challenge, T cells raised to the internal nucleoprotein (N) are also protective, presumably by expediting recovery.

Clinical Features

Following a prodrome marked by fever, cough, coryza, and conjunctivitis, an exanthem appears on the head and spreads progressively over the chest, trunk, then limbs. The rash consists of flat macules that fuse to form blotches rather larger than those of other viral exanthems. They are slow to fade and often leave the skin temporarily stained.

Common complications include otitis media, croup, bronchitis, and bronchopneumonia. Bacterial pneumonia is the usual cause of death when measles kills malnourished children. Immunologically deficient children can die from measles virus-induced giant-cell pneumonia or from acute progressive infectious encephalitis (measles inclusion body encephalitis) with no sign of a rash. However, the most dangerous complication of measles is acute postinfectious encephalitis, which occurs in about 1 in every 1000 cases and inflicts a mortality of about 15%, with permanent neurologic sequelae in many of the survivors. Subacute sclerosing panencephalitis (SSPE) is a very much rarer complication, developing in only about 1 in every 300,000 cases, some years after apparent recovery from the original infection.

Laboratory Diagnosis

The clinical diagnosis of measles is so straightforward that the laboratory is rarely called on for help. Cultivation of the virus is difficult and slow, hence is not usually attempted; if cultivation is successlully accomplished, multinucleated giant cells containing numerous acidophilic inclusions in cytoplasm and nuclei are diagnostic (see Fig. 5-3C). Measles antigen can be identified by immunofluorescence in cultured cells or, more simply and quickly, in cells aspirated directly from the nasopharynx. However, the best approach nowadays is IgM capture EIA using as antigen either sonicated virus or recombinant DNA cloned measles N protein. Serology is also employed to screen populations for their immune status. Hemagglutination inhibition (HI) was traditionally used for this purpose, but EIA is more convenient and more sensitive.

Epidemiology and Control

The epidemiology of measles prior to the introduction of vaccination in 1963 was discussed fully in Chapter 14, while in Chapter 7 we said something of the tragic situation in the developing world where over a million malnourished infants die annually from this readily preventable disease. In Chapter 15 we discussed prospects of eradication of measles by vaccination.

A live measles vaccine was developed originally by Enders then further attenuated to produce the Schwarz vaccine used today. In the developed world this vaccine should be administered subcutaneously to every child at about 15 months, after maternal antibody has completely disappeared. Seroconversion occurs in 95-98% of recipients at this age, compared with as few as 50%; if vaccinated at 6 months. The antibody titers that result from vaccination, even at the optimal age, are anything up to 10-fold lower than following natural infection, but they do generally persist for many years at protective levels. Trivial side effects are not uncommon, particularly mild fever (in about 10%>) and/or transient rash (5%).

By 1983 indigenous measles had all but disappeared from the United States, where immunization of children prior to entry into school or day-care centers is required by law, and the declared goal of measles eradication from that country seemed within reach. Since 1989, however, there has been a marked increase in the annual number of cases, particularly among unim-munized preschool infants of racial and ethnic minorities in inner city areas. Thus, it is important to redouble the effort to vaccinate all children, concentrating particularly on unimmunized immigrants, the poor in inner city ghettos, and if possible the conscientious objectors. In addition, however, several outbreaks have occurred in college students, most of whom were vaccinated in infancy. Serological surveys indicate that the percentage of people with protective levels of immunity falls progressively from 95-98% over the years following vaccination. Moreover, with relatively little virus circulating in the community to boost such waning immunity, there is a danger that nonimmune vaccinated or unvaccinated adults might first encounter the virus at an age when complications are more severe. Accordingly, it is now recommended that all children receive two doses of measles vaccine: the first at (12

to) 15 months (as combined measles-mumps-rubella vaccine, MMR) plus a booster just prior to entering either kindergarten/first grade (4-6 years of age) or junior high school (11-12 years).

In the developing world, where there is high mortality from measles in infants in the first year of life, immunization is a top priority of the World Health Organization (WHO), as part of the Expanded Immunization Programme. In these areas maternal immunity declines more rapidly than in developed countries, and infants become susceptible to measles, and to measles vaccination, by 6-9 months of age. The WHO recommends measles vaccination at 9 months or as soon as possible thereafter. Ideally, the optimum age for vaccination should be determined for each individual country, and a second dose should be given later in case of primary vaccination failure. Maintenance of the "cold chain" is also vital in the tropics. Today's vaccines are less heat-labile and are supplied freeze-dried, permitting storage at 4°C until reconstitution immediately before use

In 1990 the WHO recommended the use in such high-risk areas as West Africa of very high dosages of a less attenuated live virus strain, the Edmonslon-Zagreb vaccine, which induces immunity at 6 months of age even in the presence of residual maternal antibody. However, it was soon demonstrated statistically that vaccinees were more likely to die of infectious diseases other than measles than were those immunized at 9 months with the standard Schwarz vaccine. This paradox suggests that this particular strain, at such high dosage, suppresses T-cell immunity to a dangerous degree. Even more puzzling is the finding that girls are affected significantly more often than boys. In 1992 the WHO acted promptly to suspend the use of the high-titer Edmonston-Zagreb vaccine.

Passive immunization still has a place in protecting unvaccinated children, particularly immunocompromised children, following exposure to measles. If administered promptly, pooled normal human immunoglobulin will abort the disease; if given a few days later, the disease may still be modified. No antiviral agent is effective against measles, but bacterial superinfections, such as pneumonia or otitis media, require vigorous chemotherapy.

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